Ultralinx “This neat bit of equipment has been made to make video camera footage from devices like a phone, point-and-shoot, Micro Four Thirds and DSLR’s a lot more stable and smoother.”
Bit Rebels “This is a great solution that deserves some recognition from both the industry as a whole as well as individual consumers.”
If you have ever shot video before, you have probably thought: How do I get professional-looking footage that is smooth and stable? How do I get that gliding, floating camera look, and how do I stop shooting shaky amateur-looking footage that gives viewers a headache?
What do the pros do?
Pros use a camera stabilizer; a device that is very expensive and frustratingly hard to use. The pro stabilizers are bulky and heavy, and require training and lots of practice to master. They take forever to set up and balance. On top of that, they don’t work with smaller/lighter cameras because they are designed for heavier/larger pro cameras.
This is where the Picosteady comes in
We set out to design a stabilizer that we could use to shoot professional-looking footage with a wide range of cameras : DSLR cameras, point-and-shoot cameras, GoPro cameras, iphones or any smartphone.
More on the Picosteady:
– You will start using it minutes after you take it out of the box. Just mount your camera, balance it with the simple counterweights and you are ready to shoot.
– It will work with almost any camera including: point-and-shoot cameras, GoPro cameras, the iPhone, and most smartphones. It also works great with DSLR’s like the Canon T2i or Nikon D5100.
– The standard 1/4-20 thumbscrew will allow you to mount most cameras and the included universal smartphone holder will allow you to use the Picosteady with any smartphone or iPhone.
– Its ultra light weight (6.5 oz/180 g) and very compact size (5″ x 6.5″) means you’ll actually carry it with you, greatly improving any footage you shoot, from home video to amateur film.
– It’s affordable. It will retail at $179 (right now, it is available for kickstarters at a lower price of $139).
– It will last a very long time and handle the abuse thanks to its solid construction. We selected quality materials such as high grade aluminum and solid brass to ensure long-term durability. The balancer arm is laser cut and powdercoated.
– It is made and assembled here in the USA.
How do I use the Picosteady with an iPhone or smartphone?
The Picosteady comes standard with an universal iPhone/smartphone mount. If you only want to use your iPhone 4/4S, you can choose to upgrade to the Glif for an extra $15.
Why is the Picosteady on Kickstarter?
We have spent countless hours and a large chunk of money designing, making and testing lots of prototypes. After 10 months of evening and week-end work, we have completed the final design.
We now need funding to help us make the Picosteady a reality. We need to pay for the bulk purchases of materials and order a first production run of 100 units. This will make it possible to keep the price low and to have them manufactured here in the USA.
The Picosteady is made of custom-made parts and off-the-shelf hardware. We have already purchased and received a large portion of the off-the-shelf hardware.
We have also been in touch with several machine shops for the manufacturing of the custom parts. We have quotes in hand, production schedules and contingency plans in case of delays. Karim has extensive experience with manufacturing and existing business relationships with 2 machine shops, which will ensure we are not put on the back-burner when the time comes to place our orders.
We have completed the design and prototyping. We will outsource production and finishing of the custom-made assembly components to machine shops. We will assemble the Picosteady ourselves.
By pledging today, you are pre-ordering a Picosteady from the first production run and making sure to be among the first people to own one. You are also locking in the lower Kickstarter price of $139. If you are among the first 25 people to pre-order a Picosteady, we will even ship yours for free (USA and Canada).
Thank you so much for being a part of this project!
Please share with your family, friends and fellow amateur film makers!
On average, 90,000 people are missing in the USA at any given time, according to Todd Matthews from the National Missing and Unidentified Persons System, or NamUs, a national database for missing people.
“The first 12-24 hours are the most critical in an active missing persons investigation,” Amy Dobbs, an investigator with the Knox County Sheriff’s Office, told USA TODAY Network. “The longer it takes for a case to be reported and become an active investigation, the less likely a positive outcome will occur.”
If someone you know is missing, call 911 and report it as quickly as possible, Dobbs said. There is no mandatory time period that you need to wait to file a missing persons report. You can also report the missing person to NamUs, which will verify the information with law enforcement and list it on the NamUs site.
Photo: Romance novelist Bella Andre earns eight figures as an independent writer.
In early 2010, things weren’t going very well for San Francisco-based romance novelist Bella Andre. Brick-and-mortar bookstores were shutting down in large numbers, and after seven years, eight books and two publishers, she learned she had been axed from her latest contract.
