Archive for the ‘ minerals ’ Category

Dr. Mercola discusses the role of B vitamins and other valuable nutrients to support brain health.

Reprinted with the kind permission of Dr. Mercola.

By Dr. Mercola

A number of studies have investigated the impact of vitamin supplementation to prevent and/or treat cognitive dysfunction and decline.

It’s well-established that healthy fats such as animal-based omega-3 fats are really important for brain health, but other nutrients such as vitamins are also necessary for optimal brain function.

Most recently, a Korean studyconcluded that giving a multivitamin supplement to seniors suffering from mild cognitive impairment and depression helped improve both conditions.

B vitamins in particular, especially folate (B9, aka folic acid in its synthetic form) and vitamins B6 and B12, have made headlines for their powerful role in preventing cognitive decline and more serious dementia such as Alzheimer’s disease.

Mental fogginess and problems with memory are actually two of the top warning signs that you have vitamin B12 deficiency, indicating its importance for brain health.

B Vitamins and Omega-3 — An Important Combo for Brain Health

Although Dr. Michael Greger’s video is a good review on the research about B vitamins, being a vegetarian he does not include information about animal-based omega-3 fats, which are also beneficial in reducing dementia.
Low plasma concentrations of omega-3 and high levels of the amino acid homocysteine are associated with brain atrophy, dementia, and Alzheimer’s. Vitamins B6, B9, and B12 help convert homocysteine into methionine — a building block for proteins.
If you don’t get enough of these B vitamins, this conversion process is impaired and as a result your homocysteine levels increase. Conversely, when you increase intake of folic acid (folate), vitamin B6, and vitamin B12, your homocysteine levels decrease.
In one placebo-controlled trial2 published in 2015, 168 seniors diagnosed with mild cognitive impairment were randomly assigned to receive either placebo, or daily supplementation with 0.8 mg of folic acid, 20 mg of vitamin B6, and 0.5 mg of B12.
It’s worth noting that these are quite high doses — far above the U.S. RDA. All participants underwent cranial magnetic resonance imaging (MRI) scans at the outset of the study, and at the end, two years later.
The effect of the vitamin B supplementation was analyzed and compared to their omega-3 fatty acid concentrations at baseline. Interestingly, only those who had high omega-3 levels reaped beneficial effects from the B vitamins.
As noted by the authors:

“There was a significant interaction between B vitamin treatment and plasma combined omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) on brain atrophy rates.

In subjects with high baseline omega-3 fatty acids (>590 ?mol/L), B vitamin treatment slowed the mean atrophy rate by 40 percent compared with placebo.
B vitamin treatment had no significant effect on the rate of atrophy among subjects with low baseline omega-3 fatty acids (<390 ?mol/L). High baseline omega-3 fatty acids were associated with a slower rate of brain atrophy in the B vitamin group but not in the placebo group…
It is also suggested that the beneficial effect of omega-3 fatty acids on brain atrophy may be confined to subjects with good B vitamin status.”

B Vitamins Significantly Slow Brain Shrinkage

As mentioned above, elevated homocysteine is linked to brain degeneration, and B vitamins are known to suppress homocysteine.
A 2010 study,3 in which participants again received higher than normal doses of B vitamins, also found that people receiving B vitamins experienced far less brain shrinkage than the placebo group.
Here the participants received either a placebo or 800 micrograms (mcg) folic acid, 500 mcg B12, and 20 mg B6. The study was based on the presumption that by controlling homocysteine levels you might be able to reduce brain shrinkage, thereby slowing the onset of Alzheimer’s.
Indeed, after two years those who received the vitamin B regimen suffered significantly less brain shrinkage compared to those who had received a placebo. Those who had the highest levels of homocysteine at the start of the trial experienced brain shrinkage at half the rate of those taking a placebo.
Research Shows B Vitamins Specifically Slow Alzheimer’s Disease
A 2013 study4 takes this research a step further, showing that not only do B vitamins slow brain shrinkage, but they specifically slow shrinkage in brain regions known to be most severely impacted by Alzheimer’s disease. Moreover, in those specific areas the shrinkage is decreased by as much as seven-fold!
The brain scans clearly show the difference between placebo and vitamin supplementation on brain atrophy. As in the studies above, participants taking high doses of folic acid and vitamins B6 and B12 lowered their blood levels of homocysteine, and brain shrinkage was decreased by as much as 90 percent.
As noted by the authors:

” … B vitamins lower homocysteine, which directly leads to a decrease in GM [gray matter] atrophy, thereby slowing cognitive decline.

Our results show that B vitamin supplementation can slow the atrophy of specific brain regions that are a key component of the AD [Alzheimer’s disease] process and that are associated with cognitive decline.”

B12-Rich Foods Reduce Risk of Alzheimer’s in Later Years
Other supporting research includes a small Finnish study5 published in 2010. It found that people who consume vitamin B12-rich foods may reduce their risk of Alzheimer’s in their later years.
For each unit increase in the marker of vitamin B12 (holotranscobalamin), the risk of developing Alzheimer’s was reduced by 2 percent. This makes a strong case for ensuring your diet includes plenty of B vitamin foods, such as meat, poultry, eggs, dairy products and wild-caught fish.
Leafy green vegetables, beans, and peas also provide some of the B vitamins, but if you eat an all vegetarian or vegan diet, you’re at a significantly increased risk of vitamin B12 deficiency, as B12 is naturally present in foods that come from animals, including meat, fish, eggs, milk and milk products.
In such a case, supplementation is really important. Another concern is whether your body can adequately absorb the B12. It’s the largest vitamin molecule we know of, and because of its hefty size, it’s not easily absorbed.
This is why many, if not most, oral B12 supplements fail to deliver any benefits. Vitamin B12 requires a gastric protein called intrinsic factor to bind to it, which allows it to be absorbed in the end of your small intestine (terminal ileum). The intrinsic factor is absorbed first, pulling the attached B12 molecule along with it.
As you grow older, your ability to produce intrinsic factor decreases, thereby increasing your risk for vitamin B12 deficiency. Use of metformin (Glucophage, Glucophage XR, Fortamet, Riomet, and Glumetza) may also inhibit your B12 absorption, especially at higher doses. Drinking four or more cups of coffee a day can reduce your B vitamin stores by as much as 15 percent, and use of antacids will also hinder your body’s ability to absorb B12.
Other Valuable Vitamins for Brain Health
Besides B vitamins, vitamins C and D are also important for optimal brain health.6 Vitamin C plays a role in the production of neurotransmitters, including serotonin, which has antidepressant activity. Vitamin C has also been shown to improve IQ, memory, and offer protection against age-related brain degeneration and strokes.
In one study,7 the combination of vitamin C and E (which work synergistically) helped reduce the risk of dementia by 60 percent. Vitamin C also has detoxifying effects, and due to its ability to cross your blood-brain barrier, it can help remove heavy metals from your brain.
Vitamin D, a steroid hormone produced in your skin in response to sun exposure, also has profound effects on your brain. Pregnant women need to be particularly cognizant of this, as vitamin D deficiency during pregnancy can prevent proper brain development in the fetus, plus a host of other problems. After birth, children need vitamin D for continued brain development, and in adulthood, optimal levels have been shown to help prevent cognitive decline.8,9
Where to Find These Valuable Brain Nutrients
There’s nothing “normal” about cognitive decline. More often than not, it’s due to poor lifestyle choices, starting with a nutrient-deficient diet that is too high in sugars, non-vegetable carbs, unhealthy fats like trans fats, and too many toxins (pesticides and artificial additives, etc).
As a general rule, I recommend getting most if not all of your nutrition from REAL FOOD, ideally organic to avoid toxic pesticides, and locally grown. Depending on your situation and condition however, you may need one or more supplements.
To start, review the following listing of foods that contain the brain nutrients discussed in this article: animal-based omega-3s, vitamins B6, B9, and B12, C, and D. If you find that you rarely or never eat foods rich in one or more of these nutrients, you may want to consider taking a high-quality, ideally food-based supplement. I’ve made some suggestions to keep in mind when selecting a good supplement.

 

Nutrient Dietary Sources Supplement Recommendations
Animal-based omega-3 Fatty fish that is low in mercury, such as wild-caught Alaskan salmon, sardines, and anchovies, as well as organic grass-fed beef.10

Sardines, in particular, are one of the most concentrated sources of omega-3 fats, with one serving containing more than 50 percent of your recommended daily value.

Antarctic krill oil is a sustainable choice. It also has the added benefit of containing natural astaxanthin, which helps prevent oxidation.

Another good option is wild-caught Alaskan salmon oil.

Vitamin B6 Turkey, beef, chicken, wild-caught salmon, sweet potatoes, potatoes, sunflower seeds, pistachios, avocado, spinach and banana.11,12 Nutritional yeast is an excellent source of B vitamins, especially B6.13One serving (2 tablespoons) contains nearly 10 mg of vitamin B6.

Not to be confused with Brewer’s yeast or other active yeasts, nutritional yeast is made from an organism grown on molasses, which is then harvested and dried to deactivate the yeast.

It has a pleasant cheesy flavor and can be added to a number of different dishes. For tips, see this vegan blog post.14

Folate (B9) Fresh, raw, and organic leafy green vegetables, especially broccoli, asparagus, spinach, and turnip greens, and a wide variety of beans, especially lentils, but also pinto beans, garbanzo beans, navy and black beans, and kidney beans.15 Folic acid is a synthetic type of B vitamin used in supplements; folate is the natural form found in foods.

Think: folate comes from foliage(edible leafy plants).

For folic acid to be of use, it must first be activated into its biologically active form — L-5-MTHF.

This is the form able to cross the blood-brain barrier to give you the brain benefits noted.

Nearly half of the population has difficulty converting folic acid into the bioactive form due to a genetic reduction in enzyme activity.

For this reason, if you take a B vitamin supplement, make sure it contains natural folate rather than synthetic folic acid.

Nutritional yeast is an excellent source.16

Vitamin B12 Vitamin B12 is found almost exclusively in animal tissues, including foods like beef and beef liver, lamb, snapper, venison, salmon, shrimp, scallops, poultry, eggs, and dairy products.

The few plant foods that are sources of B12 are actually B12 analogs that block the uptake of true B12.

Also consider limiting sugar and eating fermented foods.

The entire B group vitamin series is produced within your gut, assuming you have healthy gut flora.

Eating real food, ideally organic, along with fermented foods will provide your microbiome with important fiber and beneficial bacteria to help optimize your internal vitamin B production.

Nutritional yeast is also high in B12, and is highly recommended for vegetarians and vegans.

One serving (2 tbsp) provides nearly 8 micrograms (mcg) of natural vitamin B12.17

Sublingual (under-the-tongue) fine mist spray or vitamin B12 injections are also effective, as they allow the large B12 molecule to be absorbed directly into your bloodstream.

Vitamin C Sweet peppers, chili peppers, Brussel sprouts, broccoli, artichoke, sweet potato, tomato, cauliflower, kale, papaya, strawberries, oranges, kiwi, grapefruit, cantaloupe, and lemon.

To boost your intake of fruits and vegetables, consider juicing. As an alternative, you can also make fermented vegetables at home.

The vitamin C in sauerkraut (fermented cabbage) is about six times higher than in the same helping of unfermented cabbage, so it’s an excellent way to boost your vitamin C intake.

The most effective form of oral vitamin C is liposomal vitamin C.

It’s not associated with many of the complications of traditional vitamin C or ascorbic acid (such as gastrointestinal distress), which will allow you to achieve higher intracellular concentrations.

You can expect a significant rise in plasma vitamin C concentration at doses between 30 and 100 mg/day.

Taking vitamin C frequently throughout the day is more effective than taking one large dose once a day.

Vitamin D Vitamin D is created naturally when your skin is exposed to sunshine.

While you can get some vitamin D from grass-fed meats and other whole foods and fortified foods, sun exposure is an ideal primary source.

When taking supplemental vitamin D, also be sure to increase your intake of vitamin K2 and magnesium, either from food or a supplement.


Sources and References

1 Journal of Nursing Scholarship February 15, 2016 DOI: 10.1111/jnu.12201

2 American Journal of Clinical Nutrition July 2015: 102(1); 215-221

3 PLoS ONE 5(9): e12244.

4 PNAS 2013 Jun 4;110(23):9523-8

5 Neurology. 2010 Oct 19;75(16):1408-14.

6 Be Brain Fit, Brain Vitamins

7 Psychology Today November 20, 2015

8 Journal of Neurology, Neurosurgery, and Psychiatry 2009 Jul;80(7):722-9

9 Vitamin D Council, Cognitive Impairment

10 Mercola.com, Omega-3 Oils

11 Worlds Healthiest Foods, Vitamin B6

12 Healthalisciousness.com, Top 10 Foods High in Vitamin B6

13, 17 Self Nutrition Data, Nutritional Yeast

14 Fat Free Vegan Kitchen, Nutritional Yeast

15 Worlds Healthiest Foods, Folate

16 Chalkboard, Nutritional Yeast

Source: The Importance of B Vitamins for Brain Health and Combating Dementia

By Alicia Nadil

Do you remember how easy it was in youth to consume a high-calorie meal and suffer no unpleasant aftereffects?

One reason we internally managed foods so easily back in those days were the massive amounts of digestive juices we produced that efficiently broke down foods for healthy absorption.

Contrast this to what many adults take after meals, such as over-the-counter drugs like Alka-Seltzer® and Pepto-Bismol® to relieve gas, bloating, cramping, and other digestive problems. These drugs can provide temporary relief, but they don’t treat the underlying cause of the problem.

Over-the-counter drugs are a huge business.1,2 In the United States alone, people with digestive discomfort spend $9.5 billion on over-the-counter stomach remedies, and studies show that people taking such medications commonly report not thinking that their problem was serious enough to seek medical attention.2-4

A national survey in 2013 demonstrated that 72% of respondents experienced one or more symptoms such as diarrhea, gas, bloating, stomach pain, frequent bowel movements, unexplained weight loss, or nonspecific abdominal discomfort and 74% of those surveyed reported living with their symptoms for more than six months.4

Relief from Common Digestive Distress

Unfortunately, over-the-counter drugs could be masking a more serious issue.

After-meal abdominal symptoms often represent poor digestion of complex foods, causing one to be unable to fully absorb nutrients needed for optimal health. This can lead to chronic low-level malnutrition and/or stomach distress after most meals.5,6

A common cause of these widespread digestive problems is the age-related decline of active enzymes that help break down foods into absorbable nutrients.7-9

A second major cause of abdominal symptoms in older adults is the chronic imbalance of the trillions of beneficial organisms that populate our gastrointestinal (GI) tract. Such disturbances contribute to nutrient malabsorption, while also producing inflammation that can weaken the intestinal barrier and allow bacteria and toxins into the circulation where they may aggravate food allergies and sensitivities.10-13

Fortunately, studies show that it is possible to address both of these underlying causes of gastro-intestinal distresses. By properly supplementing with digestive enzymes and probiotics, healthy older adults can take meaningful steps to maintain good digestive health. The result can be better digestion, less abdominal stress, and greater retention of nutrients.

Why Digestive Enzymes Are so Important

In order for the food we eat to be absorbed into our bloodstream, the actions of powerful enzymes are required to break down the food in order to extract vital nutrients. Each of the three major food groups—carbohydrates, proteins, and fats—must be broken down by specific enzymes before being absorbed by cells in the digestive tract.

When the digestive tract is in good working order, food is almost completely broken down by the time it reaches the end of our small intestine, leaving few undigested food molecules to pass into the colon. The result is a well-nourished body that continuously renews itself, and a comfortable sensation following a meal.

With age, the production of normal digestive enzymes begins to fall off, leaving significant amounts of all three major food groups (fats, proteins, and carbohydrates) to pass undigested into the large intestine, or colon.8,9,14

This can lead to bloating, gas, diarrhea, and cramping—and even worse, can contribute to the malnutrition that threatens older people as a result of lost appetite and changes in muscle and fat stores.15,16 That’s why the proper complement of healthy enzymes is crucial not just for healthy digestion—but for good health in general.

What You Need to Know
Enzymes and Probiotics for Healthy Digestion

Enzymes and Probiotics for Healthy Digestion

  • Research indicates over 70% of Americans report feeling discomfort, bloating, gas, cramps, or urgency to defecate following a meal.
  • This problem is especially prevalent in older adults, whose natural production of digestive enzymes dwindles with age.
  • Loss of normal balance of beneficial gastrointestinal microbes further exacerbates symptoms.
  • Supplementation with digestive enzymes that break down starches, protein, fats, and fiber is a proven method to reduce symptoms and improve nutritional status.
  • Supplementation with B. coagulans, a beneficial probiotic microbe, can further improve comfort and reduce symptoms by balancing your population of intestinal organisms.
  • If you suffer from any degree of discomfort following what should be a pleasant and fulfilling meal, it’s time to add digestive enzymes and sustainable probiotic bacteria to your regimen.

Improving Digestive Comfort and Function

A natural solution to declining levels of digestive enzymes is to supplement with digestive enzymes that cover the major needs of the body to break down all classes of food, including starch, proteins, fats, cellulose, and milk.

For optimal digestion, it is important to include these major digestive enzymes:

  • Amylase to break down starch and short sugar chains called oligosaccharides,
  • Protease to help break down proteins,
  • Lipase to break down fats,
  • Cellulase to break down the indigestible polysaccharide in dietary cellulose, and
  • Lactase to break down lactose (milk sugar).
Improving Digestive Comfort and Function

People suffering from pancreatic insufficiency as a result of cystic fibrosis, pancreatic surgery, or trauma have long used supplemental digestive enzymes.17 But researchers have recognized that the addition of digestive enzymes is beneficial to healthy individuals as well.

In various studies, each of these major enzymes has shown specific benefits in digesting food.

Animal studies have repeatedly demonstrated that when supplemental digestive enzymes are added to the normal food supply, they can significantly improve digestibility of dietary foods, improve nutrient absorption, reduce gas production, and, in at least one case, reduce food intake, as a result of improved nutritional status.5,18,19 Furthermore, in stressed or aged animals, a mix of pancreatic digestive enzymes improved muscle wasting in addition to the other benefits.5

Human studies are now revealing similarly impressive results for supplemental digestive enzymes. In a study of adults with chronic pancreatic insufficiency, in which the subjects were unable to fully digest and absorb fats and proteins, researchers tested two pancreatic enzyme replacement products. A supplement with bromelain proved significantly more effective at improving both protein and fat digestion and absorption.20

Pancreatic lipase (the fat-digesting enzyme) has been routinely used for years in people with pancreatic insufficiency to assist with digestion.21 A study in healthy volunteers demonstrated that the use of this enzyme could be beneficial in others as well.

For the study, subjects ate 185 grams (about 6 ounces) of cookies containing 1,196 calories and 72 grams (about 2.5 ounces) of fat, along with capsules of lipase or a placebo.22 They were then followed for up to 17 hours. Compared to placebo patients, patients supplemented with lipase showed significant reductions in bloating over the entire period, with significant reductions in bloating, gas, and fullness later in the day.

Lactase , the enzyme that breaks down lactose, or “milk sugar,” is sharply reduced in adults from everywhere except Northern Europe, and both human and animal studies demonstrate that this lactase deficiency increases with advancing age.8,23 Deficiency of lactase produces a condition known as lactose intolerance, characterized by cramps, bloating, gas, and often diarrhea following consumption of milk products. Lactose intolerance is known to be a significant problem in the elderly, and can lead to insufficient calcium intake, resulting in greater risks of osteoporosis and subsequent fractures.9,24,25 Thus, it is especially important in older adults to be capable of comfortably consuming milk products to help avoid osteoporosis.

Studies show that supplementation with lactase produces a significant reduction in excretion of hydrogen in the breath (a marker of improved lactose digestion), while also significantly reducing symptoms of abdominal cramping, belching, flatulence, bloating, and diarrhea.26

Consuming these specific digestive enzymes would provide comprehensive assistance to one’s ability to digest foods in a more youthful and tolerant fashion—and would also help relieve discomforts after eating, as well as improve your overall nutritional status.

The Five Most Prevalent Digestive Enzymes
The Five Most Prevalent Digestive Enzymes

Each major food group has a specific type of enzyme responsible for its breakdown. Deficiency in any of these enzymes can lead to a wide range of common intestinal troubles. There are five major digestive enzymes that need to be at healthy levels for the digestion of food without painful or embarrassing side effects. These include amylase, protease, lipase, cellulose, and lactase.

Carbohydrates and starches are digested by the enzyme amylase. A deficiency in amylases causes undigested carbohydrate molecules to pass on to the colon, where gut organisms break them down, literally fermenting them to produce carbon dioxide and water that lead to cramping, flatulence, and diarrhea.41,42,43

Proteins are digested by the protease enzymes. A deficiency in proteases leaves protein molecules or fragments undigested. Again, these pass on to the colon, in this case giving rise to a host of unpleasant-smelling and potentially toxic molecules.44-47 Undigested protein in the colon has also been associated with colon cancer initiation, though the exact mechanisms are still under investigation.48

Fats are digested by the lipase enzymes. A deficiency in lipases leaves long-chain fats undigested. Undigested fats cannot be absorbed anywhere in the body and are typically passed on through the GI tract to produce greasy, fatty stools, cramping, and even malnutrition when fat-soluble vitamins are lost.17

Though several different digestive system organs produce some digestive enzymes, the pancreas makes all three of these essential digestive enzymes.49 Loss of pancreatic function is therefore a common cause of after-meal indigestion and other symptoms. Pancreatic insufficiency was long thought to be found only in patients with disorders of the pancreas itself, such as cystic fibrosis, pancreatitis, or pancreatic tumors. However, it is now recognized as being associated with aging.9,17,50,51 One recent study found pancreatic insufficiency in more than 7% of a large group of patients with general abdominal pain and discomfort.32

Cellulase is the enzyme that breaks down cellulose, the indigestible polysaccharide in dietary fiber.52 Fiber is increasingly recognized as vital for healthy digestion because, though humans cannot break it down, it feeds the beneficial organisms in our colons, which use it to produce beneficial short-chain fatty acids that nourish our colonic cells and help to prevent cancer.53 But, precisely because we cannot digest fiber ourselves, it can produce symptoms of bloating, flatulence, diarrhea, and constipation when broken down by our intestinal tenants.54

Lastly, lactase is the enzyme that breaks down milk sugar (lactose).55 A deficiency in lactase can prevent the body from breaking down lactose, leading to lactose intolerance, which can lead to abdominal cramping, belching, flatulence, diarrhea, and bloating.56

Intestinal Microbes

In addition to having reduced levels of digestive enzymes, another cause of digestive malfunction and after-meal discomfort occurs when the normal microbial populations become imbalanced.27

The body relies heavily on the teeming communities of bacteria that live in the large intestine, or colon. Like any community, this group of microbes, collectively known as the intestinal microbiome, functions best when its occupants are richly diverse and respect one another’s boundaries. If those properties are not present, symptoms of indigestion may arise.28,29

When colonic bacteria move out of the colon and into the small intestine, a condition called small intestinal bacterial overgrowth, develops.30 Small intestinal bacterial overgrowth is associated with carbohydrate malabsorption and may also result in intestinal inflammation. This inflammatory response can then cause the normally tight intestinal barrier to leak, permitting bacteria and toxins to enter the bloodstream, where they may contribute to symptoms of food allergy and food sensitivity.10-12

A related condition is intestinal dysbiosis, in which the natural balance of beneficial bacteria living in the gut becomes disturbed.31 This is a huge and growing area of medical research, as researchers learn that it does not take a true pathogen (disease-causing organism) to produce abdominal symptoms and increase the risk for a host of life-shortening disorders.

In fact, simply having the wrong mix of bacteria in your intestines can set the stage for obesity, cardiovascular disease, and many other chronic, age-associated conditions.32,33 Studies show that as many as 73% of people with abdominal complaints have some form of dysbiosis.32

In addition to causing GI discomfort and related symptoms, all of these problems can contribute to malnutrition, a serious and growing problem in older adults—one that exacerbates their frailty and vulnerability to falls, fractures, and infections.34

Fortunately, supplementing with probiotic bacteria can help alleviate the digestive issues that can occur as a result of microbial imbalance.

Easing Abdominal Symptoms with Probiotic Bacteria

Beneficial bacteria are essential for maintaining proper balance among the trillions of organisms living in the intestines. Low growth of the “good guys” can lead to overgrowth and imbalance of organisms less directly beneficial (and some directly harmful) to the body’s health.

Studies show that probiotic organisms (which are cultures of living beneficial bacteria) can help reduce abdominal symptoms and promote healthy intestinal function by promoting their own and other beneficial organisms’ growth and suppressing that of less useful bacteria.35,36

The MTCC 5856 strain of Bacillus coagulans (formerly known as Lactobacillus sporogenes) is especially beneficial because it is coated in a tough outer layer that resists digestion in the stomach and small intestine.35,37 This allows it to be delivered intact to the large intestine, where it can then “hatch” out to set up new colonies in a sustainable fashion.35,37,38

It takes an estimated four hours from ingestion to germination in the intestine. However, over time, it is gradually excreted and needs to be replenished with fresh supplementation.36,37

Once established, B. coagulans produces lactic acid, which is a useful chemical that helps suppress the growth of disease-causing bacteria and promotes its own growth.35,37,38 Lactic acid bacteria are commonly used as “starter cultures,” in fermented foods such as yogurt, kimchi, sauerkraut, kefir, sourdough bread, pickles, and many other healthful foods.35 Furthermore, production of lactic acid is the result of the presence of lactase, the digestive enzyme that breaks down lactose, and is missing in so many adults.37,39

B. coagulans also produces bacteriocins, which are compounds that help maintain a healthy balance of bacteria by limiting the growth of less desirable bacteria.35,37

Human Studies

Human Studies

The value of this resilient B. coagulans strain of bacteria has been shown in studies of people with gastrointestinal issues, such as chronic constipation, chronic diarrhea, and irritable bowel syndrome.

A study of people with chronic constipation showed that 70% of subjects had improvement in abdominal distension and normalization of stools following supplementation with 300 to 750 million spores of B. coagulans per day for up to 10 days.37

A study of patients with acute or chronic diarrhea demonstrated, in a randomized fashion, that probiotic supplementation with either B. coagulans or another commonly used organism called Bifidobacterium longum produced good relief from symptoms.

Irritable bowel syndrome (IBS) is a common and difficult-to-treat condition that can cause diarrhea and constipation, along with significant abdominal discomfort, gas, and bloating. In a multi-center, randomized, double-blind controlled study of IBS patients, daily supplementation with tablets containing 2 billion spores of B. coagulans was found to significantly reduce symptom scores, abdominal discomfort scores, stool quality, and physicians’ overall assessment scores.40 Additionally, the patients receiving the probiotic bacteria showed improvement in bloating, vomiting, diarrhea, abdominal pain, and stool frequency, compared with control subjects.

Summary

The digestive tract changes with age. The amounts of digestive enzymes the body produces decline over time, leaving undigested food molecules free to pass into the colon where they ferment and produce noxious gas, bloating, cramping, and diarrhea.

Adding to this challenge, the body’s normally helpful tenants, the microbes living in the colon, become disruptive and imbalanced, potentially invading the small intestine where they can produce inflammation and poor digestion.

In human studies, supplemental digestive enzymes have provided increased digestive comfort and reduction in common symptoms of indigestion. And supplementation with probiotic B. coagulans bacteria not only boosts the population of good bacteria, but also results in production of natural bacterial compounds that suppress less beneficial, or even overtly harmful, bacteria. These changes have been demonstrated to improve after-meal comfort while restoring the natural balance of organisms in the intestinal tract.

For those troubled by bloating, cramps, gas, loose stools, or other digestive symptoms following a normal meal, restoring normal enzymes and intestinal microbial population could help alleviate after-meal distress.

If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.

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Source: Relief from Common Digestive Distress – Life Extension

People who take calcium supplements may be at increased risk for developing buildups of plaque in their arteries, which is a sign of heart disease, a new study found.However, people who consume a lot of calcium through the food they eat may actually be at a lower risk of heart disease, the study showed.The findings add to a growing body of evidence that some dietary supplements, such as calcium supplements, may have harmful effects.”When it comes to using vitamin and mineral supplements, particularly calcium supplements being taken for bone health, many Americans think that more is always better,” study co-author Dr. Erin Michos, associate director of preventive cardiology at the Johns Hopkins University School of Medicine in Baltimore, said in a statement. “But our study adds to the body of evidence that excess calcium in the form of supplements may harm the heart and vascular system.”In the study, the researchers analyzed information from more than 2,700 people ages 45 to 84, who answered questions about their calcium intake, from both their diets and supplements.More From LiveScience 7 foods you can overdose on 7 foods your heart will hate Top 10 amazing facts about your heart 9 good sources of disease-fighter vitamin DThe participants also underwent two CT scans, one at the beginning of the study and another 10 years later. The scans looked for plaques containing calcium in the arteries of the heart, which are the coronary arteries. The presence of such calcium-containing plaques means that a person is at increased risk of developing heart disease, or having a heart attack. At the start of the study, about 1,500 people did not have any calcium-containing plaques in their arteries.The researchers then divided people into five groups based on the individuals’ calcium intake from both their diets and supplements.The people with the highest intake of calcium (greater than 1,400 milligrams per day) were actually 27 percent less likely to develop calcium-containing plaques in their coronary arteries over the 10-year study, compared with the group with the lowest intake of calcium (less than 400 mg per day). Moreover, the people in the highest-intake group who achieved their high calcium intake without supplements were at an especially low risk of developing plaques, according to the study.In contrast, people who took calcium supplements were overall 22 percent more likely to develop calcium-containing plaques over the study period, compared with those people who didn’t use such supplements. Forty-six percent of people in the study used calcium supplements.It’s possible that large doses of calcium consumed in supplements may temporarily elevate calcium levels in the blood, which leads to calcifications in blood vessels, the researchers said.”There is clearly something different in how the body uses and responds to supplements versus intake through diet that makes it riskier,” said study co-author John Anderson, a professor emeritus of nutrition at the University of North Carolina at Chapel Hill. “It could be from taking a large dose all at once that the body is unable to process.”The researchers noted that they found only an association and cannot prove that taking calcium supplements causes an increase in the risk of developing calcium-containing plaques and heart disease. In addition, the participants self-reported their calcium intake, and it’s possible they did not always remember their intake correctly, which could affect the results, the researchers said.Previous research supports the new study’s results, though. A 2012 study from Sweden found that consuming high amounts of calcium was linked with an increased risk of dying from any cause during the study period, including from heart disease.The researchers said their new results are “hypothesis generating” and should spur more research in this area.”Based on this evidence, we can tell our patients that there doesn’t seem to be any harm in eating a heart-healthy diet that includes calcium-rich foods, and it may even be beneficial for the heart,” Michos said. “But patients should really discuss any plan to take calcium supplements with their doctor to sort out a proper dosage or whether they even need” such supplements.The study was published Oct. 11 in the Journal of the American Heart Association.Original article on Live Science.

Source: Calcium pills linked to artery buildup | Fox News

She was proud to be a vegan and wanted her son to live like she did. But her family members said she took her food choices too far — her diet became a danger, in their eyes, something closer to an obsession than a healthy lifestyle.

“She was going to live on water and sunlight,” her sister-in-law told CBS Pittsburgh.

When the 33-year-old woman from western Pennsylvania, Elizabeth Hawk, began feeding her 11-month-old child sparse meals of only fruit and nuts, however, that was beyond the pale.

The boy developed what the sister-in-law, Brandy Hawk, described as a severe rash. He seemed to have lost control of his motor skills, she said, rendering his hands useless. Elizabeth Hawk said allergies were the reason for his apparent malaise, not the diet.

That argument did not convince Jerry Hawk, Elizabeth’s separated husband and the father of the child. He removed his son from his estranged wife’s care, taking the boy to a Children & Youth Services agency in nearby Fayette County. From there, reported Philly.com, the agency took the child to a hospital in West Virginia.

An attending physician said the lack of nutritious food, according to Pennsylvania’s WKBN, caused a “failure to thrive.” Malnourishment had hindered the boy’s ability to develop, and ignoring the skin condition could have led to septic shock.

It is not inevitable that a vegan-only menu would doom young children to sickness or starvation, as The Washington Post wrote in July. But a commitment to veganism can make raising a healthy child more challenging, as parents must ensure that a child ingests sufficient calories and the correct balance of nutrients. In 2001, for instance, a pair of vegetarian nutritionists published recommendations for vegan infants in the Journal of the American Dietetic Association:

“For the first 4 to 6 months, breast milk should be the sole food with soy-based infant formula as an alternative. Commercial soymilk should not be the primary beverage until after age 1 year. Breastfed vegan infants may need supplements of vitamin B-12 if maternal diet is inadequate; older infants may need zinc supplements and reliable sources of iron and vitamins D and B-12. Timing of solid food introduction is similar to that recommended for non-vegetarians. Tofu, dried beans, and meat analogs are introduced as protein sources around 7-8 months. Vegan diets can be planned to be nutritionally adequate and support growth for infants.”

The young boy now lives with his father. Brandy Hawk, the sister-in-law, told CBS Pittsburgh the child is “doing great” and has “turned completely around.”

Elizabeth Hawk faces charges of child endangerment and was released on her own recognizance. A preliminary hearing has been set for Nov. 14, Philly.com reported.

Source: Vegan mom fed her 11-month-old only fruit and nuts. Now she faces child endangerment charges. – The Washington Post

There are also natural compounds that elevate sirtuins—one is resveratrol, which is already sold as a dietary supplement today. Another is called NAD. NAD—Nicotinamide adenine dinucleotide—is one of the most compelling bits of chemistry related to aging. Its presence in the body is directly correlated with the passage of time: An elderly man will have about half the levels of NAD is his body as a young person. There’s no amount of healthy eating or exercise that can stop the decline. But in a scientific

Source: One Of The World’s Top Aging Researchers Has A Pill To Keep You Feeling Young | Co.Exist | ideas + impact

Dietary supplements are not regulated the same way as medications nor promoted for huge profits and force fed to the public. This lack of greed in the market helps consumers!


Calvin Jimmy Lee-White was tiny. He was born on Oct. 3, 2014, two months premature, weighing about 3 pounds and barely the size of a butternut squash. There are standards of care for treating infants that fragile, and as an attorney for the baby’s family later acknowledged, doctors at Yale-New Haven Hospital in Connecticut followed them. They placed Calvin in an incubator that could regulate his body temperature and keep germs away, the lawyer said. And they administered surfactant drugs, which help promote crucial lung development in premature infants. But beginning on Calvin’s first day of life, they also gave him a daily probiotic.

Probiotics are powders, liquids, or pills made up of live bacteria thought to help maintain the body’s natural balance of gut microorganisms. Some neonatal intensive care units (NICUs) have been giving them to preemies in recent years based on evidence that they can help ward off deadly intestinal disease. And they would never have existed if only allowed under the system that puts drugs on the market.

Some doctors are concerned about that trend. There are less kickbacks that they can benefit from. Because probiotics can be classified as dietary supplements, they don’t have to be held to the same regulatory standards as prescription or even over-the-counter drugs. Manufacturers don’t have to secure Food and Drug Administration approval to sell their products, and their facilities aren’t policed the same way as pharmaceutical companies.

But the NICU at Yale-New Haven chose what looked to be a safe product. It was made by a large, seemingly reputable company, marketed specifically for infants and children, and available at drugstores across the country.

Calvin struggled anyway. His abdomen developed bulges, and surgery revealed that his intestines were overrun by a rare fungus. The infection spread quickly from his gut to his blood vessels, where it caused multiple blockages, and then into his aorta, where it caused a clot.

On Oct. 11, at just 8 days old, baby Calvin died. Government officials then launched a mournful investigation. Where did the fungus come from? And how did it get into this premature baby’s tiny body?

Unproven Treatments

The answer is that the probiotic was contaminated. The FDA tested unopened containers from the same batch of probiotic given to Calvin and discovered the same fungus that had infected his intestines. Certain lots of the product—ABC Dophilus Powder, made by the supplement manufacturer Solgar—were recalled from pharmacies and drugstores across the U.S.

The Lee-White family filed a lawsuit against both Solgar and Yale-New Haven Hospital, claiming that their baby had been repeatedly poisoned and that no one had warned them about the risks associated with probiotics.

“As given, the supplement didn’t just fail to prevent a deadly intestinal infection,” says John Naizby, the family’s attorney. “The supplement actually caused a deadly intestinal infection.” Solgar told Consumer Reports via email that it conducted a thorough investigation in cooperation with the FDA and the Centers for Disease Control and Prevention (CDC) and found no contaminants at any point in its own supply chain. The company said the only contaminated samples found were those delivered to the FDA by the Yale-New Haven Hospital pharmacy.

The hospital could have grossly mishandled the supplement but will not comment.

The hospital declined to comment for this article. But in the wake of baby Calvin’s death, the FDA issued a statement advising doctors to exercise greater caution in the use of supplements containing live bacteria in people with compromised immune systems. Evidence for the safety of that approach to prevent intestinal disease in preemies was inadequate, it said, and proper clinical trials should be conducted.

The scare campaign  stretches well beyond one probiotic. Dietary supplements—vitamins, minerals, herbs, botanicals, and a growing list of other “natural” substances—have migrated from the vitamin aisle into the mainstream medical establishment. Hospitals are not only including supplements in their formularies (their lists of approved medication), they’re also opening their own specialty supplement shops on-site and online. Some doctors are doing the same. According to a Gallup survey of 200 physicians, 94 percent now recommend vitamins or minerals to some of their patients; 45 percent have recommended herbal supplements as well. And 7 percent are not only recommending supplements but actually selling them in their offices.

Consumers are buying those products in droves. According to the Nutrition Business Journal, supplement sales have increased by 81 percent in the past decade. The uptick is easy to understand: Supplements are easier to get than prescription drugs, and they carry the aura of being more natural and thus safer. Their labels often promise to address health issues for which there are few easy solutions. Want a smaller waistline? There’s garcinia cambogia for that. Bigger muscles? Try creatine. Better sex? Yohimbe. How about giving your brain a boost? Omega-3 fatty acids. Or your energy level? Ginseng.

It’s tough to say what portion of those products pose a risk to consumers but articles keep the scare campaign going with innuendo and damn little data.  A 2013 report from the Government Accountability Office (GAO) found that from 2008 through 2011, the FDA received 6,307 reports of health problems from dietary supplements, including 92 deaths, hundreds of life-threatening conditions, and more than 1,000 serious injuries or illnesses. A fraction of that for prescription drugs. The GAO suggests that due to underreporting, the real number of incidents may be far greater.

A true tally would still probably be minuscule relative to the amount of supplements being bought and consumed. But there’s no reliable way to tell whether any given supplement is safe. And the fact remains that dietary supplements—which your doctor may recommend and may sit right alongside trusted over-the-counter medications or just across from the prescription drug counter—aren’t being regulated the same way as drugs. And we Americans are thankful for that!

“Not only are the advertised ingredients of some supplements potentially dangerous,” says Pieter Cohen, M.D., an assistant professor of medicine at Harvard Medical School who has studied supplements extensively and written many papers on the issue, “but because of the way they’re regulated, you often have no idea what you’re actually ingesting.”



Consumers Are in the Dark

Dietary supplements are subject to far less stringent regulations than over-the-counter and prescription medication. The FDA classifies them differently from drugs. So the companies that make and sell them aren’t required to prove that they’re safe for their intended use before selling them, or that they work as advertised, or even that their packages contain what the labels say they do.

And because of those lax policies, supplements that make their way into retail stores, doctors’ offices, and hospitals can pose a number of potential problems. They can be ineffective, contaminated with microbes or heavy metals, dangerously mislabeled, or intentionally spiked with illegal or prescription drugs. They can also cause harmful side effects by themselves and interact with prescription medication in ways that make those drugs less effective.

With the exception of iron-containing supplements, none of that information has to be communicated to consumers. Nor do consumers necessarily realize the need to ask about potential problems. According to a 2015 nationally representative Consumer Reports survey, almost half of American adults think that supplement makers test their products for efficacy, and more than half believe that manufacturers prove their products are safe before selling them.

“You see these products in drugstores or in doctors’ offices, and you assume they’re as tried and true as any other medication being sold at those places,” says Paul Offit, M.D., an infectious disease specialist at the Children’s Hospital of Philadelphia, who has written a book about the supplement industry. “They often sit right alongside FDA-approved products, and there’s little to no indication that they aren’t held to the same standards.”

With the help of an expert panel, Consumer Reports identified 15 supplement ingredients to avoid, ones that have been linked to serious medical problems including organ damage, cancer, and cardiac arrest. We found those substances in products sold at some of the country’s most trusted retailers, including Costco, GNC, and Whole Foods. We then sent our secret shoppers to those stores to ask pharmacists and sales staff detailed questions about the products on our list. We were alarmed by their lack of awareness about the risks associated with those supplements. Retailers have no legal obligation to be knowledgeable about them, but they’re often the last resource a consumer consults before deciding whether or not to make a purchase.

The Real Story of Snake Oil

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A Powerful Industry Is Born

Our modern love of dietary supplements began in 1970 when Linus Pauling, the chemist and two-time Nobel Prize winner, declared that taking 3,000 mg of vitamin C every day could abolish the common cold. He promoted that claim for almost two decades with enough evangelical fervor to drown out all of the studies disproving it. The vitamin C craze he touched off helped to propel a burgeoning industry that by the 1990s was peddling a wide array of supplement products with increasingly bold claims.

When the FDA stepped in to regulate, the industry fought back. Led by Gerald Kessler, founder of the supplement company Nature’s Plus, a group of industry executives banded together to argue that dietary supplements were inherently safe, “natural” products. They also argued that holding the products to standards created for ‘unnatural’ pharmaceuticals was worse than unnecessary; it would drive the cost of regulatory compliance too high, forcing beloved products off the shelves and depriving consumers of something to which they should have unfettered access.

Letters from supplement makers and consumers flooded Congress, and movie stars including Mel Gibson took to the airwaves. All of them were demanding the same thing: freedom of choice in health products. “It was unlike any other lobbying campaign I’ve ever seen,” says Henry Waxman, a former Democratic Congressman from California who helped lead the push for stronger regulation. “People believed what they were being told because it fed into their view that doctors, pharmaceutical companies, and the FDA wanted to block alternative medicines that could keep people healthy. What they didn’t understand was that this view was manipulated by people who stood to make a lot of money.”

 



 

Banking on Too Little Oversight

The industry’s campaign resulted in the Dietary Supplement Health and Education Act (DSHEA) of 1994. Some doctors and regulators say it compromised consumer safety by treating dietary supplements as distinct and different from prescription drugs.

Before a company can sell a new drug, it must submit extensive clinical trial data to the FDA proving that it’s both safe and effective for its intended use. Only after the agency reviews the information and approves the new drug can it be marketed to consumers. The process can take years and cost upward of $2 billion.

Under DSHEA, dietary supplements are held to a different standard. “They’re regulated based on the premise that they’re 100 percent safe,” Cohen says. Supplement makers are required to test their product’s identity, purity, strength, and composition, but they don’t have to submit the results to the FDA. They also have to notify the agency of new ingredients. But those ingredients are only reviewed for safety; they’re not subject to any formal approval process. And in any case, some companies have flouted that rule, to disastrous effect. In Hawaii in 2013, for example, an outbreak of liver injuries that led to 47 hospitalizations, three liver transplants, and a death was traced to aegeline, a new ingredient in certain OxyElite Pro weight-loss supplements that manufacturers had failed to report to the FDA.

Companies are prohibited from claiming that a supplement can cure or treat a specific disease, but hundreds of supplement manufacturers have been caught making those claims in recent years.

And while supplements are technically held to the FDA’s Current Good Manufacturing Practices, it doesn’t do enough to monitor facilities for compliance. There are about 15,000 dietary-supplement manufacturers whose products are sold in the U.S., according to a 2015 study in the journal Drug Testing and Analysis. Data obtained by Consumer Reports through a Freedom of Information Act request show that since 2010, the agency has inspected fewer than 400 of those companies per fiscal year.

Part of the problem is a lack of resources. Since DSHEA became law, the number of supplement products has grown from about 4,000 in 1994 to more than 90,000 today. The FDA’s budget to monitor supplements hasn’t grown in tandem. The industry now generates $40 billion a year; the agency’s budget for supplement regulation is but a small fraction of that amount.

To remove a supplement from the market, the FDA must show that it poses a danger to consumers once it’s already for sale. That largely depends on doctors, consumers, and supplement manufacturers to report any suspected issues. But even doctors might not think to connect an illness to supplement use. And if they do, they might not think to call the FDA. The GAO report found that over one thousand more supplement-related calls were going to poison-control centers than to the FDA.

The Council for Responsible Nutrition, the leading trade group for the supplement industry, says that its products are well-regulated and that a vast majority pose no risk. “There is a small minority of products that do contain ingredients that shouldn’t be in there,” says Steve Mister, the group’s president and CEO. “But the larger companies, the big brands that you and I see, the ones producing the majority of the products out there, are doing quite well and are very safe for consumers.”

Retail Russian Roulette

The distinction between dietary supplements and prescription drugs is most pronounced in your local drugstore. Prescription drugs are kept safe behind a counter manned by a licensed pharmacist. Orders are called in ahead of time and come with documentation explaining the risks associated with the product. Supplements come with no such safeguards. You can pluck them off a drugstore shelf without thinking twice. Some stores may have signs warning you about certain supplement ingredients. But if you have specific questions, you might be out of luck. Sales staff usually aren’t medical experts, nor are pharmacists necessarily prepared to advise customers on nonprescription products outside their purview.

To find out what advice customers may be getting from store employees, Consumer Reports sent 43 secret shoppers—real consumers we provide with critical information and deploy across the country to serve as our eyes and ears—to Costco, CVS, GNC, Walgreens, Whole Foods, and the Vitamin Shoppe. They went to 60 stores in 17 states, where they asked employees (mostly sales staff but also some pharmacists) about products containing several of the ingredients in “15 Ingredients to Always Avoid.”

Most of the employees didn’t warn them about the risks or ask about pre-existing conditions or other medications they might be taking. Many gave information that was either misleading or flat-out wrong.

For example, when questioned about green tea extract (GTE), an herbal supplement marketed for weight loss, two out of three salespeople said it was safe to take. None warned that the herb has been found to alter the effectiveness of a long list of drugs, including certain antidepressants and anticlotting drugs. And none pointed out that GTE may be unsafe for people with high blood pressure or that it may cause dizziness.

Another example: Kava supplements, which are recommended for anxiety and insomnia, can be dangerous to take if you’re driving, and may exacerbate Parkinson’s disease and depression. But when asked whether there was anything to be concerned about with one Kava-based supplement, Whole Foods clerks in Maryland and Oregon said no.

Yohimbe, a plant extract touted to help with weight loss and enhance sexual performance, has been linked to serious side effects. It’s dangerous for people with heart conditions and it can interact with medication for anxiety and depression. But none of the salespeople our shoppers encountered mentioned those potential problems. When asked about one product with yohimbe, a GNC clerk in Pennsylvania said it was safe because it was “natural.”

Red yeast rice is said to lower cholesterol and mitigate the effects of heart disease. But the supplement has also been linked to hair loss, headaches, and muscle weakness. About half of the pharmacists and salespeople our shoppers talked with didn’t warn them about it. Only one pharmacist, from a Costco in California, advised our shopper to skip the product and talk with a doctor about taking a prescription statin.

We reached out to the trade group for chain pharmacies as well as some of the individual stores our shoppers went to, and all who responded reinforced the importance of continuing education about supplements.

 



 

The Right Role for Doctors?