“I was hanging on by my fingernails,” says Andre, 41, who was trying to carve out a niche in contemporary romance. Peers advised her to try a different pen name, to change genres, to write anything but love stories. With a degree in economics from Stanford University and a background in music, she wasn’t short on career options.
Then a friend suggested she look into self-publishing. At the time, Amazon.com’s (AMZN) direct publishing platform, which allows just about anyone to publish and sell their books online, was beginning to gain traction among professional writers. After years of bending her stories to the will and opinions of publishers, editors and literary agents, Andre found the prospect of having complete autonomy over her material very appealing.
“As an author, I was not high up on the publishing food chain and [my ideas] were rarely ever listened to,” she says. “I took my friend’s advice and I dove right into self-publishing.”
Source: Bella Andre
Her first ebook, “Love Me”, went live in the spring of 2010 for $3.99. Within a month, she had earned $20,000 — four times as much as any book contract she had ever signed. Just a few months later, her second original ebook became the first self-published title to hit Amazon’s top-25 best sellers list. She was hooked.
Today, like many independent romance authors, Andre has become a one-woman publishing house. She’s churned out more than 30 titles and sold 3.5 million books around the world, the majority in ebook format. Revenue for Oak Press LLC, the indie publishing house she created in 2011, has been in the “eight figures,” she says. In 2014, Publisher’s Weekly named it the fastest growing independent publisher in the U.S.
Andre isn’t the only one. Despite the fact that ebook sales in the U.S. have begun to level off, romance books are much more likely to be purchased in digital format. Nearly 40% of new romance books in the first quarter of 2014 were purchased as ebooks, compared to 32% bought in paperback form, according to a recent report by Nielsen. In contrast, ebooks accounted for less than one-quarter of total new book sales during the same time period.
Say what you will about romance novels (bodice-rippers, Fabio covers and all), it’s hard to deny that some of the most exciting entrepreneurs in the U.S. today aren’t hoodie-wearing app developers — they’re women writing books for women and making millions in the process.
There is very little official data on book-author earnings available, which is why suspense writer Hugh Howey created AuthorEarnings.com, where he analyzes and publishes data on online ebook sales. According to his findings, nearly 30% of the top 100 bestsellers on Amazon were self-published in July.
And romance indie writers are leading the pack. As of mid-July, indie romance writers accounted for a whopping two-thirds of total romance ebook revenue on Amazon, compared to the 18% cut enjoyed by traditionally published authors.
“This makes a lot of people uncomfortable,” Howey says. “That’s a huge power that self-published authors have.”
In a recent analysis of debut Kindle authors, he found many more new self-published writers were earning $100,000+ annually than those who were published from the top five traditional publishers.
“[Traditional publisher books] advances are no longer high enough to support debut authors,” he wrote in the report. “And yet, at the same time, we have met and heard from hundreds of self-published authors who are not household names but are making a full-time wage from their works.”
Business is booming
As a genre, romance lends itself exceptionally well to digital publishing for a few notable reasons. Romance readers — 84% of whom are female — are a voracious bunch. Two-thirds of romance readers plow through at least two books a month, according to the RWA — twice as many as the typical American adult, Pew researchers found.
“I think ebook sales have definitely aided the romance genre,” says Erin Fry, editor and publications manager at the RWA. “And romance writers have always been at the forefront of the digital revolution. Authors can make real careers out of being self-published or combining print and digital.”
With the smash success of the “Fifty Shades of Grey” trilogy, publishers have been looking at the romance genre with dollar signs in their eyes.
Source: Barbara Freethy
E.L. James’ sexy tale of a college student’s erotic love affair with a corporate executive actually began as wildly popular “Twilight” fanfiction. When a small publisher in Australia caught on to the buzz online, it asked James to swap out the main characters and produce the story as an original ebook.
These days, Rose Fox, romance and erotica reviews editor at Publishers Weekly, says pitches for new novels written by fanfiction writers are becoming increasingly common.
Another factor driving ebook sales is that, in romance fiction, series sell. The most successful romance writers are able to churn out new material at a rapid clip to satiate their fan base. Whereas a traditionally published author may wait a year to see their book in stores after completion, the timeline is less than a month for indie authors.
“People read the next romance next series in a week and need something else right away,” Howey says. “It’s hard [for traditional publishers] to ramp up … as quickly as people can read them.”
With enough reader demand, some romance writers will pump out a new tome every few months. Andre puts out about six books per year, while Barbara Freethy, an indie romance novelist based in Northern California, published 10 in the past four years.
“Everyone goes on Netflix (NFLX) and watches all of ‘Homeland’ at once, and a lot of that is happening in romance books,” says Freethy, 55. “Ebooks are affordable, and people can read as many as they want.”
Like Andre, Freethy got her start in print before going independent in 2011. Since then, she’s sold nearly 5 million ebook versions of her self-published titles and more than tripled the revenue she made with traditional publishers. She pockets 70% of her Amazon ebook sales, versus the 25% cut she would get from a traditional publisher, which she would then have to split with her agent.
“It’s a lot more work than it was when I just wrote the books, but the reward is so much greater,” Freethy says. “I’m basically running my own multimillion-dollar business.”
Fellow indie writer Courtney Milan, who writes historical romance fiction, went from earning what she describes as an “average household income” with a traditional publisher to bringing in close to $1 million each year by putting out two books per year on her own dime.
“I just can’t figure out how it’s ever going to be economically feasible [to go back to a traditional publisher] and do what I do on my own in terms of income, and still protect what I’ve developed and want to continue to develop,” says Milan, 38, who lives in Denver.
Of course, not every romance novelist — or any novelist, for that matter — can expect overnight success. What Andre, Freethy, Milan and so many other successful indie writers shared when they began self-publishing was a built-in fanbase from their days in print.
“It’s not realistic for any new author to expect to be a runaway success, regardless of how you’re getting published,” says Fox. “Most new authors are new authors. It’s going to take a couple of tries to figure out what works for them.”
Risk and reward
To say it takes more work to self-publish is putting it lightly. At their core, the successful independent writers we spoke with are more like savvy CEOs with mini-corporations to manage than carefree writers spinning love stories.
“Instead of getting paid money to sit there and write, you’re investing money,” Fox says. “Yes, there is more to be gained if the book finds success, but there’s also more risk, and that’s what it means to be a self-publisher.”
There are five major self-publishing platforms, including Amazon, Google (GOOG), Barnes & Noble (BKS), and Kobo. It takes time and effort to format a book for each company’s unique platform. And professional writers often still need the same amount of editing time as they would with a traditional publisher. Between cover artists, editors and proofreaders, it can cost anywhere from $700 to $4,000 upfront to put out an ebook, depending on how picky you are, Milan says. It can cost even more when you try translating your books for foreign markets and producing audiobooks.
Andre employs more than a dozen contract workers in countries across the globe. They help with editing, licensing her work in foreign countries, and translating and tracking her sales. She handles marketing herself and designs all her own cover art.
“I have an economics background and I’ve always been entrepreneurial,” Andre says. “This is the perfect sweet spot for me, someone who understands how to run a business, really enjoys building a brand and marketing but also has a deep creative strain.”
Milan hired a full-time project manager last year to help with everything from audiobook quality control to managing her sales figures and schedule. When a new book is ready, she assembles a team to work on the cover design and perform several rounds of proofreading and editing.
When she needed help navigating the business, she turned to other romance writers for support.
“The true story of self-publishing [in romance] is not one individual doing well,” she says. “It’s multiple individuals working together to figure out the best way to publish digital books.”
This preference drives my daughters crazy. It drives my brothers crazy. My loving friends think I am crazy. They think that I can’t mean what I say; that I haven’t thought clearly about this, because there is so much in the world to see and do. To convince me of my errors, they enumerate the myriad people I know who are over 75 and doing quite well. They are certain that as I get closer to 75, I will push the desired age back to 80, then 85, maybe even 90.
I am sure of my position. Doubtless, death is a loss. It deprives us of experiences and milestones, of time spent with our spouse and children. In short, it deprives us of all the things we value.
But here is a simple truth that many of us seem to resist: living too long is also a loss. It renders many of us, if not disabled, then faltering and declining, a state that may not be worse than death but is nonetheless deprived. It robs us of our creativity and ability to contribute to work, society, the world. It transforms how people experience us, relate to us, and, most important, remember us. We are no longer remembered as vibrant and engaged but as feeble, ineffectual, even pathetic.
By the time I reach 75, I will have lived a complete life. I will have loved and been loved. My children will be grown and in the midst of their own rich lives. I will have seen my grandchildren born and beginning their lives. I will have pursued my life’s projects and made whatever contributions, important or not, I am going to make. And hopefully, I will not have too many mental and physical limitations. Dying at 75 will not be a tragedy. Indeed, I plan to have my memorial service before I die. And I don’t want any crying or wailing, but a warm gathering filled with fun reminiscences, stories of my awkwardness, and celebrations of a good life. After I die, my survivors can have their own memorial service if they want—that is not my business.