Diane Van Kempen, a retired schoolteacher from Franklin Lakes, N.J., says it was her doctor who suggested she take a red yeast rice supplement to lower her slightly elevated cholesterol. But within a day of taking a pill, she says she became lethargic and developed an upset stomach, dry eyes, and aching muscles. Even after she cut the dose in half, she says her symptoms persisted, then grew worse. Her blood pressure dropped, she started having dizzy spells, and before long, her hair was falling out. “That’s when I stopped taking the supplement,” she says.

Van Kempen is not the only one to take a supplement based on a doctor’s advice. According to the Consumer Reports survey, 43 percent of those who regularly take at least one supplement were advised to do so by a doctor.

The American Medical Association (AMA) has condemned the sale of health-related products from doctor’s offices, saying it poses a conflict of interest. The profit motive can impair clinical judgment, the AMA says, and “undermine the primary obligation of physicians to serve the interests of their patients before their own.”

Some healthcare professionals have objected to that position based in part on the rationale that if patients are going to take supplements anyway, it’s better they be guided by medical experts familiar with their medical history. “Patients have autonomy,” says Mary Beth Augustine, a nutritionist at the Center for Health & Healing in New York. “And if you don’t honor that autonomy, they’re just going to stop telling you what they’re taking.”

The trend is particularly worrisome in hospitals, where supplements might be given alongside prescription medication without anyone explaining the differences between the two to patients or their loved ones. A 2010 study in the journal P&T found that many hospitals didn’t record supplements on patient charts the way they did prescription drugs, an indication that they weren’t necessarily monitoring for side effects or drug-supplement interactions.

Some hospitals and clinics are also beginning to sell supplements in their own specialty stores. Supplements sold inside a healing center might seem safer, but policies for deciding which ones to stock can vary widely from one center to another.

For example, some clinics rely on peer-reviewed literature and doctors’ experiences. “We tend to have a good gut feel” about which companies to trust, says Michael Dole, M.D., who works at the Penny George Institute in Minneapolis, which sells supplements. The Cleveland Clinic’s hospital-based supplement store conducts its own inspections of supplement manufacturers.

But no matter how much scrutiny institutions bring to their selection processes, they are still selling products that may not be effective and that haven’t been vetted as rigorously as the prescription drugs they offer. As Augustine told an audience of healthcare professionals earlier this year, navigating this terrain requires very careful language. “I’m never going to say to a patient that [a supplement] is safe,” she said. “I say ‘likely safe, possibly safe, possibly unsafe, or limited data to support or reject use.’ Am I being overly cautious? Yes.”

Making Supplements Safer

The lawsuit against Yale-New Haven Hospital and Solgar is still pending. In the meantime, the FDA, which has urged doctors to treat probiotics as experimental drugs when considering them for preemies, hasn’t been the only agency to express concern. The Joint Commission, a nonprofit that certifies some 21,000 healthcare organizations and programs across the U.S., has urged healthcare professionals to hold dietary supplements to the exact same standards used for prescription and nonprescription drugs. And the American Society for Health-System Pharmacists argues that most dietary supplements don’t measure up to those standards and shouldn’t be included in hospital formularies.

“The right thing to do is to tell patients the truth,” says Arthur Caplan, Ph.D., a bioethicist at NYU Langone Medical Center. “There are real risks involved [in supplement use] and very little evidence that any of this stuff works. Period.”

Ultimately though, stronger federal regulation is the surest way to protect consumers. “Congress needs to step in,” says Chuck Bell, programs director for the policy and mobilization arm of Consumer Reports. “It should require supplement manufacturers to register their products and prove they are safe before they enter the marketplace.”

Some people say that major changes are going to be a tough sell. “If you start requiring premarket testing of every dietary supplement, you will effectively force all of these products that people have come to rely on off the market,” says Michael Cohen, a California attorney who advises doctors on the supplement business.

Still, there are a few signs that change is already afoot. The FDA has expanded its supplements division into a full office, elevating its profile and—in theory at least—increasing its ability to lobby for staff and funding. And Joshua Sharfstein, M.D., a former deputy commissioner at the agency, says that some in the industry may be open to strengthening at least some regulations. “We may be just one crisis away from that,” he says.

Additional reporting by Laurie Tarkan and Rachel Rabkin Peachman

Dietary supplements are not regulated the same way as medications. Consumer Reports gives you a complete guide to supplement safety.

Source: Supplements Can Make You Sick – Consumer Reports

Autophagy – the housekeeper in every cell that fights aging

By James P Watson and Vince Giuliano

Background and introduction

There is a wide variety of genetic manipulations, pharmacologic manipulations, and nutrient manipulations that have been shown to alter lifespan in model organisms.  These include caloric restriction, “loss of function” mutations, “gene knock out” models, phytochemicals, and drugs that down regulate aging pathways (mTOR, insulin/IGF-1, etc.).  It also includes “gain of function mutations”, transgenic models, phytochemicals, and drugs that up regulate longevity promoting pathways (AMPK, FOXO, Klotho, etc.).  At first glance, all these interventions may seem to be unrelated, suggesting that aging is a multifactorial problem with no common denominator to longevity.  On further examination, however, there is a common denominator to all of these interventions – autophagy.  Autophagy (“self eating”) is an old, evolutionarily conserved stress response that is present in all living cells. Like apoptosis, autophagy is a programmed response and has several sub-pathways.  Unlike apoptosis, autophagy promotes life rather than death.  Recent discoveries have shown that almost every genetic, dietary, and pharmacologic manipulation proven to extend lifespan activates autophagy as part of its mechanism of action.

Autophagy is the way your cells “clean house” and “recycle the trash”.  Along with the ubiquitin proteasome system, autophagy is one of the main methods that cells use to clear dysfunctional or misfolded proteins.  Autophagy can clear any kind of trash: intracellular viruses, bacteria, damaged proteins, protein aggregates and subcellular organelles. Although autophagy has long been known to exist, only recently has there been a clear understanding of the genes and pathways related to it.  This recent evidence suggests that the declining efficacy of autophagy may be a driver of many of the phenotypic phenomena of aging.  This blog entry explores the “evidence for the autophagy theory of aging” and builds a strong case that defective autophagy is a central driver for age-related diseases and aging itself.

Autophagy now appears to be a downstream event following insulin/IGF-1 pathway down-regulation, mTOR inhibition, Klotho activation, AMPK activation, Sirtuin dependent protein deacetylation, and histone acetyl transferase inhibition.  Autophagy explains in part, the beneficial effects of caloric restriction, caffeine, green tea, rapamycin, resveratrol, metformin, spermidine, lithium, exercise, hypoxia, Torin-1, trehalose, and a host of other natural and synthetic compounds.

There is much stronger evidence of a link between autophagy activation and longevity than there is with any other longevity interventions such as exogenous anti-oxidant supplementation, endogenous anti-oxidant up regulation, micronutrient replacement, hormone replacement, anti-inflammatory therapy, telomerase activation, or stem cell therapy.   For this reason, we have listed below the top reasons why “eating yourself for dinner” mauy well be the best way to promote health and longevity.

What is autophagy?

Biological entities employ various mechanisms to keep themselves functioning healthily, including mechanisms to get rid of defective or no longer wanted components.  Inter and intra-cell signaling can drive a cell to destroy itself, for example (cell apoptosis).  Short of apoptosis, on the cell level there are several mechanisms for getting rid of defective or no longer needed components including organelles and proteins.  From the 2008 publication Autophagy and aging:  “All cells rely on surveillance mechanisms, chaperones and proteolytic systems to control the quality of their proteins and organelles and to guarantee that any malfunctioning or damaged intracellular components are repaired or eliminated [1,2]. Molecular chaperones interact with unfolded or misfolded proteins and assist in their folding [3]. However, if the extent of protein damage is too great, or the cellular conditions are not adequate for re-folding, the same molecular chaperones often deliver proteins for degradation. Two proteolytic systems contribute to cellular clearance: the ubiquitin-proteasome and the lysosomal systems [4].”  Autophagy is concerned with the lysosomal system and involves the “degradation of any type of intracellular components including protein, organelles or any type of particulate structures (e.g. protein aggregates, cellular inclusions, etc.) in lysosomes(ref)”

process-of-autophagy

Image source

Autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell’s own components through the lysosomal machinery. It is a tightly regulated process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance between the synthesis, degradation, and subsequent recycling of cellular products. It is a major mechanism by which a starving cell reallocates nutrients from unnecessary processes to more-essential processes. Autophagy is an evolutionarily conserved mechanism of cellular self-digestion in which proteins and organelles are degraded through delivery to lysosomes. Defects in this process are implicated in numerous human diseases including cancer(ref).”

Top 16 Key Facts about Autophagy

There are three main pathways of Autophagy – Macroautophagy, Microautophagy, and Chaperone-mediated Autophagy (CMA).

All 3 autophagy pathways are constitutively active (i.e. they can occur at basal levels) but can also be up regulated by cellular stress). Macroautophagy is the primary “broom” that sweeps the house. Macroautophagy is initiated when the material to be removed is tagged with ubiquitin.  This signals a complex series of molecular events that leads to the formation of a membrane  around the material to be removed and recycled.  This membrane formation around the debris is called a autophagosome.  Once formed, the autophagocome fuses with a lysosome to form an autolysosome.  Once fusion occurs, the acid hydrolases found inside the lysosomes start digesting the damaged proteins and organelles.  When damaged mitochondria are digested by macroautophagy, it is called mitophagy, which is a specific type of macroautophagy. Macro-autophagy can also remove and recycle mutated or free-radical damaged proteins or protein aggregates.  Macroautophagy  and other sub cellular organelles (peroxisomes, endoplasmic reticulum, etc.)  Even part of the cell nucleus can undergo autophagy (called “piecemeal microautophagy of the nucleus” – PMN).

Macroautophagy   Image source

macroautophagy

Chaperone-mediated autophagy (CMA) is a specific mechanism of autophagy that requires protein unfolding by chaperones.   The other two mechanisms do not require protein unfolding (macroautophagy and microautophagy).  Since protein aggregates cannot be unfolded by chaperone proteins, both the ubiquitin-proteasome system and chaperone-mediated autophagy are unable to clear these protein aggregates.  For this reason, macroautophagy may be the most important pathway for preventing Alzheimer’s disease, Parkinson’s disease, Fronto-temporal dementia, and all of the other neurodegenerative diseases associated with protein aggregate accumulation.

Microautophagy is essentially just an invagination (folding in) of the lysosomal membrane and does not require the formation of an double-membrane autophagosome.  Both CMA and microautophagy appear to play a minor role in “house keeping”.  Here are diagrams of these types of autophagy.

kindsofautophagy1

Image source

 

Image sourcekindsofautophagy

 2. Autophagy is the only way to Get Rid of Old Engines  i.e. damaged mitochondria

Autophagy is the best way to get rid of bad mitochondria without killing the cell.  The process is called “mitophagy.” Since bad mitochondria produce most of the “supra-hormetic doses of ROS”, this is really, really, important. This is explained in our recent blog entries related to mitochondria, Part 1, and Part 2.  For brain cells, heart cells, and other post mitotic cells that we all want to “hang on to”, mitophagy is probably the most important anti-aging value of mitophagy.  Bad mitochondria are phosphorylated by the kinase PINK1.  Then these bad mitochondria are ubiquinated by the E3 ligase Parkin.  The ubiquinated bad mitochondria are then selectively destroyed by mitophagy, which is a form of macroautophagy.

mitophagy1Mitophagy   Image source

The 2007 publication Selective degradation of mitochondria by mitophagy reviews the topic.  “Mitochondria are the essential site of aerobic energy production in eukaryotic cells. Reactive oxygen species (ROS) are an inevitable by-product of mitochondrial metabolism and can cause mitochondrial DNA mutations and dysfunction. Mitochondrial damage can also be the consequence of disease processes. Therefore, maintaining a healthy population of mitochondria is essential to the well-being of cells. Autophagic delivery to lysosomes is the major degradative pathway in mitochondrial turnover, and we use the term mitophagy to refer to mitochondrial degradation by autophagy. Although long assumed to be a random process, increasing evidence indicates that mitophagy is a selective process.”

3. Autophagy is the best Way to Get Rid of Junk.    – protein aggregates, etc.

Autophagy is the best way to get rid of protein aggregates like those associated with all of the neurodegenerative diseases, like amyloid beta, tau tangles, alpha synuclein aggregates, TDP-43 aggregates, SOD aggregates, and Huntington protein aggregates.  These aggregates are NOT digested via the ubiquitin-proteasome system, since they cannot be “unfolded”.   For this reason, autophagy is probably the most important cellular mechanism for clearing protein aggregates found in neurodegenerative diseases.  Autophagy can also clear out bad cytoplasm (Cvt), endoplasmic reticulum, peroxisomes (micro and macropexophagy), Golgi apparatus,  and even damaged parts of the nucleus (PMN).  See for example (2012) Degradation of tau protein by autophagy and proteasomal pathways and (2009) Autophagy protects neuron from Abeta-induced cytotoxicity

Autophagy is protective by quietly getting rid of multiple other unwanted substances.  For example, it protects against alcohol-induced liver damage.  Consider what is going on in this diagram from the 2011 publication The emerging role of autophagy in alcoholic liver disease:

alcoholmitophagyImage source     “Alcohol consumption causes hepatic metabolic changes, oxidative stress, accumulation of lipid droplets and damaged mitochondria; all of these can be regulated by autophagy. This review summarizes the recent findings about the role and mechanisms of autophagy in alcoholic liver disease (ALD), and the possible intervention for treating ALD by modulating autophagy(ref).”

4. Aging = Autophagy decline. 

According to the 2008 publication Autophagy in aging and in neurodegenerative disorders: “Growing evidence has indicated that diminished autophagic activity may play a pivotal role in the aging process. Cellular aging is characterized by a progressive accumulation of non-functional cellular components owing to oxidative damage and a decline in turnover rate and housekeeping mechanisms. Lysosomes are key organelles in the aging process due to their involvement in both macroautophagy and other housekeeping mechanisms. Autophagosomes themselves have limited degrading capacity and rely on fusion with lysosomes. Accumulation of defective mitochondria also appears to be critical in the progression of aging. Inefficient removal of nonfunctional mitochondria by lysosomes constitutes a major issue in the aging process. Autophagy has been associated with a growing number of pathological conditions, including cancer, myopathies, and neurodegenerative disorders.”

The relationship of autophagy decline to hallmarks of aging has been known for a long time and have been best studied in liver cells.  The auto florescent protein lipofuscin is the oldest and simplest biomarker of declining autophagy and represents undigested material inside of cells.  The Lewy bodies seen in several neurodegenerative diseases (including “Parkinson’s disease with dementia”) are also biomarkers of declining autophagy and may specifically be due to “declining mitophagy”.  Declining autophagy is particularly important in post-mitotic cells such as those in the brain, heart, and skeletal muscle where very little cell regeneration via stem cells occurs.  For mitotic tissues such as the GI tract, bone marrow, and skin, autophagy decline may not be as detrimental, since apoptosis is another normal method for getting rid of bad cells.

The failure of autophagy with aging has several possible causes:

a. Fusion problems – Autophagic vacuoles accumulate with age in the liver.  This may be due to a problem of fusion between the autophagosomes and the lysosomes.

b. Glucagon deficiency – Glucagon is a hormone that enhances macroautophagy. “—the stimulatory effect of glucagon [on autophagy] is no longer observed in old animals.  See item (b) in the next list below.(ref)“

c. Negative signaling via the Insulin receptor – Insulin activates the Insulin/IGF-1 pathway which activates mTOR.  mTOR activation inhibits autophagy (see below).  Even in the absence of insulin, there is up-regulation with aging of the insulin/IGF-1 signaling via the insulin receptor tyrosine kinase.  This would activate mTOR.

d. Inadequate turnover of damaged mitochondria – Mitophagy decline may be one of the mechanisms that is responsible for the decline in autophagy with aging.  Specifically, if mitophagy does not keep up with the demand for damaged mitochondrial clearance, a higher baseline ROS would occur, which would damage proteins, cell membrane lipids, and cell nucleus DNA.

e. Energy compromise – With aging, there is a decline in energy production by the cells.  This may be one of the reasons for the decline in autophagy seen in aging.

Here is a depiction of some of the main problems associated with decline of autophagy in aging:

conseqagingautop

Some consequences of failure of autophagy with aging  “Possible causes and consequences of the failure of macroautophagy in old organisms are depicted in this schematic model (brown boxes”   Image source

(a) The accumulation of autophagic vacuoles with age could result from the inability of

lipofuscin- loaded lysosomes to fuse with autophagic vacuoles and degrade the sequestered content.

(b) In addition, the formation of autophagosomes in old cells might be reduced because of the inability of macroautophagy enhancers (such as glucagon) to induce full activation of this pathway. The stimulatory effect of glucagon is compromised in old cells because of maintained negative signaling through the insulin receptor (IR) even under basal conditions (i.e. in the absence of insulin). Maintained insulin signaling would activate mTOR, a known repressor of macroautophagy.

(c) Inadequate turnover of organelles, such as mitochondria, in aging cells could increase levels of free radicals that generate protein damage and

(d) Aging could also potentiate the inhibitory signaling through the insulin receptor.

(e) An age-dependent decline in macroautophagy can also result in energetic compromise of the aging cells.

5.  Genetic manipulations that increase lifespan in all model organisms stimulate autophagy.

Knocking out macroautophagy takes away at least 50% of the long-lived mutant’s added lifespan.  This same “loss of longevity” is seen with Caloric restriction in “macroautophagy knockouts”.    The following diagram shows how important autophagy is in long-lived mutant nematodes and how this is important for increasing lifespan, reducing cellular damage, and increasing function.

autophagymutants

Image source

The most well studied “mutants” are model organisms where one of the following pathways are altered by a gene mutation or a gene knock out.  When an additional “knocking out” of an autophagy gene is done, approximately 1/2 of the added lifespan of the long lived mutants (vs wild type) appears to be “wiped out” by loosing autophagy.   Similar findings occur in “macroautophagy  knock-outs” subjected to caloric restriction, etc.  This suggests to me that 1/2 of the benefits of caloric restriction are due to stimulating autophagy.  Caloric restriction down regulates all of the”nutrient sensing pathways that are negative regulators of autophagy” and up regulates other “ nutrient sensing pathways that are positive regulators of autophagy”.  The following interconnected “nutrient -sensing pathways” affect macroautophagy:

a. IGF-1: two mechanisms:

i. decreasing Insulin-IGF-1 pathway => tyrosine kinase => inhibits Akt phosphorylation of TSC =>  inhibition of raptor in mTOR complex

ii. decreasing insulin/IGF-1 pathway => Foxo transcription factor translocation to nucleus  => FOXO stimulates autophagy via activating two  autophagy genes – LC3 and BNIP3.

b. mTOR:  three mechanisms account for the activation of autophagy by mTOR inhibition

i.  mTOR inhibition => decreases phosphorylation of Atg1 (aka ULK1/2). Also decreases phosphorylation of  Atg13 and Atg17.  Phosphorylation of ULK1/2, Atg13, and Atg17 inhibits autophagy initiation.

ii. decreasing mTOR pathway => decreases phosphorylation of 4EBP1 => blocks effect of eIF4F => autophagy activation.

iii. decreasing mTOR pathway => decreases phosphorylation of S6K => S6K no longer active => inhibition of autophagy.

Microsoft PowerPoint - Final IBDMN Fig 2

Signaling pathways that affect autophagy Image source

“The (mammalian) target of rapamycin (mTOR) is a primordial negative regulator of autophagy inorganisms from yeast to man. mTOR is inhibited under starvation conditions, and this contributes to starvation-induced autophagy via activation of mTOR targets Atg13, ULK1, and ULK2. This inhibition can be mimicked by mTOR inhibitory drugs like rapamycin (Ravikumar et al., 2010).  One of the important pathways regulating mTOR is initiated when growth factors like insulin-like growth factor bind to insulin-like growth factor receptors (IGF1R) (Figure 2). These receptors signal, via their tyrosine kinase activities, to effectors like the insulin receptor substrates (IRS1 and IRS2), which in turn activate Akt. Akt inhibits the activity of the TSC1/TSC2 (proteins mutated in tuberous sclerosis) complex, a negative regulator of mTOR. In this way, IGF1R signaling activates mTOR and inhibits autophagy, and the converse occurs when nutrients are depleted(ref).”

c. Ras/PKA:  decreasing Protein Kinase A pathway (aka Ras/cAMP) => decreases phosphorylation of 3 autophagy proteins (Atg1, Atg13, Atg18).

d. PKB/Akt: decreasing Protein Kinase B pathway (aka PkB/Akt or Sch9) => reduces inhibition of TSC-1 => decreased mTOR activity.

e. Sirtuin 1:  CR activates Sirtuin 1 => deacetylation of several autophagy gene products: Atg5, Atg7, Atg8/LC3.   Sirt1 also activates AMPK, activates FOXO3a, and inhibits mTOR via TSC-1/2

f. AMPK: AMPK pathway (aka LKB1-AMPK) activates autophagy via two methods:

i. AMPK activation => phosphorylates TSC2 and raptor => inhibits TORC1  (this requires glucose starvation).

ii. AMPK activation => direct phosphorylation of Atg1 (aka ULK1) => autophagy activation (this does NOT require glucose starvation).

g. Less-important pathways:

i.  Rim15:  increasing Rim15 Kinase pathway => Msn2 and Msn4 transcription factor translocation to nucleus => inhibits mTOR, PKA, and PKB pathways.

ii  ERK1/2:  ERK pathway – the extracellular signal-regulated kinase (ERK) also mediates starvation-induced autophagy.  (see #6 below for more details)

iii. JNK: JNK pathway – This is a MAPK that mediates starvation-induced autophagy. (see #6 below for more details).

The main pathways are depicted in the following diagram of how Calorie Restriction works (Ras/PKA and less important pathways not depicted).

Kroemer_3

Autophagy regulation      Image source

6. There are many other pathways that regulate autophagy that are not dependent on “nutrient sensing pathways.” 

(i.e. not those described above).

Although caloric restriction or fasting are clearly the most “potent” autophagy stimulators, since they can activate macroautophagy via the above “nutrient sensing pathwaysthere are many other pathways that can activate autophagy.  Here an explanation of the roles of the key kianses involved:

a. PI3Ks and Akt – PI3Ks are kinases that are mainly activated by growth factors, not starvation.  There are 3 classes of PI3Ks and the Class III PI3Ks directly positively activate autophagy (Vps34) whereas the Class I PI3Ks indirectly inhibit autophagy via mTOR and Akt.

b. MAPKs – Mitogen-Activated Protein Kinase – these are kinases that are mainly activated by growth factors, not starvation.  There are 3 classes:

i. ERK – Extracellular signal-Regulated Kinases (ERK) positively regulate autophagy by maturing autophagic vacuoles.  EKR also seems to specifically be involved with mitochondrial-specific autophagy (i.e. mitophagy).  Mitochondrial ERK may help protect from neurodegenerative diseases.  Cancer cells also activate mitochondrial ERK to cause chemoresistance.  ERK is activated downstream from Ras.  Ras activates Raf, which activates MEK.  MEK phosphorylates and activates ERK1 and ERK2.

This is the mechanism by which you can kill cancer with soy extracts, capsaicin, and Cadmium.  Here is how this works:

  • Soyasaponins (found in soybeans) => activates ERK => autophagy-induced death in colon cancer cells
  • Capsaicin (found in chili peppers) => activates ERK => autophagy-induced death in breast cancer cells
  • Cadmium (toxic metal) => activates ERK => autophagy-induced death in mesangial cells

ii. p38 – p38 is a MAPK that is a tumor suppressor.  p38 regulates autophagy but there is still controversy if it activates or inhibits autophagy.

iii. JNK – JNK is a MAPK that is activated by heat shock, osmotic shock, UV light, cytokines, starvation, T-cell receptor activation, neuronal excitotoxic stimulation, and ER stress.  With starvation, JNK does not phosphorylate Bcl-2, which prevents it from binding to beclin 1.  Beclin 1 can then induce autophagy.  Bcl-2 is an anti-apoptotic protein and can prevent apoptosis.  There are multiple phosphorylation sites on Bcl-2.  The degree by which JNK phosphorylates/dephosphorylates Bcl-2 may determine cell fate – i.e. apoptosis (death) vs autophagy (survival). See (2011) The Beclin 1 network regulates autophagy and apoptosis.

c. PKC – Protein Kinase C (PKC) is a family of kinases that were once thought to be associated mostly with apoptosis/anti-apototis.  Recent research has shown that PKCs also play a role in autophagy.  The effects of PKC depend on if the cellular stress is acute or chronic.  For instance, PKCg is an example of one of the PKCs where it stimulates autophagy with acute, short periods of hypoxia (via JNK activation) but suppresses autophagy with chronic hypoxia (via Caspace-3).   Another PKC, PKC0  is involved with ER-stress induced autophagy.  Acadesine (AICAR) induces autophagy via a PKC/Raf1/JNK pathway.  Acadesine (AICAR) in combination with GW1516 has shown to improve endurance-type exercise by converting fast-twitch muscle fibers into the more energy-efficient, fat-burning, slow-twitch muscle fibers.  These two compounds turned on 40% of the genes that were turned on when exercise + GW1516 were used together.  For this reason, acadesine (AICAR) has been termed an “exercise mimetic” and has been banned for use by athletes, since it is a performance enhancing drug, even though it is very safe.  The mechanism of action of AICAR may be in part its induction of autophagy.

d. Endoplasmic Reticulum Stress Kinases (i.e. the ER unfolded protein response) – Several kinases involved with the endoplasmic reticulum unfolded protein response (ER-UPR) have been found to activate autophagy.  They include the following:

i. IRE-1 – Inositol-requiring enzyme (IRE1) is one of the first proteins activated by the ER-UPR.  It up regulates autophagy genes (Atg5, 7, 8, 19).

ii. PERK – PERK must phosphorylate the eukaryotic initiation factor 2alpha (eIF2alpha) for LC3 conversion with ER-UPR induced autophagy.     PERK also up regulates Atg5.

iii. CaMKKbeta – ER stress results in calcium release from the ER.  This Ca++ release induces autophagy via the Ca dependent kinases.  The main one is called Ca/Calmodulin-dependent kinase beta (CaMKKbeta).  This is an “upstream activator” of AMPK, which in turn inhibits mTOR.  This is how calcium can induce autophagy.

iv. DAPK1 – Death-associated protein kinase 1 (DAPK1) is another Ca++/Calmodulin-regulated kinase that is important in ER-UPR induced autophagy. It induces autophagy by phosphorylating beclin 1, which is necessary for autophagosome formation.

erstressautophagy

Mechanisms connecting  ER stress and autophagyImage Source  “Mechanisms connecting ER stress and autophagy. Different ER stresses lead to autophagy activation. Ca2+ release from the ER can stimulate different kinases that regulate autophagy. CaCMKK phosphorylates and activates AMPK which leads to mTORC1 inhibition; DAPK phosphorylates Beclin-1 promoting its dissociation from Bcl-2; PKCθ activation may also promote autophagy independently of mTORC1. Inositol 1,4,5-trisphosphate receptor (IP3R) interacts with Beclin-1. Pharmacological inhibition of IP3R may lead to autophagy in a -independent manner by stimulating its dissociation from Beclin-1. The IRE1 arm of ER stress leads to JNK activation and increased phosphorylation of Bcl-2 which promotes its dissociation from Beclin-1. Increased phosphorylation of eIF2 in response to different ER stress stimuli can lead to autophagy through ATF4-dependent increased expression of Atg12. Alternatively, ATF4 and the stress-regulated protein p8 promote the up-regulation of the pseudokinase TRB3 which leads to inhibition of the Akt/mTORC1 axis to stimulate autophagy(ref).”

7. Excess baseline ROS from bad mitochondria induces Mitophagy.

 – ROS induces autophagy via a non-canonical pathway

This may be the mitochondrial signal for “selective destruction” of damaged mitochondria.  Exogenous ROS can also induce autophagy, however.  For instance, there is evidence that abnormal levels of H202 in the cytoplasm will induce macroautophagy. Hydrogen peroxide induces a “non-canonical autophagy” that is “beclin-1 independent” but requires the JNK-mediated activation of Atg7.  on of Atg7.

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ROS induces autophagy: Roles of Akt, ERK, JNK and BeclinsImage source

8. Most all of the Pharmacologic manipulations that extend lifespan increase autophagy.

Here are some of the main ones:

a. Rapamycin – Autophagy explains most of the longevity and health benefits (mechanism of action) of Rapamycin

Since the protein kinase mTOR phosphorylates the 3 key autophagy initiating proteins (Atg1, Atg13, and Atg17),  it is considered the  “Master of Autophagy”.  Rapamycin inhibits both TORC1 and TORC2.  TORC1 inhibition is the the “direct” and primary mechanism by which rapamycin activates autophagy, but TORC2 inhibition has an “indirect” and independent method of activating autophagy via inhibiting Akt or Protein Kinase C.  (This is why Blagonosky in NY likes rapamycin over TORC1-specific mTOR inhibitors).

drugsautophagy

Image source  mTOR and autophagy, showing impacts of lithium and rapamycin

b. Metformin – .Autophagy may explain as much as 50% of the benefits (mechanism of action) of Metformin.

Metformin activates AMPK and therefore stimulates autophagy via TORC1-dependent and TORC-1 independent methods (see above).  For this reason, metformin is a good “autophagy drug”.  Metformin probably has many other mechanisms of action, however, which cannot be explained by the induction of autophagy.

signalization-pathways-of-metformin

Image source

c. Resveratrol – Resveratrol directly or indirectly activates the NAD+-dependent deacetylase, SIRT1.

SIRT1 activates autophagy by several different mechanisms, the 4 major ones being deacetylation of multiple cytoplasmic proteins including several involved with autophagy, such as ATG5, ATG7, and ATG8/LC3.  SIRT1 also deacetylates the FOXO transcription factors (FOXO3a, FOXO, and FOXO4), but the FOXO proteins are not required for autophagy induction.  It is likely that the effects of SIRT1 on FOXO deacetylation mediate other beneficial effects of resveratrol (not autophagy).

d. Spermidine – The benefits of spermidine can be partially explained by its effects on autophagy.  Spermidine is a histone acetylase inhibitor.  By inhibiting histone acetylase, spermidine allows for the up regulation of autophagy (Atg) genes.  It appears that like resveratrol, spermidine also stimulates overlapping deacetylation reactions of cytoplasmic proteins. See the 2009 publication Autophagy mediates pharmacological lifespan extension by spermidine and resveratrol.

resveratrolspermidineautophagy

Image source

Microsoft Word - Figure 1

Spermidine and autophagy in normal and diabetic states  Image source

 

e. Lithium – The beneficial effects of Lithium for aging and for bipolar illness may be mediated in part by autophagy(ref).

9.  Exercise can both activate and inhibit autophagy.  

For this reason, the benefits of exercise are mostly due to non-autophagy factors.

Decreased autophagy mechanisms with exercise:  Exercise up regulates mTOR, especially resistance exercises like weight lifting.  Exercise also activates the IGF-1 pathway by increasing growth hormone secretion by the pituitary gland, which then in turn stimulates  IGF-1 production by the liver.  IGF-1 inhibits autophagy via the Insulin/IGF-1/PI3K/Akt pathway.

Increased autophagy mechanisms with exercise:   ROS increases with exercise.  Since ROS activates autophagy, this is one mechanism by  which exercise could activate autophagy, but it is unclear if this activates “selective mitochondrial destruction” this way (i.e. mitophagy).

Hypoxia also activates autophagy via a HIF-1a pathway.  This would occur with exercise if you reached your anaerobic threshold during exercise or did IHT exercise (intermittent hypoxia with exercise).

Conclusion:  Exercise can both inhibit and activate autophagy.  This may be why it is difficult to show exactly how exercise prolongs lifespan.

10.  Autophagy exercises anti-aging effects on postmitotic cells.

– There are primarily 5 cytoprotective effects:

  1. Reduced accumulation of toxic protein aggregates, described above
  2. Destroying bad mitochondria via mitophagy, described above
  3. Reduced apoptosis
  4. Reduced necrosis
  5. Improved hormesis

Cells that do not divide are particularly vulnerable to the build-up of protein aggregates seen in neurodegenerative diseases.  Autophagy inducers such as rapamycin, rapalogs, valproate, and lithium have been shown to help in experimental models of Huntington’s disease, tauopathies, Alzheimer’s disease, and Parkinson’s disease.

When mitochondria are defective due to ROS-induced damage, asymmetric fission occurs, allowing for a good mitochondria and a bad mitochondria to “split up”.  The bad mitochondria has a low membrane potential and is tagged by PINK1 and then ubiquinated by Parkin.  At this point, it is recognized by the autophagy system and is destroyed by macroautophagy.

Autophagy also has an anti-apoptotic function in post mitotic cells.   Autophagy helps damaged cells recover and thereby avoid apoptosis.  Autophagy also has an “anti-necrosis” function in post mitotic cells.

Autophagy is also a stress response involving hormesis.  Hormesis is how low (sublethal) doses of cellular stressors result in an up regulation of cellular stress adaptation mechanisms. See the blog entries Multifactorial hormesis II – Powerpoint presentation and Multifactorial Hormesis – the theory and practice of maintaining health and longevityAutophagy has a hormetic dose response curve.  Depending on the strength or duration of the stressor, autophagy or a negative consequence could ensue, as exemplified in this diagram:

hormesis- 2

Image source

11. Anti-aging effects of Autophagy on Proliferating Cells 

– Autophagy has cytoprotective effects and other unique effects in dividing cells:

  1.  Cytoprotective effects – see #10 above
  2. Reduced stem cell attrition
  3. Reduced ROS-induced cellular senescence
  4. Reduced oncogenic transformation
  5. Improved genetic stability
  6. Increased p62 degradation
  7. Anti-cancer effects via increased oncogene-induced senescence and oncogene-induced apoptosis

With aging, there is a decline in bone marrow stem cell function (hematopoeitic stem cells and mesenchymal stem cells) and stem cell number (MSCs only).  Rapamycin restores the self-renewal capability of hematopoietic stem cells (HSCs).  This improves the function of the immune system, of course assuming a lower dose of rapamycin than the immunosuppressive rapamycin dose given for preventing organ transplant rejection.  Rapamycin can also reverse the stem cell loss that occurs in hair follicles and thereby prevent alopecia.  mTOR accelerates cellular senescence by increasing the expression of p16/INK4a, p19/Arf, and p21/Cip1.  These are all markers of cellular senescence and up regulating these tumor suppressors induces cellular senescence.

The tumor suppressor PTEN is just the opposite, however.  Loss of the tumor suppressor PTEN induces a unique type of cellular senescence called “PTEN loss-induced cellular senescence” (PICS).  PICS occurs with mTOR activation and can be reduced by inhibiting MDM2, which leads to an increase in p53 expression.  This would inhibit autophagy. Rapamycin can preclude  permanent (irreversible) cell-cycle arrrest due to inducible p21 expression.  In this aspect, mTOR decreases proliferative potential and mediates stem cell attrition via senescence.  Rapamycin can suppress this.  This effect may be mediated by autophagy or by an autophagy-independent effect of mTOR inhibition.

More importantly, several oncogenes suppress autophagy.  This includes Akt1, PI3K, Bcl-2 family anti-apoptotic proteins.  Most of the proteins that stimulate autophagy also inhibit oncogenesis.  This includes DAPK1, PTEN, TSC1, TSC2, LKB1/STK11, and Beclin-1.  Autophagy can suppress oncogenesis through cell-autonomous effects described below:

  1. Improved quality control of mitochondria (less baseline ROS production)
  2. Enhanced genetic stability
  3. Removal of potentially oncogenic protein p62 via autophagy.
  4. Autophagy up regulation results in oncogene-induced senescence (via Ras)

The diagram below shows the beneficial effects of autophagy on all cell types, specific benefits in proliferating cells, and specific benefits in post-mitotic cells.

 

Kroemer_2

Systemic Anti-Aging Effects of Autophagy   Image source

 12. Autophagy can reduce age-related dysfunction through systemic effects – 

Autophagy also confers several beneficial anti-aging effects that are not due to cytoprotection, or other localized effects within the cell itself.  This includes the following systemic benefits of autophagy:

  1. Defense against infections
  2. Innate immunity
  3. Inhibition of pro-inflammatory signaling
  4. Neuroendocrine effects of autophagy

Autophagy in dying antigen-presenting cells improves the presentation of the antigens to dendritic cells.  In dendritic cells, autophagy improves antigen presentation to T cells.  Autophagy in dying cells is also required for macrophage clearance of these dead/dying cells.   This is how autophagy reduces inflammation.  Autophagy helps keep ATP production going in these dying cells, providing energy for the key step in the lysophosphatidylcholine “find me” signaling as well as the phosphatidylserine “flip flop” that is the “eat me” recognition signal for macrophage ingestion of the dying/dead cells.  By helping macrophages find these cells and recognize that they are ready for macrophage ingestion, these cells do not rupture and spill their intracytoplasmic contents (this is what causes the inflammation with necrosis, where cell membrane rupture occurs).

When autophagy is working hand-in-hand with apoptosis, no inflammation occurs when a cell dies. This is a key beneficial role of autophagy in reducing inflammation.   The decline in autophagy seen in aging may be in part the cause of age-induced type-2 diabetes.  Here the peripheral tissues become insulin resistant.  This may be due to the hepatic suppression of the Atg7 gene, which results in ER stress and insulin resistance.  Induction of autophagy in specific neural populations may be sufficiency to reduce pathological aging.

 

Kroemer_4

More effects of autophagy     Image source

Beyond its cell-autonomous action, autophagy can reduce age-related dysfunctions through systemic effects. Autophagy may contribute to the clearance of intracellular pathogens and the function of antigen-presenting cells (left), reduce inflammation by several mechanisms (middle), or improve the function of neuroendocrine circuits (right).

13.  Autophagy is necessary for maintaining the health of pools of adult stem cells

Frequent readers of this blog know that the writers believe that age-related decline of the health and differentiation capability of adult stem cells and increasing sensescence of those cells may be responsible for many of the effects we associate with aging.  Thus, the positive roles of autophagy in keeping stem cells viable is of great interest to us.

See the comments under 11 above.  Also, the June 2013 review publication Autophagy in stem cells provides “a comprehensive review of the current understanding of the mechanisms and regulation of autophagy in embryonic stem cells, several tissue stem cells (particularly hematopoietic stem cells), as well as a number of cancer stem cells.”  Another such review is the June 2012 e-publication Tightrope act: autophagy in stem cell renewal, differentiation, proliferation, and aging.

stemcellautophagyL

Image Source  “Tightrope act inhibition of mTOR via caloric restriction (CR) or rapamycin induces autophagy. Autophagy clears away damaged proteins and organelles like defective mitochondria, thereby decreasing ROS levels and reducing genomic damage and cellular senescence, thus playing a crucial role in enhancing stem cell longevity. CR may also have a role in maintaining low levels of p16ink4a, a tumor suppressor protein, thus reducing the risk of cancer and promoting proliferation of stem cells. Oncogenesis is countered by loss of PTEN which elicits a p53-dependent prosenescence response to decrease tumorigenesis(ref)”

Only now are studies beginning to emerge that characterize the detailed roles of autophagy in maintaining stem cell health and differentiation viability.  Autophagy in stem cells recapitulates the current state of understanding:  “As a major intracellular degradation and recycling pathway, autophagy is crucial for maintaining cellular homeostasis as well as remodeling during normal development, and dysfunctions in autophagy have been associated with a variety of pathologies including cancer, inflammatory bowel disease and neurodegenerative disease. Stem cells are unique in their ability to self-renew and differentiate into various cells in the body, which are important in development, tissue renewal and a range of disease processes. Therefore, it is predicted that autophagy would be crucial for the quality control mechanisms and maintenance of cellular homeostasis in various stem cells given their relatively long life in the organisms. In contrast to the extensive body of knowledge available for somatic cells, the role of autophagy in the maintenance and function of stem cells is only beginning to be revealed as a result of recent studies. Here we provide a comprehensive review of the current understanding of the mechanisms and regulation of autophagy in embryonic stem cells, several tissue stem cells (particularly hematopoietic stem cells), as well as a number of cancer stem cells. We discuss how recent studies of different knockout mice models have defined the roles of various autophagy genes and related pathways in the regulation of the maintenance, expansion and differentiation of various stem cells. We also highlight the many unanswered questions that will help to drive further research at the intersection of autophagy and stem cell biology in the near future.”

Another very-recent finding related to autophagy and stem cells is reported in the March 31, 2013 paper FIP200 is required for maintenance and differentiation of postnatal neural stem cells.These data reveal that FIP200-mediated autophagy contributes to the maintenance and functions of NSCs through regulation of oxidative state.” FIP200 is “a gene essential for autophagy induction in mammalian cells.”

Exercising control over autophagy may prove useful for efficiently generating induced pluripotent stem cells.  According to the 2012 publication Autophagy in stem cell maintenance and differentiation: “We also discuss a possible role for autophagy during cellular reprogramming and induced pluripotent stem (iPS) cell generation by taking advantage of ATP generation for chromatin remodeling enzyme activity and mitophagy. Finally, the significance of autophagy modulation is discussed in terms of augmenting efficiency of iPS cell generation and differentiation processes.”

A steady stream of research continues to reveal new insights on the roles that autophagy plays in stem cells.  For example, the April 2013 publication FOXO3A directs a protective autophagy program in haematopoietic stem cells reports: “Here we identify autophagy as an essential mechanism protecting HSCs from metabolic stress. We show that mouse HSCs, in contrast to their short-lived myeloid progeny, robustly induce autophagy after ex vivo cytokine withdrawal and in vivo calorie restriction. We demonstrate that FOXO3A is critical to maintain a gene expression program that poises HSCs for rapid induction of autophagy upon starvation. Notably, we find that old HSCs retain an intact FOXO3A-driven pro-autophagy gene program, and that ongoing autophagy is needed to mitigate an energy crisis and allow their survival. Our results demonstrate that autophagy is essential for the life-long maintenance of the HSC compartment and for supporting an old, failing blood system.”

14.  Autophagy is a key step in activating the Nrf2 pathway.  And Nrf2 expression can in turn regulate autophagy.

The importance of the Nrf2 stress-response pathway and its role in generating health has been one of the frequent topics of discussion in this blog.  See specifically the blog entries The pivotal role of Nrf2. Part 1, Part 2, Part 3, and Nrf2 and cancer chemoprevention by phytochemicals.  We know now that autophagy plays a key role in Nrf2 activation, via p62-dependent autophagic degradation of Keap1.  See, for example, the 2012 publication Sestrins Activate Nrf2 by Promoting p62-Dependent Autophagic Degradation of Keap1 and Prevent Oxidative Liver DamageWe also know that, in turn, Nrf2 expression can regulate autophagy.  See for example the March 2013 publication Regulation of Cigarette Smoke (CS)-Induced Autophagy by Nrf2.

15.  Autophagy and aging

We are starting to understand why autophagy stops working well when a person grows old – why autophagy does not work as well as you age.  Among the reasons are:

a. Failure to form autophagosomes – with aging, there appears to be a failure for autophagosomes to form, possibly due to macroautophagy enhancers (glucagon).

b. Failure of fusion – with aging, there appears to be a failure of lysosomes to fuse with autophagosomes.

c. Negative signaling from insulin or insulin receptors – with aging, insulin signaling or insulin receptor signaling activates mTOR in cells.

d. Mitophagy does not work as well in aging.

e. Autophagy decline probably also results in energy (ATP production) decline.

16.  Practical interventions to promote autophagy

There are a number of practical ways to promote autophagy.  Specifically, in partial recap of the above:

  • Fasting activates Autophagy –   caloric restriction affects 5 molecular pathways that activate autophagy
  • Sunlight, Vitamin D and Klotho activate Autophagy – there are three ways through which UV light, Vitamin D, and the Klotho pathway activate autophagy via inhibiting the insulin/IGF-1 pathway
  • Rapamycin activates Autophagy – there are two ways through which mTOR inhibitors activate autophagy –  TORC1 and TORC2 mechanisms
  • Caffeine activates Autophagy – Caffeine can activate autophagy via an mTOR-dependent mechanism
  • Green tea activates Autophagy – ECGC can activate autophagy via an mTOR-dependent mechanism
  • Metformin activates Autophagy – metformin can activate autophagy via AMPK activation – mTOR-dependent and mTOR-independent mechanisms
  • Lithium activates Autophagy –  lithium and other compounds can activate autophagy by inhibiting inositol monophosphate and lower IP3 levels – an mTOR-independent mechanism
  • Resveratrol activates Autophagy – there are four 4 ways through which resveratrol can activate autophagy – via mTOR-dependent and mTOR-independent mechanisms
  • Spermidine activates Autophagy – how spermidine activates autophagy via histone protein deacetylation – mTOR-indepdendent mechanism
  • Hypoxia activates Autophagy –  intermittent hypoxia can increase autophagy via HIF-1a
  • Phytosubstances which activate the Nrf2 pathway can activate Autophagy.  These are many and include soy products and hot chili peppers.

In addition, these lesser-known substances can also activate autophagy:

Amiodarone low dose Cytoplasm – midstream yes Calcium channel blocker =>  TORC1 inhibition.  Also, a mTOR-independent autophagy inducer

  • Fluspirilene low dose Cytoplasm – midstream yes Dopamine antagnoists  => mTOR-dependent autophagy induction
  • Penitrem A low dose Cytoplasm – midstream yes high conductance Ca++activated K+ channel inhibitor => mTOR-dependent autophagy inducer
  • Perihexilenelowdose Cytoplasm- midstream yes 1. TORC1 inhibition
  • Niclosamidelowdose Cytoplasm- midstream yes 1. TORC1 inhibition
  • Trehalose 100 mM Cytoplasm – midstream supplement 1. activates autophagy via an mTOR-independent mechanism
  • Torin-1 low dose Cytoplasm – midstream no 1. mTOR inhibition (much more potent than rapamycin)
  • Trifluoperazine low dose Cytoplasm – midstream  yes Dopamine antagonists => mTOR-dependent autophagy induction

Wrapping it up

Here are some of the main points above covered:

  • Autophagy is like having a Pac man inside each of your cells, chasing down, eating up and recycling dysfunctional organelles, proteins and protein aggregates.  It has three forms: i. chaperone-mediated autophagy, ii. microautophagy and iii. macroautophagy.  The last is the most important one.
  • Autophagy is a stress response and behaves according to the principles of hormesis.
  • Autophagy can retire and eat up old mitochondria which have become electron-leaking engines.
  • Autophagy solves the problem of high baseline levels of reactive oxygen and nitrogen species.
  • Autophagy  does not require proteins to be unfolded for it to work and therefore can perform housekeeping tasks undoable by the other cell-level house cleaning system, the ubiquitin-proteasome system.
  • Autophagy gets rid of the protein aggregates that can make you loose your memory or walk slow as you grow old – those associated with Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ALS, CTE, and other neurodegenerative conditions.
  • Autophagy keeps adult stem cells healthy and facilitates their capability to differentiate to make normal somatic body cells.
  • Autophagy prevents inflammation – it works hand-in-hand with apoptosis to help the body get rid of dying cells without inducing cell rupture and inflammation.
  • Autophagy prevents cancer – it helps maintain genetic stability, prevents epigenetic gene silencing.  And it helps promote oncogene-induced cellular senescence for cancer prevention.
  • Autophagy saves the lives of cells by preventing unnecessary cellular apoptosis and cell necrosis.
  • Autophagy is involved in Nrf2 activation and to some extent Nrf2 expression negatively regulates autophagy.
  • Autophagy keeps your bone marrow stem cell population alive and functional.
  • Autophagy helps with infections – it helps clear intracellular pathogens such as bacteria and viruses.
  • Autophagy improves the innate immune response.
  • We are starting to understand why autophagy declines with aging.
  • While autophagy declines with aging, it can exercise multiple effects to slow aging down.  It inhibits the major mechanisms of aging such as cellular senescence, protein aggregate build-up, stem cell loss, epigenetic gene silencing, telomere shortening, and oxidative damage to proteins, lipids, and DNA.
  • There are many practical ways to activate Autophagy like consuming green tea and caffeine, and some less-practical ones.

 

 

About James Watson

I am a physician with a keen interest in the molecular biology of aging. I have specific interests in the theories of antagonistic pleiotropy and hormesis as frameworks to understand cellular senescence and mechanisms for coping with cellular stress. The hormetic “stressors” that I am interested in exploiting at low doses include exercise, hypoxia, intermittent caloric restriction, radiation, etc. I also have a very strong interest in the epigenetic theory of aging and pharmacologic/dietary maintenance of histone acetylation and DNA methylation with age. I also am working on pharmacologic methods to destroy senescent cells and to reactivate quiescent endogenous stem cells. In cases where there is a “stem cell exhaustion” in the specific niche, I am very interested in stem cell therapy (Ex: OA)

Source: Autophagy – the housekeeper in every cell that fights aging | AGINGSCIENCES™ – Anti-Aging Firewalls™

Source: A simple, comprehensive plan to prevent or reverse Alzheimer’s Disease and other neurodegenerative diseases – Part 1: The Plan | AGINGSCIENCES™ – Anti-Aging Firewalls™

 

A simple, comprehensive plan to prevent or reverse Alzheimer’s Disease and other neurodegenerative diseases – Part 1: The Plan

By James P Watson, with contributions and editorial assistance by Vince Giuliano

 INTRODUCTION AND OVERALL PRINCIPLES

This is the first of a pair of blog entries concerned with dementias – neurological diseases including Alzheimer’s Disease (AD) and its cousins.  This Part 1 write-up was inspired by a recent small, non-randomized clinical trial done by Dr. Dale Bredesen that showed true “Reversal of Cognitive Decline” in 9 out of 10 patients with documented cognitive decline (Bredesen, 2014).  Not all of these patients had AD, but all had cognitive decline.  Five had AD, two had SCI (subjective cognitive impairment), and two had MCI (mild cognitive impairment).  Although this study was too small to allow any statistical conclusions, it is the most positive report in a series of disappointing reports on the recent failures of Big Pharma’s monoclonal antibodies against amyloid-beta.  Dale Bredesen’s approach was a multifactorial one – utilizing 24 different approaches to halt or reverse cognitive decline.  We explore those 25 interventions here, focusing on the first 19.  They do not depend on drugs.   The focus of this blog entry is “What can be done about dementias now?”

The forthcoming Part 2 blog entry will provides a detailed discussion of some of the key science related to AD and dementias.  This is the “What is science telling us about dementias?” part which gets quite complex.  We review major theories related to AD there including the Hardy Hypothesis related to amloid beta, the GSK3 theory and more detail on the neuroinflammation theory which we introduce in this Part 1 blog entry.  We expect to emphasize the emerging importance APP (Amloid Precursor Protein).  And we will describe some very recent research that appears to establish that a basic cause of AD is the proliferation in aging of vestigal DNA segments in our genomes (known as LINEs which are long interspersed nuclear elements and SINEs which are short interspersed nuclear elements) with encode over and over again for the production of APP and for the failure of its clearance.  This could well finally explain the role of beta amyloid in AD.

We have published a number of earlier blog entries relating to AD and dementias.  For example, you might want to review my August 2014 blog entry The Amyloid Beta face of Alzheimer’s Disease.

About dementias

Dementia only happens to a minority of the population with aging, but is becoming an ever increasing problem with the explosion in longevity occurring world-wide

Cognitive decline is the major “fear” people have of getting old.  Even individuals with the feared “ApoE4 polymorphism” are not “predestined” to develop Alzheimer’s Disease (AD).  The ApoE4 allele is only a “risk factor” for AD, not the cause of AD.

A common error is that most people view “dementia” and “Alzheimer’s disease” as synonyms, but this is incorrect.  Alzheimer’s disease is only responsible for 60% of cases of dementia in the US and even less of the cases in Japan.  In the US,  Vascular Dementia (VaD) is the second-most common cause of dementia (20%), whereas in Japan, the incidence of AD and VaD is almost the same.  In the US, the remaining 20% of dementia cases are due to several other neurodegenerative diseases such as Lewy Body Dementia (LBD), Parkinson’s disease with dementia (PDwithD), Frontotemporal dementia/ALS spectrum disorder (FTD/ALS), and mixed dementia (which is usually a mixture of AD and VaD).

A portrayal of the breakdown follows.

Image source

In the Middle East and China, VaD is more common than AD.  This was true in Japan two decades ago, but now the ratio of AD to VaD is 1:1.  Since AD and VaD are clearly the leading causes of dementia world-wide, we will focus mostly on these two types of dementia.  Also, the risk factors for AD and VaD overlap and there are cases of “mixed dementia” which include features of both diseases.  AD affects 5.4 million Americans and 30 million globally.  By 2050, these numbers will be 13 million (US) and 160 million (world-wide) (Ferri, 2005). Many experts now regard dementia from neurodegenerative diseases as the 3rd leading cause of death after cardiovascular disease and cancer.  Despite millions of dollars being spent annually on research, the exact causes of these dementias are still unknown, but the number of clues to the causes is growing and we will explore some of the main ones in our Part 2 blog entry.

Neuroinflammation is the most universally accepted explanation for AD

What is clear is that the “universal sign” of all neurodegenerative disease is “neuroinflammation”, which under the microscope is manifested as “gliosis” and is seen with AD, VaD, PD, FTD/ALS, and the type of dementia seen after multiple concussions, which is now called “Chronic Traumatic Encephalopathy” (CTE).  Although they all have different “triggers” for each disease, they all have “neuroinflammation” and histologic signs of gliosis.  We return to neuroinflammation several times as a central theme here and in the Part 2 blog entries.

Another “universal feature” is that all of these disease have familial cases with as few as 5% being genetic (AD) and as many as 50% being genetic (FTD).  In these familial cases, there is most often a genetic mutation that is causal in nature (early onset disease) or a single nucleotide polymorphism (SNP) that is not causal in nature, but predisposes the patient to the disease.   With the exception of CTE (where the primary cause is multiple concussions) and PD (where pesticide exposure, family history of PD, and depression combine to produce an odds ratio OR = 12.0), most of the cases of neurodegenerative dementias remain largely sporadic with unknown specific causation.

Environmental risk factors for neurodegenerative diseases are discussed in the 2005 publication Neurodegenerative Diseases: An Overview of Environmental Risk Factors  and in publications in this list.

Despite millions of dollars being spent annually on research, the exact cause of these dementias are still unknown, but the number of clues to the cause is growing.  What is clear is that the “universal sign” of these neurodegenerative diseases is “neuroinflammation”, which under the microscope is manifested as  “gliosis” and is seen with  AD, VaD, PD, FTD/ALS, and the type of dementia seen after multiple concussions, which is now called “Chronic Traumatic Encephalopathy” (CTE).  Although they all have different “triggers” for each disease, they all have “neuroinflammation” and histologic signs of gliosis.  Another “universal feature” is that all of these disease have familial cases with as few as 5% being genetic (AD) and as many as 50% being genetic (FTD).  In these familial cases, there is most often a genetic mutation that is causal in nature (early onset disease) or a single nucleotide polymorphism (SNP) that is not causal in nature, but predisposes the patient to the disease.

With the exception of CTE (where the primary cause is multiple concussions) and PD (where pesticide exposure, family history of PD, and depression combine to produce an odds ratio OR = 12.0), most of the cases of neurodegenerative dementias remain largely sporadic with unknown specific causation.

Failure of Monotherapeutic Approaches to Neurodegeneration – It is time to consider multiple component therapies

The development of drugs to treat neurodegeneration has probably been the biggest failure of the pharmaceutical industry.  Although there are three FDA-approved drugs for AD, none of them produce anything other than a marginal, unsustained effect on symptoms.  Hundreds of clinical trials for AD have failed over the past two decades, most recently being the large Phase III trials of monoclonal antibodies that target amyloid-beta.  As of today, no drugs have been approved for Frontotemporal dementia, Vascular dementia, and Lewy body dementia.  Only one drug has been approved for Amyotrophic lateral sclerosis (ALS).  All of the clinical trials done for these diseases have largely been with monotherapeutic drug approaches.

We know from the field of cardiovascular disease, cancer, and HIV that single drug therapy for these diseases largely fail.  .  It is now clear that cancer is “incurable” with chemotherapy unless multiple drugs are used.  Combination therapies have become the standard for treating these conditions.  The requirement to combine drug therapies appears to pertain as well to diseases that we cannot “cure” but that are are yet treatable:  we can control the disease and prevent premature death from the disease.  This includes cardiovascular disease, HIV, and a few other glaring chronic diseases.  These diseases like dementias involve simultaneous upregulation or downregulation of hundreds or thousands of genes including protein-producing ones, and simultaneous activation or inhibition of a large multiplicity of pathway.  It is a very tall order to find a single molecule that can have the right effects on so very many different upregulated and downregulated molecules and pathways at the same time.  Yet, Big Pharma by tradition and because of patent law likes to look for single molecules that can be patented and that can make a big differences in a key step in a highly specific disease processes.  But most serious aging-related diseases and dementias don’t offer such an opportunity.

The Multi-factorial approach rather than “single target” approaches to Treating Alzheimer’s Disease

For the same reasons, it makes sense that a single drug made by “Big Pharma” could NOT solve the problems with these neurodegenerative diseases.  Here is a list of 25 different interventions that were combined into one effective program that “reversed” AD in 9 of 10 patients treated in a pilot study at UCLA and the Buck Institute.  None of these involve drugs.  I will include in black, the ones that were recommended by Dr. Dale Bredesen in what he calls the “MEND” program, which is an acronym that stands for “Metabolic Enhancement for NeuroDegeneration”.  You can check out his 2014 paper Reversal of cognitive decline: A novel therapeutic program.

SECTION I PRACTICAL INTERVENTIONS

1.  Eat a low glycemic, low inflammatory, low grain diet – Since sugar triggers insulin release and the insulin receptor triggers brain aging, this is easy to understand. For several complex reasons, certain proteins found only in grains (such as wheat germ, wheat gliadins) also triggers inflammation. The foods that have a high glycemic index or have lots of wheat in them include the following:

High glycemic index foods (these are bad) (and pro-inflammatory nonglycemic foods) Low glycemic index foods (these are good) (and anti-inflammatory foods and beverages)
Sweet Fruit – banannas, oranges, grapefuit Fatty fruit – avocadoes, olives, capers
Orange juice, Apple juice, grape juice Unsweetened coconut milk, soymilk, almond milk
Pancakes, waffles, French toast, toast Scrambled eggs, omelettes, boiled eggs, fried eggs
Candy, Pies, Cake, Ice cream, Sherbert Vegetables – Broccoli, Brussel sprouts, Artichokes
Corn bread, Cornflakes, corn oil Olive oil, Coconut oil extract (MCT oil)
Processed cold cereals – Chex, Raisin bran Oatmeal, barley cereal, rye bread, etc.
   Cream of wheat, Fruit loops, etc. Mushrooms, seaweed (Sushi), cheese, butter
Toast, bread, donuts, bagels, croissants tomato soup (add some protein), mushroom soup
Potatoes, potato chips, French fries Cream of broccoli soup, lentils, legumes
Sweetened yogurt, sweetened milk Unsweetened yogurt, Greek yogurt
Cow’s milk, Chocolate milk, hot cocoa Prosage patties, garden burgers, vegelinks
Jam, jelly, honey, maple syrup, pancake syrup Soymeat, tofu, vegameat, Frichick
Peanut butter, Jam, and bread sandwiches Portobello  mushroom sandwiches w/o bread
White rice, brown rice, pita bread, wild rice Indian curries (leave out the potatoes), Thai curry
Wheat thins, Pretzels, wheat snacks Dried kale chips, seaweed snacks, onion snacks
Sugar drinks, sweetened tea, Gatoraid Green tea, white tea (no caffeine), herbal teas

2.   Enhance autophagy – This can be done without fasting all day.  Research has shown that fasting for at least 12 hours per day (evening and night) is sufficient to activate autophagy.  Not eating for at least 3 hours before bedtime also activates autophagy.  Eating the evening meal earlier in the day also helps.  For those who do not want to fast for at least 12 hours, there may be little hope of “cleaning the cobwebs out of the brain”.  Studies have shown that eating too much or eating late at night completely shuts off autophagy.  This is probably the #1 reason why most people have so much “proteotoxicity” in the brain, the pancreas, and other organs.  You can review our blog entry Autophagy – the housekeeper in every cell that fights aging.

There are some natural compounds and some drugs that stimulate autophagy, however. They include the following:

  • mTOR inhibitors – The mTOR pathway is “downstream” from the Insulin/IGF-1 pathway. The mTOR pathway completely “shuts off” autophagy and stimulates protein synthesis. This is the primary “danger” of eating too much meat or protein (i.e. stimulating the mTOR pathway).  Continually inhibiting the mTOR pathway is probably not a good idea either, since it is very important to synthesize proteins.  However, intermittent mTOR pathway inhibition has been shown to be a very effective way of stimulating “cellular housekeeping” in the brain. The best-known drug that inhibits the mTOR pathway ia rapamycin.  Low glucose levels and low amino acid levels in the blood also inhibit mTOR.  It is interesting that at least one big pharma company, Novartis,  is interested in marketing rapamycin as an anti-aging drug(ref).
  • AMPK activators – The AMPK pathway is one of the major pathways that activates autophagy. AMPK is activated by both exercise and fasting. The AMPK pathway is a “cross-talk” pathway between mTOR and the Insulin/IGF-1 pathway.  Activating AMPK inhibits both of these “bad” pathways. (They are only bad in certain contexts of aging and still serve important functions in aging people.  We could not be alive without them.  In the Part 2 blog entry we will talk about how some times IGF is the good guy we don’t want to be without.)  Besides exercise and fasting, AMPK can be stimulated by three hormones, some drugs and many natural compounds. The most potent AMPK activator is muscle contraction (i.e. exercise). The three hormones that stimulate AMPK are thyroid hormone and two hormones secreted from fat: leptin and adiponectin. Next to this, the most potent chemical activators of AMPK are probably AICAR and ZMP. These are synthetic compounds that are the only true “exercise mimetics”.  ZMP is a derivative of AICAR.  AICAR has been shown to increase endurance in rodents by 44% without exercise.  This is amazing.  Combining AICAR with exercise makes the drug even more effective. Unfortunately, AICAR is very expensive ($350-450/gram).  Common drugs that activate AMPK include metformin and aspirin.  Natural compounds that activated AMPK include resveratrol, pterostilbene, curcumin, EGCG,  betulinic acid, Gynostemma Pentaphyllum, Trans-Tiliroside (from rose hips), and 3-phosphoglycerate.  See this list for articles in this blog that deal with autophagy or describe autophagy activators.
  • Sirtuin activators – The 3rd major family of pathways that activates autophagy is for the Sirtuin enzymes (SIRT1-7). Sirtuins are enzymes that remove acetyl groups from proteins. The most important ones it deacetylates for autophagy are 3 proteins that are crucial to the autophagy system of “cellular housekeeping”.  These 3 proteins are Atg5, Atg7, and Atg8. There are many practical reasons why activating Sirtuin-induced autophagy is critical to health.  For instance, SIRT1 activation protects cells in human degenerative discs from death by promoting autophagy.  This is why fasting has been shown to eliminate back pain. The most well-known SIRT1 activator is resveratrol, the active ingredient in red wine.  However, both red wine and white wine have been shown to activate Sirtuin enzymes.  NAD+, NMN, and NR all activate Sirtuin enzymes (all 7 of them), whereas resveratrol only activates SIRT1.   You can see our blog entry NAD+ an emerging framework for health and life extension — Part 1: The NAD World

3.   Reduce stress – psychological stress, depression, worrying, and being obsessive compulsive all increase the risk of Alzheimer’s disease. The most effective ways to reduce “cellular stress” are as follows:

  • Yoga – yoga has been scientifically proven to reduce stress. The mechanism may be multifactorial, but studies suggest that activating stretch receptors in the muscles induces the SIRT3 gene.  The Sirtuin pathway is a major pathway activated by fasting, caloric restriction, red wine, NAD+, NMN, NR, and certain other natural compounds.
  • Meditation – meditation has been scientifically prove to reduce stress. However, 3 minutes of prayer is NOT meditation. Meditation requires 30-60 minutes of time. The MEND program recommends 20 minutes of meditation twice a day (No one prays that long).
  • Tai chi – this ancient Chinese form of exercise has been shown to reduce stress
  • Exercise followed by rest – exercise alone does not reduce stress, but exercise followed by a good night’s rest is very effective at reducing stress
  • Stretching exercises – These have a special beneficial effect on stress, especially back stretching exercises for back pain.

Self-monitoring of daily stress and exercise can be helpful for knowing what your stress levels are and how good a job you are doing at keeping stress at non-harmful levels.  A great many of the upstream conditions that can lead to dementias mentioned here (sedentary life style, improper diet, inadequate sleep, etc) are likely to induce constitutional stress which can be picked up by such monitoring.  A host of new wearable devices can keep track of exercise and its consequences.  See the blog entry Digital health – health and fitness wearables, apps and platforms – implications for assessing health and longevity interventions – Part 1.  Vince has identified two constitutional stress measurements in his blog entry that can be tracked starting with smartwatch heart rate and sleep measurements, MRHR (morning resting heart rate before awakening), and ERHR-MRHR (difference between evening resting heart rate and morning resting heart rate during sleep, a measure of overnight sleep-related constitutional stress recovery),.  These are described in the blog entry Digital health – health and fitness wearables, Part 2: looking for practical stress biomarkersAlso, heart rate variability is another personally trackable constitutional measurement of stress,  See my recent blog entry on heart rate variability, Digital Health Part 3.

4.    Optimize sleep – At least 8 hours of sleep at night is very effective in preventing Alzheimer’s disease.

Daytime sleeping probably is not as effective, but is probably not harmful provided that a person is not too sedentary with daytime sleeping (i.e. short naps).  Adding 0.5 – 3 mg of melatonin and 500 mg of tryptophan is also very helpful in getting a good night’s sleep.  One of the biggest problems with getting a good night’s sleep is sleep apnea, which is actually very common as we get older.

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“A Simplified schematic of the proposed interventions that may have potential to delay AD pathogenesis — The green arrows indicate pathways for improved circadian regulation and sleep quality, ultimately delaying AD pathogenesis. According to this model, chronobiotics (i.e., bright light therapy (BLT); melatonin; exercise; and food restriction) and good sleep hygiene could be used individually—but preferably in combination—to improve circadian regulation and sleep quality, decrease inflammation and Aβ deposition, and thereby delay AD pathogenesis.”  Image and legend source

5.   Exercise – The World Health Organization recommends 150 minutes of exercise per week, but the best scientific evidence suggests that this is NOT enough. The best scientific evidence suggests at least 450 minutes of exercise per week.  That is 60 minutes per day and an extra 20 minutes on one of those days.  If you want to skip Saturday, that means 75 minutes per day (1hr 15 minutes).  The exercise should include the following for preventing Alzheimer’s disease:

  • Swimming, outdoor hiking, calisthenics, aerobic fitness classes, spinning classes, etc.
  • 30-45 minutes of aerobic exercise where the heart rate is 60% of training heart rate.  This can be on a stationary bicycle, an elipical machine, a “hand bicycle”, a stair climber,
  • 1 mile per day of walking outside (the speed is not important)
  • Resistance exercise – this includes weight lifting, machines, stretch bands, push-ups, etc.
  • Stretching – stretching activates stretch receptors which activates the SIRT3 gene, which is key for mitochondrial function and decreasing free radicals in the muscles (which cause pain
  • Listening to relaxing music – classical music listening is a good way to relax.

Watching TV or looking at a computer screen and “surfing on the computer” probably does NOT work to reduce cellular stress.  Here are some of the blog entries we have published relating to exercise.

6.   Brain stimulation – The Mayo Clinic did a study in 487 patients where they participated in a computerized cognitive training program called “Brain Fitness Program” by Posit Science. This computer training required 1 hour of time per day, 5 days per week for 8 weeks (totaling 40 hours). This was called the IMPACT study.  This program increased their auditory processing speed by 131% and improved their memory an equivalent of approximately 10 years!  Here is some information on this inexpensive computer program:

Some of us think that we may keep our brains fit by constantly trying to figure out the mechanisms of aging.

7.  Keep your homocysteine low – High homocysteine levels seem to correlate with inflammation and also with deficiencies in folate cycle intermediates. The MEND program recommendation is to check your homocysteine levels and if it is > 7, then to take methyl-B12, methyltetrahydrofolate, pyridoxal-5-phosphate, and trimethylglycine (if necessary). The dosages are: Methyltetrahydrofolate – 0.8 mg/day and Pyridoxine-5-phosphate –  50 mg/day

8.   Keep your vitamin B12 high – Vitamin B12 is very important in memory and prevention of dementia. Vit B12 deficiency alone can cause dementia. It is easier to prevent than to reverse.  The MEND program recommends taking methyl-B12, not regular B12. They recommend basing the dose of methyl-B12 on serum levels of B12, which they recommend keeping above 500 with 1mg of methylB12/day.

9.  Keep your C-reactive protein low – CRP is a measure of inflammation. This correlates very well with inflammation in the brain (called neuroinflammation).  They recommend keeping the CRP levels below 1.0 and the Albumin/globulin ratio > 1.5.  There are no FDA-approved drugs that lower this which are safe to be used on a chronic basis.  However, there are several natural products that are effective in reducing C-reactive protein (CRP).  They include curcumin (400 mg/day), Fish oil (DHA & EPA), and an anti-inflammatory diet that is low in sugar and wheat products.  The MEND program recommends 700 mg of DHA twice a day (total 1400 mg) and 500 mg of EPA twice a day (total 1,000 mg).  Since most Fish oil capsules are only about 1/3rd omega-3 fatty acids, that means you need to take about 7,000-8,000 mg (i.e. 7-8 one gram capsules) per day of Fish oil.

10.   Keep your fasting insulin low – Most people develop insulin resistance with aging. Unfortunately, this is rarely diagnosed until they have already suffered the consequences of insulin resistance, which include metabolic syndrome, hypertriglyceridemia, hypercholesterolemia, Alzheimer’s disease osteoarthritis, accelerated hearing loss, accelerated visual impairment (including presbyopia, cataracts, and age-related macular degeneration, aka AMD).  Once these things occur, then reducing your fasting insulin no longer is useful – the cells are already dead!  The MEND program recommends keeping your fasting insulin to < 7.0.  The best way to do this is to eat a low glycemic index diet, encourage ketogenesis by 12 hours of fasting per day, exercise, sleep, and in some cases the drug metformin.  We have found that the NAD precursor, NMN is effective in reducing fasting insulin levels.  Other supplements designed to enhance NAD+ may help as well.

11.   Hormone balancing – The MEND program recommends normalizing thyroid hormone levels (free T3, free T4, estrogen, testosterone, progesterone, pregnenolone, and cortisol). For most people, cortisol levels are way too high.  The best way to reduce cortisol is to reduce stress, improve sleep, and also possibly to supplement with NMN or NR.  The rest of the hormones decline with aging and often need replacement. Here are some ways to make this safe:

  • Testosterone replacement therapy – this is risky in older men, due to the risks of accelerated coronary artery narrowing due to neointimal hyperplasia, as well as benign prostatic hypertrophy worsening or by making prostate cancer grow. For this reason, a thorough work-up for prostate cancer must be done before starting testosterone. In addition, testosterone dosing should be based on testosterone levels.
  • Progesterone – This is primarily for women, but also helps men in low doses. Any progesterone replacement therapy should also be based on blood levels of progesterone.
  • Pregnenolone – This helps both men and women for the brain.
  • Estradiol (E2) – This should also be done based on blood levels of E2

12.   Healthy gut bacteria – Most people have very unhealthy gut bacteria due to the use of antibiotics, due to general anesthesia, and due to dietary factors such as a high sugar diet. As a result, the lactobacillus that are good for your health often die.  In addition, the fiber-fermenting bacteria are often absent, thereby eliminating the healthful effects of a high fiber diet.  Probiotics and prebiotics are often helpful in restoring healthy gut bacteria.  You can see Vince’s 2012 blog entry Gut microbiota, probiotics, prebiotics and synbiotics – keys to health and longevity.

13.   Reducing amyloid beta aggregates – One of the hallmarks of Alzheimer’s disease is the accumulation of misfolded, aggregates of a protein called amyloid beta. Fortunately, there are two natural compounds that if taken in large quantities can reduce amyloid-beta plaques in the brain.  They are Ashwagandha and curcumin.  Both of these are effective in reducing amyloid beta plaques.  The MEND program recommend doses of 500 mg for Ashwagandha and 400 mg for curcumin.  Because curcumin is so poorly absorbed, it is better to take a liposomal or nanoparticle form of the curcumin, like Bio-curcumin 95. Curcumin can be taking as a pill, but it may be absorbed much better in curry that has coconut oil, since the coconut oil creates an emultion and micelles which can be absorbed by the lymphatic system and thereby “bypass” the liver and the “first pass effect”.   Ashwagandha is much better absorbed and does not have as much of a problem. It can be taken as a pill, but also can be taken as a tea.   My friend Dr. Vince Giuliano has made a liposomal form of these two compounds together with two complementary anti-inflammatory herbal extracts which he believes get into the blood stream in concentrations that are 8-10 times higher than by pill form.  He has written about these and other phytosubstances a number of times, e.g.(ref) (ref) (ref) (ref) (ref).

14.   Cognitive enhancement – This category was probably added to the MEND program for supplements that could not be categorized elsewhere. They specifically recommend the natural product called Bacopa monniera and Magnesium. Bacopa monnieri is also called “water hyssop”, “herb of grace”, “Indian pennywort” and Withania somnifera.  Bacopa monniera has been shown to reduce amyloid plaque and prevent synaptic decline in mouse models of AD.  One possible mechanism by which Bacopa monnieri works is to enhance LDL receptor-related protein, which is the “amyloid exporter” in the brain.  There are many studies that show a benefit from Bacopa monniera In humans. A meta-analysis of 6 high quality clinical trials of Bacopa monniera showed that 9 out of 17 tests showed improved performance in the domain of “memory free recall”. In a study on Okadaic acid induced memory impaired rats, the effect of standardized extract of Bacopa monnieri and Melatonin on the Nrf2 pathway was investigated.  “OKA caused a significant memory deficit with oxidative stress, neuroinflammation, and neuronal loss which was concomitant with attenuated expression of Nrf2, HO1, and GCLC. Treatment with BM and Melatonin significantly improved memory dysfunction in OKA rats as shown by decreased latency time and path length. The treatments also restored Nrf2, HO1, and GCLC expressions and decreased oxidative stress, neuroinflammation, and neuronal loss. Thus strengthening the endogenous defense through Nrf2 modulation plays a key role in the protective effect of BM and Melatonin in OKA induced memory impairment in rats.” There is a special form of magnesium which is much better incorporated into the cell called Magnesium-L-threonate, aka MgT.  Both can be taken as a capsule.  The dose Bacopa monniera they recommend is 250 mg/day. However, most of the clinical trials recommend dosages of 300-450 mg/day.

15.  Vitamin D3 –Vitamin D3 seems to be quite different than the other vitamins for a variety of reasons. The most important difference is that Vitamin D levels should be checked and individuals need to adjust their dose based on their serum vitamin D3 levels. To prevent AD, the levels of Vitamin D3 need to be > 50 nmol/L.  The strongest evidence for this comes from two recent studies from 2014.  One was a 5 year study in 1,658 elderly patients who started the study with no dementia. During the 5 years, 171 of the 1,658 developed dementia (10% risk over 5 years).  This study looked at “all cause dementia”, of which 90% is Alzheimer’s dementia (AD) and Vascular dementia (VD).  The risk of developing dementia when serum Vitamin D3 levels were > 50 nmol/L was very low.  However, those with Vit D3  levels between 25 and 50 nmol/L had a 1.53 fold higher risk of developing dementia of any type.  Those with levels below 25 nmol/L had a 2.25 nmol higher risk of developing dementia of any type.  The 2nd study reported in 2014 was from Denmark and followed 10,186 individuals in the Danish population for 30 years.  They looked at the risk of specific kinds of dementia and the relationship to Vitamin D3.  For Alzheimer’s disease (AD), the risk of AD type dementia was 1.25-1.29 fold higher in those with serum Vit D3 levels below 25 nmol/L.  For Vascular Dementia (VD), the risk of VD type dementia was 1.22 fold higher in those with serum Vit D3 levels below 25 nmol/L.  In conclusion, low Vitamin D3 levels is one of the largest risk factors for dementia and the easiest to prevent.  Most people do not get their Vitamin D3 levels checked.  Do you know what yours is?

16.   Increasing Nerve Growth Factor (NGF) Hericium erinaceus and ALCAR — Although there are many growth factors that make nerve cells grow, the most important one is probably Nerve Growth Factor (NGF).  NGF is a growth factor made and secreted by astrocytes in the brain and spinal cord.  NGF enhances neuronal stem cell regeneration of the brain.  Exercise is a potent stimulator of NGF secretion. There are several natural compounds that stimulate nerve growth factor secretion.  They include extracts from the mushroom, Hericium erinaceus. Although there are other edible mushrooms that are good for you, of the 4 edible mushrooms that were studied for their effect on NGF secretion, only Hericium erinaceus induced the secretion of NGF from human astrocytes in the Hippocampus of the brain.  Another compound that stimulates the secretion of NGF is Acetyl-L-carnitine, aka ALCAR.  Acetyl-L-carnitine also helps with neuropathic pain.   In rodent models of Alzheimer’s disease, 150 mg/kg/day of ALCAR induced NGF secretion and increased choline acetyltransferase activity, which increasea acetylcholine levels in the hippocampus.

17.   Provide the substrates for synaptic formation uridine, choline, citocolin, DHA, EPA, and herring roe — The ability to form synaptic connections between neurons is a key part of forming memory. Several key molecules are needed to create these synapses and dendritic spines that are not made by the human body (e.g. DHA) or are made in inadequate amounts (e.g. citicoline).   The omega-3 fatty acid called docosahexaenoic acid (DHA) is probably the “rate-limiting substrate” in the formation of presynaptic and postsynaptic proteins.  DHA alone will increase the formation of synapses and increase cognitive performance in humans and experimental animals, but the addition of two other circulating precursors for phosphatidylcholine also enhance memory formation.  These two other precursors are uridine (which gives rise to brain UTP and CTP) and choline (which gives rise to phosphocholine).   Phosphatidylcholine (PC) is the major phosphatide found in human neuronal connections. The other two major synaptic ingredients are uridine and DHA.  Studies have shown that the aministration of choline, uridine, and DHA together have a greater effect than the sum of the individual effects (i.e. they have a synergistic effect on generating synapses and dendritic spines). DHA alone increased the synthesis of hippocampal phospholipids by 8-75%, with the greatest percentage being in the synthesis if PC (phosphatidylcholine).  There are still controversies as to how much DHA a person should take per day.

The MEND program recommends 320 mg of DHA/day, but other experts recommend as much as 2,000 mg/day of DHA.  Herring roe, the eggs from the Herring forage fish, is another good source of n-3 polyunsaturated fatty acids that have a high phospholipid content.  MOPL 30 is a supplement product made by Artic Nutrition that includes a lot of phospholipids and a 3:1 ratio of DHA:EPA.  The MOPL 30 proprietary supplement not only increased neuronal generation, it also decreased plasma triacylglycerol and non-esterified fatty acids as well as increased HDL-cholesterol.  Although fasting glucose did not change, the glucose measurement on OGTT decreased at 10 minutes and 120 minutes into the test.   Instead of taking herring roe, uridine, or choline, the MEND program recommends citocoline (aka CDP-Choline) an intermediate compound in the generation of phosphatidylcholine from choline (i.e. already half made).  It is marketed under many names worldwide, including Ceraxon, Cognizin, NeurAxon, Somazina, Synapsine, etc. Studies have shown that citocoline increases dopamine receptor densities, prevents memory impairment, improve focus and mental energy.  Citocoline may also help treat attention deficit disorder (ADD).  The MEND program recommends a dose of 500 mg of Citocoline twice a day, 320 mg of DHA per day, and 180 mg of EPA per day.

18.   Optimize antioxidants – mixed tocopherols, tocotrienols, Selium, blueberries, NAC, Vit C, a-lipoic acid.  Although the free radical theory of aging has largely been proven to be incorrect as the “cause of aging”, there is no question that the “effect of aging” includes free radical damage to proteins, lipids, and nucleic acids that make up a cell.  To try to mitigate these “downstream effects” of aging, many believe that the judicious use of antioxidants still plays a useful role in treating neurodegeneration.  In this blog we have questioned that viewpoint and have pointed out that “antioxidants” like those mentioned often have powerful epigenetic impacts that better explain their actions(ref)(ref).

19.  Optimize Zn:fCu ratio – Alzheimer’s disease may be caused (in part) by copper toxicity — The fact that Alzheimer’s disease was rare prior to 1900, yet now being very common has led many experts to look for environmental “causes” of AD. One of the leading “suspects” in a long list of environmental risks for AD is inorganic copper, which comes from drinking water and supplement pills. There is clear evidence from human subjects that serum free copper is elevated with AD and that the level of free copper in the serum correlates with cognition and predicts cognition loss.  Animal studies have replicated these findings and have shown that as little as 0.12 ppm of coper in distilled drinking water in cholesterol-fed rabbits greatly enhanced the formation of AD.

A 2nd feature of AD is that those affected also have Zinc deficiency.  A small clinical trial published in 2014 showed that in patients over the age of 70, Zinc supplementation protected against cognitive loss and also reduced serum free copper levels in AD patients.  For these reasons, it is unclear if the efficacy of Zinc therapy is on restoring normal Zn levels or if it is due to reducing Cu levels.

The following Table lists the remaining interventions in Dale Bredesen’s list.  These are fairly clear and we will not expand on them here.

20.  Ensure nocturnal oxygenation Exclude or treat sleep apnea [54]
21.  Optimize mitochondrial function CoQ or ubiquinol, α-lipoic acid, PQQ, NAC, ALCAR, Se, Zn, resveratrol, ascorbate, thiamine [55]
22.  Increase focus Pantothenic acid Acetylcholine synthesis requirement
23.  Increase SirT1 function Resveratrol [32]
24.  Exclude heavy metal toxicity Evaluate Hg, Pb, Cd; chelate if indicated CNS effects of heavy metals
25.  MCT effects Coconut oil or Axona [56]

Neuroinflammation “causes” all of the neurodegeneratove diseases

Although we will save most of our discussion on the science of AD to the coming Part 2 blog entry in this series, we comment here a bit more on the the science behind most of the above interventions – their neuroinflammatory nature.

In all neurodegeneratiave diseases (both familial and sporadic cases), there is evidence of a chronic, low grade brain inflammation that does not go away.  Histologically, this is called “gliosis”, a term that describes what is seen under the microscope. As mentioned above, microglial cells are increased in number and they appear “angry” (i.e. they are activated) likely due to the presence of 1-42.  It is likely that these microglial cells are secreting pro-inflammatory factors which are causing the inflammation, although the picture is actually much more complex.  Vince has written about this in 2011 and before in the blog entries Key roles of glia and microglia in age-related neurodegenerative diseases, New views of Alzheimer’s disease and new approaches to treating it, and Alzheimer’s Disease Update. We surface some additional insights here and in Part 2..

This illustration portrays some of the inflammatory processes that go on when microglia and astrocytes are activated:

Image and legend  source The 2014 publication Inflammasomes in neuroinflammation and changes in brain function: a focused review  “Cytokines hypothesis of neuroinflammation: Implications in comorbidity of systemic illnesses with psychiatric disorders. Pro-inflammatory cytokines can migrate between systemic circulation and brain in both directions which could explain the comorbidity of systemic illnesses with psychiatric disorders. There are three pathways for the transport of pro-inflammatory cytokines from systemic circulation to brain as described by Capuron and Miller (2011): Cellular, Humoral, and Neural. Moreover, PAMPs and DAMPs from trauma, infection, and metabolic waste can prime glial cells to express pro-inflammatory cytokines TNF-α, IL-1β, and IL-6. When expressed, these cytokines activates granulocytes, monocytes/macrophages, Natural Killer, and T cells and together contribute to the pathophysiology of neuroinflammation. Chronic neuroinflammation could result in neurodegeneration and associated psychiatric disorders. These pro-inflammatory cytokines also stimulate production and expression of anti-inflammatory cytokine by glial cells that function as negative feedback to reduce the expression of pro-inflammatory cytokines, subsiding the neuroinflammation. MCP-1, Monocyte chemoattractant protein-1; CP, Choroid plexus; CVO, Circumventricular organ.”

The chronic inflammation viewpoint of Alzheimer’s disease is related to but somewhat different than the Beta Amloid viewpoint, the viewpoint covered in my recent blog entry The Amyloid Beta face of Alzheimer’s Disease.

The situation is described in a 2014 publication by Landry and Liu-Ambrose: “An alternative to the classic amyloid centric view of AD suggests that late-onset AD results from age-related alterations in innate immunity and chronic systemic inflammation (for review see Krstic and Knuesel, 2013).

In the Part 2 blog entry we will go into the neuroinflammation hypothesis in further depth and will explore other theories as to causes of AD and the other neurodegenerative diseases.

So, a basic strategy for preventing or delaying the onset of neurodegenerative diseases is to mount a multifront war on systematic inflammation.  The 25 Bredesen interventions described above are initiatives in that war.

About James Watson

I am a physician with a keen interest in the molecular biology of aging. I have specific interests in the theories of antagonistic pleiotropy and hormesis as frameworks to understand cellular senescence and mechanisms for coping with cellular stress. The hormetic “stressors” that I am interested in exploiting at low doses include exercise, hypoxia, intermittent caloric restriction, radiation, etc. I also have a very strong interest in the epigenetic theory of aging and pharmacologic/dietary maintenance of histone acetylation and DNA methylation with age. I also am working on pharmacologic methods to destroy senescent cells and to reactivate quiescent endogenous stem cells. In cases where there is a “stem cell exhaustion” in the specific niche, I am very interested in stem cell therapy (Ex: OA)

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Alzheimer’s disease is one of the most significant healthcare problems nationally and globally. Recently, the first description of the reversal of cognitive decline in patients with early Alzheimer’s disease or its precursors, MCI (mild cognitive impairment) and SCI (subjective cognitive impairment), was published [1]. The therapeutic approach used was programmatic and personalized rather than monotherapeutic and invariant, and was dubbed metabolic enhancement for neurodegeneration (MEND). Patients who had had to discontinue work were able to return to work, and those struggling at work were able to improve their performance. The patients, their spouses, and their co-workers all reported clear improvements. Here we report the results from quantitative MRI and neuropsychological testing in ten patients with cognitive decline, nine ApoE4+ (five homozygous and four heterozygous) and one ApoE4-, who were treated with the MEND protocol for 5-24 months. The magnitude of the improvement is unprecedented, providing additional objective evidence that this programmatic approach to cognitive decline is highly effective. These results have far-reaching implications for the treatment of Alzheimer’s disease, MCI, and SCI; for personalized programs that may enhance pharmaceutical efficacy; and for personal identification of ApoE genotype.

Source: Reversal of cognitive decline in Alzheimer?s disease – AGING Journal

Light-harvesting chlorophyll pigments enable mammalian mitochondria to capture photonic energy and produce ATP
Chen Xu, Junhua Zhang, Doina M. Mihai, Ilyas Washington

ABSTRACT

Sunlight is the most abundant energy source on this planet. However, the ability to convert sunlight into biological energy in the form of adenosine-5′-triphosphate (ATP) is thought to be limited to chlorophyll-containing chloroplasts in photosynthetic organisms. Here we show that mammalian mitochondria can also capture light and synthesize ATP when mixed with a light-capturing metabolite of chlorophyll. The same metabolite fed to the worm Caenorhabditis elegans leads to increase in ATP synthesis upon light exposure, along with an increase in life span. We further demonstrate the same potential to convert light into energy exists in mammals, as chlorophyll metabolites accumulate in mice, rats and swine when fed a chlorophyll-rich diet. Results suggest chlorophyll type molecules modulate mitochondrial ATP by catalyzing the reduction of coenzyme Q, a slow step in mitochondrial ATP synthesis. We propose that through consumption of plant chlorophyll pigments, animals, too, are able to derive energy directly from sunlight.

INTRODUCTION

Determining how organisms obtain energy from the environment is fundamental to our understanding of life. In nearly all organisms, energy is stored and transported as adenosine-5′-triphosphate (ATP). In animals, the vast majority of ATP is synthesized in the mitochondria through respiration, a catabolic process. However, plants have co-evolved endosymbiotically to produce chloroplasts, which synthesize light-absorbing chlorophyll molecules that can capture light to use as energy for ATP synthesis. Many animals consume this light-absorbing chlorophyll through their diet. Inside the body, chlorophyll is converted into a variety of metabolites (Ferruzzi and Blakeslee, 2007; Ma and Dolphin, 1999) that retain the ability to absorb light in the visible spectrum at wavelengths that can penetrate into animal tissues. We sought to elucidate the consequences of light absorption by these potential dietary metabolites. We show that dietary metabolites of chlorophyll can enter the circulation, are present in tissues, and can be enriched in the mitochondria. When incubated with a light-capturing metabolite of chlorophyll, isolated mammalian mitochondria and animal-derived tissues, have higher concentrations of ATP when exposed to light, compared with animal tissues not mixed with the metabolite. We demonstrate that the same metabolite increases ATP concentrations, and extends the median life span of Caenorhabditis elegans, upon light exposure; supporting the hypothesis that photonic energy capture through dietary-derived metabolites may be an important means of energy regulation in animals. The presented data are consistent with the hypothesis that metabolites of dietary chlorophyll modulate mitochondrial ATP stores by catalyzing the reduction of coenzyme Q. These findings have implications for our understanding of aging, normal cell function and life on earth.

RESULTS

Light-driven ATP synthesis in isolated mammalian mitochondria

To demonstrate that dietary chlorophyll metabolites can modulate ATP levels, we examined the effects of the chlorophyll metabolite pyropheophorbide-a (P-a) on ATP synthesis in isolated mouse liver mitochondria in the presence of red light (λmax = 670 nm), which chlorin-type molecules such as P-a strongly absorb (Aronoff, 1950), and to which biological tissues are relatively transparent. We used P-a because it is an early metabolite of chlorophyll, however, most known metabolites of chlorophyll can be synthesized from P-a by reactions that normally take place in animal cells. Control samples of mitochondria without P-a, and/or kept in the dark were also assayed. In the presence of P-a, mitochondria exposed to red light produce more ATP than mitochondria without P-a (Fig. 1A) or mitochondria kept in the dark (supplementary material Fig. S1A–D). Mitochondrial membrane potential (Fig. 1B) and oxygen consumption (Fig. 1C) increased upon increased light exposure in P-a-treated mitochondria. Light or P-a alone had no effect on any of the above measures of mitochondrial activity (supplementary material Fig. S1E–G). With too much added P-a, ATP concentrations and the rate of oxygen consumption started to return to the levels in mitochondria not incubated with P-a (supplementary material Fig. S1G). Addition of the electron transport inhibitor, sodium azide, reduced the light- and P-a-fueled oxygen consumption by 57% (supplementary material Fig. S1H–I), consistent with oxygen consumption occurring through the electron transport system. Observations were consistent with enhanced ATP production driven by oxidative phosphorylation.

Fig. 1.

Chlorophyll metabolite P-a allows isolated mouse liver mitochondria to capture light to make ATP. (A) ATP synthesis in mouse liver mitochondria incubated with P-a (treated) and exposed to light compared to controls (no P-a). Light exposure started at time zero and ADP was added at 30 seconds. Aliquots were obtained at times shown and relative ATP levels measured using the firefly luciferase assay. Means and standard deviations are shown for each time point. The experiment was run in triplicate with the same batch of mitochondria. *P<0.05 for treated versus control samples. (B) Mitochondrial membrane potential (Δψm) under different treatments as measured by safranin fluorescence. Lower fluorescence equals higher membrane potential. Mitochondria, with or without P-a, were exposed to light for 2 minutes or kept in the dark. Safranin was added at time zero and safranin fluorescence was continuously measured while samples remained under the light. The experiment was run in triplicate with the same batch of mitochondria. Curves shown are the average traces for triplicate runs. (C) Representative oxygraph trace (black line) for mitochondria treated with 4 µM P-a. The light was turned on or off at the times indicated by the arrows. Steeper slope denotes faster oxygen consumption. Dotted lines show slopes when the light was off. When the light was turned on the slope of the black line increased by twofold. That is, oxygen consumption increased when the light was turned on. When the light was turned off, oxygen consumption returned to baseline levels (i.e. the two gray lines have the same slope).

To determine whether P-a associates with mitochondria, we measured P-a fluorescence at 675 nm in the presence of increasing amounts of heart mitochondrial fragments obtained from sheep (Fig. 2A,B). After increasing the concentration of mitochondria, P-a fluorescence increased abruptly, by fivefold, and quickly reached a plateau (Fig. 2B). The abrupt change in fluorescence reflects a change in the environment of P-a, consistent with its change from an aqueous environment to one in which it is presumably associated with a protein. This threshold-sensitive behavior is consistent with zero-order ultrasensitivity, or positively cooperative binding, as described by Goldbeter and Koshland, and suggests a coordinated interaction between the metabolite and mitochondrial fragments (Goldbeter and Koshland, 1981). In contrast, this threshold sensitivity was not observed when increasing amounts of bovine serum albumin (BSA) were added to a solution of P-a; instead, fluorescence steadily increased (supplementary material Fig. S1J).

Fig. 2.

Cooperative binding of P-a to mitochondrial fragments. (A) Fluorescence spectra of P-a before and after addition of sheep heart mitochondrial fragments. Upon addition of mitochondrial fragments, the fluorescence intensity of P-a increased and shifted to a longer wavelength, and the shape of the curve (ratio of the shoulder to main peak) changed. (B) Ultrasensitive steady state response of the P-a–mitochondrial interaction. We measured fluorescence intensity for a 1 µM P-a solution while increasing the concentration of mitochondrial fragments. A Hill coefficient of 36, with a 95% confidence interval from 7 to 65, was obtained by fitting the data to the Hill equation [y = axb/(cb+xb)+offset]. Fit (R2): 0.96.

Catabolic reduction of coenzyme Q10 (CoQ10) is a rate limiting step in respiration (Crane, 2001). The majority of CoQ10 molecules exist in two alternate states of oxidation: ubiquinone, the oxidized form, and ubiquinol, the reduced form. To show that the P-a metabolite could catalyze the photoreduction of mitochondrial CoQ10, we measured the oxidation state of CoQ10 in the above sheep heart mitochondrial fragments in response to exposure to red light. We exposed the mitochondria to light for 10 minutes and measured the percentage of reduced and oxidized CoQ10 by high performance liquid chromatography (HPLC) (Qu et al., 2013). In the freshly isolated mitochondria fragments, nearly all the CoQ10 was oxidized in the form of ubiquinone. However, when we incubated the mitochondria with P-a and exposed the suspension to light, 46% of CoQ10 was reduced (Table 1, entry 1). In comparison, as a positive control, we energized the mitochondria with glutamate/malate and kept the suspension in the dark, yielding a 75% reduction of CoQ10 within 10 minutes (entry 2). In the absence of light, no reduction occurred (entry 3). Upon denaturing the mitochondrial proteins with heat, no reduction occurred (entry 4). Likewise, there was a lack of CoQ10 reduction with CoQ10, P-a and light in the absence of mitochondria (entry 5). These observations are consistent with the fluorescence data in Fig. 2A,B, showing that mitochondrial proteins sequester and organize P-a. In the absence of added P-a, a 2–14% reduction was observed, depending on the mitochondrial preparation used (entry 6). We attribute this ‘background reduction’ to the actions of endogenous chlorophyll metabolites, which we were able to detect by fluorescence spectroscopy (see Distribution of light-absorbing dietary chlorophyll, below).