Let me be clear about my wish. I’m neither asking for more time than is likely nor foreshortening my life. Today I am, as far as my physician and I know, very healthy, with no chronic illness. I just climbed Kilimanjaro with two of my nephews. So I am not talking about bargaining with God to live to 75 because I have a terminal illness. Nor am I talking about waking up one morning 18 years from now and ending my life through euthanasia or suicide. Since the 1990s, I have actively opposed legalizing euthanasia and physician-assisted suicide. People who want to die in one of these ways tend to suffer not from unremitting pain but from depression, hopelessness, and fear of losing their dignity and control. The people they leave behind inevitably feel they have somehow failed. The answer to these symptoms is not ending a life but getting help. I have long argued that we should focus on giving all terminally ill people a good, compassionate death—not euthanasia or assisted suicide for a tiny minority.
I am talking about how long I want to live and the kind and amount of health care I will consent to after 75. Americans seem to be obsessed with exercising, doing mental puzzles, consuming various juice and protein concoctions, sticking to strict diets, and popping vitamins and supplements, all in a valiant effort to cheat death and prolong life as long as possible. This has become so pervasive that it now defines a cultural type: what I call the American immortal.
I reject this aspiration. I think this manic desperation to endlessly extend life is misguided and potentially destructive. For many reasons, 75 is a pretty good age to aim to stop.
What are those reasons? Let’s begin with demography. We are growing old, and our older years are not of high quality. Since the mid-19th century, Americans have been living longer. In 1900, the life expectancy of an average American at birth was approximately 47 years. By 1930, it was 59.7; by 1960, 69.7; by 1990, 75.4. Today, a newborn can expect to live about 79 years. (On average, women live longer than men. In the United States, the gap is about five years. According to the National Vital Statistics Report, life expectancy for American males born in 2011 is 76.3, and for females it is 81.1.)
In the early part of the 20th century, life expectancy increased as vaccines, antibiotics, and better medical care saved more children from premature death and effectively treated infections. Once cured, people who had been sick largely returned to their normal, healthy lives without residual disabilities. Since 1960, however, increases in longevity have been achieved mainly by extending the lives of people over 60. Rather than saving more young people, we are stretching out old age.
The American immortal desperately wants to believe in the “compression of morbidity.” Developed in 1980 by James F. Fries, now a professor emeritus of medicine at Stanford, this theory postulates that as we extend our life spans into the 80s and 90s, we will be living healthier lives—more time before we have disabilities, and fewer disabilities overall. The claim is that with longer life, an ever smaller proportion of our lives will be spent in a state of decline.
Compression of morbidity is a quintessentially American idea. It tells us exactly what we want to believe: that we will live longer lives and then abruptly die with hardly any aches, pains, or physical deterioration—the morbidity traditionally associated with growing old. It promises a kind of fountain of youth until the ever-receding time of death. It is this dream—or fantasy—that drives the American immortal and has fueled interest and investment in regenerative medicine and replacement organs.
But as life has gotten longer, has it gotten healthier? Is 70 the new 50?
Not quite. It is true that compared with their counterparts 50 years ago, seniors today are less disabled and more mobile. But over recent decades, increases in longevity seem to have been accompanied by increases in disability—not decreases. For instance, using data from the National Health Interview Survey, Eileen Crimmins, a researcher at the University of Southern California, and a colleague assessed physical functioning in adults, analyzing whether people could walk a quarter of a mile; climb 10 stairs; stand or sit for two hours; and stand up, bend, or kneel without using special equipment. The results show that as people age, there is a progressive erosion of physical functioning. More important, Crimmins found that between 1998 and 2006, the loss of functional mobility in the elderly increased. In 1998, about 28 percent of American men 80 and older had a functional limitation; by 2006, that figure was nearly 42 percent. And for women the result was even worse: more than half of women 80 and older had a functional limitation. Crimmins’s conclusion: There was an “increase in the life expectancy with disease and a decrease in the years without disease. The same is true for functioning loss, an increase in expected years unable to function.”
This was confirmed by a recent worldwide assessment of “healthy life expectancy” conducted by the Harvard School of Public Health and the Institute for Health Metrics and Evaluation at the University of Washington. The researchers included not just physical but also mental disabilities such as depression and dementia. They found not a compression of morbidity but in fact an expansion—an “increase in the absolute number of years lost to disability as life expectancy rises.”