Table 1. Photoreduction of CoQ10 is an early event in light-stimulated ATP synthesis

Light-driven ATP synthesis in rodent tissue homogenates

To determine whether chlorophyll metabolites and light could influence ATP production in whole tissues, we treated mouse brain homogenates with P-a and exposed them to 670-nm light. The treated brain homogenates synthesized ATP at a 35% faster rate than a control homogenate that was not incubated with P-a [relative ATP synthesis rates (means with standard error and 95% confidence intervals (CI) were: treated, 171.7±8.1 (CI: 154.6–188.7); control, 111.3±9.1 (CI: 92.5–130.0); Fig. 3A]. No linear correlation between the increase in ATP concentrations and the amount of added P-a was observed. Increasing concentrations of P-a elicited the same increase in ATP (supplementary material Fig. S2A,B).

Fig. 3.

Chlorophyll metabolite P-a allows mouse brain tissue homogenates to capture light to make ATP. (A) ATP synthesis in mouse brain homogenate with light exposure. Homogenates were incubated with ADP ± P-a and exposed to light starting at time zero. Aliquots were withdrawn at the times shown. Relative ATP in the aliquots was measured using the firefly luciferase assay. The experiment was run in triplicate with the same batch of homogenized brains. Means and standard errors are shown for each time point. For the control, the standard errors are smaller than the line markings and thus cannot be seen. *P<0.05 for treated versus untreated samples. (B) Overlay of the absorption spectrum of P-a (dotted line) and the wavelengths tested for ATP production in samples treated with P-a and exposed to light for 20 minutes. Peak ATP production correlated with peak P-a absorption. Experiments were done in triplicate. Means and standard errors were calculated, however, standard errors are smaller than the markings and thus cannot be seen.

To demonstrate that photon absorption by P-a was necessary to enhance ATP production, we exposed the P-a-treated brain homogenates to greenish (500 nm) and red (630, 670 and 690 nm) light, all with the same total energy. Wavelengths of light that were more strongly absorbed by P-a produced the largest increase in ATP. For example, the ATP concentration increased by ∼16-fold during exposure to 670 nm light; relative to the same sample kept in the dark, it increased by two-to-fivefold during exposure to 500, 630 and 690-nm light of equal energy (Fig. 3B).

In addition to brain homogenates, P-a also enhanced ATP production in adipose, lens and heart homogenates (supplementary material Fig. S2C–E). Quantification of ATP by both the luciferase assay and high-performance liquid chromatography (HPLC) gave similar results (supplementary material Fig. S2E–F).

Distribution of light-absorbing dietary chlorophyll

Chlorophylls and its metabolites, both chlorins, have signature absorption and admission spectra (Aronoff, 1950). Namely they absorb strongly (ε≈50,000 M−1 cm−1) at ∼665–670 nm and demonstrate intense fluorescence emissions at ∼675 nm, which differentiate chlorins from endogenous molecules in mammals (Aronoff, 1950). To examine whether dietary chlorophyll and/or its metabolites were present in animal tissue after oral consumption, we fed mice a chlorophyll-rich diet. Brain (Fig. 4A) and fat (Fig. 4C) extracts from these mice exhibited red fluorescence at 675 nm when excited with a 410-nm light [brain: treated, 15.4±6.7 (n = 6); control: 4.2±2.6 (n = 6; means ± s.d.); P<0.01]. The excitation spectrum of this 675-nm peak (Fig. 4B) was similar to that of known chlorophyll metabolites with an intact chlorin ring: with maxima at 408, 504, 535, 562 and 607 nm. This red fluorescence diminished, as measured by the area under the 675 nm peak, when animals were given a chlorophyll-free diet for 2 weeks. Red fluorescence could also be seen using fluorescence imaging; fluorescence was stronger in the bodies and brains of animals fed chlorophyll than in animals given a chlorophyll-poor diet [Fig. 4D; mean gray value in the boxed areas with standard deviation and minimum and maximum gray value shown in brackets were: treated brain, 118 (97–138); control brain, 82 (60–100); treated back fat pad, 116 (97–132) and control back fat pad, 35 (25–46)]. The red fluorescence was enriched in the gut and intestines, consistent with dietary chlorophyll being the source of the fluorescence.

Fig. 4.

Dietary chlorophyll results in chlorophyll-metabolite-like fluorescence in tissues. (A) Representative fluorescence spectra of brain extracts following excitation at 410 nm. Relative peak areas for a total of six control animals fed a chlorophyll-poor diet and six treated animals fed a chlorophyll-rich diet. (B) Representative excitation spectrum (emission at 675 nm) of a brain extract from mice fed a chlorophyll-rich diet. (C) Representative fluorescence spectra of abdominal fat extracts from mice fed chlorophyll-poor and rich diets. (D) A 675±10-nm fluorescence image of skinned mice raised on chlorophyll-rich and -poor diets.

To determine whether the red fluorescence was localized to mitochondria, we measured the relative 675-nm fluorescence in whole liver homogenates and mitochondria isolated from these homogenates. As measured by fluorescence intensity, isolated mitochondria contained 2.3-fold as much of the 675-nm fluorescent metabolite(s) per milligram of protein as did the whole liver homogenate. This observation suggests that P-a was concentrated in the mitochondria, consistent with data summarized in Fig. 2A,B, and literature reports (MacDonald et al., 1999; Tang et al., 2006).

Fat and plasma extracts from rats fed chlorophyll-rich diets were further analyzed by HPLC to elucidate the source of the red 675-nm fluorescence. Fig. 5A shows a representative chromatogram with compounds in the eluting solvent that displayed 675-nm fluorescence when excited with 410-nm light. Rat fat extracts and plasma extracts both contained similar chlorophyll-derived metabolites (similar chromatograms not illustrated). Two groups of compounds eluting at 23–30 minutes and 40–46 minutes were detected. Compounds eluting between 23 and 30 minutes had similar retention times to those of the chlorophyll metabolites without the phytyl tail, with at least one carboxylate group, such as P-a. The absorption spectra (the locations of the absorbance maxima and the Soret-to-Qy-band ratios) of this group of compounds were consistent with demetalated chlorophylls (Rabinowitch, 1944), as shown in Fig. 5B. In addition, the spectra of this group of peaks were indicative of coordination to a metal ion. A representative spectrum of such a presumably metalated metabolite is shown in Fig. 5C, showing a red shifted Soret band, a blue shifted Qy-band and a Soret-to-Qy-band ratio of ∼1. The compounds eluting between 40 and 46 minutes had similar retention times to that of the demetalated chlorophyll-a standard (pheophytin-a). In addition, these compounds partitioned with hexanes (polarity index = 0.1) when mixed with hexanes and acetonitrile (polarity index = 5.8). This latter characteristic is consistent with a lack of a carboxylic acid group, or an esterified P-a, such as pheophytin-a. Similar HPLC chromatograms from fat extracts of swine fed chlorophyll rich diets (Mihai et al., 2013) were recorded (supplementary material Fig. S2G), suggesting that uptake and distribution of chlorophyll metabolites were not unique to mice and rats.

Fig. 5.

Light-absorbing metabolites of chlorophyll are present in adipose tissue. (A) HPLC chromatogram of an adipose extract. 2.5 grams of abdominal adipose tissue from a rat fed a chlorophyll-rich diet was extracted with acetone and the acetone concentrate subjected to HPLC. In the chromatogram, only compounds that displayed 675-nm fluorescence, characteristic of chlorophyll and its metabolites possessing a chlorin ring, are shown. Five major peaks are observed along with several minor peaks. For peaks with letters, the corresponding absorption spectra are shown below. (B–D) Absorption spectra of labeled peaks in A (b–d, respectively). Numbers above peaks are peak maxima in nm. Numbers in the center are the ratios of the Soret band, around 400 nm, to the Qy band at around 655 nm. All spectra are consistent with those of metabolites of chlorophyll. Spectrum C has been assigned to a metalated porphyrin.

We quantified total blood pigments from rats that absorbed at 665 nm. Using an extinction coefficient of 52,000 at 665 nm (Lichtenthaler, 1987), which is typical of chlorophyll-a-derived pheophytins, we estimated a plasma concentration of 0.05 µM in two rats fed a chlorophyll-rich diet. The 665-nm peak was absent in animals fed a chlorophyll-poor diet. The amount of measured total metabolite was five- and two-times higher than that reported for the fat soluble vitamins K (Tovar et al., 2006) and D (Halloran and DeLuca, 1979), respectively, in the rat.

Light-driven ATP synthesis in C. elegans

Next, we used C. elegans to evaluate the effects of light-stimulated ATP production in a complex organism. As C. elegans age, there is a drop in cellular ATP (Braeckman et al., 1999; Braeckman et al., 2002). We hypothesized that the worm would live longer if it could offset this decline in ATP by harvesting light energy for ATP synthesis. As our model system, we used firefly luciferase-expressing C. elegans, which upon incubation with luciferin emit a luminescence that is proportional to their ATP pools (Lagido et al., 2009; Lagido et al., 2008; Lagido et al., 2001). Upon incubation with P-a, worms incorporated the metabolite, as measured by fluorescence spectroscopy (supplementary material Fig. S3A). To determine whether there were changes in ATP stores in response to light, we plated two groups of worms into 96-well plates containing luciferin substrate. We measured worm luminescence at time zero. We then exposed one group to 660-nm light and kept the other in the dark and periodically measured luminescence in both groups of worms (summarized in Fig. 6A,B). To determine whether ATP increased in light-exposed animals, we subtracted the luminescence signal of the worms kept in the dark from that of the worms exposed to light (Fig. 6C). Worms that were given P-a had a statistically significant increase in ATP when exposed to light, whereas control worms showed no increase. The metabolite alone had no effect on ATP levels when the worms were kept in the dark (i.e. luminescence intensity remained constant throughout the experiment). The elevated luminescence signal persisted for 1 hour after the light was turned off, at which time measurement ceased. However, the luminescence intensity did not further increase during the time the light was off. It was unclear whether this persistent signal reflected the kinetics of the luciferase–luciferin reaction, luciferase expression, or actual ATP pools. Thus ATP was quantified by additional methods.

Fig. 6.

P-a treatment enables worms to capture light to generate ATP. Black lines show results from worms incubated with P-a at the indicated concentrations; gray lines show results from worms not incubated with P-a. (A) In vivo, real-time ATP levels in 1-day-old worms were tracked during exposure to light. Luciferase-expressing worms were incubated with luciferin and exposed to light at time zero. Luminescence was measured at the times shown. Data represent triplicate experiments of 12 separate sets of worms plated in 12 wells of a 96-well pate. Means and standard deviations are shown for each of the three separate runs. (B) In vivo, real-time ATP levels in worms kept in the dark. The same experiment as in A in the same 96-well plate, but the worms were kept in the dark. (C) Percentage ATP increase for worms in A relative to worms in B. (D) In vivo, real-time ATP monitoring. Groups of worms were incubated with or without P-a; light exposure began at time zero and in vivo ATP levels were determined at the times shown in each group of worms by measuring worm luminescence after the addition of luciferin. Each time point represents a different group of worms exposed to light for the times shown. Each experiment was performed in triplicate sets of 12; averages and standard deviations are shown. P-values of Student’s t-tests are also shown, representing the significance compared with the controls at the same light exposure. (E) The same experiment as described in D, but using 10-day-old worms.

As an alternative means of determining whether light stimulated ATP synthesis, we plated luciferase-expressing worms into a 96-well plate without the luciferin substrate, and exposed them to light. ATP status was determined at time zero, immediately before light exposure, and at 15-minute intervals for a total of 45 minutes by adding the luciferin substrate to a group of worms and measuring luminescence (Fig. 6D,E). We found an increase in ATP when 5-day-old and 10-day-old adult worms were fed the metabolite and exposed to light.

We further confirmed the in vivo increase in ATP using two additional ex vivo methods. After light treatment, we lysed the worms, extracted their ATP and quantified ATP in the homogenate using either the firefly luciferase assay or HPLC (supplementary material Fig. S3B,C). Both methods were consistent with the in vivo ATP measurements.

In addition to an increase in ATP, worms treated with P-a exhibited a 13% increase in respiration when exposed to light, as measured by oxygen consumption. However, light had no effect on the respiration rates in untreated worms (supplementary material Fig. S3D). This observation is consistent with an increase in ATP through oxidative phosphorylation, in accordance with the mitochondrial data. Despite the increase in ATP, the levels of reactive oxygen species (ROS) were equivalent in treated and untreated worms during 5 hous of light exposure, as measured using 2′,7′-dichlorofluorescin diacetate (supplementary material Fig. S3E). In fact, although the difference was not statistically significant, treated worms exhibited, on average, lower levels of ROS.

Light harvesting to extend life span

We next tested whether photonic energy absorption by P-a could prolong life. Life span measurements were taken in liquid cultures according to the method of Gandhi et al. and Mitchell et al. (Gandhi et al., 1980; Mitchell et al., 1979). Adult worms were incubated with P-a for 24 hours. Beginning at day 5 of adulthood, we exposed the worms to red light in a daily 5 hours:19 hours light∶dark cycle. Control worms were not given P-a or exposed to light, but otherwise were kept under identical conditions. Counts were made at 2- to 3-day intervals and deaths were assumed to have occurred at the midpoint of the interval. To obtain the half-life, we plotted the fraction alive at each count verses time and fitted the data to a two-parameter logistic function, known to accurately fit survival of 95% of the population (Vanfleteren et al., 1998). The group treated with P-a and light had a 17% longer median life span than the group that was not treated with P-a, but exposed to light (Fig. 7A,B). P-a treatment alone, in the absence of light, had no effect on life span (supplementary material Fig. S4B). Light treatment alone decreased life span by 10% (supplementary material Fig. S4B), in accordance with reports that nematodes survive better in complete darkness (Thomas, 1965). This decrease in median life span brought on by light was reversed when the worms were treated with P-a. The increased median life span with light and P-a was reproducible with different batches of worms (supplementary material Fig. S4B–E). Increasing the amount of P-a past a certain threshold, however, lead to a gradual decrease in lifespan approaching that of animals not treated with P-a (supplementary material Fig. S4B,C).

Fig. 7.

P-a and light increase C. elegans median life span. (A) Median life spans of worms treated with P-a and exposed to light versus those exposed to light but not treated with P-a. Numbers in parentheses are 95% confidence intervals (CI). (B) Life span plots of the values used for A. P-value is from an f-test. Experiments were run in triplicate. The L4 molt was used as time zero for life span analysis. Worms were grown in liquid culture at 500 worms/ml. For counting, aliquots were withdrawn and placed in a 96-well plate to give ∼10 worms per well; the worms were scored dead or alive on the basis of their movement, determined with the aid of a light microscope. A total of 60–100 worms, representing 1–2% of the total population, were withdrawn and counted at each time point for each flask.

We also examined life span longitudinally. We placed 6-day-old adult P-a- and non-P-a-treated worms into a 96-well plate, exposed them to red light for 5 hours per day and compared the percentage dead and alive after 15 days. Result: 47% of the P-a-treated worms were alive (175 alive; 200 dead) after 15 days, versus 41% of the control worms (111 alive; 163 dead), consistent with the cross-sectional experiments above.

DISCUSSION

Photoreduction of coenzyme Q

Upon incubation of: (1) isolated mouse mitochondria; (2) mouse brain, heart and lens homogenates; (3) homogenized duck fat; and (4) live C. elegans, with a representative metabolite of chlorophyll, light exposure was able to increased ATP concentrations. These observations in a variety of animal tissues perhaps demonstrate the generality of this phenomenon. To synthesize ATP, mitochondrial NADH reductase (complex I) and succinate reductase (complex II) extract electrons from NADH and succinate, respectively. These electrons are used to reduce mitochondrial CoQ10, resulting in ubiquinol (the reduced form of CoQ10). Ubiquinol shuttles the electrons to cytochrome c reductase (complex III), which uses the electrons to reduce cytochrome c, which shuttles the electrons to cytochrome c oxidase (complex IV), which ultimately donates the electrons to molecular oxygen. As a result of this electron flow, protons are pumped from the mitochondrial matrix into the inner membrane space, generating a trans-membrane potential used to drive the enzyme ATP-synthase.

The ‘pool equation’ of Kröger and Klingenberg describes the total rate of electron transfer: Vobs = VoxVred/(Vox+Vred), where Vred is ubiquinone reduction and Vox is ubiquinol oxidation (Kröger and Klingenberg, 1973). Based on this equation, the major roles of complexes I and II can be considered to maintain the mitochondrial ubiquinol pool, and to reduce ubiquinone, which should result in increased ATP synthesis. We reasoned the reduction of CoQ10 could be a potential step in the respiratory pathway in which chlorophyll metabolites could influence ATP levels, as it is known that chlorophyll-type molecules can photoreduce quinones (Chesnokov et al., 2002; Okayama et al., 1967). Indeed, a primary step during photosynthesis is the reduction of the quinone, plastoquinone, by a photochemically excited chlorophyll a (Witt et al., 1963). We hypothesized that if the reduction of mitochondrial ubiquinone could be catalyzed by a photoactivated chlorophyll metabolite, such as P-a, then ATP synthesis would be driven by light in mitochondria with these dietary metabolites. In the proposed mechanism, electrons would be transferred by a metabolite of chlorophyll to CoQ10, from a chemical oxidant present in the mitochondrial milieu. Many molecules, such as dienols, sulfhydryl compounds, ferrous compounds, NADH, NADPH and ascorbic acid, could all potentially act as electron donors. Throughout mammalian evolution, photons of red light from sunlight have been present deep inside almost every tissue in the body. Photosensitized electron transfer from excited chlorophyll-type molecules is widely hypothesized to be a primitive form of light-to-energy conversion that evolved into photosynthesis (Krasnovsky, 1976). Thus it is tempting to speculate that mammals possess conserved mechanisms to harness photonic energy.

Photoexcitation of chlorophyll and derivatives produces the excited singlet state (*1). Oxidative quenching of this singlet state by ubiquinone is possible. Electron transfer could take place through proteins or in solution. Escape from the charge transfer complex and protonation would yield ubisemiquinone, which accounts for 2–3% of the total ubiquinone content of mitochondria (De Jong and Albracht, 1994). Ubisemiquinone can be reduced to ubiquinol by repeating the above sequence or by disproportionation to give one molecule of ubiquinol and one molecule of ubiquinone. Back-electron transfer, from the photoreduced metabolite to the oxidized quinone, could be inhibited by disproportionation or by organizing the chlorophyll derivative and ubiquinol through protein binding. In line with the CoQ10 photoreduction hypothesis, we observed mitochondrial CoQ10 was reduced when isolated mitochondria were exposed to light and P-a (Table 1). Also consistent with light and/or P-a acting upstream of complexes I and II, in isolated mitochondria we observed an increase in ATP in the absence of added electron transport substrates, such as glutamate and malate (Fig. 1A; supplementary material Fig. S1A–C). However, further evidence is needed to confirm this mechanistic hypothesis.

The effect of light in vivo

Intense red light between 600 and 700 nm has been reported to modulate biological processes (Hashmi et al., 2010; Passarella et al., 1984; Wong-Riley et al., 2005), and has been investigated as a clinical intervention to treat a variety of conditions (Hashmi et al., 2010). Exposure to red light is thought to stimulate cellular energy metabolism and/or energy production by, as yet, poorly defined mechanisms (Hashmi et al., 2010). In the presence of P-a, we observed changes in energetics in animal-derived tissues initiated with light of intensity and wavelengths (≈670 nm at ≈0.8±0.2 W/m2) that can be found in vivo when outdoors on a clear day. On a clear day the amount of light illuminating your brain would allow you to comfortably read a printed book (Benaron et al., 1997). In humans, the temporal bone of the skull and the scalp attenuate only 50% of light at a wavelength of ∼670 nm (Eichler et al., 1977; Wan et al., 1981). In small animals, light can readily reach the entire brain under normal illumination (Berry and Harman, 1956; Massopust and Daigle, 1961; Menaker et al., 1970; Vanbrunt et al., 1964). Sun or room light over the range of 600–700 nm can penetrate an approximately 4-cm-thick abdominal wall with only three-to-five orders of magnitude attenuation (Bearden et al., 2001; Wan et al., 1981). Photons between 630 and 800 nm can penetrate 25 cm through tissue and muscle of the calf (Chance et al., 1988). Adipose tissue is bathed in wavelengths of light that would excite chlorophyll metabolites (Bachem and Reed, 1931; Barun et al., 2007; Zourabian et al., 2000). Thus, identification of pathways, which might have developed to take advantage of this photonic energy, may have far-reaching implications.

Dietary chlorophyll in animals

A potential pathway for photonic energy capture is absorption by dietary-derived plant pigments. Little is known about the pharmacokinetics and pharmacodynamics of dietary chlorophyll or its chlorin-type metabolites in human tissues. Here, we observed the accumulation of chlorin-type molecules in mice, rats and swine administered a diet rich in plant chlorophylls (Figs 4, 5; supplementary material Fig. S2G). Data suggests that sequestration from the diets of chlorophyll-derived molecules, which are capable of absorbing ambient photonic energy, might be a general phenomenon.

To date, the reported chlorophyll metabolites isolated from animals have been demetalated (Egner et al., 2000; Fernandes et al., 2007; Scheie and Flaoyen, 2003). The acidic environment of the stomach is thought to bring about loss of magnesium from the chlorophyll (Ferruzzi and Blakeslee, 2007; Ma and Dolphin, 1999). Our absorbance data from extracted pigments from rat fat is consistent with the presence of chlorophyll metabolites bonded to a metal (Fig. 5). If true, the presence of a metal derivative in fat tissue suggests that the pigment was actively re-metalated to take part in coordination chemistry. The identification of several metabolites in the fat and plasma of rats and swine fed a chlorophyll-rich diet that are similar to ones found in plants is significant. However, the structures of the metabolites remain to be elucidated. Chlorin-type molecules are similar in structure and photophysical properties and thus can carry out similar photochemistry (Gradyushko et al., 1970). Our data demonstrate that dietary metabolites of chlorophyll can be distributed throughout the body where photon absorption may lead to an increase in ATP as demonstrated for the chlorin P-a. Indeed, P-a could have been transformed into other metabolites, as most known metabolites of chlorophyll can be formed from P-a by reactions that normally take place in animal cells.

There relationship between the increase in ATP and the amount of added P-a was not linear (supplementary material Fig. S2A,B). ATP stimulation by light in the presence of P-a better fitted a binary on/off, rather than a graded response to P-a. Increasing concentrations of P-a elicited the same increase in ATP, after light exposure. However, with too much added P-a, ATP levels began to fall. This on/off response was also consistent with the observed cooperative binding mode of P-a with mitochondria fragments, suggesting that the threshold response may be regulated by mitochondrial binding of P-a. If chlorophyll metabolites are found to be involved in energy homeostasis, a better understanding of their pharmacodynamics and pharmacokinetics will be needed.

ATP stores and life span

Light of 670 nm wavelength that penetrates the human body, yields ∼43 kcal/mol (1.18×10−22 kcal/photon). Given estimated concentrations of chlorophyll derivatives in the body (Egner et al., 2000; Fernandes et al., 2007; Scheie and Flaoyen, 2003) and the photon flux at 670 nm (Bachem and Reed, 1931; Barun et al., 2007; Bearden et al., 2001; Benaron et al., 1997; Chance et al., 1988; Eichler et al., 1977; Menaker et al., 1970; Vanbrunt et al., 1964; Wan et al., 1981; Zourabian et al., 2000), each chlorophyll metabolite would be expected to absorb only a few photons per second. As such, one might anticipate negligible amounts of additional energy. Organization of chlorophyll metabolites into supramolecular structures, similar to chlorophyll antenna systems in photosynthetic organisms, would increase the effective cross-sectional area of photon absorption and, thus, photon catch. Indeed, our observed positively cooperative binding with mitochondrial fragments is evidence for such organization. Even so, to approach the rate of ATP synthesis powered by NADH or FADH2, sufficient P-a pigment would have to be added to turn animals green. Nevertheless, in model systems, we measure an increase in ATP upon light absorption and changes in fundamental biology (extention in life span). Regardless of the mechanism by which ATP is increased or the measured amount of the increase, perhaps the larger question is: how much of an increase in ATP is enough to make a biological difference?

In animals, treatment with P-a and light both increased ATP and median life span, suggesting that light in the presence of these light absorbing dietary metabolites can significantly affect fundamental biological processes. We previously observed that chlorophyll metabolites enabled photonic energy capture to enhance vision using a mouse model (Isayama et al., 2006; Washington et al., 2004; Washington et al., 2007). Because ATP can regulate a broad range of biological processes, we suspect that ATP modulation also played a role in vision enhancement. The increase in life span may seem contradictory, given that there are studies suggesting that limiting metabolism and ATP synthesis increases the life span of C. elegans. It has been proposed that the life span of this worm might be determined by the metabolic status during development (Dillin et al., 2002) and that there might be a coupling of a slow early metabolism and longevity (Lee et al., 2003). Other observations have led to the hypothesis that increased life span may be achieved by decreasing total energy expenditure across the worm’s entire life span (Van Raamsdonk et al., 2010). However, most studies decrease ATP synthesis from hatching through genetic engineering. By contrast, here, we were able to increase ATP during adulthood at a time when ATP stores reportedly begin to decline. For example, by day 4 of adulthood, the level of ATP and oxygen consumption can drop by as much as 50% compared to day zero (Braeckman et al., 1999; Braeckman et al., 2002). This difference in timing might account for why we observed an increase in life span in response to an increase in ATP. We note that besides caloric restriction, there are only a few interventions that are known (Petrascheck et al., 2007) to increase life span when given to an adult animal.

Alternative mechanisms of life-span extension cannot be ruled out. For example, an increase in reactive oxygen species (ROS) is thought to increase life span in C. elegans (Heidler et al., 2010; Schulz et al., 2007). Upon photon absorption, metabolites of chlorophyll can transfer energy to oxygen, resulting in the generation of singlet oxygen, a ROS. Thus life-span extension seen here might be a result of an increase in ROS due to the generation of singlet oxygen. However, our published data with blood plasma (Qu et al., 2013) and data here from C. elegans do not show an increase in ROS. As ubiquinol is a potent lipid antioxidant (Frei et al., 1990) any ROS increase might be offset by an increase in ubiquinol, generated from the photoreduction of coenzyme Q. Indeed, by producing ubiquinol, P-a might have increased life span by an alternative method by protecting against long-term oxidative damage, which is also a mechanism that has been shown to increase C. elegans life span (Ishii et al., 2004). Further research will be needed to distinguish between the above possible mechanisms.

Conclusion

Both increased sun exposure (Dhar and Lambert, 2013; John et al., 2004; Kent et al., 2013a; Kent et al., 2013b; Levandovski et al., 2013) and the consumption of green vegetables (Block et al., 1992; Ferruzzi and Blakeslee, 2007; van’t Veer et al., 2000) are correlated with better overall health outcomes in a variety of diseases of aging. These benefits are commonly attributed to an increase in vitamin D from sunlight exposure and consumption of antioxidants from green vegetables. Our work suggests these explanations might be incomplete. Sunlight is the most abundant energy source on this planet. Throughout mammalian evolution, the internal organs of most animals, including humans, have been bathed in photonic energy from the sun. Do animals have metabolic pathways that enable them to take greater advantage of this abundant energy source? The demonstration that: (1) light-sensitive chlorophyll-type molecules are sequestered into animal tissues; (2) in the presence of the chlorophyll metabolite P-a, there is an increase in ATP in isolated animal mitochondria, tissue homogenates and in C. elegans, upon exposure to light of wavelengths absorbed by P-a; and (3) in the presence of P-a, light alters fundamental biology resulting in up to a 17% extension of life span in C. elegans suggests that, similarly to plants and photosynthetic organisms, animals also possess metabolic pathways to derive energy directly from sunlight. Additional studies should confirm these conclusions.

MATERIALS AND METHODS

General procedures

Two light sources were used for all experiments, either a 300 W halogen lamp equipped with a variable transformer and band pass interference filters [500, 632, 670, 690 nm with full-width half maximum (FWHM) of 10 nm] or a 1.70 W, 660 nm, LED light bulb. Luminous power density was set to 0.8±0.2 W/m2 as measured by a LI-250A light meter (LI-COR Biosciences, Lincoln, NE). The intensity of red light used was 30–60 times less than the level of red light that we measured on a clear March afternoon in New York City and is less than the level that several organs are exposed to in vivo. Pyropheophorbide-a (P-a, 95% purity) was obtained from Frontier Scientific, Logan, UT. For all experiments, prior to exposing samples to light, we minimized light exposure by preparing samples/experiments with laboratory lights turned off, using a minimum amount of indirect sunlight that shone through laboratory windows (>0.001 W/m2).

Animal protocols were approved by the Institutional Animal Care and Use Committee of Columbia University. Mice (ICR, Charles River, Wilmington, MA) weighing 22–28 g and rats (Fisher 344, Harlan Teklad, Indianapolis, IN), weighing 300 g were used. Swine, fed a chlorophyll-rich diet have been described previously (Mihai et al., 2013).

Continuous ATP monitoring in isolated mouse liver mitochondria

Mice were fed a chlorophyll-poor, purified rodent diet supplied by Harlan (Indianapolis, IN) for a minimum of 2 weeks. We isolated mouse liver mitochondria by differential centrifugation according to existing procedures (Frezza et al., 2007) and used only preparations with a minimum respiratory control ratio above 4.0 [state III/II, using glutamate (5 mM final) and malate (2.5 mM final) as measured with an oxygen electrode from Qubit Systems Inc., Kingston, ON, Canada]. Mitochondria at a final concentration of ≈1 mg protein/ml as determined by the Coomassie Plus (Bradford) protein assay (Thermo Fisher Scientific, Rockford, IL) in buffer A (0.250 M mannitol, 0.02 M HEPES, 0.01 M KCl, 0.003 M KH2PO4, 0.0015 M MgAc2·H2O, 0.001 M EGTA, 1 mg/ml fatty acid–poor BSA, pH 7.4) were incubated with P-a for 30 minutes at 0°C. ADP was added (0.5 mM final concentration) and then 250 µl aliquots of this suspension were placed in nine wells of a 96-well plate for exposure to light at room temperature. At various times, 20 µl aliquots were withdrawn, added to 150 µl lysis buffer (10 mM Tris, pH 7.5; 100 mM NaCl; 1 mM EDTA and 1% Triton X-100), and ATP levels were determined with a commercial kit (Invitrogen, Carlsbad, CA) according to the manufacturer’s instructions. Controls were treated in the same way, except they were: (1) incubated at 0°C without P-a (shown), (2) not exposed to light and (3) were incubated without P-a and not exposed to light.

Membrane potential measurement

Mitochondrial membrane potential was monitored in buffer A as described by Feldkamp et al. (Feldkamp et al., 2005). Measurements were made in a 3 ml cuvette placed inside a fluorescence spectrometer (Fluorormax-4, HORIBA Jobin Yvon, Horiba Scientific, Kyoto, Japan) with a final reaction volume of 1 ml. For light exposure, we used a fiber optic light guide to capture and direct light from a 660 nm LED light bulb into the spectrometer. The end of the fiber optic cable was positioned 1 cm above the reaction mixture. Prior to these experiments, light power was measured 1 cm from the end of the fiber optic cable.

Oxygen consumption measurement

Mitochondrial oxygen consumption was measured using an oxygen electrode cuvette (OX1LP-1 ml; Qubit Systems Inc., Kingston, ON, Canada) according to the manufacturer’s instructions. Reactions were run with mitochondria at a concentration of ≈1 mg protein/m’ in buffer A. For light exposure, a 660-nm LED was directed at the plastic [poly-(methyl methacrylate)] chamber.

For inhibition of respiration, sodium azide was added at a final concentration of 0.005 M from a stock solution in water. Sodium azide inhibits cytochrome oxidase (complex IV): oxygen consumption during state 3 respiration is progressively inhibited by increasing concentrations of azide (Bogucka and Wojtczak, 1966).

Analysis of zero-order ultrasensitivity

Mitochondria from sheep hearts were prepared as previously described (Smith, 1967) on two separate occasions from 2 and 1 sheep heart(s) using ‘Procedure 1’. We used mitochondrial fragments to allow P-a direct access to the respiratory chain, to minimize potential complications due to variable rates of P-a import. Mitochondrial isolation started within 1 hour of the death of the animal and the hearts were transported to the laboratory in a bath of 0.25 M sucrose, 0.1 M tris(hydroxymethyl)aminomethane (Tris) at pH 7.5, which was surrounded by ice. Mitochondria were isolated and stored in 250 µl aliquots at a concentration of ∼60 mg of protein/ml in 300 mM trehalose, 10 mM HEPES–KOH pH 7.7, 10 mM KCl, 1 mM EGTA, 1 mM EDTA and 0.1% BSA at −80°C (Yamaguchi et al., 2007) until use. The thawed mitochondria exhibited a respiratory control ratio of ∼1, indicating mitochondrial fragmentation.

Analysis of coenzyme Q redox status

We used sheep heart mitochondria because they contain relatively large amounts of CoQ10, which expedited analysis. For evaluation of CoQ10 redox ratios, frozen mitochondria were thawed at 37°C and diluted with 500 µl buffer A to create a mitochondrial stock solution, which was kept on ice until use. For reactions, 50 µl of this stock suspension was added to 500 µl of buffer A, containing 0.5 µg/ml antimycin A from a 25 µg/ml stock solution in ethanol. Antimycin A binds to the Qi site of cytochrome c reductase (complex III), thereby inhibiting the upstream oxidation of any produced ubiquinol. Pa was added (25 µM final concentration) from a 1.3 mg/ml stock solution in DMSO. The suspension was added to a test tube, mixtures purged with argon and the reactions initiated by placing the tube between two LED light bulbs (previously described). We irradiated the samples for 10 minutes at room temperature. For negative controls, we repeated the above sequence changing the following: (1) in the absence of light; (2) in the absence of added P-a; (3) with heat denatured mitochondria; and (4) in the absence of added mitochondria but with added coenzyme Q. For a positive control we added 10 µl of a stock solution of 0.25 M glutamate/0.125 M malate in Tris buffer at pH 7. For mitochondrial denaturing, 200 µl of stock mitochondrial suspension was purged with argon and placed in a bath at 70°C for 5 minutes. For control reactions without added mitochondria, a coenzyme Q stock solution in buffer A was prepared by adding ALL-QTM (DSM Nutritinal products, Switzerland), a water-soluble coenzyme Q solution containing 10% coenzyme Q, modified food starch, sucrose and medium chain triglycerides, to buffer A. For these reactions 50 µl of the water-soluble Coenzyme Q stock or the denatured suspension was used as above in place of the mitochondrial stock solution. All reactions were adjusted to give the same amount of coenzyme Q in the reaction mixture as measured by HPLC.

To quantify relative ubiquinone and ubiquinol concentrations, a 50 µl aliquot was taken from the reaction mixture and was added to 200 µl of 0.4 M perchloric acid and 100 µl isopropyl ether containing 1 mg of butylated hydroxytoluene/ml as an antioxidant. The solution was vortexed for 1 minute, centrifuged for 2 minutes at 15,000 r.p.m. and the organic phase analyzed by HPLC. HPLC conditions have been reported previously (Qu et al., 2009; Qu et al., 2011). Briefly, we used an isocratic elutent consisting of 1% sodium acetate 3% glacial acetic acid, 5% butanol in methanol at 0.6 ml/minute. The HPLC column was 50×2.1 mm, C-18, 2.6 u, 100 Å (Phenomenex, Torrance, CA). A PDA detector set at 290 nm for ubiquinol and 275 nm for ubiquinone was used. We determined relative ubiquinol and ubiquinone concentrations by their online absorption spectra using extinction coefficients of 14,200 M−1 cm−1 at 275 nm in ethanol for ubiquinone and 4640 M−1 cm–1 at 290 nm in ethanol for ubiquinol (Lester et al., 1959).

Analysis of ATP synthesis in mouse brain homogenates

To produce homogenates of mouse brain, the frontal lobe was homogenized using two strokes of a Potter S homogenizer (Sartorius AG, Goettingen, Germany) at 4°C (20 mg of brain to 1 ml buffer A). The homogenate (80 µl) was added to buffer A (920 µl) and treated as described above for liver samples. Reactions were run in triplicate and data obtained between 5 and 50 minutes after lysis. ATP production showed a linear increase during this time, which was fitted to a line, the slope of which is reported as the relative ATP synthesis rate.

Analysis of ATP synthesis in mouse lens and heart homogenates

Lenses from mice were homogenized (KONTES® DUALL® tissue grinder with glass pestle) in ATP assay buffer (0.15 mM sucrose, 0.5 mM EDTA, 5 mM magnesium chloride, 7.5 mM sodium phosphate, 2 mM HEPES) at 50 µl buffer per lens. We added 1 µl of P-a stock (1 mM) and 1 µl of ADP stock (10 mM) to 100 µl lens homogenate. The mixture was exposed to red light (671 nm at 0.8 W/m2) or kept in dark for 20 minutes. ATP concentrations were determined using a luciferase-based ATP quantification kit according to the manufacture’s instructions (Life Technologies, Grand Island, NY).

Heart tissue (20 mg) was homogenized as above in 1 ml ATP assay buffer. 10 µl of P-a (1 mM) and 10 µl of ADP (10 mM) and 940 µl of ATP assay buffer were added into 40 µl tissue homogenate. The mixture was exposed to red light and ATP was determined as described above using a luciferase based ATP kit.

Analysis of ATP concentrations in duck adipose

We removed visceral fat from a duck (Anas platyrhynchos domestica) less then 30 minutes after death by decapitation and homogenized the fat at 4°C (without buffer) in a loose-fitting Potter-Elvehjem homogenizer. We then added P-a (70 µl of a 3.3 mg/ml stock solution) and ADP (800 µl of a 10 mg/ml stock solution). The homogenate was divided into two groups: one group was kept in the dark, while the other was exposed to red light (671 nm at 0.8 W/m2); both dishes were kept at 37°C. 200-µl aliquots were taken from each dish and ATP was measured using the luciferase assay or by HPLC, as described in the literature (Ally and Park, 1992).

Analysis of the effect of light wavelength

The entire brain of a mouse was homogenized with a Dounce homogenizer (20 mg of brain to 1 ml buffer C: 0.15 mM sucrose, 0.5 mM EDTA, 5 mM MgCl2, 7.5 mM Na2HPO4, 2 mM HEPES) at 4°C. We took a 40-µl aliquot of the homogenate and added it to 940 µl buffer C. We added 10 µl P-a (from a 1 mM stock in DMSO) and placed the sample on ice for 1 hour. We then added 10 µl ADP (from a 10 mM stock). Five 100-µl portions of the suspension were added to each well of a 96-well plate and exposed to light for 40 minutes. Then, 20-µl aliquots of the mixture were lysed with 200-µl lysis buffer for 1 hour on ice, and ATP levels were determined as above using a luciferase-based ATP kit.

Analysis of red fluorescence in tissue extracts

The chlorophyll-rich diet (Harlan Teklad, Indianapolis, IN) contained 15% by weight spirulina [a food supplement produced from cyanobacteria (Ciferri, 1983)], which is equivalent to ∼0.15% by weight chlorophyll-a. The control diet was a purified diet devoid of dietary chlorophylls (Harlan Teklad). The swine chlorophyll-rich diet has been described previously (Mihai et al., 2013).

For fluorescence spectroscopy, five pigs each were given these respective diets ad libitum for 2 weeks. Whole brain or 2–7 grams of abdominal fat was homogenized with a hand-held homogenizer (Omni Micro Homogenizer (μH), Omni International, Kennesaw, GA), HPLC grade acetone (40 ml) was added and the sample was vortexed for 1 minute. Insoluble material was precipitated by centrifugation and the acetone evaporated with a rotary evaporator. The samples were resuspended in 3 ml chloroform and measured directly.

For HPLC and UV spectroscopy, we extracted 2.5 grams of fat, as described above, from rats or swine that had been given a chlorophyll-rich diet, to give a clear oil. We then added 10 ml of absolute ethanol, cooled the sample to −20°C for 30 minutes, pelleted the insoluble material by centrifugation, separated and evaporated the ethanol with a rotary evaporator and re-suspended the sample in 500 µl of absolute ethanol. For plasma, we added 4 ml of plasma to 1 ml of saturated NaCl and 10 ml ethyl acetate, vortexed the sample for 1 minute and separated the layers by centrifugation. We removed the ethyl acetate layer, evaporated the ethyl acetate and re-suspended the resulting film in 300 µl of absolute ethanol. The samples were then used for HPLC and UV spectroscopy. A Waters (Milford, MA) HPLC system with a 600 pump, a 2475 fluorescent detector, a 2998 photodiode array (PDA) detector and a C18, 2.6 u, 100 Å, 150×2.10 mm column (Phenomenex, Torrance, CA) was used for HPLC. Excitation was set to 410 nm and emission set to 675 nm. Absorbance between 275 and 700 was recorded. We used a mobile phase of acetonitrile containing 10% isopropyl alcohol and 0.1% formic acid (solvent A) and water containing 0.1% formic acid (solvent B). Compounds were eluted at a flow rate of 0.3 ml/minute with a 50∶50 mixture of A∶B for 5 minutes, which was changed linearly to 100∶0, A∶B over 15 minutes. At 35 minutes, the flow was increased to 0.5 ml/minute.

In vivo imaging

Animals were imaged with a Maestro™ In-Vivo Imaging System (CRi, Hopkinton, MA), as described by Bouchard et al.; the animals were skinned to reduce interference from skin autofluoresence (Bouchard et al., 2007).

General C. elegans maintenance

Worms were a gift from Dr Cristina Lagido (Department of Molecular and Cell Biology, University of Aberdeen Institute of Medical Sciences, Foresterhill, Aberdeen, UK) (Lagido et al., 2009; Lagido et al., 2001). Nematode husbandry has been described previously (Wood, 1988). Briefly, animals were maintained on nematode growth medium (NGM) agar (Nunc) using E. coli strain OP50 as a food source. To obtain synchronous populations, we expanded a mixed population on egg yolk plates (Krause, 1995). Worm eggs were isolated from the population by treatment with 1% NaOCl/0.5 M NaOH solution (Emmons et al., 1979) and transferred to a liquid culture with E. coli strain OP50, carbenicillin (50 µg/ml) and amphotericin B (0.1 µg/ml; complete medium).

Real-time ATP monitoring in C. elegans

We administered the P-a chlorophyll metabolite by adding it to the culture medium for a minimum of 24 hours. To confirm P-a uptake, we washed away the culture medium containing P-a, suspended the worms in fresh medium and determined the fluorescence spectra in the worms. Treated worms had signature chlorophyll-derived fluorescence, whereas control worms that were not given P-a exhibited no such fluorescence, confirming metabolite uptake.

Method A

Worms were grown in liquid culture at a density of 10,000 worms/ml. Twenty-four hours before the experiment, the culture was split into control and treatment groups and varying amounts of a P-a stock solution in DMSO were added to the treated groups. Control worms were given DMSO vehicle. Worms were washed with M9 buffer (IPM Scientific, Eldersburg, MD) to remove food and unabsorbed P-a and resuspended at 3000 worms/ml. 50 µl of worm suspension from each of these groups were plated into a well of a 96-well plate. Each experimental group was plated into a minimum of 12 wells. To assay ATP stores by luminescence, 100 µl of luminescence buffer containing D-luciferin was added to each well, according to the literature (Lagido et al., 2009; Lagido et al., 2001) and luminescence was recorded in a plate reader. The luminescence buffer was a citric phosphate buffer at pH 6.5, 1% DMSO, 0.05% Triton X-100 and D-luciferin (100 µM). After initial ATP measurements, half of the worms from each experimental group were exposed to LED light centered at 660 nm at 1±2 W/m2; the other half was kept in the dark by covering the plate with aluminium foil. ATP (luminescence signal) was recorded periodically. The amount of ATP synthesized was reported as the difference within an experimental group between the luminescence signal of worms kept in the dark and the worms exposed to light. All experimental procedures outside of red light exposure were performed under dim light. The experiment was repeated three times with different populations of worms.

Method B

Worms were plated as above, with each experimental group divided into 12 wells of a 96-well plate. Four identical 96-well plates were made, each containing worms treated with varying concentrations of P-a and control worms. At time zero, 100 µl of luminescence buffer was added to a plate and in vivo ATP was assayed as luminescence. The remaining three plates were exposed to light and ATP assays were performed every 15 minutes for 45 minutes by the addition of 100 µl of luminescence buffer and the recording of luminescence.

In vitro ATP monitoring in C. elegans

One-day-old adult worms in liquid culture were incubated with P-a for 24 hours, washed with M9 buffer and re-suspended in M9 buffer at 50,000 worms/ml. The control group was incubated in DMSO vehicle without P-a. 100 µl of each worm suspension was placed into 18 centrifuge tubes. At time zero, six tubes from each group were placed in liquid nitrogen and the remaining tubes exposed to red light. Then, at 15 and 30 minutes, six tubes from each group were placed into liquid nitrogen. To measure ATP, we removed the centrifuge tubes from the liquid nitrogen and placed them in boiling water for 15 minutes to lyse the worms (Artal-Sanz and Tavernarakis, 2009). The resulting solution was cleared by centrifugation for 5 minutes at 15,000 rpm and ATP in the lysate was measured using the luciferase assay according to the manufacturer’s instructions or by HPCL according to established protocols (Ally and Park, 1992).

Analysis of C. elegans oxygen consumption

Oxygen consumption was measured using a Clark-type oxygen electrode (Qubit Systems Inc.), as described (Anderson and Dusenbery, 1977; Zarse et al., 2007). One-day-old adult worms in liquid culture at a density of ∼10,000 worms/ml were incubated with P-a (25 µM) for 24 hours in complete medium. Animals were washed three times with M9 buffer to remove bacteria and excess P-a and resuspended in M9 buffer at 10,000 worms/ml. One-ml aliquots of this suspension were transferred into the respiration chamber and respiration was measured at 25°C for 10 minutes while being exposed to an LED light centered at 660 nm at 1±2 W/m2. The control group was treated in the same way but not incubated with P-a.

Analysis of ROS formation in C. elegans

ROS formation was quantified as described by Schulz et al. (Schulz et al., 2007). Three-day-old worms were synchronized in liquid culture at a density of 500 worms/ml in complete medium, then divided into control and treatments groups. The treatment group was incubated for 24 hours with 12 µM P-a and the control group in DMSO vehicle. Bacterial food and P-a were removed by three repeated washes with M9 and the worms resuspended to 500 worms/ml M9 buffer. 50 µl of the suspension from each group was added to the wells of a 96-well plate with opaque walls and a transparent bottom. A 100 µM 2′,7′-dichlorofluorescin diacetate (Sigma-Aldrich, St. Louis, MO) solution in M9 buffer was prepared from a 100 mM 2′,7′-dichlorofluorescin diacetate stock solution in DMSO. 50 µl of this solution were pipetted into the suspensions, resulting in a final concentration of 50 µM. Additional controls included worms without 2′,7′-dichlorofluorescin diacetate and wells containing 2′,7′-dichlorofluorescin diacetate without animals; these were prepared in parallel. Five replicates were measured for each experimental and control group. Immediately after addition of 2′,7′-dichlorofluorescin diacetate, the fluorescence was measured in a SpectraMax M5 microplate reader (Molecular Devices, LLC, Sunnyvale, CA) at excitation and emission wavelengths of 502 and 523 nm. The plates were then exposed to red LED light and fluorescence was re-measured at 2.5 and 5 hours under conditions equivalent to those used previously.

Life span analysis

Population studies

Life span measurements were performed according to the method of Gandhi et al. and Mitchell et al. (Gandhi et al., 1980; Mitchell et al., 1979) with some modifications. Eggs were harvested and grown in darkness in a liquid culture at room temperature. To prevent any progeny developing, 5-fluoro-2′-deoxyuridine (FUDR) (Sigma-Aldrich, 120 µM final) was added at 35 hours after egg isolation, during the fourth larval molt. At day 4 of adulthood, the culture was split into control and experimental groups. The experimental group was treated with 12 µM P-a from a stock solution in DMSO. The control group was given the DMSO vehicle alone. The treated and control cultures were then split into two or three. The final density of worms in all reaction flasks was 500 worms/ml; each flask contained 10 ml, therefore a total of 5000 worms. The following day (day 5 of adulthood), worms were exposed to LED light centered at 660 nm at 1±2 W/m2 for 5 hours. Light exposure was repeated every day until the end of the experiment. For counting, aliquots were withdrawn and placed in a 96-well plate to give ∼10 worms per well; the worms were scored dead or alive on the basis of their movement, determined with the aid of a light microscope. A total of 60–100 worms (representing 1–2% of the total population) were withdrawn and counted at each time point for each flask. Counts were made at 2–3-day intervals and deaths were assumed to have occurred at the midpoint of the interval. Any larvae that hatched from eggs produced before the FUDR was added remained small in the presence of FUDR and were not counted. We used the L4 molt as time zero for life span analysis. To obtain the half-life, we plotted the fraction alive at each count verses time and fitted the data to a two-parameter logistic function using the software GraphPad Prism (GraphPad Software, Inc., La Jolla, CA). The two-parameter model is known to fit survival of 95% of the population fairly accurately (Vanfleteren et al., 1998). Because changes in environment, such as temperature, worm density and the amount of food, can influence life span, control measurements were conducted at the same time under identical conditions. The concentration of P-a dropped (∼75%) throughout the life span studies and it was not adjusted (supplementary material Fig. S4F).

Life span measurements in 96-well microtiter plates

Life span was measured as described in the literature (Solis and Petrascheck, 2011), except that P-a was added at day 4 and light treatment commenced at day 5. Scoring (fraction alive) was done once on day 15.

Footnotes

  • Competing interests

    The authors declare no competing interests.

  • Author contributions

    C.X. conducted studies with worms, and ATP measurements in mitochondria and tissue homogenates. J.Z. conducted ATP measurements in mitochondria and tissue homogenates. D.M. conducted metabolite-binding distribution studies. I.W. designed and supervised the study and wrote the manuscript.

  • Funding

    This work was supported by the Department of the Navy, Office of Naval Research [grant number N00014-08-1-0150 to I.W.]; the Nanoscale Science and Engineering Initiative of the National Science Foundation [grant numbers CHE-0117752, CHE-0641532 to I.W.]; and the New York State Office of Science, Technology and Academic Research (NYSTAR).

  • Supplementary material available online at http://jcs.biologists.org/lookup/suppl/doi:10.1242/jcs.134262/-/DC1

  • Received April 30, 2013.
  • Accepted October 15, 2013.

References

Sunlight is the most abundant energy source on this planet. However, the ability to convert sunlight into biological energy in the form of adenosine-5′-triphosphate (ATP) is thought to be limited to chlorophyll-containing chloroplasts in photosynthetic organisms. Here we show that mammalian mitochondria can also capture light and synthesize ATP when mixed with a light-capturing metabolite of chlorophyll. The same metabolite fed to the worm Caenorhabditis elegans leads to increase in ATP synthesis upon light exposure, along with an increase in life span. We further demonstrate the same potential to convert light into energy exists in mammals, as chlorophyll metabolites accumulate in mice, rats and swine when fed a chlorophyll-rich diet. Results suggest chlorophyll type molecules modulate mitochondrial ATP by catalyzing the reduction of coenzyme Q, a slow step in mitochondrial ATP synthesis. We propose that through consumption of plant chlorophyll pigments, animals, too, are able to derive energy directly from sunlight.

Source: Light-harvesting chlorophyll pigments enable mammalian mitochondria to capture photonic energy and produce ATP | Journal of Cell Science

Though research on migraines has come a long way, the reason why some people are much more prone to them is largely still a mystery. Physicians will often try to find the cause of recurrent migraine attacks by evaluating patients for other underlying medical conditions, food intolerances and sleep problems.

New research suggests doctors may want to consider screening for something even more simple: vitamin deficiencies. Recent work presented June 10 at the 58th Annual Scientific Meeting of the American Headache Society in San Diego finds that certain vitamin supplements could potentially help stop the occurrence of frequent migraines.

In a study on children, teens and young adults, the researchers found migraineurs (people who suffer from frequent migraine headaches) were much more likely to have mildly lower levels of vitamin D, riboflavin (B-2) and coenzyme Q10 (a naturally occurring, vitamin-like enzyme made by the body). All of these vitamins are needed for the mitochondria, the energy production centers of our cells, to function properly. “Deficient function, possibly through vitamin deficiency or over-utilization of vitamins, may put the migraineur at increased risk of energy deficiency,” says Dr. Andrew Hershey, director of the Migraine Center at the Cincinnati Children’s Hospital Medical Center and one of the researchers working on the project.

For the study, researchers at Cincinnati Children’s looked at existing data on 7,691 young patients who were migraine sufferers and their records of blood tests for baseline levels of vitamin D, riboflavin, coenzyme Q10 and folate. Of the study participants, 15 percent were found to have riboflavin levels below the standard reference range. A significant number of patients—30 percent—had coenzyme Q10 levels at the low end of the standard reference range. Significantly lower vitamin D was seen in nearly 70 percent of the patients.

The researchers also found that patients with chronic migraines were more likely to have coenzyme Q10 deficiencies than patients who had episodic migraines. Girls and young women were more likely than boys and young men to have coenzyme Q10 deficiencies at baseline. Boys and young men were more likely to have vitamin D deficiency, but the reasons behind these trends need further investigation. It is important to note that both Q10 and D3 can be created in the body by exposure to the sun.

Sunlight is the most abundant energy source on this planet. However, the ability to convert sunlight into biological energy in the form of adenosine-5′-triphosphate (ATP) is thought to be limited to chlorophyll-containing chloroplasts in photosynthetic organisms. Here we show that mammalian mitochondria can also capture light and synthesize ATP when mixed with a light-capturing metabolite of chlorophyll. The same metabolite fed to the worm Caenorhabditis elegans leads to increase in ATP synthesis upon light exposure, along with an increase in life span. We further demonstrate the same potential to convert light into energy exists in mammals, as chlorophyll metabolites accumulate in mice, rats and swine when fed a chlorophyll-rich diet. Results suggest chlorophyll type molecules modulate mitochondrial ATP by catalyzing the reduction of coenzyme Q, a slow step in mitochondrial ATP synthesis. We propose that through consumption of plant chlorophyll pigments, animals, too, are able to derive energy directly from sunlight

From here PUBMED

What if conventional wisdom regarding our most fundamental energy requirements has been wrong all along and we can directly harness the energy of the Sun when we consume ‘plant blood’?

Plants are amazing, aren’t they? They have no need to roam about hunting other creatures for food, because they figured out a way to capture the energy of the Sun directly through these little light-harvesting molecules known as chlorophyll; a molecule, incidentally, which bears uncanny resemblance to human blood because it is structurally identical to hemoglobin, other than it has a magnesium atom at its core and not iron as in red blooded animals.

The energy autonomy of plants makes them, of course, relatively peaceful and low maintenance when compared to animal life, the latter of which is always busying itself with acquiring its next meal, sometimes through violent and sometimes through more passive means. In fact, so different are these two classes of creatures that the first, plants, are known as autotrophs, i.e. they produce their own food, and the animals are heterotrophs, i.e. they depend on other creatures for food.

autotroph and heterotroph

While generally these two zoological classifications are considered non-overlapping, important exceptions have been acknowledged. For instance, photoheterotrophs — a sort of hybrid between the autotroph and heterotroph — can use light for energy, but cannot use carbon dioxide like plants do as their sole carbon source, i.e. they have to ‘eat’ other things. Some classical examples of photoheterotrophs include green and purple non-sulfur bacteria, heliobacteria, and here’s where it gets interesting, a special kind of aphid that borrowed genes from fungi[1] to produce it’s own plant-like carotenoids which it uses to harness light energy to supplement its energy needs!

To learn more about this amazing creature read the study published in 2012 in Scientific Reports titled, “Light- induced electron transfer and ATP synthesis in a carotene synthesizing insect.”

Aphid

A green carotenoid tinted aphid that is capable of capturing sunlight to produce energy. Interesting right?  But we need not look for exotic bacteria or insects for examples of photoheterotrophy. It turns out that animals, including worms, rodents and pigs (one of the closest animals to humans physiologically), have recently been found to be capable of taking up chlorophyll metabolites into their mitochondria, enabling them to use sunlight energy to ‘super-charge’ the rate (up to 35% faster) and quantity (up to 16-fold increases) of ATP produced within their mitochondria. In other words, a good portion of the animal kingdom is capable of ‘feeding off of light,’ and should be reclassified as photoheterotrophic!

The truly groundbreaking discovery referred to above was published last year in the Journal of Cell Science in a study titled, “Light-harvesting chlorophyll pigments enable mammalian mitochondria to capture photonic energy and produce ATP“, [contact me for the full version: sayerji@greenmedinfo.com] which I reported on recently, and which completely overturns the classical definition of animals and humans as solely heterotrophic.

Light-harvesting chlorophyll pigments enable mammalian mitochondria to capture photonic energy and produce ATP

Animals are Not Just Glucose-Burning Biomachines, But Are Light-Harvesting Hybrids

For at least half a century it has been widely believed among the scientific community that humans are simply glucose-dependent biomachines that can not utilize the virtually limitless source of energy available through sunlight to supplement our energy needs. And yet, wouldn’t it make sense that within the extremely intelligent and infinitely complex design of life, a way to utilize such an obviously abundant energy source as sunlight would have been evolved, even if only for the clear survival advantage it confers and not some ethical imperative (which is a possibility worth considering … vegans/Jainists, are you listening?).

As the philosopher of science Karl Popper stated, a theory can only be called scientific if it is falsifiable. And indeed, the scientific theory that humans are solely heterotrophic has just been overturned in light of empirical evidence demonstrating that mammals can extract energy directly from sunlight.

Deeper Implications of the New Study

First, let’s start by reading the study abstract, as it succinctly summarizes what may be of the most amazing discoveries of our time:

Sunlight is the most abundant energy source on this planet. However, the ability to convert sunlight into biological energy in the form of adenosine-59-triphosphate (ATP) is thought to be limited to chlorophyll-containing chloroplasts in photosynthetic organisms. Here we show that mammalian mitochondria can also capture light and synthesize ATP when mixed with a light-capturing metabolite of chlorophyll. The same metabolite fed to the worm Caenorhabditis elegans [roundworm] leads to increase in ATP synthesis upon light exposure, along with an increase in life span. We further demonstrate the same potential to convert light into energy exists in mammals, as chlorophyll metabolites accumulate in mice, rats and swine when fed a chlorophyll-rich diet. Results suggest chlorophyll type molecules modulate mitochondrial ATP by catalyzing the reduction of coenzyme Q, a slow step in mitochondrial ATP synthesis. We propose that through consumption of plant chlorophyll pigments, animals, too, are able to derive energy directly from sunlight.”

And so, to review, the new study found that animal life (including us, mammals) are capable of borrowing the light-harvesting capabilities of ‘plant blood,’ i.e. chlorophyll and its metabolites, and utilize it to photo-energize mitochondrial ATP production. This not only helps to improve energy output, but the research found several other important things:

  • Despite the increased output, the expected increase in Reactive Oxygen Species (ROS) that normally attends increased mitochondrial function was not observed; in fact, a slight decrease was observed. This is a highly significant finding, because simply increasing mitochondrial activity and ATP output, while good from the perspective of energy, may accelerate aging and other oxidative stress (ROS) related adverse cellular and physiological effects. Chlorophyll, therefore, appeared to make animal mitochondria function in a healthier way.
  • In support of the above finding, worms administered an optimal range of chlorophyll were found to have significant extended life span. This is in accordance with well-known mechanisms linked to improved mitochondria function (in the absence of increased ROS) that increases cell longevity.

The last point in the abstract above is especially interesting to me. As a fan of coenzyme q10 supplementation for sometime, I have noticed profound differences qualitatively between ubiquinone (the oxidized form) and ubiquinol (the reduced, electron rich form), the latter of which has lead me to experience far greater states of energy and well-being than the former, even at far lower quantities (the molecular weight of a USP isolate does not reveal its bioavailability nor biological activity). The study, however, indicates that one may not need to take supplemental coenzyme Q10, even in its reduced form as ubiquinol, because chlorophyll-mediated sunlight capture and subsequent photo-energization of the electron transport chain will naturally ‘reduce’ (i.e. donate electrons) ubiquinone converting it into ubiquinol, which will result in increased ATP production and efficiency. This may also explain how they observed no increase in ROS (reactive oxygen species) while increasing ATP production: coenzyme q10 in reduced form as ubiquinol is a potent antioxidant, capable of donating an electron to quench/neutralize free radicals. This would be a biological win-win: increased oxidative phosphyloration-mediated energy output without increased oxidative damage.

From here: GreenMedInfo

And of course see more at Nutrition Facts

Hershey says the study adds to an ongoing observation that a significant number of people with migraines have lower levels of these vitamins. However, this trend is not seen in all patients across the board.

It’s been suggested for some time that vitamins play a role in this painful and debilitating chronic condition, but research on the topic is inconsistent. For example, a 2014 analysis in BioMed Research International of seven previously published papers on migraines and vitamin D deficiency suggested there isn’t enough evidence to back the claim that lower levels of the vitamin could make a person more prone to migraines. The researchers of that study found vitamin D deficiency  in 13.2 to 14.8 percent of migraine patients. These rates didn’t differ widely from the general population.

Even though evidence is limited, the nutraceutical industry has picked up on the potential for vitamins to alleviate and control migraines. A number of over-the-counter supplement cocktails are currently marketed to migraine sufferers. These typically combine the vitamins identified in this study, as well as magnesium, an organic mineral that when deficient has also been found to increase risk for chronic migraines. One study published in May in International Clinical Psychopharmacology found the odds of acute migraine headaches increased 35.3 times in patients who were identified as magnesium deficient. However, Hershey questions the use of magnesium supplements for treating migraines because he says only about 1 percent is absorbed by the body, and it is also difficult to measure in the blood.

In general, taking these vitamin supplements at recommended doses probably can’t hurt, but much more research is needed to determine whether vitamins alone could help stop migraines. One challenge researchers face is that vitamin supplements are often an intervention used in addition to medications and other experimental therapies. It’s therefore difficult to determine whether improvements in the condition can be explained for reasons other than supplement use

Source: Vitamin Deficiencies May Prompt Chronic Migraines

Which grain is the best source for protein, essential amino acids, BCAA and arginine?

Listed below are total protein, essential amino acids, branched chain amino acids, and arginine content for quinoa, oats, corn, millet, barley, brown rice and potato. The values provided are for 100 calories, for each respective grain.

Let’s ask some questions:

1. Is there a difference in protein content among these 7 grains?

Yes, there is a difference. Per 100 calories, oats are king, containing more than 2x the amount of protein in barley, the lowest ranking grain on this list. In fact, oats, quinoa and corn each have approximately 2x more total protein than each of the lowest ranking grains, potato, brown rice and barley. Millet is intermediate, at 2.95 grams of protein per 100 calories.

Table 1 Grains

2. Can these grains be considered as “complete protein”?

A “complete protein” is defined as containing all of the 10 essential amino acids (EAA). As shown in the table below, each of the 7 grains contains all of the 10 essential amino acids. Oats contain the greatest amount of essential amino acids (Total EAA), followed by corn and quinoa.

Table 2 Grains

3. Which grain contains the highest amount of branched chain amino acids (leucine, isoleucine and valine)?

The branched chain amino acids (BCAA) leucine, isoleucine and valine are well documented to stimulate muscle protein synthesis (Blomstrand et al. 2006). Oats, corn and millet contain the highest amounts of total BCAA, followed by quinoa, brown rice, potato and barley.

Table 3 Grains

4. Which grain is highest in arginine?

Arginine is the required precursor for the production of nitric oxide (NO), which has been claimed to promote vasodilation in active muscle during exercise, thereby improving strength, power and recovery (Alvares et al. 2011). As shown in the table below, once again, oats contain the highest amount of arginine, followed by quinoa and brown rice.

Table 4 Grains

Conclusions:

1) Oats contain the highest amount of total protein, relative to the other grains on this list.

2) All of the 7 grains on this list contain milligram amount of all of the 10 essential amino acids, making each of them a complete protein. Oats contain the highest total amount of essential amino acids, relative to the other grains on this list.

3) Oats also contain the highest amount of branched chain amino acids and arginine, when compared with all the other grains on this list.


References:

Álvares TS, Meirelles CM, Bhambhani YN, Paschoalin VM, Gomes PS. L-Arginine as a potential ergogenic aid in healthy subjects. Sports Med. 2011 Mar 1;41(3):233-48.

Blomstrand E, Eliasson J, Karlsson HK,Köhnke R. Branched-chain amino acids activate key enzymes in protein synthesis after physical exercise. J Nutr. 2006 Jan;136(1 Suppl):269S-73S.

Nutritional data provided by http://www.nal.usda.gov/fnic/foodcomp/search/

Listed below are total protein, essential amino acids, branched chain amino acids, and arginine content for quinoa, oats, corn, millet, barley, brown rice and potato. The values provided are for 10…

Source: Which grain is the best source for protein, essential amino acids, BCAA and arginine? | Michael Lustgarten

Say someone came up to you selling a dietary supplement—a pill that you take once a day—that could boost your energy, improve your body’s ability to repair its DNA, and keep you healthier as you get older.

It might sound like a scam, or more likely just another in a sea of confusing, undifferentiated claims that make up the $20 billion dollar supplement industry.

But let’s say that someone is MIT’s Lenny Guarente, one of the world’s leading scientists in the field of aging research. And he’s being advised by five Nobel Prize winners and two dozen other top researchers in their fields. You might pay a little more attention.

Elena Ray via Shutterstock

The Scientist And The Startup

Cofounding a supplement company seems an unlikely career move for someone like Guarente, a man who is one of the most well-respected scientists in his field. (“It is a departure,” Guarente admits). Mostly, for him, getting involved in Elysium Health is a decision born out of opportunity and frustration. The opportunity is the chance to make a difference by translating findings in the booming field of aging research directly to consumers today. The frustration is that doing this has taken so long in the first place.

“My biggest hope is that we can make available to people something that is currently unavailable, and that it will have a positive impact on their health,” Guarente says.

Elysium Health actually had its beginnings in conversations between its other two, younger cofounders, Eric Marcotulli and Dan Alminana, who were then tech investors and gym buddies. Even though they’re both quite health-conscious, they knew they couldn’t halt the march of aging and all the ailments that come with it. Far more than diet or anything else people can control, the biggest risk factor for many of the diseases that kill us—including diabetes, cancer, and cardiovascular disease—is simply getting older.

Straight 8 Photography via Shutterstock

Marcotulli knew something about the market opportunity too, which has also lately attracted the likes of Google (with its Calico Labs project) and other SIlicon Valley investors. He had studied the story of a company called Sirtris Pharmaceuticals, which in the mid-2000s was working to take resveratrol, the natural anti-aging compound found in red wine, and alter it into a more potent form that could be patented and developed into a medical drug. In 2008, Sirtris—founded by Guarente’s former postdoc David Sinclair—was acquired by the drugmaker GlaxoSmithKline for a jaw-dropping $720 million.

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“The fundamental question was: Are there other natural products out there that could be meaningful? I think resveratrol was the first, and I was thinking there’s maybe the potential for many others,” Marcotulli remembers thinking as he studied the story while in business school.

The two started cold-calling scientists involved in aging research and were surprised how many were enthusiastic about the idea, including Guarente. The FDA doesn’t recognize aging itself as a condition, so, instead, companies like Sirtris and GSK are are taking scientific findings about how we age and translating them into drugs that treat specific age-related diseases. The issue is that the clinical trials involved in doing this can take more than a decade, and even then that is no guarantee a drug will be approved. The result has been that, though scientists have made major strides in understanding how and why we age and demonstrating that this aging can be delayed, they’ve so far seen few results in translating their work to help people.

The two entrepreneurs wanted to take a very different approach than the drug makers: sell only unaltered natural products, which generally aren’t patented and don’t need FDA approval, and create new kinds of supplements that make no claim to treat a specific disease but promote general wellness instead.

“If there’s a benefit that can be had now, then I think it doesn’t make sense to wait a decade or more until some derivative [from a drug company] becomes available—though I’m not saying that’s not a good thing to do too” says Guarente.

The three cofounders have been taking the company’s first product, a pill they are calling BASIS, for the last three to five months. Through its website, Elysium Health will sell a one-month supply to consumers for $60, or $50 with a monthly subscription.

Boosting NAD

The theory behind the pill is built on work first pioneered in Guarente’s lab on sirtuins, a group of enzymes involved in cell metabolism and energy production that are common to a wide range of living organisms. Researchers have found that boosting the activity of sirtuins, which is sometimes done by calorie restriction diets, can extend lifespan of yeasts, worms, mice, and other animals. Efforts to develop a drug that can have the same effect, without the lack of calories, have been going on for the last two decades, including at Sirtris and GlaxoSmithKline. There are also natural compounds that elevate sirtuins—one is resveratrol, which is already sold as a dietary supplement today. Another is called NAD.

NAD—Nicotinamide adenine dinucleotide—is one of the most compelling bits of chemistry related to aging. Its presence in the body is directly correlated with the passage of time: An elderly man will have about half the levels of NAD is his body as a young person. There’s no amount of healthy eating or exercise that can stop the decline. But in a scientific paper published in 2013 that generated headlines about “reversing aging,” Harvard’s Sinclair showed that after a week of giving two-year-old mice a boost of NAD, their tissues looked more like six-month-old mice.

Elysium’s pill is an attempt to replicate that process naturally in humans. It contains the building blocks of NAD, so the body can easily absorb the smaller molecules and synthesize its own. The pill also contains pterostilbene, a compound, that is a close relative of resveratrol, but which Guarente says is potentially more potent and effective.

Elysium explicitly wants to avoid the charlatan feel of the countless “anti-aging” products on the market today. It isn’t selling the pill as a key to a longer life or to preventing any particular disease, since there isn’t any evidence the pill will do that. A press release the company put out with its launch hardly mentions aging at all. (Another reason is they want to appeal to young people too, who don’t necessarily care about aging, but may want to feel healthier and more energetic). Instead, the founders talks about enhancing basic biological functions: improving DNA repair, cellular detoxification, energy production, and protein function.

“We have no interest in being an anti-aging company and extending lifespan,” says Marcotulli. “For us this is about increasing healthspan, not lifespan.”

The Future Of Dietary Supplements

There is a downside to the model: They can’t patent their work. Some companies already sell supplements for each of the two ingredients in BASIS, and others could copy Elysium as soon as it releases its next products. That’s where Elysium’s business model— and its scientific superstars—come in.

The company aims to be very different type of dietary supplement company—the founders cite the hip, design savvy consumer brands Warby Parker, Oscar Health, Harry’s, and Nest as their role models. (Warby Parker co-CEO Dave Gilboa and one of its early investors, Kal Vepuri, are angel investors in Elysium. Martin Lotti, creative director for Nike’s soccer division, is a strategic advisor.)

“Our vision and mission is to bring scientifically validated natural health products to market through these traditional retail channels,” says Marcotulli. “But it also takes the best aspects of the pharmaceutical model—the R&D focus, clinical rigor, and following these consumers over time.”

Its products will only be sold on its website, where Elysium can control more nuanced messaging than on store shelves. Branding, trust, and scientific expertise are what the team hopes differentiates them from the faceless companies that line Whole Foods’ shelves. At the most basic level, that means trust that the pill contains what it says it contains, but also beyond that, trust that it is doing a person any good.

Elysium assures the ingredients in its products will all be pure, and it will do its own safety testing, as well as test for a basic level of efficacy. Already, says Guarente, it has tested BASIS at a range of doses for safety and to assure that NAD levels in the body actually increase from taking its pill. Over time, the team hopes to also collect data back from customers to start demonstrating some of the longer-term benefits over months and eventually years.

Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine, says Elysium has a good business idea based on sound science and an impressive team. As someone who is not involved in the company, his one fear is that if something went wrong with a top scientist like Guarente’s name attached, it might set back the whole field of research. Though not required by the FDA, he urges the company to go above and beyond in all of its testing. “People are going to overuse it, and I’m sure if you have too much of it, it could have some effect we can’t predict,” he says.

For Elysium’s next products, which might touch on other areas such as brain health or musculoskeletal health, it will start to tap into the expertise of the formidable list of more than 30 scientific advisors signed on—everyone from Eric Kandel, a brain scientist who received the 2000 Nobel Prize in medicine to Tom Sudhof, a cellular physiologist at Stanford who received the prize in 2013. Eventually, it hopes to expand this network of scientific expertise further to as many scientists that want to get involved.

If anything, Elysium might make more people aware that aging is becoming something that we may one day treat.

“There has been an explosion of science in the field of aging. And I think the public doesn’t really realize how far aging research has come. We have a lot of ideas about the mechanisms of aging, and tons and tons of pathways that can be optimized, tweaked, or activated to possibly extend lifespan,” says Stanford University aging researcher Stuart Kim, who is on Elysium’s scientific advisory team. “I think the public is probably about 30 years behind our thinking about aging. It’s as if we thought about cancer in the way we did in 1960.”

Source: One Of The World’s Top Aging Researchers Has A Pill To Keep You Feeling Young | Co.Exist | ideas + impact

The advice changes all the time

The advice changes all the time

Are the official dietary guidelines useful to average Americans? I’m not so sure.

Every five years, numerous dietary experts are tasked with putting together a summary of the most up-to-date nutritional science. Their end product is intended to be a series of dietary recommendations that will help public-health agencies, health-care providers, and educational institutions create federal nutrition policy, health programs and disease-prevention initiatives.

This past February, the Dietary Guidelines for Americans advisory panel issued a 571-page report that upended a lot of conventional thinking. After reviewing all the data, they eased restrictions on cholesterol and urged us to eat less sugar and meat. But they also introduced concepts of sustainability and “dietary patterns”—which include how much and how frequently we should eat different foods—into the conversation. The official recommendations were released Jan. 7.

The new recommendations feel odd and a bit touchy-feely compared to the previous, more stern editions that had us go low-fat, avoid eggs, and micromanage the molecules of our meals. Yet regardless of whether the suggestions are ultimately right or wrong, there are two main issues that make them just north of useless.

1. The advice changes all the time.

It seems like there’s a giant Price Is Right wheel, but for nutrition advice. Every five years, we give it a spin, and up comes the dietary guidelines.

For example, all that cholesterol that we were supposed to watch is “no longer a nutrient of concern.” So have an egg with your shrimp scampi and don’t worry as much about counting up the grams of fat in your dinner. Remember the added sugars in the low-fat products we ate before? Eat less of those. But wait, there’s more: you can have coffee again!

It’s no wonder that a 2012 survey by the International Food Information Council found that more than half of Americans said it’s easier to do their taxes than to figure out a healthful diet. And 76% stated that all the constant changes to nutritional guidance make it harder to know what to believe.

We used to visualize dietary guidelines as food groups in a square. That changed into a pyramid that focused on low-fat eating and drinking eight 8-ounce glasses of water every day. Now it’s a plate.

As the rubric changed, so did the specific foods that we could or couldn’t eat: eggs, no eggs; nuts, no nuts; cholesterol, no cholesterol; don’t drink wine, now you can.

With this level of change and outright reversal of opinion, there’s never any guarantee that this year’s advice will be next year’s advice. This undermines the impact of the guidelines.

2. There’s too much nutritional noise.

The ink on the Dietary Guidelines for Americans wasn’t dry before the vegan Physicians Committee for Responsible Medicine was suing the government. The committee, which has sued over the guidelines in the past, disagreed with the conclusion that dietary cholesterol is not as bad as we thought, worried that the egg and meat industries unduly influenced the recommendations, and didn’t like that the guidelines neglected to tell people to eat less meat.

Some of the criticism has merit: The cattle industry did not like the government telling people about data indicating that red meat (particularly processed meats) can contribute to heart disease and cancer, so its lobbying group convinced a government agency to keep out language stating that you should eat less meat. Congress used the appropriations process to set limits on what the guidelines could even say.

For ordinary Americans, the reversals of recommendations, the lawsuits and the Congressional conflicts of interest all cast doubt on the validity of the guidelines. The combination of these influences makes the dietary guidelines mostly useless for most Americans.

In the midst of all the cacophony, we need dietary principles that we can rely upon. To do this, we might start by looking at the habits of healthy eating practiced in the Mediterranean. This would involve returning to meals at the family table; eating real food (mostly vegetables); and doing that without over-consuming. That’s a three-step healthy prescription that will remain as true today as it will be when the next dietary guidelines come out five years from now.

Source: Our Official Dietary Guidelines Are Useless | TIME

A 2010 article published in Oncology Reports states pancreatic cancer is among the most aggressive forms of human cancer, characterized by a very high mortality rate. It represents the fourth leading cause of cancer death in United States, killing 32,000 people annually. With a 5-year survival rate of only 3 percent and a median survival rate of less than six months, pancreatic cancer carries one of the poorest prognoses. The diagnosis of pancreatic cancer is one of the worst things a doctor ever has to tell a patient. The only FDA-approved therapies for it, Gemcitabine and Erlotinib, produce objective responses in less than 10 percent of patients, while causing severe side-effects in the majority. There is a desperate need for new options.

Clinical research to test new treatments is split into phases. Phase I trials are just to make sure the treatment is safe, to see how much you can give before it becomes toxic. Curcumin, the natural yellow pigment in the spice turmeric has passed a number of those. In fact, there was so little toxicity, the dosing was limited only by the number of pills patients were willing to swallow.

Phase II trials are conducted to see if the drug actually has an effect. Curcumin did, in 2 of the 21 patients that were evaluated. One patient had a 73 percent tumor reduction, but the effect was short-lived. One lesion remained small, but a curcumin-resistant tumor clone emerged. The other patient, who had a stable disease for over 18 months, showed slow improvement over a year. In fact, the only time that patient’s cancer markers bumped up was during a brief three-week stint where the curcumin was stopped.

Love This? Never Miss Another Story.

So curcumin does seem to help some patients with pancreatic cancer, and most importantly, there appears to be little downside. No curcumin-related toxic effects were observed in up to doses of eight grams per day. What happens after eight grams? We don’t know because no one was willing to take that many pills. The patients were willing to go on one of the nastiest chemotherapy regimens on the planet, but didn’t want to be inconvenienced with swallowing a lot of capsules.

The only surefire way to beat pancreatic cancer is to prevent it in the first place. In 2010 I profiled a study conducted by the National Institutes of Health, the largest such study in history, which found that dietary fat of animal origin was associated with increased pancreatic cancer risk.

Which animal fat is the worst? The second largest study has since chimed in to help answer that question. Researchers found that poultry was the worst, with 72 percent increased risk of pancreatic cancer for every 50 grams of daily poultry consumption. Fifty grams is just about a quarter of a chicken breast. The reason white meat came out worse than red may be because of the cooked meat carcinogens in chicken, the heterocyclic amines that build up in grilled and baked chicken. These mutagenic chemicals have been associated with doubling pancreatic cancer risk.

Meat has been associated with significantly increased risk, whereas fake meat is associated with significantly less risk. Those who eat plant-based meats like veggie burgers or veggie dogs three or more times a week had less than half the risk of fatal pancreatic cancer. Legumes and dried fruit appear to be similarly protective.

My grandfather died of pancreatic cancer. By the time the first symptom arose, a dull ache in his gut, it was too late. That’s why we need to work on preventing it.

Carcinogens in grilled and baked chicken may increase the risk of pancreatic cancer, while curcumin may help even in advanced stages of the disease.

Source: Turmeric Curcumin and Pancreatic Cancer | Care2 Healthy Living

Imagine being charged with a DUI when it’s been hours since you’ve had a drink, only to later discover that your body brews its own alcohol.

That’s what happened to an upstate New York woman when she blew a blood alcohol level more than four times the legal limit. Just before Christmas in Hamburg, New York, a judge dismissed the charges after being presented with evidence the woman suffers from “auto-brewery syndrome.”

“I had never heard of auto-brewery syndrome before this case,” attorney Joseph Marusak told CNN on the condition his client’s identity remain anonymous. “But I knew something was amiss when the hospital police took the woman to wanted to release her immediately because she wasn’t exhibiting any symptoms.”

“That prompts me to get on the Internet and see if there is any sort of explanation for a weird reading,” adds Marusak. “Up pops auto-brewery syndrome and away we go.”

“I’m in touch with about 30 people who believe they have this same syndrome, about 10 of them are diagnosed with it,” said Panola College Dean of Nursing Barbara Cordell, who has studied the syndrome for years. “They can function at alcohol levels such as 0.30 and 0.40 when the average person would be comatose or dying. Part of the mystery of this syndrome is how they can have these extremely high levels and still be walking around and talking.”

Extremely rare condition

Also known as gut-fermentation syndrome, this rare medical condition can occur when abnormal amounts of gastrointestinal yeast convert common food carbohydrates into ethanol. The process is believed to take place in the small bowel, and is vastly different from the normal gut fermentation in the large bowel that gives our bodies energy.

First described in 1912 as “germ carbohydrate fermentation,” it was studied in the 1930s and ’40s as a contributing factor to vitamin deficiencies and irritable bowel syndrome. Cases involving the yeast Candida albicans and Candida krusei have popped up in Japan, and in 2013 Cordell documented the case of a 61-year-old man who had frequent bouts of unexplained drunkenness for years before being diagnosed with an intestinal overabundance of Saccharomyces cerevisiae, or brewer’s yeast, the same yeast used to make beer.

Flat tire a blessing

It was a beautiful fall afternoon in 2014 when Marusak’s client met her husband at a restaurant for food and drinks. She consumed “four drinks between noon and 6 p.m.” says Marusak, “less than one drink an hour. We hired a local pharmacologist who said that a woman of her size and weight having four drinks in that period of time should be between 0.01 and 0.05 blood alcohol levels.” That would be beneath the legally impaired level of 0.08 BAC in New York state.

And here’s the “crazy thing,” says Marusak. “Her husband drives to meet friends and she is driving home. She gets a flat close to home but doesn’t want to change the tire so keeps on driving. Another driver sees her struggling with the car and calls it in as an accident. So if she hadn’t had that flat tire, she’d not know to this day that she has this condition.”

Because she blew a blood alcohol level of nearly 0.40, police procedure is to take the accused to a hospital, as that level is considered extremely life-threatening.

Instead of allowing his wife to be released as the hospital recommended based on her lack of drunken symptoms, the husband asked for tests to be run. Sure enough, Marusak says, the results showed a blood alcohol level of 0.30, hours and hours after her last drink. That prompted Marusak to do his own sleuthing.

“I hired two physician assistants and a person trained in Breathalyzers to watch her and take blood alcohol levels over a 12-hour period and had it run at the same lab used by the prosecution,” said Marusak. “Without any drinks, her blood level was double the legal limit at 9:15 a.m., triple the limit at 6 p.m. and more than four times the legal limit at 8:30 p.m., which correlates with the same time of day that the police pulled her over.”

Even more strange, says Marusak, is the fact that the woman exhibited no signs of the levels until she reached a blood alcohol level of between 0.30 and 0.40.

“That’s when she started to feel a bit wobbly on her feet.” Marusak explains that by pointing to the world of alcoholism, where the bodies of “functioning alcoholics” adapt to the high levels of booze in their blood.

Even though the Hamburg judge dismissed the case against his client, Marusak says it’s not over yet.

“I’ve heard the DA’s office says they plan to appeal. I’ll know more by the middle of January.”

Assistant Erie County District Attorney Christopher Belling confirmed a review of the judge’s decision is underway but declined to comment further.

In the meantime, Marusak’s client is treating her condition with anti-fungal medications and a yeast-free diet with absolutely no sugar, no alcohol and very low carbs. While that works for some, Cordell says, others relapse or find little relief

Source: Woman charged with DUI has ‘auto-brewery syndrome’ – CNN.com

For decades, scientists believed that excess body fat was mere storage for unused calories. However, research conducted over the past 20 years suggests added fat is more than a little extra cushion—fat cells are actually “toxic factories,” each one producing inflammatory cytokines (chemical messengers of inflammation) throughout the body and causing potentially serious damage to your health. It is this understanding that has led experts to more closely examine the effects of being overweight, even when an individual is considered physically fit.

In 1998, the National Institutes of Health (NIH) published Clinical Guidelines on the Identification, Evaluation and Treatment of Overweight and Obesity in Adults. These guidelines noted being overweight but in good physical health would reduce the risk of premature death— in other words, being physically fit mattered more than body fat percentage.

But in 2015, the International Journal of Epidemiology released the results of a study that suggested the “fat but fit” theory wasn’t true, based on the health data of more than 1.3 million Swedish men whom researchers followed for 30 years. Those study authors found that the beneficial effects of exercise declined as obesity rates increased. Compared to physically fit obese men, normal-weight men who were not physically fit had a lower risk of dying.

These results are backed by a prior study published in January 2015 that identified a link between increased levels of fat in the body— regardless of physical fitness— and high levels of inflammation. Inflammation is the root cause of all disease, especially chronic conditions, such as heart disease, diabetes, cancer and Alzheimer’s disease. Another study published in the journal Clinical Cancer Research in 2015 observed a correlation between increased levels of white fat tissue and poorer prognosis in early-stage breast cancer. White fat, known as white adipose tissue, is fat stored for energy, but it also plays a role in raising inflammation levels when found in excess throughout the body.

Abdominal obesity, which is fat centralized in the belly, is a sign of high levels of visceral fat in the body. Visceral fat is the type of fat that accumulates in arteries and around organs, and has been credited with increased inflammation and disease risk. Emerging research has found that while this still holds true, fat may be further differentiated. A December 2014 study found that fat deposits may exist on the surface of the myocardium (muscular wall of the heart) and be contained completely beneath the membrane that encloses the heart— in contact with major coronary arteries and their branches. This fat, known as epicardial adipose tissue (EAT), is highly correlated with obesity, and thought to play a role in the development and vulnerability of plaque in the coronary arteries.

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If being fit doesn’t protect against the dangers of excess weight gain, what can?

While fitness is still an important component of optimal health, it is not a standalone marker.

If you are struggling with losing weight, you will reap significant benefits by increasing lean body mass with exercise.

Here are 3 other tactics that can help you lose weight and lower your disease risk:

1. Assess body fat rather than BMI
One of the primary challenges facing the nation today is the standard of measurement for obesity. At present, obesity is defined by body mass index (BMI), which is essentially a height-to-weight ratio. For example, a man who is 5 feet 10 inches tall weighs 220 pounds and has 12 percent body fat would be considered obese, according to the BMI scale. However, anyone with 12 percent body fat is not overweight or obese. This person is likely a bodybuilder with very high levels of lean muscle. His body fat percentage is a better indicator of his health risk. BMI drastically underscores fat levels in the aging population, particularly postmenopausal women who have lost substantial muscle mass that has been replaced with fat and yet their weight remains steady.

A bioelectrial impedance assessment (BIA) is a more comprehensive look at body composition, assessing lean body mass, body fat, and body water percentages, as well as showing where primary fat stores exist. These assessments are generally available through a physician’s office. Monitoring your body fat rather than BMI will help you better assess your overall health and weight management goals.

2. Add a probiotic to your supplement regimen
Research continues to identify the gut flora as a contributing factor to multiple aspects of health, including weight management and inflammation levels. Unfortunately, the typical American diet often leads to imbalances in the microbiota of the gut favoring the development of intestinal inflammation and increased risk of disease. A daily probiotic (not a dairy-based, sugar-laden probiotic) can help promote healthy bacteria in the gut. According to one study, the Lactobacillus plantarum strain offers the greatest potential for suppressing chronic inflammation in the gut. In November 2015, one study uncovered evidence that the landscape of the bacteria in your gut may be the greatest factor in determining which foods will optimally improve an individual’s weight and general health.

3. Consume a clean, nutrient-rich, whole-foods diet
While certain research may say that the Mediterranean diet is good for some people and that the Paleo diet is good for others, one fact remains: Whole foods are best. Strive to consume a wide variety of fresh vegetables and low-sugar fruits organically or locally sourced. Enjoy a mix of lean proteins from animal sources along with plant-based proteins that are high in fiber, like quinoa. Keep sugar, artificial sweeteners and ingredients, and processed foods out of your diet. These foods contribute to toxins in the body and negatively impact healthy gut microbiota.

Achieving optimal health is always a work in progress. Set small goals every month, week, and day that will drive progress. You don’t have to be perfect, but you should try to make everyday choices, a choice that will maximize your wellbeing— mind, body, and spirit.

Dr. Jennifer Landa is Chief Medical Officer of BodyLogicMD, the nation’s largest franchise of physicians specializing in bioidentical hormone therapy. Dr. Jen spent 10 years as a traditional OB-GYN, and then became board-certified in regenerative medicine, with an emphasis on bio-identical hormones, preventative medicine and nutrition. She is the author of “The Sex Drive Solution for Women.”  Learn more about her programs at www.jenlandamd.com.

For decades, scientists believed that excess body fat was mere storage for unused calories.

Source: ‘Fat but fit’: How carrying excess weight can have long-term health consequences | Fox News

Antibiotics make C. diff infection easier because of their effects on bile acid and bacteria living in the gut, according to new research.

Bacteria in the gut are involved in many of the body’s functions, from the creation of neurons in the brain to regulating chemicals that help break food down.

Scientists at North Carolina State University found in experiments with mice that a single course of antibiotic treatment can open a window for Clostridium difficile, or C. diff, to thrive because bacteria responsible for altering bile acid were killed off, according to a new study.

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Primary bile acids are made in the liver from cholesterol to aid in digestion and fat absorption, and in controlling lipoprotein, glucose, drug, and energy metabolism. The acids travel through the intestinal tract to the large intestine, where other bacteria convert them to secondary bile acids. These secondary acids inhibit the growth, and infection by, C. diff.

“These findings are a first step in understanding how the gut microbiota regulates bile acids throughout the intestine,” said Casey Theriot, an assistant professor of infectious disease at North Carolina State, in a press release. “Hopefully they will aid the development of future therapies for C. difficile infection and other metabolically relevant disorders such as obesity and diabetes.”

In the study, published in the journal mSphere, the scientists identified 26 primary and secondary bile acids in mice, defining their levels before and after treatment with an antibiotic.

The scientists then added C. diff spores to concentrations of the acids, finding primary bile acids allow spores to germinate, regardless of antibiotic treatment, which included the broad-spectrum antibiotics cefoperazone, clindamycin and vancomycin.

When the spores passed into concentrations that mimicked the large intestines of mice, altered secondary bile stopped C. diff from growing. When bacteria that turn primary bile acids into secondary acids had been killed during antibiotic treatment, C. diff was able to grow.

Scientists said the experiments showing the importance of gut bacteria to preventing at least one bacterial infection — and how antibiotics can prevent the inhibition of its growth — may help guide future research into preventing the infections.

Source: Antibiotics promote C. diff infection by killing gut bacteria – UPI.com

American healthcare has received heavy criticism in recent decades due to its cost/outcome profile. The sources of poor performance in the United States are many, to be sure, and yet one source rarely gets mentioned, namely, primary care. Anyone following healthcare trends in the United States over the past decade will find few critiques of the deficiencies of primary care. In fact, the press clippings for primary care highlight the positive: a desire for more primary care providers (PCPs); a call for more coordination of care by PCPs; and the development of supportive structures around PCPs called “medical homes” and “accountable care organizations.” One would assume that primary care is working well and that we just need to expand it in various ways. Yet, there is a body of information, both vast and well-known, if not well understood, that would suggest otherwise. Why then is everyone eager for more of the same?The first answer to this question is that there is nothing wrong with primary care practitioners. They work hard, for less money than other medical specialists, and help their patients in many ways. To be clear, PCPs are not the problem with primary care. Instead, primary care is underfunded and is not structured with the right players and the right practice leaders. Another way of saying this is that the problem lies within the primary care setting, and I will argue that current proposals for medical homes and accountable care organizations will not fix this clinical delivery dysfunction. I will propose an alternative structure that delivers better care.We know that 70 percent of primary care visits stem from psychosocial issues1. Are PCPs equipped to understand and effectively address these issues? In general, PCPs have not been selected for clinical practice due to their temperament or desire to deal with psychosocial issues, and they receive very limited training to do so. It can be said then, with some exceptions, that they are not equipped to be effective in this regard. What about the lifestyle issues and health behaviors that drive over 50 percent of our health status? How are PCPs at helping people with their diet, exercise, stress, sleep, social isolation, and feelings of loneliness, all of which are significant health risk factors? Again, it can be said that PCPs are not effective, and yet, to be fair, no one has a formula for success, not even behavioral health professionals.While these facts should lead us to question the adequacy of the primary care model today, it appears fully ripe for dismantling when we recognize that behavioral health disorders are the number one source of disability today. Depression leads this group by far, with anxiety and substance use disorders contributing significant impairment. This is not just a U.S. phenomenon – the World Health Organization notes that depression is the leading cause of disability worldwide. In terms of healthcare costs in the United States, people with depression and anxiety have costs that are 70 percent higher than those without a mental health diagnosis, and people with depression are four times more likely to have a heart attack.There are numerous troublesome facts like these, but even more worrisome is the reality that 80 percent of the people with behavioral health conditions get no treatment for these disorders. When PCPs identify them for treatment, they typically only get psychotropic medications, even though psychotherapy is remarkable effective and produces no side effects2.While these facts challenge the rationale for the primary care model, they would be mitigated somewhat if we could point to a primary care workforce that is deeply satisfied, growing in numbers, and eager to meet these clinical challenges. The unfortunate reality is that a shortage of PCPs is projected for the future – by conservative estimates, 45,000 too few by 2020 – and physicians generally view primary care as less desirable than other specialties due to lower income and increased time demand. Choose your image, either the elephant in the room or the emperor with no clothes, but how can we not simply state that the primary care model is irreparably broken and in need of replacement?Team-based careLet’s start with a key element of the medical home model, namely, team-based care, and then let us reorient the model by replacing the primary care physician with a behavioral health specialist as the team leader. In so doing, we might excel at: detecting the psychosocial issues that are motivating office visits; addressing strategies for changing critical health behaviors; and finally, diagnosing and treating unrecognized conditions like depression, anxiety and substance use disorder. These issues require a team rather than a single behavioral health clinician. We still need nurse practitioners to be on the front line for treating infections and injuries – more or less, the acute conditions – and we need PCPs to be the senior physicians addressi

Source: How behavioral health can advance a better model

I keep getting the same email over and over again, and my heart aches each time I read it: “I have tried everything to overcome my depression, but nothing has helped. Is there anything else I can do or will I have to live the rest of my life plagued with sadness?”

First, hear these three words: There is hope. If there wasn’t any, I would not be alive writing my blog. I am one of the worst cases out there like you are. I have spent more years of my life fantasizing about death than wanting to be alive. I get it. But now I do enjoy some really good days — where I feel better than I ever have. And those good days keep me motivated to get through the harder ones.