How can this be? My father illustrates the situation well. About a decade ago, just shy of his 77th birthday, he began having pain in his abdomen. Like every good doctor, he kept denying that it was anything important. But after three weeks with no improvement, he was persuaded to see his physician. He had in fact had a heart attack, which led to a cardiac catheterization and ultimately a bypass. Since then, he has not been the same. Once the prototype of a hyperactive Emanuel, suddenly his walking, his talking, his humor got slower. Today he can swim, read the newspaper, needle his kids on the phone, and still live with my mother in their own house. But everything seems sluggish. Although he didn’t die from the heart attack, no one would say he is living a vibrant life. When he discussed it with me, my father said, “I have slowed down tremendously. That is a fact. I no longer make rounds at the hospital or teach.” Despite this, he also said he was happy.
As Crimmins puts it, over the past 50 years, health care hasn’t slowed the aging process so much as it has slowed the dying process. And, as my father demonstrates, the contemporary dying process has been elongated. Death usually results from the complications of chronic illness—heart disease, cancer, emphysema, stroke, Alzheimer’s, diabetes.
Take the example of stroke. The good news is that we have made major strides in reducing mortality from strokes. Between 2000 and 2010, the number of deaths from stroke declined by more than 20 percent. The bad news is that many of the roughly 6.8 million Americans who have survived a stroke suffer from paralysis or an inability to speak. And many of the estimated 13 million more Americans who have survived a “silent” stroke suffer from more-subtle brain dysfunction such as aberrations in thought processes, mood regulation, and cognitive functioning. Worse, it is projected that over the next 15 years there will be a 50 percent increase in the number of Americans suffering from stroke-induced disabilities. Unfortunately, the same phenomenon is repeated with many other diseases.
So American immortals may live longer than their parents, but they are likely to be more incapacitated. Does that sound very desirable? Not to me.
The situation becomes of even greater concern when we confront the most dreadful of all possibilities: living with dementia and other acquired mental disabilities. Right now approximately 5 million Americans over 65 have Alzheimer’s; one in three Americans 85 and older has Alzheimer’s. And the prospect of that changing in the next few decades is not good. Numerous recent trials of drugs that were supposed to stall Alzheimer’s—much less reverse or prevent it—have failed so miserably that researchers are rethinking the whole disease paradigm that informed much of the research over the past few decades. Instead of predicting a cure in the foreseeable future, many are warning of a tsunami of dementia—a nearly 300 percent increase in the number of older Americans with dementia by 2050.
Half of people 80 and older with functional limitations. A third of people 85 and older with Alzheimer’s. That still leaves many, many elderly people who have escaped physical and mental disability. If we are among the lucky ones, then why stop at 75? Why not live as long as possible?
Even if we aren’t demented, our mental functioning deteriorates as we grow older. Age-associated declines in mental-processing speed, working and long-term memory, and problem-solving are well established. Conversely, distractibility increases. We cannot focus and stay with a project as well as we could when we were young. As we move slower with age, we also think slower.
It is not just mental slowing. We literally lose our creativity. About a decade ago, I began working with a prominent health economist who was about to turn 80. Our collaboration was incredibly productive. We published numerous papers that influenced the evolving debates around health-care reform. My colleague is brilliant and continues to be a major contributor, and he celebrated his 90th birthday this year. But he is an outlier—a very rare individual.
American immortals operate on the assumption that they will be precisely such outliers. But the fact is that by 75, creativity, originality, and productivity are pretty much gone for the vast, vast majority of us. Einstein famously said, “A person who has not made his great contribution to science before the age of 30 will never do so.” He was extreme in his assessment. And wrong. Dean Keith Simonton, at the University of California at Davis, a luminary among researchers on age and creativity, synthesized numerous studies to demonstrate a typical age-creativity curve: creativity rises rapidly as a career commences, peaks about 20 years into the career, at about age 40 or 45, and then enters a slow, age-related decline. There are some, but not huge, variations among disciplines. Currently, the average age at which Nobel Prize–winning physicists make their discovery—not get the prize—is 48. Theoretical chemists and physicists make their major contribution slightly earlier than empirical researchers do. Similarly, poets tend to peak earlier than novelists do. Simonton’s own study of classical composers shows that the typical composer writes his first major work at age 26, peaks at about age 40 with both his best work and maximum output, and then declines, writing his last significant musical composition at 52. (All the composers studied were male.)