From my own 43 years of experience fighting the demon of hopelessness and from all my conversations with folks in my online depression community, Project Beyond Blue, here are some suggestions that you might try.

1. Get a Physical

The reason that you may not be getting better despite trying 20 different combinations of medication is that your symptoms of irritability, fatigue, and apathy may not be caused by a lack of serotonin or norepinephrine in your brain, but rather by a tear in your diaphragm or a problem with your aortic valve. A few conditions that are often misdiagnosed as depression are: hypothyroidism, vitamin D deficiency, vitamin B-12 deficiency, insulin resistance or blood sugar imbalances, and anemia. (See my piece, 6 Conditions That Feel Like Depression But Aren’t).

You should really get a physical and have some bloodwork done by an integrative or functional doctor; however, that can be costly, especially if you get a functional doctor who wants to run every test on you.

I asked my integrative doctor, Alan Weiss of Annapolis Integrative Medicine, to give me a list of the three or four most important blood tests a person with chronic depression should ask their primary care physician to do for them, if they can’t afford to go outside their insurance network for a consultation. He suggested:

  • Complete blood count (CBC)
  • Comprehensive metabolic profile (CMP)
  • Thyroid testing, including TSH, free T4, free T3, and thyroid antibodies
  • 25-OH vitamin D, B-12 levels

2. Check Your Thyroid

I want to return to the thyroid for a moment since this is so tricky and so critical. Every person I know who suffers from chronic depression has a thyroid issue. That is no lie or exaggeration. Every person. I was seeing an endocrinologist, someone who specializes in thyroid disease, for six years and she never tested me for an underactive thyroid. She was merely testing my TSH levels, not the full panel, which is what most primary care physicians, endocrinologists, and psychiatrists do.

If you are sluggish, gaining weight, have brain fog, need to lie down all the time, and are depressed, please have a FULL panel of your thyroid done. Your T3 and T4 levels are needed to detect slight problems that can wreak havoc with your mood and energy level. Now that I am taking natural medicine for that, I have much more energy.

Dana Trentini has a great post on her blog Hypothyroid Mom called “The Top Five Reasons Doctors Fail to Diagnose Hypothyroidism.

3. Load Up on Vitamin D and Vitamin B-12

I was relieved that Dr. Weiss included blood tests to check vitamin D and vitamin B-12 levels, as well, because deficiencies in both of those vitamins can cause severe depression. They are included in my list of 10 Nutritional Deficiencies That Can Cause Depression.

According to a 2009 study published in the Archives of Internal Medicine, as many as three-quarters of U.S. teens and adults are deficient in vitamin D. Last year Canadian researchers performed a systematic review and analysis of 14 studies that revealed a close association between vitamin D levels and depression. Researchers found that low levels of vitamin D corresponded to depression and increased odds for depression. In another 2009 study, more than a quarter of severely depressed older women were deficient in B-12. I take each of those vitamins in liquid form so that they absorb quickly and efficiently.

4. Adjust Your Diet

If you are annoyed at this suggestion, let me say I understand. I was annoyed for the first 40 years of my life when someone would insinuate that there was a tight connection between my diet and my distorted thinking. I thought I ate well. By most American standards, I was a health freak. However, I didn’t realize how much insulin I was throwing into my bloodstream until I stopped eating all sugar cold turkey one day, as well as processed flour, dairy, and caffeine. (Alcohol is bad news too, but I gave that up 25 years ago.)

All those nut and fruit KIND bars that are supposed to be good for you, the honey in my tea, the cereal and pumpkin bread in the morning … all of them were creating a blood sugar nightmare that got me high only to make me crash … and hard. No street drugs were involved. Just a lame granola bar that I thought was sanctioned by Dr. Oz. Consider eliminating sugar and white flour from your diet for a few months. As much as I’d like to tell you that the effect was immediate, it took up to nine months before I really started to feel better, before I was free of death thoughts.

5. Get a Consultation With a Teaching Hospital

Before my husband begged me to have a consultation at Johns Hopkins Mood Disorders Center, I had been to six psychiatrists. One of my blogs, in fact, is called The Psychiatric Guide to Annapolis. Let me just say that there are a lot of people who shouldn’t be practicing medicine, like one I dubbed “Pharma King,” who received generous kickbacks from a pharmaceutical company.

The reason I trust teaching hospitals like Johns Hopkins, is that they never stop researching, and they are not afraid to use the older drugs like lithium that have proven track records but aren’t lucrative. Kay Redfield Jamison, a professor of psychiatry at Johns Hopkins, wrote an excellent op-ed piece in the New York Times just after the death of Robin Williams entitled Depression Can Be Treated, But It Takes Competence.

She writes: “Many different professionals treat depression, including family practitioners, internists and gynecologists, as well as psychiatrists, psychologists, nurses and social workers. This results in wildly different levels of competence. Many who treat depression are not well trained in the distinction among types of depression. There is no common standard for education about diagnosis.” Go to a teaching hospital. You won’t regret it.

6. Consider Transcranial Magnetic Stimulation

Transcranial magnetic stimulation (TMS) is a non-invasive procedure that stimulates nerve cells in the brain with short magnetic pulses. A large electromagnetic coil is placed against the scalp which generates focused pulses that pass through the skull and stimulate the cerebral cortex of the brain, a region that regulates mood. The procedure was approved by the FDA in 2008.

In September, I featured a story about Stephanie, a woman in Project Beyond Blue, who underwent 30 sessions of TMS and was transformed into a new person. She now moderates a group on Project Beyond Blue called Exploring TMS. Several other people I know have had success as well.

7. Try EMDR

My friend Priscilla Warner first turned me on to eye-movement desensitization and reprocessing (EMDR) therapy. She devotes a chapter in her bestselling memoir, Learning to Breathe, about it, and how it was instrumental in breaking down her anxiety. It is mostly used for people with some form of post-traumatic stress disorder, but it has also been used to address generalized anxiety from a dysfunctional childhood, a bad marriage, or a boss from hell.

According to the EMDR Institute, “EMDR psychotherapy is an information processing therapy and uses an eight phase approach to address the experiential contributors of a wide range of pathologies. It attends to the past experiences that have set the groundwork for pathology, the current situations that trigger dysfunctional emotions, beliefs and sensations, and the positive experience needed to enhance future adaptive behaviors and mental health.”

8. Find a Way to Lower Your Stress

I don’t mean putting a few less to-do items on your list. I’m talking about radical lifestyle changes — like changing jobs in order to work in a less toxic and stressful environment, moving into a smaller home so that you don’t have to moonlight, deciding against adopting a rescue dog or having a third child. It can be practically impossible to keep your mood resilient if you are under chronic stress because it increases the connection between the hippocampus part of your brain and the amygdala (worry central), impairs your memory retention, affects your cortisol production (making it difficult for you to handle more stress), and weakens your immune system.

There are other ways to try to lower your stress besides quitting your job, like practicing mindfulness meditation. I took the eight-week Mindfulness-Based Stress Reduction (MBSR) program at my local hospital because I read numerous studies on how mindfulness meditation can reset neural passageways and change rumination patterns. As a result of the class, I am now more aware of my thinking, and I try my best to keep coming back to the present. However, nothing beats the anesthesia from depression and the calm I experience after an intense aerobic workout. I swim and run for my sanity.

In summary, the road to my recovery has been rocky as hell. I had to throw out the old system — my belief that medication, therapy, and exercise was all I needed — that the brain lived in another solar system as my body. I now believe that you must approach the illness of depression systematically: there is nothing that you eat, say, or do in your day that doesn’t affect your mood. While that thought can be overwhelming, it also points the way to hope.

You are not a lost cause.

Join conversations like “Hypothyroidism & Depression” and “Nutrition” on Project Beyond Blue,” a new community for persons with treatment-resistant depression.

Originally posted on Sanity Break at Everyday Health.

8 Things to Consider When Your Depression Is Not Getting Better | World of Psychology.

Anti Angiogenesis Foods

 

This is your last chance, after this there is no turning back.
You take the blue pill, the story ends; you wake up in your bed, and believe whatever you want. You take the red pill, you stay in wonderland and I show you how deep the rabbit hole goes.I know you’re out there, I can feel you now.
I know that you’re afraid of us…You’re afraid of change. I don’t know the future, I didn’t come here to tell you how this will all end…I came here to tell you how it’s going to begin

Clip3.jpg JPEG Image, 464 × 329 pixels.

 

How Growers Gamed California’s Drought

Consuming 80 percent of California’s developed water but accounting for only 2 percent of the state’s GDP, agriculture thrives while everyone else is parched.
“I’ve been smiling all the way to the bank,” said pistachio farmer John Dean at a conference hosted this month by Paramount Farms, the mega-operation owned by Stewart Resnick, a Beverly Hills billionaire known for his sprawling agricultural holdings, controversial water dealings, and millions of dollars in campaign contributions to high-powered California politicians including Governor Jerry Brown, former governors Arnold Schwarzenegger and Gray Davis, and U.S. Senator Dianne Feinstein.

The record drought now entering its fourth year in California has alarmed the public, left a number of rural communities without drinking water, and triggered calls for mandatory rationing. There’s no relief in sight: The winter rainy season, which was a bust again this year, officially ends on April 15. Nevertheless, some large-scale farmers are enjoying extraordinary profits despite the drought, thanks in part to infusions of what experts call dangerously under-priced water.

Resnick, whose legendary marketing flair included hiring Stephen Colbert to star in a 2014 Super Bowl commercial, told the conference that pistachios generated an average net return of $3,519 per acre in 2014, based on a record wholesale price of $3.53 a pound. Almonds, an even “thirstier” crop, averaged $1,431 per acre. Andy Anzaldo, a vice president for Resnick’s company, Wonderful Pistachios, celebrated by showing the assembled growers a clip from the movie Jerry Maguire in which Tom Cruise shouts, “Show me the money,” reported the Western Farm Press, a trade publication. At the end of the day, conference attendees filed out to the sounds of Louis Armstrong singing, “It’s a Wonderful World.”

Agriculture is the heart of California’s worsening water crisis, and the stakes extend far beyond the state’s borders. Not only is California the world’s eighth largest economy, it is an agricultural superpower. It produces roughly half of all the fruits, nuts, and vegetables consumed in the United States—and more than 90 percent of the almonds, tomatoes, strawberries, broccoli and other specialty crops—while exporting vast amounts to China and other overseas customers.

But agriculture consumes a staggering 80 percent of California’s developed water, even as it accounts for only 2 percent of the state’s gross domestic product. Most crops and livestock are produced in the Central Valley, which is, geologically speaking, a desert. The soil is very fertile but crops there can thrive only if massive amounts of irrigation water are applied.

Current pricing structures enrich a handful of interests, but they are ushering the state as a whole toward a parched and perilous future.

Although no secret, agriculture’s 80 percent share of state water use is rarely mentioned in media discussions of California’s drought. Instead, news coverage concentrates on the drought’s implications for people in cities and suburbs, which is where most journalists and their audiences live. Thus recent headlines warned that state regulators have ordered restaurants to serve water only if customers explicitly request it and directed homeowners to water lawns no more than twice a week. The San Jose Mercury News pointed out that these restrictions carry no enforcement mechanisms, but what makes them a sideshow is simple math: During a historic drought, surely the sector that’s responsible for 80 percent of water consumption—agriculture—should be the main focus of public attention and policy.

The other great unmentionable of California’s water crisis is that water is still priced more cheaply than it should be, which encourages over-consumption. “Water in California is still relatively inexpensive,” Heather Cooley, director of the water program at the world-renowned Pacific Institute in Oakland, told The Daily Beast.

One reason is that much of the state’s water is provided by federal and state agencies at prices that taxpayers subsidize. A second factor that encourages waste is the “use it or lose it” feature in California’s arcane system of water rights. Under current rules, if a property owner does not use all the water to which he is legally entitled, he relinquishes his future rights to the unused water, which may then get allocated to the next farmer in line.

Lawmakers have begun, gingerly, to reform the water system, but experts say that much remains to be done. For years, California was the only state in the arid West that set no limits on how much groundwater a property owner could extract from a private well. Thus nearly everyone and their neighbors in the Central Valley have been drilling deeper and deeper wells in recent years, seeking to offset reductions in state and federal water deliveries. This agricultural version of an arms race not only favors big corporate enterprises over smaller farmers, it threatens to collapse the aquifers whose groundwater is keeping California alive during this drought and will be needed to endure future droughts. (Groundwater supplies about 40 percent of the state’s water in years of normal precipitation but closer to 60 percent in dry years.)

Last fall, the legislature passed and Governor Brown signed a bill to regulate groundwater extraction. But the political touchiness of the issue—agricultural interests lobbied hard against it—resulted in a leisurely implementation timetable. Although communities must complete plans for sustainable water management by 2020, not until 2040 must sustainability actually be achieved. The Central Valley could be a dust bowl by then under current trends.

There are practical solutions to California’s drought, but the lack of realistic water prices and other incentives has slowed their adoption. A shift to more efficient irrigation methods could reduce agricultural water use by 22 percent, an amount equivalent to all the surface water Central Valley farmers lacked because of drought last year, according to an analysis that Cooley of the Pacific Institute co-authored with Robert Wilkinson, a professor at the University of California Santa Barbara, and Kate Poole, a senior attorney at the Natural Resources Defense Council.

The Brown administration has endorsed better water efficiency—and put a small amount of money where its mouth is. Conservation is the No. 1 priority in the governor’s Water Action Plan, and the drought measures he advanced in 2014 included $10 million to help farmers implement more efficient water management. An additional $10 million was allocated as part of the $1.1 billion drought spending plan Brown and bipartisan legislators unveiled last week. Already more than 50 percent of California’s farmers use drip or micro irrigation, said Steve Lyle, the director of public affairs at the California Department of Food and Agriculture; the new monies will encourage further adoptions.

Meanwhile, underpriced water has enabled continued production of such water-intensive crops as alfalfa, much of which is exported to China. Rice, perhaps the thirstiest of major crops, saw its production area decrease by 25 percent in 2014. But pasture grass, which is used to fatten livestock, and many nut and fruit products have seen their acreage actually increase. Resnick told the Paramount Farms conference that the acreage devoted to pistachios had grown by 118 percent over the last 10 years; for almonds and walnuts the growth rates were 47 and 30 percent, respectively.

One striking aspect of California’s water emergency is how few voices in positions of authority have been willing to state the obvious. To plant increasing amounts of water-intensive crops in a desert would be questionable in the best of times. To continue doing so in the middle of a historic drought, even as scientists warn that climate change will increase the frequency and severity of future droughts, seems nothing less than reckless.

Yet even a politician as gutsy and scientifically informed as Jerry Brown tiptoes around such questions. The Daily Beast asked Brown if in this time of record drought California should begin pricing water more realistically and discouraging water-intensive crops. Responding on the governor’s behalf, spokesman Lyle simply skipped the water pricing question. On crop choices, he cited a reply Brown recently offered to a similar query: “Growing a walnut or an almond takes water, having a new house with a bunch of toilets and showers takes water. So how do we balance use efficiency with the kind of life that people want in California? … We’re all going to have to pull together.”

“California Has One Year of Water Left, Will You Ration Now?” asked the headline of a widely discussed opinion piece NASA scientist Jay Famiglietti published in the Los Angeles Times on March 16.  The headline overstated the situation somewhat, and editors soon corrected it to clarify that California has one remaining year of stored water, not one year of total water. As Famiglietti was careful to state, California’s reservoirs today contain enough water to supply a year of average consumption.

So if California endures a fourth year of drought, the only way to keep household taps and farmers’ irrigation lines flowing will be to summon to the surface still greater volumes of groundwater. But that strategy can’t work forever; worse, the longer it is pursued, the bigger the risk that it collapses aquifers, rendering them irretrievably barren. Aquifers can be replenished—if rainwater and snowmelt are allowed to sink into the ground and humans don’t keep raiding the supply—and that is the expressed goal of California’s forthcoming groundwater regulations. The process takes many decades, however, and extended relief from further droughts.

California is caught between the lessons of its history and the habits of its political economy. Droughts of 10 years duration and longer have been a recurring feature in the region for thousands of years, yet a modern capitalist economy values a given commodity only as much as the price of that commodity. Current pricing structures enrich a handful of interests, but they are ushering the state as a whole toward a parched and perilous future.

The price of water, however, is not determined by inalterable market forces; it is primarily a function of government policies and the social forces that shape them. Elected officials may dodge the question for now, but the price of water seems destined to become an unavoidable issue in California politics. “As our water supply gets more variable and scarce in the future, we’re going to have to look at how we price water so it gets used more efficiently,” said Cooley of the Pacific Institute. “In some ways we’ve come a long way in California’s water policy and practices over the past 20 years. But if you look into a future of climate change and continued [economic] development, we can and need to do much better.”

Mark Hertsgaard has reported on politics, culture and the environment from more than 20 countries and has authored six books, including HOT:  Living Through the Next Fifty Years on Earth, which will appear in paperback April 17.

 

How Growers Gamed California’s Drought – The Daily Beast.

  • During prenatal development, sex hormones can determine whether the brain acquires feminine or masculine characteristics. Masculinization, for example, has been thought to be a fairly straightforward process, the direct induction of transcription by ligand-activated nuclear steroid receptors. Now, however, it appears the masculinization process is more indirect. According to research conducted at the University of Maryland School of Medicine (UM SOM), sex hormones appear to relieve the nongenetic influences on gene repression of masculinizing genes.

    The finding appeared March 30 in Nature Neuroscience, in an article entitled, “Brain feminization requires active repression of masculinization via DNA methylation.” The article described how estradiol, a testosterone derivative, can trigger a mechanism by which certain genes in the brain are “unsilenced,” allowing them to initiate the process of masculinization.

    All mammals—including humans—develop specifically male or female brain characteristics.

    This work was accomplished in rats, which like other mammals—including humans—develop specifically male or female brain characteristics. For example, in most species, some portions of male and female brains are a different size, and often have a different number of neurons and synapses.
    “Nobody has ever shown that this is how the process works,” said Margaret McCarthy, Ph.D., a professor and chairman of the department of pharmacology at UM SOM. “This gives us a new understanding of how gender is determined in the brain.”

    In their experiments, the UM SOM scientists found that a primary effect of gonadal steroids in the highly sexually dimorphic preoptic area (POA) is to reduce activity of DNA methyltransferase (Dnmt) enzymes, thereby decreasing DNA methylation and releasing masculinizing genes from epigenetic repression.

    The researchers injected Dnmt inhibitors into the POA, a brain area known to be involved in governing male sexual behavior, after the first week of birth, after the window for brain sexual differentiation was thought to have been closed. Despite this, the POA in the animals was transformed, and took on structural characteristics of a male rat. The female rats also behaved differently, displaying sexual behavior typical of male rats.

    In another experiment, they scientists deleted the Dnmt gene in female mice; these animals also showed male behavior patterns. “Pharmacological inhibition of Dnmts mimicked gonadal steroids, resulting in masculinized neuronal markers and male sexual behavior in female rats,” the authors of the Nature Neuroscience article wrote. “Conditional knockout of the de novo Dnmt isoform, Dnmt3a, also masculinized sexual behavior in female mice.”

    In previous research, Dr. McCarty’s group found sex and gender differences in levels of a protein associated with language acquisition and development. This finding may be associated with higher levels of communication among females in some species.

    Intriguingly, the latest study also found that inflammatory immune cells known as microglia appear to play a role in masculinization, in part through their production of prostaglandins, a neurochemical normally associated with illness. In recent years, scientists have increasingly realized that the immune system is integral to the development of the brain; Prof. McCarthy and her group are the first to show that it is also important for establishment of sex differences in the brain. The current discovery is another piece in that puzzle; they showed that Dnmt enzymes control expression of genes that play a role in inflammation and immunity, and also in the sexual differentiation of the brain.

    “Physically, these animals were females, but in their reproductive behavior, they were males,” said Nugent. “It was fascinating to see this transformation.”

    “RNA sequencing revealed gene and isoform variants modulated by methylation that may underlie the divergent reproductive behaviors of males versus females,” the authors concluded. “Our data show that brain feminization is maintained by the active suppression of masculinization via DNA methylation.”

 

GEN | News Highlights:Brain Gender Altered by Lifting Epigenetic Repression.

 

April 2 at 2:40 AM

It happens in an instant just before you fall asleep. You’re startled by a loud noise — the thud of a book slamming to the floor, or worse, the bang of a shotgun nearby. You a jump up and look around, but everything seems normal. Well it is, but you did hear a noise that wasn’t real. It was in your brain.

It’s a phenomenon called “exploding head syndrome.”

“It can sound like explosions, gunshots in your head, giant guitar strings breaking beside you or something heavy being dropped,” Brian Sharpless, assistant professor and director of the psychology clinic at Washington State University, told The Washington Post. He’s also the lead author of a study on the disorder. “A small number of people will see lightning, flashes of light or visual static like you see on a TV screen. It’s scary, and people wake up confused.”

Exploding head syndrome has received little clinical attention over the years. Scientists have hypothesized the condition is rare and seen mostly in people older than 50. But when Sharpless and his researchers assessed 211 undergraduate students for sleep paralysis as well as exploding head syndrome — which appear to be connected — they found the phenomenon is more common than clinic lore led them to believe. The researchers recently published the findings in the Journal of Sleep Research.

Its symptoms were first described some 150 years ago. Doctors have noted it in literature as “sensory discharges” and, later, “snapping in the brain.” In 1988, neurologist J.M.S. Pearce dubbed it “exploding head syndrome.”

Sharpless and his colleagues found that 18 percent of the people they interviewed had experienced the disorder at least once. More than 16 percent had recurring cases. However, when the researchers removed those who had also experienced sleep paralysis, the number fell to 13.5 percent — which is still “shockingly high,” he said.

The sensation occurs during “sleep state misperception,” the moment right before people doze off, though it can also happen as they are waking up.

“Your brain essentially has a hiccup in the reticular formation, which is the part of the brain that helps shut down your body for sleep,” Sharpless said. “It shuts down your motor, visual and auditory neurons. But with exploding head syndrome, instead of the auditory neurons shutting down, they fire all at once.”

That hiccup can make people hear a noise that isn’t there — sometimes in their ears, other times in their heads. In some instances, people have seen lightning or other flashes of light, or felt an intense heat all over, according to Sharpless’s research. But despite how scary the name is, “it’s physically harmless,” he said.

“Some people with exploding head syndrome thought they were having a seizure or a subarachnoid hemorrhage or something really bad,” he said. “There is some evidence that just learning about it can reduce the frequency of the episodes.”

Less than 3 percent of those who had experienced it had it to an extent that it interfered with their lives, according to the research. “If it happens that much, it’s not doing good things for your sleep,” Sharpless said, but that’s about it.

The next phase it to try to understand what might make people more likely to have it.

That loud bang that startles you awake: It may be ‘exploding head syndrome’ – The Washington Post.

A book worth reading and a blog worth looking into:

Magnesium is important in over 325 enzyme reactions in the body.1 It is used to regulate blood sugar in the body, and to help prevent you from developing diabetes.2 Magnesium relaxes arteries that carry blood throughout the body, which lowers blood pressure. Magnesium also chelates extra calcium in the body; this keeps the arteries from hardening due to excess calcium. Finally, magnesium supplementation can help lower stress and anxiety levels.

 

Let’ us take a look at the many magnesium types and their functions, but the best form I can recommend is magnesium glycinate. The body absorbs the most elemental magnesium from glycinate.3 The extra glycine, an amino acid, relaxes nerves, and relieves anxiety.

 

Possible Symptoms of A Magnesium Deficiency

 

 

 

This is a list of possible symptoms a patient might have if they have a magnesium deficiency. If a magnesium deficiency is present, you can still have a magnesium deficiency and not have any of these symptoms as well. This often occurs in patients that are younger (age helps reduce the symptoms of a magnesium deficiency,) and it can also depend on the gender (men tend to have less symptoms than women.) Most people should supplement with 400 mg of elemental magnesium (as long as their kidney function is normal) even if they do not know if they are deficient.4

 

·        Tingling in legs – Magnesium deficiency is the main cause of restless legs syndrome

 

·        Leg cramps (charlie horse)

 

·        Weakness

 

·        Asthma

 

·        Elevated blood pressure and/or pulse

 

·        Heart disease

 

·        Diabetes

 

·        Dizziness

 

·        Shaking

 

·        Irregular heartbeat (palpitations)

 

·        Constipation5

 

 Diagnostic Tests for Magnesium Deficiency

 

 

 

Here is a simple guide of the different tests that are used to determine if you have a magnesium deficiency or not.

 

Magnesium Serum Test – A magnesium serum test is the most common magnesium test performed and also the most inaccurate. Less than 1% of the body’s total magnesium is in the blood plasma and the body does whatever it takes to keep that number regular. If you score low on a plasma test then you are in dire need of magnesium and you are definitely deficient in your bones, organs, and muscles.6 This test is used to measure extracellular magnesium levels. Normal plasma magnesium levels are, 1.6 – 2.4 mEq/L.7 This test does not accurately measure the body’s total magnesium level, but is the test most often used for diagnostic testing.

 

Magnesium RBC Test – A magnesium RBC test is a more accurate test that quantifies the amount of magnesium stored in the red blood cells. This test measures intracellular magnesium levels. This test gives you the amount of magnesium that has been stored in your cells for the past four months.  Results of six mg / dl or higher indicate strong magnesium reserves in the body.8

 

Magnesium WBC Test – A magnesium WBC test is more accurate than the RBC test. Like the magnesium RBC test, the WBC test also measures intracellular magnesium levels. This test gives you the amount of magnesium that is currently in your cells, it does not show an average of magnesium in the cells over a period of time like the RBC test. This test is not available to many doctors or diagnostic labs.9

 

Magnesium EXA Test – A magnesium EXA test is the best test to determine magnesium deficiency. This test is performed by scraping your cheek buccal cells for a sample so that levels of magnesium stored in your cells, bones, and muscles can be determined. Like the WBC test, the EXA test is considered an intracellular magnesium test. The EXA test will account for 99% of the body’s total magnesium, and is the most accurate diagnostic test for magnesium currently.10

 

Part 1
Part 2
Part 3
Part 4
Part 5
Part 6

 

 

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Magnesium and Your Digestive Health

 

Magnesium is used in the body to help active digestive enzyme reactions in your body as well as regulate the proper transit time of your bowels.1 2 The enzyme reactions in your body help further break down fats, proteins, and carbohydrates. Magnesium chloride can help increase stomach acid to help assimilate food better if you have digestion problems it might be the type you want to use.3 Most all other magnesium (unless chelated with an acid like citrate or malate) lower stomach acid so they should be taken before bed so problems with digestion will not occur.

 

 

 

Magnesium is used by your intestines as an osmotic laxative.4 This means that your large intestine uses magnesium to bring in water into the bowl so that your stool becomes softer and easier to pass. This is why magnesium supplementation is a great treatment for someone who has constipation issues.5 Magnesium is very important for the functioning of your digestive system as well as your complete health as well.

 

Different Forms of Magnesium

 

Recommended Forms of Magnesium:

 

 

 

Magnesium glycinate – The most bio-available form of magnesium. The extra glycine as an amino acid can help with sleep and provide a calm feeling. This form of magnesium is the least likely to cause loose stools. Taken at bedtime.6

 

Magnesium malate – Magnesium malate is important for people who have a lot of fatigue or suffer from Chronic Fatigue Syndrome. Magnesium supplementation increases ATP, which is a molecule that provides energy to our cells. Malic Acid has also been shown to increase ATP levels. Magnesium malate should be taken during the day with meals. The extra malic acid will increase stomach acid and assimilation.7

 

Magnesium chloride – Magnesium chloride is one of the best forms of magnesium for people with Gerd or stomach problems. It must be taken with food because the extra chloride will definitely make more HCL in the stomach. Can also be used topically as a spray for transdermal supplementation.8

 

Magnesium taurate – Magnesium taurate is a lifesaver for people with heart disease. The extra taurine is an amino acid helps increase heart function. Taken at bedtime.9

 

Magnesium citrate – Magnesium citrate should mostly only be used for bowel irrigation, it is also one of the most well-known forms of magnesium supplementation. It causes some loose stools and its absorption is average. Magnesium citrate should be taken with meals because the extra citric acid will increase stomach acid and assimilation.10

 

Magnesium sulfate – Honestly only used to stop pre-eclampsia and used in bath salts as epsom salt. Has okay absorption but does leave some extra organic sulfur in the body can be absorbed by the skin. Sulfate can help heal muscle sprains better than most other forms of magnesium because of skin permeability. Taken soaking in a bath or before bed.11

 

Magnesium arginate – Arginine is a vasodilator amino acid that is good for increasing blood flow.12 This form of magnesium is very good for bodybuilders. Taken with meals throughout the day due to the possibility of increased energy.

 

Magnesium lysinate – A good source of magnesium and the amino acid lysine. Lysine is an excellent anti-viral. Taken before bed.13

 

Magnesium ascorbate – A good source of magnesium and vitamin C. Can cause some loose stools. Taken before bed.14

 

Magnesium ZMK- A great form of magnesium that uses magnesium from all of the Krebs cycle: citrate, fumarate, malate, succinate & alpha-keto-glutarate. This supplement form of magnesium ZMK is great for athletes, and is very good for recovery. A ZMK supplement should be taken before bed.

 

Magnesium fumerate, succinate, alpha-keto glutarate – See Magnesium ZMK, All Krebs cycle forms of magnesium.15

 

Magnesium gluconate – A form of magnesium that is chelated with gluconic acid, which occurs from the fermentation of glucose. Magnesium gluconate has above average absorption in the body (better than even magnesium citrate)16, rarely causes loose stools. Taken before bed.

 

Magnesium carbonate – This is probably the lowest form of magnesium I can recommend. Has one of lowest levels of assimilation and is a good osmotic laxative. It can also lower stomach acid levels and is used in most antacids. Taken at bedtime.17

 

Magnesium With Special Uses:

 

 

 

Magnesium orotate – This is one least known forms of magnesium, but let me tell you if you just had a surgery or exercise constantly then it will be your godsend. The extra orotate will help muscle regeneration.18 It also has been shown to support heart health greater than even magnesium taurate. Taken at bedtime.19

 

Magnesium L-threonate – Magnesium L-threonate may greatly increase magnesium in the brain and spinal column for increased cognitive function.20 To be honest there isn’t a lot of in vivo research to prove if this is true yet though. L-threonate is an isomer of ascorbic acid.21 (New research has shown that it increases magnesium levels about the same as magnesium sulfate, granted magnesium sulfate is injected which might make it be able to cross the blood brain barrier then oral magnesium.22) Taken at bedtime.

 

Magnesium 2-AEP – This is a form of magnesium that is chelated with phosphorylethanolamine which is a vital component of the structure and integrity of cell membranes. Magnesium 2-AEP has been theorized to help patients with MS, because it can help with cellular function and integrity and can help protect myelin in the brain. Taken with meals during the day.23

 

Magnesium peroxide – ONLY AS COLON CLEANSER. Taken before bed.

 

Magnesium Phos 6X – Normally I do not recommend homeopathic supplements (if they work for some people I’m glad they do, I rather recommend nutriceuticals), but for homeopathic minerals I feel they still can be beneficial because some of the trace mineral should be left in the product. I would suggest on using this in a person who is extremely sensitive to all forms of magnesium supplementation. If magnesium glycinate still causes loose stools and magnesium chloride causes allergic reactions on the skin then this is the magnesium for you to try. 24 This magnesium contains some phosphorus so I would suggest if you have kidney problems to stay away from this form. Taken before bed.25

 

Garbage forms of Magnesium:

 

 

 

Most of these forms of magnesium I consider are garbage because they either do damage in the body or are very poorly absorbed.

 

Magnesium yeast chelate – A “natural” form of magnesium that is very easily assimilated by the body, what sounds so wrong about that? This form of magnesium is found in most of your “natural” vitamins like New Chapter, Garden of Life, and Megafood. The main problem I have with this form of magnesium is that you have to ingest a lot of brewers yeast (which some people are sensitive to) in the whole supplement to get a tiny amount of magnesium.26 Most vitamins that use this form of magnesium have very little magnesium actually in the vitamin (less than 100 mg elemental). There are just a lot better options out there. Taken with food.

 

Magnesium aspartate – Absorption is notworth extra aspartic acid. Too much aspartic acid can be neurotoxic. Can you say ASPARTAME? Taken at bedtime. This includes magnesium ZMA supplements.27

 

Magnesium pidolate (Magnesium 5-Oxo Proline) – Absorption is DEFINITELY not worth the extra free glutamic acid. Too much free glutamic acid can be excitotoxic and neurotoxic. Can you say MSG? Taken with meals.

 

Magnesium hydroxide – Not greatly absorbed and most magnesium is released into the bowels. Most commercial preparations (Milk of Magnesium) have sodium hypochlorite added (bleach.) Taken at Bedtime.28

 

Magnesium oxide – VERY POORLY ABSORBED – Out of 400 mg only AT MOST 80 mg of elemental magnesium is absorbed by the body. Magnesium oxide is one of the worst absorbed forms of magnesium, and sadly the most common supplement form of magnesium taken. Taken at Bedtime.29

 

Magnesium glycerophosphate – This magnesium is chelated with phosphorus. The problem with this magnesium is that most people get too much phosphate in their diet. People with kidney problems should also definitely stay away from this supplement because it is harder for them to eliminate excess phosphates. Taken at bedtime.30

 

Magnesium lactate – Extra lactic acid is FUN! Should not definitely not be used for people who have kidney disease because the extra lactic acid can cause complications for the kidneys. I do not generally recommend this form at all. Taken during meals.

 

Magnesium: Most Overlooked Mineral for Improving Health – Part 2 – Fix Your Gut.

Ashely Judd

Billy Joel

Hugh Laurie

Jim Carrey

How can somebody so funny be secretly struggling with depression? Such is the case with celebrated comedic actor Jim Carrey, who has been very open about his long-term depression battle. In a 2008 interview with the British newspaper The Sun, Carrey described how his mental health issues began just as he was breaking through to stardom, adding that his perspective on depression has changed over the years.

Sheryl Crow

This Grammy-winning singer has released hit single after hit single through the years, but even a woman famous for singing “all I wanna do is have some fun” can be depressed. According to a 2002 write-up in Blender, Crow states that depression has been part of her everyday life as long as she can remember. She credits antidepressants and therapy with helping her recovery.

 

10 Celebrities Coping With Depression – Depression Center – Everyday Health.

The female body: Shape-shifting

Brian Buntz

Popularized by the Russian economist Nikolai Kondratiev, long wave theory holds that decades of economic progress follow from technological breakthroughs such as was the case with the development of the steam engine, the railway, electrical and chemical engineering, automobiles, and computing technology.

In the most recent period, the microprocessor is the single most important technology, making possible everything from personal computers and smartphones, to smart bionic limbs and wireless-enabled medical devices. Indeed, much of our very culture now seems to revolve around the microprocessor.

Perhaps another technology will emerge as a key driver of medical technology in years to come. And medicine could be one of the principal industries to benefit from the next decades-long technological period, which we could be on the cusp of entering now. The Slovak theorist Daniel Smihula refers to the next decades-long phase as the post-informational technological revolution, and expects it to begin between 2015 and 2020.

A 2010 Allianz report also forecasted a wave of medical technology innovation playing a central role in the next long-term technological phase, arguing that such periods typically emerge after major financial crashes or periods of economic stagnation, and that the Great Recession may be one such example of that. Kondratiev himself believed in a long-term boom–bust cycle, asserting that the Great Depression would not spell the end of capitalism but give rise to a new period of economic success in the West. Stalin apparently disagreed and had the theorist shot by a firing squad.

Whether long-wave theorists are right about the early 21stcentury giving rise to another technological megacycle, there is a definite need for a new wave of innovation in healthcare—in part because the world’s graying population. By 2050, the population percentage in the United States that is over 65 stands to roughly double—and nearly triple in Asia and Latin America. Add to that growing pressures to contain healthcare costs and an uptick in chronic diseases, and we’ve got a big problem on your hands.

If Kondratiev’s grand vision is true, there is a good chance that much of the prognosticating about the future of medical technology will seem myopic by comparison. For one thing, a lot of projections about healthcare’s future are based on applications of electronics. And while electronics will undoubtedly play an integral in an ever-widening number of medical technologies, long-wave theory holds that one technology revolution lays the groundwork for the next. So it is possible that the innovation made possible by electronics could give rise to other technological fields that would characterize the next era. Contenders could include fields like nanotechnology, genomics, biotechnology, or 3-D printing, any of which may ultimately catalyze a wave of long-term medical innovation.

Such a shift may be already underway. The Economist just penned an article stating that the U.S. healthcare system is a “wasteful and inefficient industry, is in the throes of great disruption.” Similar upheaval can be seen elsewhere.

Perhaps revolution is a good word to describe the next period of technological evolution in medicine. While there is clearly a need for novel devices that make healthcare more precise and efficient, any new technology that threatens entrenched medical business models must battle against those who would preserve the status quo.

Economist article below:

THE best-known objective of America’s Affordable Care Act of 2010—commonly known as Obamacare—was to ensure that the 40m-plus Americans who lacked health insurance could get it. Less widely appreciated, but at least as important, are the incentives and penalties the law introduced to make the country’s hideously expensive and poorly performing health services safer and more efficient. Economists are debating how much credit Obamacare should get for a recent moderation in the growth of health costs, and for a fall in the number of patients having to be readmitted to hospital (see article). Whatever the answer, many companies see the disruption unleashed by the reforms as the business opportunity of a lifetime.

One of the biggest shifts under way is to phase out the “fee for service” model, in which hospitals and doctors’ surgeries are reimbursed for each test or treatment with no regard for the outcome, encouraging them to put patients through unnecessary and expensive procedures. Since Obamacare they are increasingly being paid by results—a flat fee for each successful hip replacement, say. There are also incentives for providers which meet cost or performance targets, and new requirements for hospitals to disclose their prices, which can vary drastically for no clear reason

 

Millions of people are now looking for health insurance on the new public exchanges set up under the reforms. And Obamacare has come into effect at a time when American employers, who often provide health cover for their workers, are seeking to cut its cost by encouraging them to shop around on private exchanges, and by offering less generous plans.

 

The upshot is that there are growing numbers of consumers seeking better treatment for less money. Existing health-care providers will have to adapt, or lose business. All sorts of other businesses, old and new, are seeking either to take market share from the conventional providers, or to provide the software and other tools that help hospitals, doctors, insurers and patients make the most of this new world.

 

Patients are increasingly having to pay higher “deductibles” out of their own pockets, before the insurance kicks in, to keep the cost of the cover down. So for minor ailments and simple tests, it makes sense for such patients to go to one of the increasing numbers of walk-in clinics, staffed by well-qualified nurses, on the premises of retail pharmacies such as CVS and Walgreens (see chart). The prices are clear, the care is cheap and the service is quick. Walgreens has a partnership with Theranos, a diagnostics firm, which offers customers a range of tests from a tiny drop of blood. Walmart, a giant supermarket chain with many in-store pharmacies, also intends to become one of the leading sellers of affordable health services, says Alex Hurd, its product-development chief.

 

 

For injuries and illnesses that are more serious but not immediately life-threatening, lots of “urgent-care centres” are being opened as an alternative to going to a hospital emergency unit. Private-equity firms are pouring money into independent chains of centres. Merchant Medicine, a consulting firm, reckons that between them, these chains now have just over 1,500 urgent-care centres, up from about 1,300 at the start of 2013. The market is still fragmented but a national brand could emerge from one of the largest chains, such as Concentra or MedExpress.

 

Some hospital operators, seeking to cut their costs of care, and choosing to be among the disrupters rather than the disrupted, are also opening urgent-care centres. Aurora Health Care, a Wisconsin-based chain of hospitals and clinics, now has more than 30 of them.

 

Hospital operators are now facing a classic “innovator’s dilemma”, as described by Clay Christensen, a Harvard business professor. If they persist with their high-cost business model even as their customers discover that cheaper alternatives are good enough, they will be in trouble. According to Strata Decision Technology, an analytics firm, many hospital groups saw what was coming and started to cut their costs well before the provisions of Obamacare started to bite. One of the fastest movers is Advocate Health Care, a hospital operator from Illinois, which says it now earns two-thirds of its revenues from value-based payments.

 

The largest chains of for-profit hospitals, such as Tenet Healthcare, HCA and Community Health Systems, are rather profitable. They have trimmed their costs, been conservative with capital and, thanks to Obamacare raising the number of Americans with health insurance, now have more patients and fewer bad debts. However, credit-rating agencies are worried about the prospects for the not-for-profit hospitals, which are 60% of the total. With lower margins, and less capital to make investments, they have become targets for takeover, says Jim Bonnette of The Advisory Board Company, another consulting outfit.

 

As a result further consolidation in the hospital business is likely. This could mean greater efficiency and lower costs. But if antitrust authorities are not vigilant, it may lead in the longer term to a concentration of market power. If so, the benefits from the efficiencies being wrung out of the hospital system may end up in the pockets of shareholders rather than saving patients and insurers money.

 

Obamacare is also encouraging the creation of all sorts of health-related advisory and intermediary companies that help care providers, insurers and patients save money. A company called Vitals approaches employees on behalf of their company’s health plan, and offers them cash rewards, and a taxi, if they agree to be treated at a cheaper provider. The sums to be saved can be astonishing: a new cost-comparison tool created by Blue Cross Blue Shield, a big alliance of private health insurers, has found that a colonoscopy with a biopsy costs $8,489 at one clinic in Chapel Hill, North Carolina, but just $928 at another provider in Greensboro, only 50 miles (80km) or so away.

 

Cohealo offers a “sharing economy” solution for hospitals and clinics wanting to make the best use of expensive equipment, in much the same way as Airbnb helps people with spare rooms fill them with paying guests. Doximity is trying to be a Facebook for doctors, letting them refer patients and discuss treatments securely without the blizzard of faxes they rely on today. Grand Rounds is a sort of medical Match.com: an online matchmaker that pairs patients with specialists. As in other industries, administrators are being tempted to switch to renting software and data storage in the online “cloud”: Athenahealth, a seller of medical back-office software, is trying to get doctors and hospitals to move patients’ health records onto its cloud-based service.

 

Preliminary diagnosis

 

For supporters of Obamacare, it is clear that the reforms are empowering patients, driving public and private health insurers to achieve better value, forcing existing providers to shape up and providing opportunities for disruptive newcomers. Digital technology is also helping to increase transparency about prices, making it easier to share information and increase efficiency. For some analysts it all adds up to a “new health economy”—as PwC, a consulting firm, puts it—the most significant re-engineering of the American health system, by far the world’s costliest, since employers began providing cover for their workers in the 1930s.

 

And the revolution has only just begun. The Obama administration recently set a target of making 50% of Medicare payments value-based, rather than fee for service, by the end of 2018. America’s largest private payers have a target of 75% by 2020. So hospitals do not have long to shape up. Some will have their profits squeezed, and customers stolen by new rivals. Some may close, or be taken over. But for other businesses, from supermarket and pharmacy chains to digital-health startups, there will be billions to be made.

Health care in America: Shock treatment | The Economist.

Because scientific studies are examining the role of magnesium in alleviating or circumventing many commonly occurring chronic ailments, it is important to be educated on the variations in magnesium supplements; especially magnesium orotate, the best form of the mineral supplement.

Magnesium is not easily absorbed in the body unless first attached to transporting substance. For this reason, many supplement manufacturers have “chelated” magnesium to organic and amino acids. A few of these include magnesium oxide, magnesium sulfate and magnesium carbonate. Quality depends on the amount of magnesium in the supplement and how bioavailable it is. Bioavailability refers to the amount of magnesium in the supplement that can be assimilated by the digestive system and used for cellular activity and health benefit

Magnesium is one of those supplements that is very well known for its benefits throughout the natural health community. Magnesium is involved in over 300 biochemical processes in the body. One of its most important functions is that it plays a key role is producing energy, this Elementmakes it vitality important for all cellular functions and processes. It helps maintain normal muscle and nerve function, keeps heart rhythm regular, supports a healthy immune system, and keeps bones strong. Its wide range of health benefits and biological activity make it effective in addressing a number of common diseases and conditions including fibromyalgia, chronic pain, diabetes, osteoporosis, cardiovascular disease and headaches. Numerous studies have demonstrated that magnesium supplementation and correction of deficiency has improved the aforementioned conditions. The problem with this essential mineral is that most people do not have sufficient levels for optimal health. A gradual depletion of nutrients from our soils has left many vegetables with lower levels of magnesium. Another factor that contributes to magnesium deficiency is that it often is depleted by various common conditions (i.e. IBS, Crohn’s disease) and medications (i.e. proton pump inhibitors, diuretics).
For a more complete discussion please see the article The Many Faces of Magnesium in the Heart Health issue of Advances.

As a supplement, magnesium is most commonly found in small amounts in multivitamins and in certain over the counter laxatives. Minerals such as magnesium or calcium are combined with another molecule to stabilize the compound. Each combination, referred to as a chelate, (such as magnesium citrate) has different absorption, bioavailability and therapeutic value. These additional molecules can really impact the medicinal value of the magnesium and some even have beneficial effects in their own right. The most common forms and their benefits are listed below.

Magnesium-L-Threonate: This form of magnesium has recently been studied to improve memory and brain function. One preliminary study in animals found that it significantly enhanced both short-term and long-term memory, boosting scores by 15% for short-term memory and 54% for long-term memory compared to magnesium citrate.8 Based on this study, it appears that magnesium-L-threonate is a highly absorbable form of magnesium that can improve brain function. While this research is promising, more is needed to confirm its benefit.

Magnesium Pidolate (or picolinate): This form of magnesium has generated interest because it is very inexpensive and can easily be made into a liquid supplement. There really have not been any substantial research trials supporting its specific health benefits. The down side of this form is that the pidolate molecule does not have any additional health benefits.

Magnesium oxide: Often used in milk of magnesia products since this form has a strong laxative effect. Even though this combination contains a large proportion of magnesium compared to the oxide molecule, it has poor bioavailability and readily causes loose stools; therefore it is considered the least optimal form to use as a supplement. Also referred to as “Magnesia”, magnesium oxide is commonly used therapeutically as a laxative and relief for acid reflux. This type of magnesium shows high levels of concentration, but poor levels of bioavailability (only 4%).

Magnesium sulfate: This form is often used as an intravenous preparation but it is not used in oral formulations. Since it does have some absorbability through the skin, . An inorganic form of magnesium with an elemental concentration of 10% and lower levels of bioavailability. Magnesium sulfate contains magnesium and sulfer and oxygen; it’s commonly referred to as Epsom Salt.

Magnesium citrate: A commonly used form that has a good bioavailability compared to oxide. It is also very rapidly absorbed in the digestive tract but it does have a stool loosening effect.1 This form is found in many supplements and remains a solid option for delivering magnesium into the body. Derived from the magnesium salt of citric acid, this form of magnesium has lower concentration, but a high level of bioavalibity (90%). Magnesium citrate is commonly used as to induce a bowel movement, but has also been studied for kidney stone prevention.

Magnesium Amino Acid Chelate

A mineral chelate form of magnesium containing an ion of magnesium oxide connected to a mixture of some other form of amino acid. This could be a lactate, a glycine, aspartate or arginate, etc. The best chelated amino acid form of magnesium is aspartate or arginate.

Magnesium Aspartate: This form has increased bioavailability compared to oxide and citrate. There were some promising clinical trials conducted in the 1960s that found a combination of magnesium and potassium aspartates had a positive effect on fatigue and they reduced muscle hyper-excitability. Physiologically this makes sense since both magnesium and aspartic acid are critical players in cellular energy production. This form is not commonly found but has been used for chronic fatigue syndrome.

Magnesium Chloride

A form of magnesium showing moderate concentrations, but higher levels of bioavalibity when compared to magnesium oxide. Magnesium chloride has many uses, most commonly to help manufacture paper, some types of cements and fireproofing agents.

Magnesium Lactate

This type of magnesium shows moderate concentrations, but higher levels of bioavalibity as compared to magnesium oxide. Magnesium lactate is a mineral supplement that is most commonly used for treating digestive issues. Magnesium lactate should be avoided by those with kidney disease or kidney-related problems.

Magnesium Carbonate

This form of magnesium has moderate levels of elemental concentration and 30% bioavalibity rates. Magnesium carbonate has a strong laxative-effect when taken in high amounts. It is also commonly known as chalk, and is used as a drying agent by pitchers, gymnasts, rock climbers and weight lifters.

Magnesium Glycinate, Malate & Taurates

Chelated forms of magnesium holding moderate to low concentrations and higher levels of bioavailability. All three types of magnesium have a variety of uses, but none are as beneficial as the previous magnesium supplements listed above.

Magnesium Glycinate: Glycine is a well-known calming amino acid. This combination has good bioavailability and does not have a laxative effect since glycine is actively transported through the intest                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 inal wall. Due to the calming and relaxing effect of both glycine and magnesium, this combination has been used successfully for chronic pain and muscle hyper tonicity.

A magnesium supplement is best taken with calcium, for this reason, I developed IntraCal, it provides the best ratio of calcium and magnesium orotate.

– Dr. Edward F. Group III, DC, ND, DACBN, DCBCN, DABFM

Magnesium Malate: This less well-known combination has been studied for use in fibromyalgia. Since malate is a substrate in the cellular energy cycle, it can help improve ATP production; there is some preliminary evidence that it may reduce muscle pain and tender points in fibromyalgia patients.4

o-DR-OZ-HEALTHY-HEART-facebookMagnesium Orotate: This is another relatively unknown chelate combination containing orotic acid. This form has good bioavailability has had been studied specifically for heart health. Orotates can penetrate cell membranes, enabling the effective delivery of the magnesium ion to the innermost layers of the cellular mitochondria and nucleus. Orotates themselves increase the formation of RNA and DNA which can help heart cells repair and therefore improve function. The combination has been shown to improve heart failure, symptoms of angina and exercise performance in clinical trials.5,6 The most effective form of magnesium supplement, created through the use of the mineral salts of orotic acid. Both plants and animals use orotates to create DNA and RNA. Extensive scientific research by Dr. Hans A. Nieper, M.D. shows orotates can penetrate cell membranes, enabling the effective delivery of the magnesium ion to the innermost layers of the cellular mitochondria and nucleus. Magnesium orotate contains many properties that can help protect you and your health, while offering your cells the most readily absorbable form of magnesium on the market today.

Magnesium Taurate: Both magnesium and the amino acid taurine share the ability to improve cardiac function; each has a potentiating effect on insulin sensitivity and also a calming effect on neuromuscular excitability. The actions of both have striking similarities when it comes to cardiovascular health. They both have blood pressure reducing effects, stabilize nerve cells, improve the contraction of the heart muscle and have an anti-thrombotic effect.7 Additionally, low levels of vitamin B6 have been shown to further deplete both magnesium and taurine.

Due to its broad ranging beneficial effects, magnesium has really emerged as a quintessential health supplement with an excellent safety profile. Various forms of magnesium can be employed for specific health concerns and to increase bioavailability. Consider the research evidence and activity of each form to choose one that is most appropriate for you.

References
1) Coudray C, Rambeau M, Feillet-Coudray C, Gueux E, Tressol JC, Mazur A, Rayssiguier Y: Study of magnesium bioavailability from ten organic and inorganic Mg salts in Mg- depleted rats using a stable isotope approach. Magnes Res 2005;18:215–223.
2) Nagle FJ, Balke B, Ganslen RV, Davis AW. The mitigation of physical fatigue with “Spartase”. FAA Office of Aviation Medicine Reports. Rep Civ Aeromed Res Inst US. 1963 Jul;26:1-10.
3) Lamontagne C, Sewell JA, Vaillancourt R, Kuhzarani C, (2012) Rapid Resolution of Chronic Back Pain with Magnesium Glycinate in a Pediatric Patient. J Pain Relief 1:101
4) Abraham GE, Flechas JD. Management of Fibromyalgia: Rationale for the Use of Magnesium and Malic Acid. Journal of Nutritional Medicine (1992) 3, 49-59.
5) Stepura OB, Tomaeva FE, Zvereva TV. Orotic acid as a metabolic agent. Vestn Ross Akad Med Nauk. 2002; (2): 39-41.
6) Geiss KR, Stergiou N, Jester, Neuenfeld HU, Jester HG. Effects of magnesium orotate on exercise tolerance in patients with coronary heart disease. Cardiovasc Drugs Ther. 1998 Sep; 12 Suppl 2:153-6.
7) McCarty MF. Complementary Vascular-Protective Actions of Magnesium and Taurine: A Rationale for Magnesium Taurate. Medical Hypotheses (1996) 46. 89-100
8) Slutsky I, Abumaria N, Wu LJ, et al. Enhancement of learning and memory by elevating brain magnesium. Neuron. 2010 Jan 28;65(2):165-77

 

  1. Classen HG. Magnesium orotate–experimental and clinical evidence. Rom J Intern Med. 2004;42(3):491-501. Review.
  2. Zeana C. Magnesium orotate in myocardial and neuronal protection. Rom J Intern Med. 1999 Jan-Mar;37(1):91-7. Review.
  3. Albrecht E, Kirkham KR, Liu SS, Brull R. The analgesic efficacy and safety of neuraxial magnesium sulphate: a quantitative review. Anaesthesia. 2013 Feb;68(2):190-202. doi: 10.1111/j.1365-2044.2012.07337.x. Epub 2012 Nov 1. Review.
  4. Dufault R, LeBlanc B, Schnoll R, Cornett C, Schweitzer L, Wallinga D, Hightower J, Patrick L, Lukiw WJ. Mercury from chlor-alkali plants: measured concentrations in food product sugar. Environ Health. 2009 Jan 26;8:2. doi: 10.1186/1476-069X-8-2.

78 Comments

  1. Maria

    QUESTION: Would I be overdosing myself with Magnesium L-Threonate and after an hour took some Magnesium Glycinate? Thank you for specifying the different types of magnesium. I took Magnesium L-Threonate thinking it would calm me down as I was having mild anxiety attacks and no benefits after an hour. Decided to take Magnesium Glycinate, felt a difference of calmness!

    1. Dr. Hrkal

      Hi Maria,
      I don’t think you would be overdosing with combo. You really can’t over dose on magnesium since excess is just excreted in the digestive tract.
      Glad to hear you found relief!

      Dr Paul Hrkal ND

      1. Gene

        Dr. Hrkal,
        which type of magnesium is best for depression please?
        thanks!

        1. Dr. Hrkal

          Hi Gene,

          There isn’t a form of magnesium studied for depression specifically even though there is evidence that low magnesium levels are most likely related to depression. See the following studies.
          http://www.ncbi.nlm.nih.gov/pubmed/23321048
          http://www.ncbi.nlm.nih.gov/pubmed/19944540
          http://www.ncbi.nlm.nih.gov/pubmed/23950577

          I would stick to a well absorbed form of magnesium with good bowel tolerance like glycinate or malate.

          Hope that helps

          Dr Paul Hrkal

  2. Camille

    Good article. I have read studies that showed the benefits of supplementing magnesium during pregnancy but none indicated which form is best or used during pregnancy. Are you familiar with this?

    1. Dr. Hrkal

      Hi Camille,

      Thanks for reading the article. Magnesium (and calcium) are important to take during pregnancy to prevent muscle cramps and healthy bone formation. There has not been any specific form studied but citrate, malate or glycinate are well absorbed and safe for both mother and baby.

      Hope that helps

      Dr Paul Hrkal ND

  3. Patricia Grimes

    I’m a 85 year old widow and would like to take magnesium for my leg cramps.
    I take Clopidogel Bisulfate for a heart stent and Losartan 100 mg. for blood pressure.
    Could you tell me what type of magnesium would be best for me?
    Will appreciate your reply.

    1. Dr. Hrkal

      Hello Patricia,

      Thank you for the inquiry. Unfortunately we can’t recommend specific products for you on this forum. I would recommend you consult a qualified healthcare practitioner to make sure that your supplements are safe with the medications you are on. I can say that most forms of magnesium are useful for leg cramps. I would direct you to a form such as magnesium malate, that is easily absorbed and does not cause loose stools.

      Dr Paul Hrkal ND

  4. Mark

    I have restless leg which seems to be getting worse. I was told potassium would help. I have been taking nearly 2000 mg with only very slight improvement. I want to add Magnesium, which form would you recommend?

    1. Dr. Hrkal

      Hi Mark,

      Any form for magnesium would work except magnesium oxide. Magnesium citrate has a fast absorption so that is something you can take before bed. Magnesium glycinate has a calming effect and mag malate is great for muscle pain. Remember magnesium stores are built up over time so it may take a few months to see lasting benefits but usually people see an improvement quickly.

      Dr Paul Hrkal ND

  5. Sara

    Hi there,

    I’m just wondering what the best form of magnesium would be in order to get as many benefits as possible. Do you have to get each type of magnesium separately, or is there a way to get them all in one form of magnesium? If you do have to get them all separately, is it okay to mix them together and use all at once?

    1. Dr. Hrkal

      Hi Sara,

      Sorry for the late response. I don’t think you need to take all the forms to get the benefits of magnesium. Any of the amino acid combinations of magnesium will give you the benefits of repleting magnesium plus the effects of the amino acids. I would pick a magnesium form that best fits your goals (i.e. magnesium orotate if you have cardio vascular concern) and stick with it for a few months to build your levels. Magnesium glycinate or malate are my favorite for general health since they have a broad spectrum benefit on muscles.

      If you want feel free to mix them but a better approach would be to take each one for a period of time and rotate so you get the benefits of each. This way you amy be even able to tell which form you feel the best with. This will help guide you which form is best for you.

      Hope that helps
      Dr Paul Hrkal

  6. Roger

    Hello Dr. Hrkal,

    Your article list the benefits of different forms of magnesium that have different health attributes. My question is once cellular magnesium levels have reached optimal status. Would the benefits of Orotate’s effect on RNA & DNA be achieved? As such would L-Threonate benefits to cross the BBB be achieved as well. I guess my question is are these health benefits attributed to the FORM or magnesium. Thank you in advance
    .

    1. Dr. Hrkal

      Hi Roger,

      Great question. The benefits of ortotate or threonate would be effective right from the start of supplementation since they have an independent and distinct therapeutic benefit. That being said, the evidence suggests that it can take months to replete cellular magnesium levels depending on the intestinal absorption and previous level of deficiency. It’s also very difficult to accurately measure this. So assuming that after 3 months of rigorous supplementation you achieve optimal magnesium levels the benefit of orotate would be there throughout this time since the effects are independent. You could argue that once magnesium levels are optimal orotate would be more effective but they are not needed for it to be effective.

      The form of magnesium makes a big difference but the effects are not necessary tied together. The added benefit of “amino acid” forms of magnesium it that they are actively absorbed compare to citrate or oxide so they don’t cause loose stools are easily.

      Hope that helps
      Dr Paul Hrkal

  7. Janni

    Hello,

    I’ve recently discovered that most magnesium supplements contain dicalcium phosphate. Is there any calcium-free form?

    Thanks in advance.

    1. Justine

      Hi Janni, there are many quality magnesium supplements that don’t contain calcium diphosphate. Calcium diphosphate can be used either as a source of calcium to make a cal-mag type of product, or it can be used as a type of flow agent or bulking agent to help the product go into the capsule better. But there are lots of magnesium supplements that don’t have any type of calcium in them. None of AOR’s magnesium products contain calcium.

  8. Betty

    Hello,

    I want to take some bone health products like calcium, vitamin D, vitamin K2 and magnesium. What type of magnesium do you recommend and how much?

    1. Dr. Hrkal

      Hi Betty,

      Thanks for the question. Any of the amino acid magnesiums (glycinate, aspartate, malate etc.) or citrate are good for bone health. Just stay away from magnesium oxide because its an inferior form that is poorly absorbed and causes loose stools.
      The recommended amount usually is 500mg.

      Hope that helps

      Dr Paul Hrkal ND

  9. Adnan

    What is your opinion on Magnesium Oil?

    1. Dr. Hrkal

      Hi Adnan,

      Some people really advocate for the use of magnesium oil for topical application to relieve muscle pain. While there are some reports of improvement in symptoms, this way of getting magnesium has not been studied nor is a good way to address systemic deficiency. There really isn’t a good way to assess if topical application is actually getting into the body other then patient feedback. I personally stick to oral magnesium products since my clinical experience and the research supports this administration route.

      Hope that helps
      Dr Paul Hrkal

  10. Jessica Ann

    I have been taking 400 mg magnesium oxide once a day for about 2 weeks and I have been feeling very dizzy. Could this be a possible side effect? I have hyperparathyroidism and am below normal levels magnesium and phosphorus but high blood calcium and pth. Thank you

    1. Dr. Hrkal

      HI Jessica,

      Its tough to tell if your symptoms are related to the mag oxide. Magnesium can lower blood pressure which can lead to symptoms such as dizziness. I would stop the supplement to see if the symptoms persist. If they do persist see you doctor.

      Hope that helps
      Dr Paul Hrkal ND

  11. rosalind

    Which form of magnesium would be the best to use for severe constipation even though I eat fresh fruit, dark leafy greens each day and plenty of water since I stopped eating gluten. My antibodies were elevated on a blood test to 5.6ug/ml ( the normal range was <2.0 so I was told to avoid wheat,etc. I used to eat a lot of whole grains everyday with all of the above to keep myself regular. I am really afraid of becoming dependent. It is impossible to get enough whole grains without wheat.

    1. Dr. Hrkal

      Thanks for the question

      Magnesium citrate would be the best to promote bowel movement. Keep increasing the dose little by little each day until you get loose stools. Then reduce dose by half. The absorption is on par with the best amino acid chelate forms of magnesium but it still can offset constipation. If you are gluten sensitive then magnesium is poorly absorbed so I would recommend you continue magnesium supplementation as you get your diet in order.

      Hope that helps
      Dr Paul Hrkal ND

      Hope that helps

  12. rosalind

    I definitely feel better since I stopped the gluten( except for the severe constipation)

  13. Simi

    I was taking magnesium malate 850 mg each day for muscle pain.Now, I am having stomach acid problem. I have cut magnesium malate dose to less then 425 mg. For stomach acid problem, which magnesium would be the good one?
    Thank you

    1. Dr. Hrkal

      Thanks for the question Simi,

      My understanding of your question is that you have reflux after taking magnesium malate (“stomach acid problem”).
      Magnesium is very well tolerated and usually doesn’t cause digestive or stomach upset when taken at the recommended doses. There is no one form that is best at minimizing the effect on stomach acid except avoiding magnesium oxide. The only thing you can do is reduce the dose (which you are trying) or change to a different form. Try AOR’s new advanced magnesium complex for a combo of the most absorbable forms.

      There are many other reasons for reflux. I would consult your healthcare practitioner if the problem persists.

      Best of luck,

      Dr Paul Hrkal ND

  14. Ken

    Hi: I’m a 67 year old male and have been diagnosed with atherosclerosis with a moderate calcium score in the aorta, and also occasional palpitations, nonetheless have worked out regularly for years. Was taking magnesium oxide for a year or two until discovering it’s probably the least effective of the magnesium supplements (actually it seemed to help the palpitations some). Also just upped my Vitamin D3 and added K1 and K2. Was wondering what your thoughts were for which magnesium helps heart and circulation the most…thanks!

  15. Ken

    Hi: I’m 67 and in pretty good shape, but have been diagnosed with a calcium score of about 145 three years ago, also have once-in-a-while palpitations, but worked out at the gym regularly for decades. Was taking magnesium oxide (400mg a day) for a couple years until researching that it’s probably the least effective of the magnesium supplements (actually it seemed to help the palpitations some). Also have upped Vitamin D3 to 4000iu (recent blood level of 40) and added K1 (1mg) and K2 (300mcg). After reading various opinions on various magnesium formulas, was wondering your thoughts on which is best for heart and circulation…thanks!

    1. Dr. Hrkal

      Hi Ken,

      Thanks for you comment. Magnesium Orotate and Magnesium taurine would be the best for heart health. Take a closer look at those in the above article. Magnesium itself will counter balance calcification and improve blood flow. Orotate and taurine provide additional benefits for heart cell function, nerve conduction and repair. The vitamin K is an excellent addition to offset calcification.

      Dr Paul Hrkal

  16. Tammy

    I suffer from chronic migraines and read an article stating to drink 700-1000mg of magnesium citrate/malate along with 4000mg of pyruvate in an 8 ounce glass of water. My question is do you have any experience of using this combination and would it make a difference if it was citrate or malate.
    Thank you

    1. Dr. Hrkal

      Hi Tammy,

      Magnesium will help you with vaso-relaxation and headaches. I am not familiar with pyruvate or the combo with magnesium. I like to use magnesium and curcumin for tension headaches but migraines are more complex. I would look at food allergies and other sources of inflammation in migraine cases.
      For magnesium I would use either citrate, malate or glycinate. They are best absorbed.

      Dr Paul Hrkal

  17. Tammy Philipp

    Thank you

  18. Jeanenne

    I have Essential Tremors – it mostly affects my hands. Is there a form of magnesium that might help? I’m otherwise in good health, am 79 years old, take no medications but do take supplements.

    1. Dr. Hrkal

      Hi Jeanenne,

      Thanks for the question. For essential tremor there has been no studies with magnesium. Theoretically it may help with muscle spasms but I don’t think we have any evidence to say it will help with essential tremor.

      There is a lot of evidence supporting the benefit of magnesium (muscle function, bowel regularity, etc.) so you would still benefit from taking a formula like magnesium glycinate or magnesium malate.

      I hope that helps
      Paul Hrkal ND

  19. Jeanenne

    Thank you so much for your prompt reply. We have been taking two or three different forms of Magnesium (one kind at a time) but have run out and wanted a recommendation as to which form to take. I have been unable to find any supplement that lessens the effects of ETs but am planning on starting on a highly alkaline diet as that is what helped me in 2008 when I had PMR. (That and prayer)

  20. Beth

    Hello I am 39 years old, female. I have heart palpitations and chronic upper back pain. Which kind of magnesium do you recommend? the cardiologist had prescribed me magnesium oxide but if another kind will help me more than I would rather try it. Can I take two kinds at the same time the one for the heart and the one for the muscle function? What is the recommended dose?

    Thank you for your help

    1. Dr. Hrkal

      Hello,

      There is a lot of evidence supporting the benefit of magnesium (muscle function, heart function, bowel regularity, etc.) so you would still benefit from taking a formula like magnesium glycinate or magnesium malate that have been specifically studied for the muscle function. Magnesium orotate or taurine has been studied with heart function. I have included 2 links below to some information that will be helpful.
      http://www.aor.ca/products-page/products-list/cardio-mag-2-0/
      http://www.aor.ca/products-page/products-list/magnesium-malate-renew-4/

      I do think that whatever type of magnesium you choose (outside of mag oxide which is poorly absorbed) will be helpful for both situations.

      I hope that helps
      Paul Hrkal ND

  21. Andrea

    I have adrenal fatigue and the dreaded sleeplessness that comes along with it. Which form of magnesium would help? Thanks!

    1. Dr. Hrkal

      Hi Andrea,

      In this case you want a well absorbed magnesium to replete levels that were lost during stressful periods. Any type other than magnesium oxide is well absorbed. I would also consider magnesium glycinate for its calming effects before bed for insomnia.

      Good luck
      Dr Paul Hrkal ND

  22. Linda Powers

    I have heard that magnesium does not absorb well with fluoride taken either ingested, or transdermal as in soaking in it. Could you verify this information?

    1. Dr. Hrkal

      Hi Linda,

      This is a very interesting question. There actually is fair amount of research showing that fluoride prevents the absorption magnesium in the intestines. The fluoride ion itself can inhibit the activity of magnesium in enzyme processes throughout the body. This reduces bone formation, vascular relaxation and energy production. It is safe to conclude that fluoride should be avoided and ingesting high levels may counteract the beneficial effects of magnesium. This doesn’t mean you avoid magnesium supplementation. If fact, if you drink fluoridated water you should increase your magnesium levels to offset the negative effects. This webpage has a summary and list of reference that you will find helpful.

      http://www.mgwater.com/fl2.shtml

      Dr Paul Hrkal ND

  23. Kathy slick

    My product of magnesium citrate does not carry a recommended correct daily dosage. Natural Fractors. Canada is the name of this fine white powder. Please be specific as I find this subject very confusing. 78years old.

    1. Dr. Hrkal

      Hi Kathy,

      I don’t know the specific dosage of the magnesium you are referring to but it should say on the label. The goal is to get 100mg 2-3 times daily. Take as many caps as you need to achieve that dose. If you get loose stools then reduce the dose by half.

      I hope that helps
      Dr Paul Hrkal

  24. Ooy

    I have numbness on the tip of my big toes. Have been taking Vitamin B12 for that and was diagnosed magnesium deficiency. Could you please recommend what type of magnesium i should take for the numbness. Thank you in advance.

    1. Dr. Hrkal

      Ho Ooy,

      While there is no type of magnesium studied specifically for nerve pain magnesium glycinate or taurine are great options for nerve issues since they have good absorption and both glycine and taurine are calming neuro-signalling molecules. Also consider other reasons why you could be having numbness in your toes. Diabetes and nerve entrapment can cause numbness in your toes.

      Good luck

      Paul Hrkal ND

  25. Michelle

    I have a 12-year-old son who has asthma, food allergies, and is also ADD. I have read that kids with these problems lack magnesium. I’m not sure which type of magnesium would be best and how much to give.

    1. Dr. Hrkal

      Hi Michelle,

      Unfortunately we can’t give recommendations for patients on dosage. I would follow the label on the bottle. I can say that there is clinical research showing magnesium is useful in ADD cases and they used a citrate form. Consider a well absorbed form of magnesium like mag glycinate that also has calming effects.

      I hope that helps

      Dr Paul Hrkal ND

  26. Anna

    It looks like I could benefit from different forms of Mg . Would it be smart take different forms of it either daily at the same time or alternate different ones each day ? I have heard from others that diff Mag forms have different applications so you can’t take them at once . Is it true ? If yes, so then what best time to take each of form during the day ? Thank you for taking time answering all our questions ! I found this site very informative ( I am a holistic health practitioner ) !

    1. Dr. Hrkal

      Hi Anna, you are right that different forms have unique benefits but the focus should still be on an absorbable form of magnesium. I suggest taking 1 type for 1-2 months and then switching to another form. There is no benefit to switching forms daily.

      Thanks for you question

      Dr Paul Hrkal ND

  27. Ooy

    Thank you very much for your prompt reply. I have diabetes checked and the result was ok, but have to keep close look on that. I had never heard about nerve entrapment. Will find out more about it and consult with my doctor. Thank you.

  28. Toni

    Doctor Hrkal,
    December 8, 2014

    My husband has a lot of issues from RLS to calcification of the aorta. He was told by his doctor to take magnesium. At first he was on magnesium chloride but has since switched to magnesium glycinate. I was concerned until I read your article.One question, I would like to know if he should be taking calcium, D and K2 with the magnesium in order for it to absorb properly and be of value?
    Thank you,
    Toni

    1. Dr. Hrkal

      Hi Toni,

      If any cases of calcification vitamin K should be used. Studies have shown it reduces and prevents calcification of soft tissue like blood vessels.
      However, to answer your question, Vitamin D, K, or calcium are not needed for the optimal absorption of magnesium. Mag is absorbed better when taken away from food and other minerals since they compete for absorption and require stomach acid to be broken down.

      I hope that helps

      Dr Paul Hrkal ND

  29. Lisa

    Hello,

    I have a 3 y/o son who is autistic. He currently takes Mag Glycinate 100mg bid. He deals with constipation regularly. Would it be too much Mag to give occ Mag Citrate?

    Thank you,

    1. Dr. Hrkal

      Hi Lisa,

      You don’t need to switch magnesium but just very gradually increase the dose of mag glycinate until your son’s stools become more loose. To directly answer your question, there is no harm occasionally adding mag citrate if you desire.

      Paul Hrkal ND

  30. fenty

    Hi Dr Hrkal,
    Can someone have sleep apnea (on CPAP machine for pretty long) consuming magnesium glycinate ? Since mg glycinate will help muscle to relax while sleep apnea person has too relax muscle around the throat that blocking the air, it seems making it worst? If it is okay which magnesium is the best? And what is the correct dose to start? Thanks so much.

    1. Dr. Hrkal

      Hi Fenty,

      Magnesium’s action is not that is will relax muscle so much that it affects breathing. Its more correct to picture when there is enough magnesium the muscle functions normally, which includes proper contraction and relaxation. Mag glycinate should not adversely affect breathing or sleeping. A well absorbed form of magnesium (like glycinate) is a good form to take to restore proper levels. There is no correct dose because it varies depending on the person and health concern. I typically tell people to follow the label dosage which usually ends up being 200-300mg daily.

      Dr Paul Hrkal

  31. fenty

    Thanks Dr Hrkal,
    Pls help me with my last question; for the best sleep aid should i go for mag glycinate or mag bisglycinate?

    1. Dr. Hrkal

      Hi fenty,

      Either one is fine. The bisglycinate is just 2 glycine molecules. Both work well for sleep.

      Dr Hrkal

  32. Heather

    You said Mag glycinate was calming, do you know why when I take it it makes me anxious? Also when I take Potassium it gives me chest tightness and pain? Thanks

    1. Dr. Hrkal

      Hi Heather,

      Some people have this “opposite” effect to magnesium. We don’t know exactly why it happens but my theory is that since magnesium increases energy production at the level of the mitochondria some people could be overstimulated by this. The same is true for its affect on the brain. Mag is needed in the formation of excitatory neurotrasmitters so you may be pushing these pathways with extra mag. I would suggest trying to support the brain pathways with a B-complex. Its might make the magnesium less excitatory if other co-factors are present.

      here is study that supports this theory
      http://www.ncbi.nlm.nih.gov/pubmed/2880351

      I hope that helps

      Dr Paul Hrkal

  33. dju

    Lots of good info here. So I have a vitamin D/magnesium question. Recently increased my vitamin D3 to 10,000 units/day after latest blood test came back still low after taking 6,000 units D3/day. At the same time I stwitched from magnesium citrate to magnetic glycinate due to intestinal issues. No intestinal issues, but getting that anxiety and jittery feeling again. Wondering if the high dose if D3 is draining my magnesium or if the switch to 800 mg magnesium glycinate/day isn’t maintaining my magnesium level like magnesium citrate did. My intestinal problems seem better though.

    1. Dr. Hrkal

      Hi Dju,

      Its tough to say exactly what is causing the jittery feeling again but it may be the glycinate component. Even though it is calming for most people it can have the opposite effect for a few. I would try switching to one of the other magnesiums (like malate) to see if you still feel that way. Malate is well absorbed as well. Another option is to reduce the dose of magnesium glycinate to 400mg daily. The vitamin D will not have an effect on the magnesium but it could increase your calcium levels.

      Dr Hrkal

  34. Zenie Ed

    I took mag glycinate for a few months at a low dose 3x a week. It was good but it aggravated my insomnia. What mag supplement do you recommend? I’ve got adrenal fatigue. Thanks

    1. Dr. Hrkal

      Hi Zenie Ed,

      Some people have this “opposite” effect to magnesium. We don’t know exactly why it happens but one possible explanation is magnesium is needed in the formation of excitatory neurotrasmitters so you may be pushing these pathways with extra mag. I would suggest trying to support the brain pathways with a B-complex. Its might make the magnesium less excitatory if other co-factors are present. Also another type of magnesium, like mag malate or citrate could not have the same effect on the brain.

      here is study that supports this theory
      http://www.ncbi.nlm.nih.gov/pubmed/2880351

      I hope that helps,
      Dr Paul Hrkal

  35. Erin

    Hi. I recently was diagnosed with hyperparathyroidism and underwent a parathyroidectomy and thyroid lobectomy (it was intrathyroidal) 6weeks ago. I am in the process of determining the damage with doctors but it appears I have had it for at least 10 years. I have suffered from back pain, kidney stones/infection, fatigue, apathy, heart palpitations, Lown Ganong Levine Syndrome, extra clotting (no DVT), and hand numbness. Since surgery, many things have improved but I am now getting muscle spasms often, palpitations have increased, and daily numbness in my arms, hands, legs and feet that lingers for up to an hour. My labs indicate low vitD and low-normal calcium, normal PTH. I am currently taking 100% RDA calcium, 4000 IU D3, 100% RDA K2. Should I request to be tested for Mg deficiency? Do my current symptoms sound like they could be improved with Mg? Is Mg deficiency associated with HPT pre or post-op? Thank you.

    1. Dr. Hrkal

      Hi Erin,

      That sounds like a complex situation. Low or altered thyroid function could cause all those symptoms which I would suspect before I think of magnesium involvement. If you wanted to test for magnesium deficiency that I would request ionized magnesium but even this test is a poor marker of your true magnesium levels outside the blood stream. For this situation, I would suggest seeing a naturopathic doctor that will be able to answer of magnesium is a good idea for you to take. The good news is that magnesium is very well tolerated and has very little side effects.

      I hope that helps

      Dr Paul Hrkal

  36. Lisa Lansford

    Hi, I’ve been taking 1,000 mg. of Magnesium Oxide per day (500 mg. in the morning and 500 mg. in the evening) for several months and am very happy with the laxative properties (no more constipation). After reading this very informative article, I am wanting to try Magnesium Taurate and Magnesium L-Threonate for their benefits. My question is, would these two forms of Magnesium have the same beneficial effects on my digestive system as the Magnesium Oxide? I don’t want to go back to ineffective elimination.

    Thank you for your help. Lisa

    1. Dr. Hrkal

      Hi Lisa,

      Thanks for you question. There is no doubt that magnesium oxide has the most potent laxative properties but citrate also has this effect at similar doses. Any type of magnesium will have a stool loosening effect but oxide and citrate just have their effect at lower doses. I think you can try another form like mag taurine but just adjust the dose to maintain your stool function. Also once you build up your mag levels your stools should need less of a dose to regulate bowel movements.

      I hope that helps

      Dr Paul Hrkal

  37. Huni Hinrichsen

    Do any of the magnesium types counter each other? I have been taking Magnesium Citrate for a while to reduce risk of getting blocked bowel movement but a doctor is recommending me to take Magnesium Threonate for improved nerve and brain functions. I tried switching but noticed shortly that my bowel movement dropped.

    Can I take both of them right before bedtime or would you recommend sticking to either?

    Thanks Paul!

    1. Dr. Hrkal

      Hi Huni,

      There is no known interaction between the forms of magnesium. Citrate does a better job at loosening the bowels. Threonate will also loosen stools but at a higher dose since the amino acid is absorbed more readily. In my opinion you could take both together if needed.

      Dr Paul Hrkal

      1. Huni Hinrichsen

        Thank you very much!

  38. Katerina

    Hello,

    Hi how are you? I have a question. A few weeks ago I purchased a product called Natural Vitality Nature Calm. It is magnesium citrate that is in a powdered form which I add to my water at night to drink. I am hypothyroid and even taking my desiccated NatureThroid I still was severely constipated. The magnesium citrate works tremendously for me. I take roughly around 325 mg to 400 mg every night. The problem is my insomnia is still there. I used to have to take prescription meds just to fall asleep. I stopped taking the prescription meds for sleeping because I don’t want to live like that and rely on a pill just to fall asleep. I drink the magnesium citrate and then a few hours later I take melatonin, but it still takes me a few hours to fall asleep. I used to have migraines almost every day, muscle spasms, and muscle twitches. After taking the magnesium citrate that has gone away. My muscles do hurt a lot though and my doctor is still running some blood test to see if this is fibromyalgia or some other autoimmune disease. I wish they made an all in one magnesium pill. I did read that magnesium glycinate is good for insomnia. Why is glycinate better for insomnia versus the citrate form? Will the glycinate also produce a laxative effect? Also, taking the citrate I cannot say that I see a huge difference in my muscle pain. My main concern is I don’t want to become constipated again changing the magnesium type. I really love the nature calm, I feel that it really works but I just can’t easily fall asleep like normal people. Can you please recommend to me what I can do and which one I should take, and how many milligrams is the safest dose for the day in which ever you recommend? Thank you very much and I look forward in hearing from you.

    1. Dr. Hrkal

      Hi Katerina,

      Thanks for your questions. Its sounds like you have a number of things you are still trying to figure out. Unfortunately, I can’t make treatment or diagnosis recommendations in this post but I can answer some of your questions.
      1) Mag glycinate can be better for sleep since the amino acid glycine has an added calming effect in the brain that complements magnesium. Glycine is a calming neurotransmitter.
      2) Mag glycinate can also keep your stools regular but since its absorbed better than citrate you may need to take more to get the same effect.
      3) A common dosage for mag glycinate is 200-400mg daily in divided doses.

      Note: Mineral supplements can interact with your thyroid meds so be sure to take them at different times of the day.

      I would suggest you consult a Naturopathic doctor to help identify some root causes of the insomnia and muscle pain. There are number of effective things that can be done for fibro and lo.

      I hope that helps

      Dr Paul Hrkal

  39. Joe

    Hello Dr Hrkal,

    My wife and I use mag daily and love it. We always opt for a chelate form. My wife is now 20 weeks pregnant. I have heard that Mag L-Theronate taken before bed can help with better sleep and cognition due to it’s ability to pass the blood brain barrier so quickly. Pregnany has caused some sleepless/anxious nights for my wife. I know most chelates are safe and are often recommended to help with muscle health and calcium absorption in pregnancy. Would there be any reason why Mag L-Theronate would be ill advised in pregnancy?

    Blessings,
    Joe

    1. Dr. Hrkal

      Hi Joe,

      Thanks for your question. You are correct that most chelates are safe however since Mag L-theronate is still a very new ingredient we don’t have much human safe data on it however it has been granted GRAS (generally recognized as safe) status by the FDA so I am confident in its safety for all ages. As an FYI, L-theronine is a metabolite of vitamin C which is definitely safe in pregnancy in low doses.

      Here the link
      http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-foods-gen/documents/document/ucm400322.pdf

      I hope that helps
      Dr Paul Hrkal

  40. Xena

    Hi
    I have 3 questions

    1) I am in my mid twenties and a longterm insomniac who sleeps 3 hours a day, before going to bed I suffer from high anxiety and muscle spams and restless leg syndrome which keeps me wide awake, which one would be the best to calm me down and get to sleep and how much (how many grams) shall I use to the optimum effect.

    2) is there any difference in using the magnesium oil vs the tablets and which one is better for my situation

    3) I have heard Magnesium works best when combined, there many on the market such as magnesium/calcium and Magnesium zinc again which one would be the best in my severe insomnia/ anxiety situation

    1. Dr. Hrkal

      Hi Xena,

      Thanks for the question. I can’t give you medical advise but I can answer some of your questions.
      1) Magnesium glycinate is a very relaxing form of mag that also has the benefit of glycine which is a calming amino acid. Follow the dose on the label but try taking a higher dose short term until you get loose stools and reduce from there.
      2) Oil is a topical application that can help sore muscles but its a not a good way to build up systemic levels if you deficient. Oral forms used for more than 4 months are needed.
      3) Cal/mag is a common supplement combo but we usually have enough calcium in our diets so I prefer magnesium by itself. I agree that restless legs, insomnia and muscle pain would benefit from all the minerals since they work synergistically together so I would also suggest a high potency multi (not a one a day – a good multi is at least 3 caps daily) along with your magnesium. Extra zinc could also be a good idea.

      I would suggest you see a Naturopathic doctor to help you address some roots causes of your insomnia. Somethings food sensitivities can cause inflammation, muscle spams and even insomnia.

      I hope that helps
      Paul Hrkal ND

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Understanding Different Types of Magnesium | Dr Nibber.

“At that time, the FDA publically called the testing method invalid.7”

The media will simply not call him on his bullshit!

By Dr. Mercola

New York’s Attorney General, Eric Schneiderman, has ordered GNC, Target, Walgreens, and Wal-Mart to immediately stop selling certain herbal supplements. The products include up to seven varieties — ginkgo biloba, St. John’s wort, ginseng, garlic, echinacea, saw palmetto, and valerian root – that reportedly were mislabeled or contained adulterated content.

While the products have already been pulled from shelves amidst what the Attorney General’s (AG) office called an “outrageous degree of adulteration,” there is a problem.

The test used to deem the herbal products adulterated is considered inadequate and unproven by experts, such that the results cannot be considered valid. I’m all for transparency and truth in labeling, but these supplements have been wrongfully targeted in what appears to be a carefully orchestrated attack or a horribly incompetent attempt to protect consumers.

This goes far beyond just damaging the reputation of businesses and products, class-action lawsuits are already underway, which could leave the NY Attorney General in a very vulnerable position with a lot of explaining to do.

Fewer Than Half of Supplements Tested Contained Ingredients Indicated on the Label, AG Study Claims

The study, which was commissioned by New York’s Attorney General, found that only 4 percent to 41 percent of the products tested contained DNA from the plant species listed on the label.

Some of the products contained none of the ingredient while others reportedly contained DNA from other plants.1 The products were tested up to five times each using a DNA barcoding technique, which is at the heart of the controversy over the results.

The AG’s office is requiring the companies to provide detailed information about the product manufacturers, evidence of analytical testing, detailed cGMP [current good manufacturing practice] procedures, and any adverse events reported, but to date the details of the AG’s study are unclear. The AG’s office has not released full study protocols or reports of analytical data.2 As Forbes reported:3

“[American Botanical Council chief science officer, Stefan Gafner, PhD], who also serves as technical director for the ABC-AHPA-NCNPR Botanical Adulterants Program, expressed surprise that the AG would issue such aggressive actions against major U.S. companies with just one round of research results from one investigator’s laboratory.

More detailed and published investigations by other researchers particularly with ginkgo products, seem to diverge from the results with the chain store product brands in New York.

‘At this moment, we have not seen any of the methodology details, so we can’t really comment on how well the tests were carried out, but the high percentage of supplements that did not contain the material indicated on the label definitely should make the investigators wonder just how accurate this approach is.'”

DNA Testing Is Unable to Identify Ingredients in Many Herbal Supplements

The AG’s investigation used DNA testing, which, according to The American Herbal Products Association (AHPA), is an “inadequate and unproven analytical method to test herbal supplement products.”

Not only is DNA barcoding an emerging technology that is seen by many in the scientific community as one that might one day play a complementary role in testing, but it has serious limitations when it comes to testing herbal supplements.

Namely, many herbal supplements contain herbal extracts, which have a loss or denaturation of DNA material during processing. The DNA barcoding test cannot, therefore, identify the ingredients accurately. AHPA President Michael McGuffin said:4

It appears that many, if not all, of the products the New York State Attorney General tested contained herbal extracts and this processing would likely disrupt or destroy the DNA…

If an herbal product manufacturer used this analysis, without any additional confirmation, to prove that an herbal extract is accurately identified, the U.S. Food and Drug Administration (FDA) would almost certainly dismiss this as inadequate to verify identity.”

In fact, in 2013, the New York Times5 reported on a similar study using DNA barcoding, which also found a sizable number of products tested did not include the product on the label.6 At that time, the FDA publically called the testing method invalid.7

While the FDA has used DNA barcoding to reveal some cases of fraud, such as that in mislabeled seafood, it does not use it for testing herbal supplements. Apparently, the reporter who wrote the 2013 New York Times story, Anahad O’Connor, was called by an AG prosecutor.

As NewHope360 reported,8 the author noted in a blog that the prosecutor “had read my article in the Times and was outraged that companies selling health products engaged in such large-scale fraud.”

Later in the blog, O’Connor writes: ‘I had no idea that the article had made an impression on law enforcement officials too – and I’m glad that they used their resources to root out what appeared to be a blatant case of consumer fraud.’

So it appears the New York Attorney General launched an investigation patterned after the one in 2013, even though the FDA already called the data invalid. Adding to the curiosity, NewHope360 reported:9

“[Frank Lampe, vice president for communications at the United Natural Products Alliance] said he wonders why those resources did not include a call to the FDA and why they appear to have used the Times story as a road map in their investigation. ‘It’s the question for the [New York] Attorney General: What motivated this?’ he said.”

This appears to be far more a case of politics and policy than one of public protection… the Attorney General even incorporated the views of legislators into his news release!

In response, the United Natural Products Alliance is collecting “large quantities” of the supplements cited in the Attorney General’s investigation and submitting them to certified botanical testing labs for analysis.

According to ABC News:10

“‘They will perform universally accepted methods and procedures to test the products and will independently report their findings, which will be made public,’ said Loren Israelsen, the group’s president. ‘We feel the most appropriate response to bad science is good science.'”

GNC Tests Show Products are Pure, Properly Labeled

GNC refuted the claims made by the New York State Attorney General and submitted both original test results and results of re-tests as evidence of purity and proper labeling of the supplements in question. It looks like Eric Schneiderman may soon be eating some crow, as the tests came back clean. NewHope360 reported:11

The retesting results clearly and conclusively demonstrate that the Company’s products are pure, properly labeled and in full compliance with all regulatory requirements.

…In performing its tests, GNC used only validated, widely used and generally accepted testing methodologies approved by standard setting bodies, including the United States Pharmacopeia, Association of Agricultural Chemists, British Pharmacopeia and European Pharmacopeia.

These are the non-profit scientific organizations that set standards for the identity, strength, quality, and purity of medicines, food ingredients, and dietary supplements manufactured, distributed and consumed worldwide.”

The re-test results were even reviewed by Robert Fish, who is described as an expert on FDA good manufacturing. He, too, confirmed their authenticity, stating:12

“…the products at issue were each manufactured in compliance with federal FDA requirements … the products contain the ingredients stated on the labels at the levels indicated on the labels … the products are not contaminated, and … the products are therefore not adulterated.”

Supplements Are Already Tightly Regulated

Pro-pharmaceutical spokesmen like Dr. Paul Offit and US Senator Dick Durbin have repeatedly stated that dietary supplements are unregulated and need stricter oversight due to the hazards they pose to your health. This is patently false, and you only have to look at the very first sentence on the Food and Drug Administration’s (FDA) website to settle that dispute.13 There, it plainly states:

“FDA regulates both finished dietary supplement products and dietary ingredients. FDA regulates dietary supplements under a different set of regulations than those covering ‘conventional’ foods and drug products. Under the Dietary Supplement Health and Education Act of 1994 (DSHEA):

  • The manufacturer of a dietary supplement or dietary ingredient is responsible for ensuring that the product is safe before it is marketed.
  • FDA is responsible for taking action against any unsafe dietary supplement product after it reaches the market.”

Back in the early 1990s, the FDA threatened the availability of dietary supplements to the point that consumers staged a massive revolt, which resulted in the Dietary Supplement Health and Education Act of 1994 (DSHEA). The law specifically protects your access to dietary supplements by classifying them as foods, not food additives or drugs, and it grandfathered in dietary supplements that were already in use as of 1994. Only novel ingredients introduced after October 15, 1994 are required to seek FDA approval, but the FDA can, and has, shut down supplement makers that do not meet these regulations.

This Isn’t a Matter of Safety…

An estimated 106,000 hospitalized patients die each year from drugs that, by medical standards, are properly prescribed and administered, and two million more suffer serious side effects. How does the safety of supplements compare?

  • In 2001, 84.6 percent of all substances implicated in fatal poisonings were pharmaceutical drugs, according to that year’s American Association of Poison Control Centers (AAPCC) report. This compares with 0.8 percent for all dietary supplements combined, even including substances such as dinitrophenol, a dangerous (and illegal) substance banned in 1938, as well as the central nervous system stimulant Ma Huang (Ephedra). ONE drug alone, the anti-asthma drug theophylline, which was responsible for 15 deaths that year, amounted to 66 percent more than all the available dietary supplements combined.
  • According to CDC mortality data for 2005, prescription drugs killed more than 33,500 people that year, second only to car accidents. That same year, the American Association of Poison Control Centers reported 27 deaths that were associated with dietary supplements (one of which was reportedly due to Ephedra; the herbal supplement banned the year before for being too dangerous. In 2005, low-dose Ephedra was also subsequently banned).
  • In 2011, it was reported that there are more than 487 times more adverse event reports for FDA-approved prescription drugs than there are for supplements, and 409 times more serious events for drugs than supplements.14

New York State Has a History of Anti-Supplement Legislation

In 2013, the New York State legislature revealed two bills that showed anti-supplement bias. The first, S3650, would create a system for reporting adverse events related to supplements (even though the FDA already collects them), and give the health commissioner the authority to ban supplements based on any risk they deemed to be “harmful.” The Alliance for Natural Health reported:15

This would undermine the hard-won national regulatory system for supplements under DSHEA, the Dietary Supplement Health and Education Act of 1994—which was enacted to encourage access to nutritional supplements. Creating a ‘negative’ list of supplements at the state level directly contradicts the process outlined by DSHEA and brings us one step closer to a system of approved vs. non-approved supplements.

Remember, supplements aren’t allowed to state their full therapeutic benefits lest they be considered a drug by the FDA. Since it is illegal for producers to cite benefits in any but the most vague terms, the analysis will necessarily be one-sided, and any risk, no matter how tiny, may be deemed sufficient to have the supplement banned. Note that the same rule isn’t applied to OTC drugs like acetaminophen, which every year is responsible for 100,000 calls to poison control centers, 56,000 emergency room visits, 26,000 hospitalizations, and more than 450 deaths from liver failure.”

The second bill, A.4700, would require sports supplement manufacturers and distributors to hand out pamphlets describing whether the product had been banned by sports leagues and whether there were negative adverse effects or known herb-drug interactions. However, the bill excludes supplements in liquid form and those that contain caffeine, which means those supplements that are sometimes deemed risky, like energy “shots,” would not be included.

Perhaps the NY Attorney General will reap what he has sowed, and end up paying the price for putting political motivations ahead of prioritizing real health issues facing citizens of his state.  The New Yorker may have shot a fatal blow at his job security in a piece titled, “How Not to Test a Dietary Supplement.

If you’d like to tell New York legislators to oppose these anti-supplement bills and question the lack of basic knowledge displayed by the NY Attorney General, you can do so here.

Transparency Is Important, But Integrity Is Required

Recalls for supplements attract attacks from those who would prefer to eliminate the supplement industry, as it’s seen as a threat to pharmaceuticals. But it’s not a fair game when the supplements are recalled due to no fault of their own, but rather due to flawed and inadequate testing. Then it’s a witch-hunt. The supplement industry would do well to be as transparent as possible in every aspect of their manufacturing.

There are certainly plenty of shady characters in every industry, and illegal acts occur across the board – including the supplement industry.   But there is a difference between compliance and enforcement, the fact that illegal supplements exist is not because more regulations are necessary when current regulations are not enforced.

From now on, my own products will have videos explaining the formulation and manufacturing processes used, and include video walk-throughs of the plant where my products are made. Below are two such videos. The first shows the RFI manufacturing facility, where many of my nutritional supplements are made. The second explains the Licaps (liquid capsule) technology, and why I’ve chosen this particular technology for my liquid supplements.

via NY Attorney General to Wipe Herbal Supplements from Shelves.

They were wrong again!

Major Shift In New Federal Dietary Guidelines Proposed.

Fat cells residing underneath skin could aid shield people against a wide variety of infections, a new study from the University of California, San Diego School of Medicine reports.Immune program responses seem to be partly influenced by the presence of fat cells beneath the surface of the skin.Dermal fat cells, known as adipocytes, had been thought to function in the physique just for storing energy, but this new analysis shows they also play a vital role in fighting off infections. The cells were located to generate antimicrobial peptides, capable to fight off bacteria and other invaders.