This age-creativity relationship is a statistical association, the product of averages; individuals vary from this trajectory. Indeed, everyone in a creative profession thinks they will be, like my collaborator, in the long tail of the curve. There are late bloomers. As my friends who enumerate them do, we hold on to them for hope. It is true, people can continue to be productive past 75—to write and publish, to draw, carve, and sculpt, to compose. But there is no getting around the data. By definition, few of us can be exceptions. Moreover, we need to ask how much of what “Old Thinkers,” as Harvey C. Lehman called them in his 1953 Age and Achievement, produce is novel rather than reiterative and repetitive of previous ideas. The age-creativity curve—especially the decline—endures across cultures and throughout history, suggesting some deep underlying biological determinism probably related to brain plasticity.
We can only speculate about the biology. The connections between neurons are subject to an intense process of natural selection. The neural connections that are most heavily used are reinforced and retained, while those that are rarely, if ever, used atrophy and disappear over time. Although brain plasticity persists throughout life, we do not get totally rewired. As we age, we forge a very extensive network of connections established through a lifetime of experiences, thoughts, feelings, actions, and memories. We are subject to who we have been. It is difficult, if not impossible, to generate new, creative thoughts, because we don’t develop a new set of neural connections that can supersede the existing network. It is much more difficult for older people to learn new languages. All of those mental puzzles are an effort to slow the erosion of the neural connections we have. Once you squeeze the creativity out of the neural networks established over your initial career, they are not likely to develop strong new brain connections to generate innovative ideas—except maybe in those Old Thinkers like my outlier colleague, who happen to be in the minority endowed with superior plasticity.
Maybe mental functions—processing, memory, problem-solving—slow at 75. Maybe creating something novel is very rare after that age. But isn’t this a peculiar obsession? Isn’t there more to life than being totally physically fit and continuing to add to one’s creative legacy?
One university professor told me that as he has aged (he is 70) he has published less frequently, but he now contributes in other ways. He mentors students, helping them translate their passions into research projects and advising them on the balance of career and family. And people in other fields can do the same: mentor the next generation.
Mentorship is hugely important. It lets us transmit our collective memory and draw on the wisdom of elders. It is too often undervalued, dismissed as a way to occupy seniors who refuse to retire and who keep repeating the same stories. But it also illuminates a key issue with aging: the constricting of our ambitions and expectations.
We accommodate our physical and mental limitations. Our expectations shrink. Aware of our diminishing capacities, we choose ever more restricted activities and projects, to ensure we can fulfill them. Indeed, this constriction happens almost imperceptibly. Over time, and without our conscious choice, we transform our lives. We don’t notice that we are aspiring to and doing less and less. And so we remain content, but the canvas is now tiny. The American immortal, once a vital figure in his or her profession and community, is happy to cultivate avocational interests, to take up bird watching, bicycle riding, pottery, and the like. And then, as walking becomes harder and the pain of arthritis limits the fingers’ mobility, life comes to center around sitting in the den reading or listening to books on tape and doing crossword puzzles. And then …
Maybe this is too dismissive. There is more to life than youthful passions focused on career and creating. There is posterity: children and grandchildren and great-grandchildren.
But here, too, living as long as possible has drawbacks we often won’t admit to ourselves. I will leave aside the very real and oppressive financial and caregiving burdens that many, if not most, adults in the so-called sandwich generation are now experiencing, caught between the care of children and parents. Our living too long places real emotional weights on our progeny.
Unless there has been terrible abuse, no child wants his or her parents to die. It is a huge loss at any age. It creates a tremendous, unfillable hole. But parents also cast a big shadow for most children. Whether estranged, disengaged, or deeply loving, they set expectations, render judgments, impose their opinions, interfere, and are generally a looming presence for even adult children. This can be wonderful. It can be annoying. It can be destructive. But it is inescapable as long as the parent is alive. Examples abound in life and literature: Lear, the quintessential Jewish mother, the Tiger Mom. And while children can never fully escape this weight even after a parent dies, there is much less pressure to conform to parental expectations and demands after they are gone.
Living parents also occupy the role of head of the family. They make it hard for grown children to become the patriarch or matriarch. When parents routinely live to 95, children must caretake into their own retirement. That doesn’t leave them much time on their own—and it is all old age. When parents live to 75, children have had the joys of a rich relationship with their parents, but also have enough time for their own lives, out of their parents’ shadows.
But there is something even more important than parental shadowing: memories. How do we want to be remembered by our children and grandchildren? We wish our children to remember us in our prime. Active, vigorous, engaged, animated, astute, enthusiastic, funny, warm, loving. Not stooped and sluggish, forgetful and repetitive, constantly asking “What did she say?” We want to be remembered as independent, not experienced as burdens.