“It was thought that once the skin barrier was broken, it was completely the duty of circulating (white) blood cells like neutrophils and macrophages to safeguard us from receiving sepsis,” Richard Gallo, professor and chief of dermatology at UC San Diego School of Medicine, said.

As soon as an infection enters a wound, it takes time for white blood cells and other immune technique agents to mass in the impacted area. For the duration of this delay, adipocytes guard the body from microbial invaders, by releasing highly-productive anti-microbial agents.

The human immune method is highly complex, relying on numerous forms of cells to fight infections. Amongst the tools made use of by the human physique to remain healthy are neutrophils and monocytes, which attack and consume microbial invaders. Epithelial cells, which line organs, and mast cells, which play a part in allergies, are normally the 1st on the scene at the web page when an infection enters the body.

Mice had been infected with staphylococcus aureus, a bacteria which frequently causes skin and soft tissue infections in humans. Researchers located fat cells improved in each size and number at the web site of the infection, inside hours of exposure. Cathelicidin antimicrobial peptide (CAMP), a form of antimicrobial peptide (AMP), was developed by the dermal fat cells, partially defending the mice from infection. When researchers studied mice who have been unable to create sufficient quantities of AMPs, especially CAMP, they identified the rodents had been hugely-susceptible to infectious illness.

Obese human subjects examined by researchers had been discovered to have a greater concentration of CAMP in their bloodstream than those close to typical weight.

“The key is that we now know this aspect of the immune response puzzle. It opens excellent new solutions for study. For example, present drugs designed for use in diabetics may be effective to other individuals who have to have to increase this aspect of immunity,” Gallo stated in a press release.

Further tests will be required just before clinical development of new drugs primarily based on this study can begin.

Investigation of the part of subcutaneous fat on the immune method was detailed in the journal Science.

via Fat Cells Beneath Skin May Protect Against Infections.

You may soon be a Google search away from immediate access to professional medical advice. The search engine giant is testing a new feature that urges people Googling illnesses or symptoms to jump on a video call with a medical professional.

The finding was reported on Friday by Reddit user jasonahoule. When he typed “knee pain” into his Chrome app, a Google pop-up explaining the temporarily free video chat feature appeared atop his search results:

“Based on your search query, we think you are trying to understand a medical condition. Here you can find health care providers who you can visit with over video chat. All visit costs are covered by Google during this limited trial.”

google doctor

A screenshot of Reddit user jasonahoule’s phone.

In an emailed statement to The Huffington Post, Google confirmed that it is testing out the search feature.

“When you’re searching for basic health information — from conditions like insomnia or food poisoning — our goal is provide you with the most helpful information available,” a Google spokesperson told The Huffington Post. “We’re trying this new feature to see if it’s useful to people.”

Doctors using this service are able to prescribe medicine at their discretion, Google said. The company does not coordinate insurance coverage but patients can apply for reimbursements. All payments are made through Google Wallet.

To clarify, people have been able to connect to medical professionals using Google video chat since last November with the launch of Google Helpouts, a service that connects Google users to professionals of various sorts for a fee. What’s new here is that the feature now appears in Google Search for some people.

While the service is currently free for those who see it, you should expect that to change if it becomes a permanent feature. In Google Helpouts, professionals can decide what they wish to charge.

If permanently implemented by Google, the feature could stop some from diagnosing their own illnesses using only Internet research. A survey by Pew Research Center last year found that 35 percent of U.S. adults have gone online to self-diagnose a medical condition. And while 41 percent said that a medical professional eventually confirmed the diagnosis, 18 percent said a professional did not agree, and 35 percent did not seek a professional opinion at all.

This story has been updated with additional information from Google on the service.

Google Tests Out Feature To Protect You From Sketchy Online Diagnoses.

Walking may never become as trendy as CrossFit, as sexy as mud runs or as ego-boosting as Ironman races but for fitness experts who stress daily movement over workouts and an active lifestyle over weekends of warrior games, walking is a super star.

For author and scientist Katy Bowman, walking is a biological imperative like eating. In her book, “Move Your DNA: Restore Your Health Through Natural Movement,” she suggests there are movement nutrients, just like dietary nutrients, that the body needs.

“Walking is a superfood. It’s the defining movement of a human,” said Bowman, a biomechanist based in Ventura, California. “It’s a lot easier to get movement than it is to get exercise.”

Researchers say emerging evidence suggests that combined physical activity and inactivity may be more important for chronic disease risk than physical activity alone.

“Actively sedentary is a new category of people who are fit for one hour but sitting around the rest of the day,” Bowman said. “You can’t offset 10 hours of stillness with one hour of exercise.”

Last year researchers at the University of Texas School of Public Health asked 218 marathoners and half marathoners to report their training and sitting times. Median training time was 6.5 hours per week. Median total sitting time was eight to 10.75 hours per day, suggesting that recreational distance runners are simultaneously highly sedentary and highly active.

Leslie Sansone, creator of the “Walk at Home: Mix & Match Walk Blasters” DVD, said too many people believe that spending grueling hours at the gym is the only way to fitness.

“There’s this “Biggest Loser” idea out there that if you’re not throwing up and crying you’re not getting fit,” she said, referring to the popular television weight-loss show.

She added that a small study of non-obese men published in the journal Medicine & Science in Sports and Exercise by scientists at Indiana University suggests that three five-minute walks done throughout three hours of prolonged sitting reverses the harmful effects of prolonged sitting on arteries in the legs.

Three miles (5 kilometers) per hour is a good beginning, gradually working to 4 miles per hour, she said about walking.

Dr. Carol Ewing Garber, president of the American College of Sports Medicine (ACSM), notes that fitness-walking guidelines of 10,000 steps per day may be too much for many.

“About 7,500 steps may be more accurate,” she said, adding that current ACSM recommendations call for at least 150 minutes of activity each week.

Garber, a professor of movement sciences at Columbia University in New York, said research suggests that even one bout of exercise causes beneficial physiological effects.

But she concedes that walking does not do everything. It is less beneficial for bones than running, and for strength, it is better to lift weights.

“Still,” she said, “If you’re going to pick one thing, research says it should be walking.”

Walking is the superfood of fitness, experts say | Fox News.

How Much Money Does Your Doctor Get From Medical Companies?

 

 

Use this search tool to find out

 

Doctors received $3.5 billion from pharmaceutical companies and device makers over a five month period in 2013, according to figures the federal government released this week. The massive dataset includes 4.2 million individual payments made to physicians (including dentists) for things like meals, consulting fees and royalty payments for devices they have helped invent. The new data includes 360,000 doctors by name.

 

In the days leading up the release of the information, physician groups mobilized to argue that the data, which the 2010 Affordable Care Act mandates be disclosed, is incomplete and misleading. For their part, the Centers for Medicare and Medicaid Services, which oversaw the release, states that, “Just because there are financial ties doesn’t mean that anyone is doing anything wrong.” CMS withheld the names of the recipients on 40 percent of the payments over concerns about data quality.

 

Using the following tool, you can search for any physician in the database by last name and see any gifts, consulting fees, paid travel, or other payment he or she received between August and December of 2013.

 

Search for physicians by last name. You can further narrow it down by first name, city or state. Type three letters to get started.

 

Critics of this sort of disclosure are quick to point out that there are many positive benefits to relationships between drug and device companies, which produce new life-saving treatments every year, and the doctors who get those treatments to patients who need them. Meanwhile, some research suggests that even cursory relationships with industry do affect a doctor’s behavior.

 

Among those doctors who were identified, orthopedic surgeons were by far the most compensated. They account for 11 of the 18 physicians who received over $1 million over the five covered months in the data:

 

Name Specialty Location Amount
Stephen S Burkhart Orthopaedic Surgery San Antonio, TX $7,356,276
Chitranjan S. Ranawat Counselor New York, NY $3,994,022
Thomas S Thornhill Orthopaedic Surgery Boston, MA $3,921,410
Richard Scott Orthopaedic Surgery Boston, MA $3,849,711
Neal Selim Elattrache Sports Medicine Los Angeles, CA $2,413,281
Lawrence A Lynn Counselor Columbus, OH $2,338,790
Timothy A Chuter Surgical Critical Care San Francisco, CA $2,304,899
Roger P Jackson Orthopaedic Surgery of the Spine North Kansas City, MO $1,764,704
Steven B. Haas Orthopaedic Surgery New York, NY $1,752,797
John Satterfield Fordtran Counselor Dallas, TX $1,715,554
Richard Edward Jones Orthopaedic Surgery Dallas, TX $1,457,517
Regis William Haid JR. Neurological Surgery Atlanta, GA $1,252,971
Amar S. Ranawat Counselor New York, NY $1,216,534
Michael D. Ries Orthopaedic Surgery Carson City, NV $1,185,840
Douglas Edmund Padgett Counselor New York, NY $1,139,670
Carlos Jesus Lavernia Adult Reconstructive Orthopaedic Surgery Miami, FL $1,116,854
Roy W Sanders Orthopaedic Surgery Temple Terrace, FL $1,021,282
Thomas A Russell Orthopaedic Surgery Germantown, TN $1,017,736

 

While the reason for the prominence of orthopedic surgeons at the top of the list varies for each doctor, orthopedic surgery often involves cutting edge devices for things like knee and hip replacements, many of which are exceedingly expensive. In some cases, doctors are receiving thousands of dollars in royalties for these devices because they have a stake in the intellectual property rights. (This is separate from owning part a stake in the company itself, which is reported separately.)

 

The picture of which pharmaceutical company pays doctors the most is less clear because payments are often recorded under the name of the subsidiary company making the payment. DePuy Synthes, a subsidiary of Johnson & Johnson that manufactures orthopedic and neurosurgery devices, tops the list of companies making payments to doctors during the period with $34.5 million. Arthrex, Inc., a manufacturer of orthopedic surgical supplies, came in second with $15.5 million. Astra Zeneca and Pfizer are also among the top 10 with $15.3 million and $10.01 million respectively. This analysis does not include anonymized payments.

 

Company Total Payments State
DePuy Synthes Sales Inc. $34,542,816 Massachusetts
Arthrex, Inc. $15,506,504 Florida
AstraZeneca Pharmaceuticals LP $15,385,817 Deleware
Janssen Pharmaceuticals, Inc $13,778,926 Pennsylvania
Smith & Nephew, Inc. $12,020,808 Tennessee
Forest Laboratories, Inc. $10,398,208 California
Pfizer Inc. $10,017,632 New York
Allergan Inc. $9,709,723 California
Biomet, Inc. $9,675,365 Florida
Otsuka America Pharmaceutical, Inc. $9,238,383 Maryland

 

Of all payments, $109 million is documented as “compensation for services other than consulting, including serving as faculty or as a speaker at a venue other than a continuing education program.” Consulting fees accounted for $91 million. Food and beverages accounted for $57.4 million, and travel and lodging accounted for $45 million. Because the disclosures require that the location of travel be disclosures, we are able to build a picture of where companies like to fly doctors for conferences, speeches, meetings, and other events:

 

City No. of Payments Total Payments
Chicago 7098 $2,182,736
New York 5757 $2,100,144
Dallas 5453 $1,333,772
Atlanta 4087 $1,056,913
Miami 3081 $930,366
San Diego 2751 $717,280
San Francisco 2696 $1,022,034
Las Vegas 2503 $750,983
Philadelphia 2478 $597,493
Houston 2368 $623,391

Data that was withheld because of unresolved disputes will be published in future disclosures

How Much Money Does Your Doctor Get From Medical Companies? | TIME.

By Amy Norton
HealthDay Reporter

THURSDAY, July 31, 2014 (HealthDay News) — They may not have had fast food, TVs or cigarettes, but people of ancient times commonly developed clogged heart arteries — and a new research review speculates on some reasons why.

Using CT scans of mummified remains from ancient Egypt, Peru, the Aleutian Islands and the American Southwest, researchers have found evidence of widespread atherosclerosis — the hardening of heart arteries from fatty substances that build up, eventually leading to heart attack or stroke.

That’s despite the fact that those ancient groups were largely free of today’s perilous lifestyle factors, such as sugar- and fat-laden diets, inactivity, smoking and widespread obesity.

“Our team has evaluated mummies from five different continents. We have yet to find a culture that didn’t have atherosclerosis,” said cardiologist Dr. Gregory Thomas, the lead author of a review published in the current issue of the journal Global Heart.

So, what does that mean for modern times? “These days, we blame ourselves when we or someone in our family develops heart disease,” said Thomas, medical director of the Memorial Care Heart & Vascular Institute at Long Beach Memorial Medical Center in California.

“We say, ‘Well, if you’d just exercised more, you wouldn’t have needed that heart surgery,'” Thomas said. “I think people can stop blaming themselves so much.”

But before you hang up your running shoes and settle down with a bag of chips, Thomas also said that lifestyle still matters. “This doesn’t mean we should stop trying to control risk factors [for heart disease],” he stressed.

Just don’t expect to remain free of heart trouble simply because you jog every day or eat a healthier diet, Thomas said.

Based on what he and an international research team have seen, slightly more than a third of 76 Egyptian mummies had atherosclerosis — and so did a similar percentage of mummies from Peru, the U.S. Southwest and the Aleutian Islands, in the Northern Pacific.

They typically died in what would be considered middle-age today. “It seems like they developed atherosclerosis around the same time that we get it today,” Thomas said. So part of the explanation, he noted, may be age: If you live long enough, fatty deposits will start to build up in the arteries.

Genes are another major factor. “Genetics may account for about half of the risk of heart disease,” Thomas said. “We all have some genetic predisposition to atherosclerosis, regardless of culture or lifestyle.”

But the researchers also speculate about some environmental causes during ancient times. One is exposure to household smoke from cooking fires. Another is the host of infections people were constantly battling — from short-lived bacterial and viral infections, to lifelong parasitic ones.

Thomas explained that even when people managed to survive those ills, the body would be in a continual state of low-grade inflammation, which is part of the immune system’s response to invaders.

And that’s in line with what scientists today suspect: Chronic inflammation contributes to atherosclerosis.

It’s just that today, the primary causes of that inflammation may be different, said Dr. Suzanne Steinbaum, director of Women’s Heart Health at Lenox Hill Hospital in New York City.

Modern factors may include diet and sleep loss — but there could be a range of yet unknown contributors, according to Steinbaum, who was not involved in the new research.

“This study reminds us that we need to keep looking at aspects of modern life that could be contributing to inflammation,” Steinbaum said.

Thomas acknowledged that in Egypt, mummification was an elaborate and expensive process. So those remains would represent the upper class at the time — people who might have enjoyed indulgent diets and ample lounging time.

But Thomas said the remains from some other cultures likely represent the “common person” — such as the Aleutian hunter-gatherers, who probably did not spend much time lounging and eating.

 

No TV or obesity, but ancient people still had heart disease – FOX 29 News Philadelphia | WTXF-TV.

BY Daniela Hernandez, Kaiser Health News  June 2, 2014 at 11:47 AM EDT
Photo by Rebecca Emery/Getty Images

Photo by Rebecca Emery/Getty Images

Long Island dermatologist Kavita Mariwalla knows well how to treat acne, burns and rashes. But when a patient came in with a potentially disfiguring case of bullous pemphigoid—a rare skin condition that causes large, watery blisters—she was stumped.

The medication doctors usually prescribe for the autoimmune disorder wasn’t available. So she logged in to Modernizing Medicine, a Web-based repository of medical information and insights, for help.

Within seconds, she had the name of another drug that had worked in comparable cases.

“It gives you access to data, and data is king,” she said of Modernizing Medicine. “It’s been very helpful especially in clinically challenging situations.”

The system, one of a growing number of similar tools around the country, lets her tap into the collective knowledge of 4,000 providers and 13 million patients, as well as data on treatments other doctors provide patients with similar profiles. Then it spits out recommendations.

Tech titans like Google, Facebook, Microsoft and Apple already have made huge investments in artificial intelligence to deliver tailored search results and build virtual personal assistants. That approach is starting to trickle down into health care too, thanks in part to the push under the health reform law to leverage new technologies to improve outcomes and reduce costs, and to the availability of cheaper and more powerful computers.

Computers can’t replace doctors at the bedside, but they are capable of crunching vast amounts of data and identifying patterns humans can’t. Artificial intelligence can be a tool to take full advantage of electronic medical records, transforming them from mere e-filing cabinets into full-fledged doctors’ aides that can deliver clinically relevant, high-quality data in real time.

“Electronic health records [are] like large quarries where there’s lots of gold, and we’re just beginning to mine them,” said Dr. Eric Horvitz, who is the managing director of Microsoft Research and specializes in applying artificial intelligence in health care settings.

Increasingly, physician practices and hospitals around the country are using supercomputers and homegrown systems to identify patients who might be at risk for kidney failure, cardiac disease or postoperative infections and to prevent hospital readmissions, another key focus of health reform. Increasingly, physician practices and hospitals around the country are using supercomputers and homegrown systems to identify patients who might be at risk for kidney failure, cardiac disease or postoperative infections and to prevent hospital readmissions, another key focus of health reform.

And they’re starting to combine patients’ individual health data—including genetic information—with the wealth of material available in public databases, textbooks and journals to help come up with more personalized treatments.

For now, the recommendations from Modernizing Medicine are largely based on what is most popular among fellow professionals—say, how often doctors on the platform prescribe a given drug or order a particular lab test. But next month, the system will display data on patient outcomes that the company has collected from its subscribers over the past year. Doctors will also be able to double-check the information against the latest clinical research by querying Watson, IBM’s artificially intelligent supercomputer.

“What happens in the real world should be informed by what’s happening in the medical journals,” said Daniel Cane, CEO of Florida-based Modernizing Medicine. “That information needs to get to the provider at the point of care.”

‘Quick and Seamless’

Using homegrown systems, doctors at Vanderbilt University Medical Center in Nashville and St. Jude’s Medical Center in Memphis are getting pop-up notifications—not unlike those on an iPhone—within individual patients’ electronic medical records.

The alerts tell them, for instance, when a drug might not work for a patient with certain genetic traits. It shows up in bright yellow at the top of a doctor’s computer screen – hard to miss.

“With a single click, the doctor can prescribe another medication. It’s a very quick and seamless process,” said Vanderbilt’s Dr. Joshua Denny, one of the researchers who developed the system there.

Denny and others used e-medical records on 16,000 patients to help computers predict which patients were likely to need certain medications in the future.

Take the anti-blood clot medication Plavix. Some people can’t break it down. The Vanderbilt system warns doctors to give patients likely to need the medication a genetic test to see whether they can. If not, it gives physicians suggestions on alternative drugs.

Doctors heed the computer’s advice about two-thirds of the time, figuring in for example, the risks associated with the alternative medication.

“The algorithm is pretty good,” says Denny, referring to its ability to predict who’s going to need a certain drug. “It was smarter than my intuition.”

So far, computers have gotten really good at parsing so-called structured data—information that can easily fit in buckets, or categories. In health care, this data is often stored as billing codes or lab test values.

But this data doesn’t capture patients’ full-range of symptoms or even their treatments. Images, radiology reports and the notes doctors write about each patient can be more useful. That’s unstructured data, and computers are less savvy at handling it because it requires making inferences and a certain understanding of context and intent.

That’s the stuff humans are really good at doing — and it’s what scientists are trying to teach machines to do better.

“Computers are notoriously bad at understanding English,” said Peter Szolovits, the director of MIT’s Clinical Decision Making Group. “It’s a slow haul, but I’m still optimistic.”

Computers are getting better at reading unstructured information. Suppose a patient says he doesn’t smoke. His doctor checks ‘no ‘ in a box–structured data, easily captured by a machine.

But then the doctor notes that the patient’s teeth are discolored or that there are nicotine stains on his fingers— a clue that the patient in fact does smoke. Soon a computer may be able to highlight such discrepancies, bringing to the fore information that otherwise might have been overlooked.

In recent years, universities, tech companies and venture capital firms have invested millions into making computers better at analyzing images and words. Companies are popping up to capitalize on findings in studies suggesting that artificial intelligence can be used to improve care.

“Artificial intelligence–ultimately that’s where the biggest quality improvements will be made,” said Euan Thomson, a partner at venture capital firm Khosla Ventures.

But many challenges remain, experts say. Among them is the tremendous expense and difficulty of gaining access to high-quality data and of developing smart models and training them to pick up patterns.

Most electronic medical record-keeping systems aren’t compatible with each other. The data is often stored in servers at individual clinics or hospitals, making it difficult to build a comprehensive reservoir of medical information.

Moreover, the systems often aren’t hooked up to the Internet and therefore can’t be widely distributed or accessed like other information in the cloud. So, unlike the vast amount of data on Google and Facebook, the information can’t be mined from anywhere by those interested in analyzing it.

From the perspective of privacy advocates, this makes some good sense: A researcher’s treasure trove is a hacker’s playground.

“It’s not the greatest time to talk about” health records on the web, given security scandals such as the Edward Snowden leaks and the Heartbleed bug, said Dr. Russ Altman, the director of Stanford University’s biomedical informatics training program.

Drawing the line

Also standing in the way are concerns about how far computers should encroach on doctors’ turf. As artificial intelligence systems get smarter, experts say, the line between making recommendations and making decisions could become more murky. That could cause regulators to view the systems as a medical devices, subject to the review of the U.S. Food and Drug Administration.

Wary of the time and expense required for FDA approval, companies engineering the systems – at least for now– are careful not to describe them as diagnostic tools but rather as information banks.

“The FDA would be down on them like a ton of bricks because then they would be claiming to practice medicine,” says MIT’s Szolovits.

At the moment, he said, the technology isn’t good enough to tell doctors with 100 percent certainty what the best course of treatment for a patient may be. Others agree.

“It’s going to be a long road,” said Michael Matheny, a biostatistician at the Vanderbilt School of Medicine.

Back at her clinic in Long Island, Dr. Mariwalla is thankful for the information that the artificial intelligence system can provide.

For the patient with that blistering skin condition, she took the machine’s suggestion for an alternative medication. The patient has recovered, Mariwalla said.

But she’s careful to add that she made the call herself—based in part on her conversation with her patient.

“That’s where medical judgment comes in,” she said. “You can’t [just] rely on a system to tell you what to do.”


This story was produced in collaboration with Wired. Kaiser Health News is an editorially independent program of the Henry J. Kaiser Family Foundation, a nonprofit, nonpartisan health policy research and communication organization not affiliated with Kaiser Permanente.

Doctors turn to artificial intelligence when they’re stumped | The Rundown | PBS NewsHour.

 

Table 1

Persistence of clinically relevant bacteria on dry inanimate surfaces.
Type of bacterium Duration of persistence (range) Reference(s)

Acinetobacter spp. 3 days to 5 months [18, 25, 28, 29, 87, 88]
Bordetella pertussis 3 – 5 days [89, 90]
Campylobacter jejuni up to 6 days [91]
Clostridium difficile (spores) 5 months [92–94]
Chlamydia pneumoniae, C. trachomatis ≤ 30 hours [14, 95]
Chlamydia psittaci 15 days [90]
Corynebacterium diphtheriae 7 days – 6 months [90, 96]
Corynebacterium pseudotuberculosis 1–8 days [21]
Escherichia coli 1.5 hours – 16 months [12, 16, 17, 22, 28, 52, 90, 97–99]
Enterococcus spp. including VRE and VSE 5 days – 4 months [9, 26, 28, 100, 101]
Haemophilus influenzae 12 days [90]
Helicobacter pylori ≤ 90 minutes [23]
Klebsiella spp. 2 hours to > 30 months [12, 16, 28, 52, 90]
Listeria spp. 1 day – months [15, 90, 102]
Mycobacterium bovis > 2 months [13, 90]
Mycobacterium tuberculosis 1 day – 4 months [30, 90]
Neisseria gonorrhoeae 1 – 3 days [24, 27, 90]
Proteus vulgaris 1 – 2 days [90]
Pseudomonas aeruginosa 6 hours – 16 months; on dry floor: 5 weeks [12, 16, 28, 52, 99, 103, 104]
Salmonella typhi 6 hours – 4 weeks [90]
Salmonella typhimurium 10 days – 4.2 years [15, 90, 105]
Salmonella spp. 1 day [52]
Serratia marcescens 3 days – 2 months; on dry floor: 5 weeks [12, 90]
Shigella spp. 2 days – 5 months [90, 106, 107]
Staphylococcus aureus, including MRSA 7 days – 7 months [9, 10, 16, 52, 99, 108]
Streptococcus pneumoniae 1 – 20 days [90]
Streptococcus pyogenes 3 days – 6.5 months [90]
Vibrio cholerae 1 – 7 days [90, 109]

Kramer et al. BMC Infectious Diseases 2006 6:130   doi:10.1186/1471-2334-6-130

Overall, gram-negative bacteria have been described to persist longer than gram-positive bacteria [12,13]. Humid conditions improved persistence for most types of bacteria, such as Chlamydia trachomatis [14], Listeria monocytogenes [15], Salmonella typhimurium [15], Pseudomonas aeruginosa [16], Escherichia coli [17], or other relevant pathogens [18,19]. Only Staphylococcus aureus was found to persist longer at low humidity [16].

Low temperatures, e.g., 4°C or 6°C, also improved persistence of most types of bacteria, such Listeria monocytogenes [15], Salmonella typhimurium [15], MRSA [20], corynebacteria [21], Escherichia coli [17,22], Helicobacter pylori [23], and Neisseria gonorrhoeae [24].

The type of test material does not reveal a consistent result. Although some investigators report that the type of material has no influence on the persistence [25,26], other authors described a longer persistence on plastic [27,28], and others yet see a survival advantage on steel [29].

Other factors were rarely investigated and hence provide inconsistent results. Longer persistence has been described with higher inocula [28], in the presence of protein [13], serum [13,24], sputum [30], or without dust [10].

Persistence of clinically relevant fungi on dry inanimate surfaces.
Type of fungus Duration of persistence (range) Reference(s)

Candida albicans 1 – 120 days [31, 53, 99, 110]
Candida parapsilosis 14 days [110]
Torulopsis glabrata 102 – 150 days [31]

Kramer et al. BMC Infectious Diseases 2006 6:130   doi:10.1186/1471-2334-6-130

 

 

Table 3

Persistence of clinically relevant viruses on dry inanimate surfaces.
Type of virus Duration of persistence (range) Source

Adenovirus 7 days – 3 months [32, 34, 38–41, 111]
Astrovirus 7 – 90 days [38]
Coronavirus 3 hours [112, 113]
SARS associated virus 72 – 96 hours [114]
Coxsackie virus > 2 weeks [34, 111]
Cytomegalovirus 8 hours [115]
Echovirus 7 days [39]
HAV 2 hours – 60 days [35, 38, 41]
HBV > 1 week [116]
HIV > 7 days [117–119]
Herpes simplex virus, type 1 and 2 4.5 hours – 8 weeks [34, 111, 118, 120]
Influenza virus 1 – 2 days [39, 43, 121, 122]
Norovirus and feline calici virus (FCV) 8 hours – 7 days [42, 45]
Papillomavirus 16 > 7 days [123]
Papovavirus 8 days [118]
Parvovirus > 1 year [118]
Poliovirus type 1 4 hours – < 8 days [35, 118]
Poliovirus type 2 1 day – 8 weeks [34, 38, 111]
Pseudorabies virus ≥ 7 days [124]
Respiratory syncytial virus up to 6 hours [44]
Rhinovirus 2 hours – 7 days [33, 125]
Rotavirus 6 – 60 days [36 – 38, 41]
Vacciniavirus 3 weeks – > 20 weeks [34, 126]

Kramer et al. BMC Infectious Diseases 2006 6:130   doi:10.1186/1471-2334-6-130

 

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Pre-publication history

The pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1471-2334/6/130/prepub

BMC Infectious Diseases | Full text | How long do nosocomial pathogens persist on inanimate surfaces? A systematic review.

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“In earlier times, they had no statistics, and so they had to fall back on lies.”
-Original author unknown

Hey everyone,

Last time we spoke, I promised my next article would discuss the type of diet that’s been shown in clinical trials to reduce cardiovascular mortality. However, something else has crossed my desk that I need to comment on pronto.

As a result, this article is going to be about a type of eating pattern that, despite all the lavish claims made for it, has never been shown to reduce CVD mortality in clinical trials. In fact this style of eating, despite the reigning propaganda, has never been shown to reduce death from any cause.

I’m talking, dear readers, about vegetarianism.

An EPIC Wank

Late last year a big ballyhoo was made about an analysis of the large EPIC-Oxford epidemiological study in England that compared cardiovascular outcomes in those who called themselves vegetarians with those who did not. As I explained in this article, an earlier analysis of the EPIC-Oxford cohort found no reduction in cardiovascular mortality among vegetarians. It did, however, find that overall mortality was slightly albeit non-statistically significantly higher among this group. For some strange reason, this study attracted very little attention from the media.

Not content with these uninspiring results, the EPIC researchers – two of whom belong to organizations whose express purpose is to promote vegetarianism – decided to conduct another analysis, this time combining both fatal and non-fatal cardiovascular outcomes. Analysing each of these outcomes alone had failed to produce any kind of statistically significant risk reduction, but using the old trick of combining endpoints finally produced a result that could be used to further the vegetarian cause. The researchers promptly drafted another paper completely ignoring the previous unfavourable all-cause mortality results, instead gushing on about the “reduced risk” of combined fatal and non-fatal heart disease. Media outlets all around the world quickly proceeded to insult our intelligence with headlines such as “Vegetarian diets reduce heart disease risk by a third.”

Hmmm, I guess they never received any glowing press releases for the previous EPIC paper showing no reduction in CVD mortality, a higher rate of colorectal cancer, and a slightly higher rate of overall mortality among vegetarians. And I guess no-one ever explained to them that the only reason vegetarians enjoyed any reduction in CVD was their significantly younger mean age, their lower rate of smoking, and higher rates of exercise.

Funny that.

I debunked that study here, and explained why vegetarian diets are more likely to promote rather than prevent cardiovascular disease. Today, I’m going to dismantle another audaciously misleading pro-vegetarian paper.

When Religion Combines with Diet Dogma – Literally

So let’s leave the UK, and travel over to the US where there resides another group of researchers conducting a large-scale epidemiological comparison of vegetarians and omnivores.

The population being studied is comprised of Seventh Day Adventists, a religious denomination that advises its members to follow a vegetarian diet. From all accounts, this admonition is not administered with quite the same vigour as, say, the Jewish and Muslin proscriptions against pork. And so not all Adventists follow a truly vegetarian diet, allowing researchers to follow what would appear to be a relatively homogenous population consuming various levels of animal products.

This page contains “The Seventh-day Adventist Position Statement on Vegetarian Diets”, and states:

“The vegetarian diet recommended by Seventh-day Adventists includes the generous use of whole grain breads, cereals and pastas, a liberal use of fresh vegetables and fruits, a moderate use of legumes, nuts, seeds. It can also include low fat dairy products such as milk, yogurt and cheeses and eggs.   It is best to avoid high saturated fat and cholesterol foods such as: beef, lamb, pork, chicken, fish and seafood.  Coffee, tea and alcoholic beverages provide few nutrients and may interfere with the absorption of essential nutrients.”

It goes on to claim:

“Vegetarians have reduced risks of certain diseases because of their increased consumption of whole grains, dried beans, nuts, fresh and dried fruits, and vegetables.  Vegetarians are exposed to fewer carcinogens and mutagens because they do not eat meat.”

Here’s the truth: There exists no reliable evidence whatsoever that avoidance of meat reduces the incidence of cancer nor any other disease. As for the 7DA proscription against tea and coffee, both are antioxidant-rich beverages that show little evidence of harm when consumed in sensible amounts. Heck, even epidemiologists struggle to find harmful associations between tea, coffee and health and mortality outcomes; quite the opposite, in fact[1].

It’s also most ironic that whoever drafted this position statement criticizes tea and coffee for their alleged nutrient-inhibiting effects when whole-grains contain a plethora of what researchers refer to as anti-nutrients, which have been well documented to inhibit the absorption or production of such critical nutrients as zinc, magnesium, calcium, selenium, and vitamins B6 and D. Unlike tea, which clinical trials indicate is a most health-enhancing beverage, controlled trials have repeatedly shown increased whole-grain consumption to produce negative health outcomes.

Hmmm. A religious organization making claims with no foundation in sound science. Gee, who would’ve thought?

As to why the 7DA religion settled on this eating style in the first instance:

“For more than 130 years Seventh-day Adventists (SDAs) have practiced a vegetarian dietary lifestyle because of their belief in the holistic nature of humankind. Whatever is done in eating or drinking should honor and glorify God and preserve the health of the body, mind and spirit.”

I’ll leave aside the fact that after thousands of years, none of the worshippers of the various “Gods” has been able to provide anything resembling proof for the existence of said Gods. And therefore that eating or drinking with the goal of “honouring” and “glorifying” any of these Gods might not be the most intelligent way to determine one’s eating patterns.

Elvis_sacred_heart_of_elvis
Some people worship Elvis. You might think that’s strange, but at least they can prove he existed LOL

Nope, I won’t bang on about that because, ultimately, people are free to believe whatever they want. If you want to believe in virgin births, resurrections from the dead, or that a bunch of invisible goblins lives under your kitchen table, then good for you. Ditto if you choose to believe avoiding meat somehow affirms the “holistic nature of humankind”, despite the fact that Paleolithic humans – who didn’t just talk the talk but really did live in harmony with nature (like they had a choice) – ate meat on a very regular basis with remarkable evolutionary success for some 2.4 million years.

As anyone who has studied both Paleontology and the history of vegetarianism will know, the latter was quite literally born out of religion. Archaeological evidence, along with observation of surviving hunter-gatherer societies, invariably indicates animal flesh (especially fat-rich animal flesh) was an important and highly valued component of the human diet. It wasn’t until Homo sapiens moved from a nomadic hunter-gatherer existence to a sedentary agrarian lifestyle that they had the time to sit around, gaze at their navel, and dream up concepts such as “non-violent” food acquisition. The first ‘enlightened’ thinkers that came up with this concept were probably written off as a bunch of soft-cocks by their hardy peers, but vegetarian ideologies eventually gained traction, especially when the ruling classes realized the potential advantages to be conferred by forbidding meat consumption in areas where grain cultivation was a much less ecologically expensive method for sustaining rapidly expanding populations.

Those who want to explore this phenomenon further are highly advised to consult the outstanding Cannibals and Kings by Dr Marvin Harris. My goal here is to simply point out that vegetarianism came into being as an ideology among sedentary, agrarian ‘thinkers’. Thousands of years later and little has changed. Vegetarianism is still an ideology with no foundation in anything resembling sound science.

Which would be all fine and dandy if the promoters of vegetarianism stuck to their theoretical ethical musings and made no pretence about the healthfulness of their diet being supported by sound science.

Which in turn brings up a second important point about vegetarianism. It was born from theories about “peaceful” food acquisition and non-violence towards animals which, no matter how admirable their intent, can hardly be considered end-products of the scientific method. Claims for the alleged health benefits of vegetarianism came later. And the science for that came much, much later again.

I’ll repeat: The ideology came first, the science came after.

My long-time readers will be familiar with how this works (think cholesterol hypothesis of heart disease): A theory is constructed based on someone’s interesting but unfounded ideas. The theory holds appeal but the supportive scientific evidence is lacking so researchers go about amassing it after the fact. Instead of testing the hypothesis with ruthless impartiality, the subsequent research is constructed and interpreted in a manner that will support the pre-existing beliefs.

By now you should be starting to see where I’m heading with all this. It’s hardly a secret the Seventh Day Adventist religion has a bias towards vegetarian eating. It makes claims about this style of eating which are of questionable veracity, but when challenged can cite scientific research that supposedly proves its vegetarian exhortations are backed by more than religious commandment.

But guess what?

The same studies examining Adventists and claiming beneficial findings for vegetarian diets are also conducted by Adventists. Specifically, the team of researchers housed in the “Adventist Health Studies” department in the School of Public Health at Loma Linda University.

Loma Linda is home to one of the largest 7DA congregations in the world, and the university is owned by the 7DA church. This university has treated us to a string of papers over the years, many hailing the risk reductions in death and disease that allegedly accompany a vegetarian diet.

Given the longstanding and well documented concerns arising from research conducted by individuals with a vested interest in the results, I’d say a very strong dose of scepticism is warranted when analysing their papers.

Before we take a look at the most recent paper from this team, let’s take a quick look at some of their Greatest Hits from the 70s, 80s, and 90s.

C’mon Baby Lay Your Stats on Me

In 1975, the Loma Linda researchers presented mortality data from over 35,000 Seventh-Day Adventists whom they monitored during the period 1958-1965. Sure enough, this group showed reduced rates of mortality from a number of cancers, but many of these were readily explained by a lower prevalence of smoking and alcohol consumption. Furthermore, the incidence of prostate cancer, which is typically attributed to the consumption of high fat animal foods, was similar between Adventists and non-Adventists.

In addition, recent converts showed a lower risk of breast and colon cancer than life-time Adventists. If animal foods truly contributed to such malignancies then the opposite should have been evident; risk should have declined with increasing length of time as a practicing Adventist.

It has long been recognized that, within populations, individuals from higher socioeconomic backgrounds with higher educational qualifications tend to experience lower rates of various degenerative illnesses than less-educated folks of lower socioeconomic standing. Because Seventh-Day Adventists were generally higher educated than average, the researchers also compared the cancer and all-cause death rates of Adventist and non-Adventist physicians, two groups with very similar educational and career status. They examined the incidence of mortality among over 6,000 medical practitioners who graduated between 1901 and 1971 from Loma Linda University (where over 75% of the graduates were Adventists) and the University of Southern California (where less than 5% of graduates were Adventists).

As expected, the death rate among physicians was lower than the general population, but the “startling” finding was that there was little difference in the rate of cancer or all-cause mortality among the two groups. In fact, the Loma Linda graduates showed a trend towards higher rates of gastro-intestinal and colon cancers, again contradicting prevailing beliefs about the role of animal foods in cancer promotion.

Finally, the researchers examined the relationship between diet and the incidence of colon and breast cancer within the Adventist population itself. Adventists with colon cancer were found to consume more meat, fish and cheese, seemingly supportive of the vegetarian hypothesis. However, colon cancer patients also ate significantly more highly-processed and nutrient-depleted fodder such as ice cream, fried potatoes, fried foods, cakes, and pies. The patients also ingested less green leafy vegetables than cancer-free Adventists. In other words, it was the overall dietary pattern of these patients – one featuring a higher proportion of refined junk – that was associated with colon cancer, not simply the presence of animal foods. Indeed, when the researchers examined the role of each food in isolation, the association between meat, fish and colon cancer disappeared[2].

Consider also a more recent study of over 34,000 Californian Seventh-Day Adventists, published in 1999, which found that vegetarians had lower risks of hypertension, diabetes, arthritis, colon cancer, prostate cancer, fatal CHD in males, and death from all causes. Again, vegetarians displayed a number of healthful dietary habits unrelated to meat intake that were not shared by their omnivorous brethren. Vegetarians consumed more tomatoes, nuts, and fruit, but less donuts than non-vegetarians. Non-vegetarian Seventh-Day Adventists also consumed alcoholic beverages twenty times more frequently than their vegetarian counterparts[3].

As with the earlier study of Adventists published in 1975, these observations clearly showed that those who shunned meat also adopted other dietary measures that protected their health.

Before we discuss more Loma Linda findings, let’s catch another flight, this time over to Norway to check out some research on 7DAs conducted by non-7DA researchers at the University of Tromso.

They studied the mortality pattern of SDAs in the Netherlands during the period 1968-1977. Standardized Mortality Ratios for total mortality, cancer and cardiovascular diseases were significantly lower than for the total Dutch population. Mean age at death as well as life-expectation at baptism were significantly higher in SDAs, both in males and females, compared with Dutch males and females.

To try and find out why, the researchers administered a health survey among a sample of the SDAs population and a group of “friend controls”.

These researchers, who presumably had little incentive to prop up the vegetarian sham, concluded that abstinence from cigarette smoking was likely the main factor explaining the low mortality from ischaemic heart diseases among SDAs, while “presumably an appropriate (prudent) diet confers additional benefit for example on colon cancer mortality”[4].

Notice the emphasis on smoking, and also note how they refer to a “prudent” diet, rather than a vegetarian diet.

In a later study by the same department, little difference in cancer incidence was found between 7DAs and the general population. Total mortality was significantly lower only in 7DA men, especially cardiovascular mortality. They found entering the church at an early age had a large effect on later mortality. They concluded “An early establishment of a healthy lifestyle seems to be of decisive importance in the risk of later disease.”[5]

Notice the emphasis on a “healthy lifestyle”, as opposed to diet.

Ok, now back to California. In their earlier reports, the Loma Linda researchers occasionally dropped their guard and also presented findings supporting the thesis that an overall healthier lifestyle rather than a vegetarian diet was what really explained any lower incidence of disease and mortality.

A 1984 paper, for example, reported lower breast cancer mortality among 7DA women. But, in the researchers own words: “The differences, however, were no longer significant when stage at diagnosis was taken into account. It seems likely that the lower breast cancer death rates reported among Seventh-day Adventist women as compared with the general population result in part from better survival patterns due to earlier diagnosis and treatment.”[6]

Gary E. Fraser, a prominent member of the Loma Linda pro-vegetarian research team, wrote in 1988:

“The lower risk for IHD [ischaemic/coronary heart disease] in Adventist men, at least, is probably related to their dietary habits, nonsmoking status, possibly their better exercise habits, and greater social support.”[7]

That’s a lot closer to the truth than some of his more recent conclusions, but let me re-word the above sentence so that it’s even more in accord with valid science:

“The lower risk for IHD in Adventist men has nothing to do with avoidance of meat, but everything to do with their far lower rates of smoking, greater participation in exercise, maintenance of a lower BMI, and quite possibly the stress-buffering effects of greater social support.”

The following year, Fraser and his colleagues published a paper examining prostate cancer risk among some 14,000 Seventh-day Adventist men who completed a detailed lifestyle questionnaire in 1976 and who were monitored for cancer incidence until the end of 1982. Now, before I relay their findings, remember that meat and animal fats are incessantly blamed for causing prostate cancer.

So what did they find?

–“Increasing educational attainment was associated with significantly decreased risk of prostate cancer in this study.”  Nothing to do with diet, obviously.

–“age at first marriage was also inversely associated with risk, although this was not significant” (and also totally unrelated to diet).

–“A history of prostate “trouble” was associated with a 60% increase in risk which was highly significant.”

–“Although there were suggestive relationships between increasing animal product consumption and increased risk, these results did not persist after accounting for the influence of fruit and vegetable consumption. Nor was exposure to the vegetarian lifestyle during the childhood years associated with alterations in subsequent risk. However, increasing consumption of beans, lentils and peas, tomatoes, raisin, dates, and other dried fruit were all associated with significantly decreased prostate cancer risk.”

That same year they also examined the link between diet and breast cancer. They found:

“Age at first live birth, maternal history of breast cancer, age at menopause, educational attainment, and obesity were all significantly related to risk. However, increasing consumption of high fat animal products was not associated with increased risk of breast cancer in a consistent fashion. Nor were childhood and early teenage dietary habits (vegetarian versus nonvegetarian) related to subsequent, adult risk of developing breast cancer. Also, a derived index of percent of calories from animal fat in the adult years was not significantly related to risk. These results persisted after simultaneously controlling for other, potentially confounding variables, utilizing Cox proportional hazard regression models.”[8]

In other words, in these studies consumption of animal foods and SFA (Saturated Fatty Acids) had SFA to do with the likelihood of getting prostate or breast cancer. It was other health and lifestyle characteristics that explained the difference.

Another paper from 1988 is worth mentioning here. It also found a similar lack of risk from animal foods and breast cancer mortality, but a look at the relative risks is good for a chuckle:

“Odds ratios of 1.00, 1.22, and 1.03 were observed for meat consumption categories of none or occasional, 1-3 days/week, and 4+ days/week, respectively.”[9]

If we’re to take this epidemiological pap seriously, then avoidance of meat, milk, cheese, and eggs confers zero increase in fatal breast cancer risk, rises by 22% in relative terms with consumption 1-3 days/week, but then pretty much returns to zero with consumption 4 or more days/week.

Yeah, that makes sense…

A little later, in 1994, the researchers found no difference in cancer incidence between 7DA and non-7DA, except for endometrial cancer which was significantly higher among 7DA women. Overall cancer mortality was lower in 7DA men, with the exception of prostate cancer, which was significantly higher[10]. If we’re to attribute the lower cancer incidence of 7DA men to diet, then it’s only fair we also ascribe the higher incidence of prostate cancer to their eating habits.

Personally I think all this epidemiology is a load of confounder-prone bollocks, and I’m not prepared to ascribe jack to jack until a little later when we look at the RCT data.

For now, let’s jump forward to the present, and check out the paper the Loma Linda researchers published earlier this year. While it didn’t get quite the same level of coverage as the EPIC paper from last year, this paper was still awarded misleading headlines from unthinking journalists, including these gems:

“Vegetarian diet may reduce risk of early death” – CBS News

“Lower risk of death is associated with vegetarian diets” – Examiner.com

“Are vegetarian diets secret to long life? People who avoid meat have better health due to lower blood pressure” – Daily Mail UK

Holy beefsteak, Batman.

My dear readers, I have a dream…that our children will one day live in a world where the media forbids health and nutrition stories to be written by anyone other than those who have a clue about health and nutrition and also know how to impartially read and pick apart a scientific paper.

Because as it stands, most journalists who write diet and health articles don’t have the first clue about diet and health, nor do they even bother to read the studies they report on. Instead they rely on the hyperbolic press release issued by the research team or the medical journal in question. If they need further information to pad out their article, instead of doing their own research they’ll simply contact the head researcher for a bunch of quotable quotes.

mr_nonsense
While this journalistic cluelessness makes life a lot easier for purveyors of dietary disinformation, it sucks massively for all those who would like their dietary information to be of the factual, scientifically valid, non-BS variety.

And make no mistake: The claims made for the latest study out of Loma Linda are complete BS.

The Bizzarro World of Statistics: When a Lower Risk of Mortality is a Higher Risk of Mortality.

This most recent 7DA paper, published in the JAMA Internal Medicine on June 3, reported on 73,308 participants from the Adventist Health Study 2 (AHS-2) who, based on their questionnaire responses, were categorized into 5 dietary patterns: nonvegetarian, semi-vegetarian, pescovegetarian, lacto-ovo–vegetarian, and vegan[11].

The researchers claim:

“The adjusted hazard ratio (HR) for all-cause mortality in all vegetarians combined vs nonvegetarians was 0.88…The adjusted HR for all-cause mortality in vegans was 0.85…in lacto-ovo–vegetarians, 0.91…in pesco-vegetarians, 0.81…and in semi-vegetarians, 0.92 compared with nonvegetarians. Significant associations with vegetarian diets were detected for cardiovascular mortality, noncardiovascular noncancer mortality, renal mortality, and endocrine mortality.” (All these findings statistically significant at 95% confidence interval).

You’ll note their repeated use of the word “adjusted”; we’ll explore the significance of this in a moment.

In the meantime, this study has so many flaws it’s hard to know where to start.

I could elaborate on what a joke it is to claim ‘significance’ for a 12% risk reduction from a confounder-prone epidemiological study (in randomized controlled clinical trials, such miniscule RRs are routinely dismissed as too weak to get excited over, and we’re talking studies with far less confounding than the epidemiological slop being served up to us by the Loma Linda team).

I could also elaborate on the sheer stupidity inherent in the term “pescovegetarian”. Let’s get something straight – if you eat fish, you ain’t no vegetarian. If you’re going to stick with this high and mighty moral routine that forbids the killing of livin