At age 75 we reach that unique, albeit somewhat arbitrarily chosen, moment when we have lived a rich and complete life, and have hopefully imparted the right memories to our children. Living the American immortal’s dream dramatically increases the chances that we will not get our wish—that memories of vitality will be crowded out by the agonies of decline. Yes, with effort our children will be able to recall that great family vacation, that funny scene at Thanksgiving, that embarrassing faux pas at a wedding. But the most-recent years—the years with progressing disabilities and the need to make caregiving arrangements—will inevitably become the predominant and salient memories. The old joys have to be actively conjured up.
Of course, our children won’t admit it. They love us and fear the loss that will be created by our death. And a loss it will be. A huge loss. They don’t want to confront our mortality, and they certainly don’t want to wish for our death. But even if we manage not to become burdens to them, our shadowing them until their old age is also a loss. And leaving them—and our grandchildren—with memories framed not by our vivacity but by our frailty is the ultimate tragedy.
Seventy-five. That is all I want to live. But if I am not going to engage in euthanasia or suicide, and I won’t, is this all just idle chatter? Don’t I lack the courage of my convictions?
No. My view does have important practical implications. One is personal and two involve policy.
Once I have lived to 75, my approach to my health care will completely change. I won’t actively end my life. But I won’t try to prolong it, either. Today, when the doctor recommends a test or treatment, especially one that will extend our lives, it becomes incumbent upon us to give a good reason why we don’t want it. The momentum of medicine and family means we will almost invariably get it.
My attitude flips this default on its head. I take guidance from what Sir William Osler wrote in his classic turn-of-the-century medical textbook, The Principles and Practice of Medicine: “Pneumonia may well be called the friend of the aged. Taken off by it in an acute, short, not often painful illness, the old man escapes those ‘cold gradations of decay’ so distressing to himself and to his friends.”
My Osler-inspired philosophy is this: At 75 and beyond, I will need a good reason to even visit the doctor and take any medical test or treatment, no matter how routine and painless. And that good reason is not “It will prolong your life.” I will stop getting any regular preventive tests, screenings, or interventions. I will accept only palliative—not curative—treatments if I am suffering pain or other disability.
This means colonoscopies and other cancer-screening tests are out—and before 75. If I were diagnosed with cancer now, at 57, I would probably be treated, unless the prognosis was very poor. But 65 will be my last colonoscopy. No screening for prostate cancer at any age. (When a urologist gave me a PSA test even after I said I wasn’t interested and called me with the results, I hung up before he could tell me. He ordered the test for himself, I told him, not for me.) After 75, if I develop cancer, I will refuse treatment. Similarly, no cardiac stress test. No pacemaker and certainly no implantable defibrillator. No heart-valve replacement or bypass surgery. If I develop emphysema or some similar disease that involves frequent exacerbations that would, normally, land me in the hospital, I will accept treatment to ameliorate the discomfort caused by the feeling of suffocation, but will refuse to be hauled off.
What about simple stuff? Flu shots are out. Certainly if there were to be a flu pandemic, a younger person who has yet to live a complete life ought to get the vaccine or any antiviral drugs. A big challenge is antibiotics for pneumonia or skin and urinary infections. Antibiotics are cheap and largely effective in curing infections. It is really hard for us to say no. Indeed, even people who are sure they don’t want life-extending treatments find it hard to refuse antibiotics. But, as Osler reminds us, unlike the decays associated with chronic conditions, death from these infections is quick and relatively painless. So, no to antibiotics.
Obviously, a do-not-resuscitate order and a complete advance directive indicating no ventilators, dialysis, surgery, antibiotics, or any other medication—nothing except palliative care even if I am conscious but not mentally competent—have been written and recorded. In short, no life-sustaining interventions. I will die when whatever comes first takes me.
As for the two policy implications, one relates to using life expectancy as a measure of the quality of health care. Japan has the third-highest life expectancy, at 84.4 years (behind Monaco and Macau), while the United States is a disappointing No. 42, at 79.5 years. But we should not care about catching up with—or measure ourselves against—Japan. Once a country has a life expectancy past 75 for both men and women, this measure should be ignored. (The one exception is increasing the life expectancy of some subgroups, such as black males, who have a life expectancy of just 72.1 years. That is dreadful, and should be a major focus of attention.) Instead, we should look much more carefully at children’s health measures, where the U.S. lags, and shamefully: in preterm deliveries before 37 weeks (currently one in eight U.S. births), which are correlated with poor outcomes in vision, with cerebral palsy, and with various problems related to brain development; in infant mortality (the U.S. is at 6.17 infant deaths per 1,000 live births, while Japan is at 2.13 and Norway is at 2.48); and in adolescent mortality (where the U.S. has an appalling record—at the bottom among high-income countries).
A second policy implication relates to biomedical research. We need more research on Alzheimer’s, the growing disabilities of old age, and chronic conditions—not on prolonging the dying process.
Many people, especially those sympathetic to the American immortal, will recoil and reject my view. They will think of every exception, as if these prove that the central theory is wrong. Like my friends, they will think me crazy, posturing—or worse. They might condemn me as being against the elderly.
Again, let me be clear: I am not saying that those who want to live as long as possible are unethical or wrong. I am certainly not scorning or dismissing people who want to live on despite their physical and mental limitations. I’m not even trying to convince anyone I’m right. Indeed, I often advise people in this age group on how to get the best medical care available in the United States for their ailments. That is their choice, and I want to support them.
And I am not advocating 75 as the official statistic of a complete, good life in order to save resources, ration health care, or address public-policy issues arising from the increases in life expectancy. What I am trying to do is delineate my views for a good life and make my friends and others think about how they want to live as they grow older. I want them to think of an alternative to succumbing to that slow constriction of activities and aspirations imperceptibly imposed by aging. Are we to embrace the “American immortal” or my “75 and no more” view?
I think the rejection of my view is literally natural. After all, evolution has inculcated in us a drive to live as long as possible. We are programmed to struggle to survive. Consequently, most people feel there is something vaguely wrong with saying 75 and no more. We are eternally optimistic Americans who chafe at limits, especially limits imposed on our own lives. We are sure we are exceptional.
I also think my view conjures up spiritual and existential reasons for people to scorn and reject it. Many of us have suppressed, actively or passively, thinking about God, heaven and hell, and whether we return to the worms. We are agnostics or atheists, or just don’t think about whether there is a God and why she should care at all about mere mortals. We also avoid constantly thinking about the purpose of our lives and the mark we will leave. Is making money, chasing the dream, all worth it? Indeed, most of us have found a way to live our lives comfortably without acknowledging, much less answering, these big questions on a regular basis. We have gotten into a productive routine that helps us ignore them. And I don’t purport to have the answers.
But 75 defines a clear point in time: for me, 2032. It removes the fuzziness of trying to live as long as possible. Its specificity forces us to think about the end of our lives and engage with the deepest existential questions and ponder what we want to leave our children and grandchildren, our community, our fellow Americans, the world. The deadline also forces each of us to ask whether our consumption is worth our contribution. As most of us learned in college during late-night bull sessions, these questions foster deep anxiety and discomfort. The specificity of 75 means we can no longer just continue to ignore them and maintain our easy, socially acceptable agnosticism. For me, 18 more years with which to wade through these questions is preferable to years of trying to hang on to every additional day and forget the psychic pain they bring up, while enduring the physical pain of an elongated dying process.
Seventy-five years is all I want to live. I want to celebrate my life while I am still in my prime. My daughters and dear friends will continue to try to convince me that I am wrong and can live a valuable life much longer. And I retain the right to change my mind and offer a vigorous and reasoned defense of living as long as possible. That, after all, would mean still being creative after 75.
New Approach Described for Targeting Immune System Attack on Cancer
Scientists at Louisiana State University Health New Orleans say they have identified the crucial role the Chop inflammatory protein plays in the body’s ability to fight cancer. Results demonstrate, for the first time, that Chop regulates the activity and accumulation of cells that suppress the body’s immune response against tumors, according to the researchers.
The LSU Health New Orleans research team showed that when they removed Chop, the T cells of the immune system mounted an effective attack on the cancer cells. These findings reveal Chop as a target for the development of new immunotherapies to treat cancer.
The research is described in a paper (“The Stress-Response Sensor Chop Regulates the Function and Accumulation of Myeloid-Derived Suppressor Cells in Tumors”) published in Immunity.
Myeloid-derived suppressor cells (MDSCs) are involved in cancer, inflammation, and infection. MDSCs not only inhibit the immune response that destroys cancer cells, but they also promote the growth of new blood vessels that feed tumors, as well as the spread of cancer.
“Although we know what MDSCs do, very little has been known about what governs how they function,” noted Paulo Rodriguez, Ph.D., assistant research professor of microbiology, immunology, and parasitology at LSU Health New Orleans’ Stanley S. Scott Cancer Center. “This has limited the development of strategies to block the harmful activity of MDSCs.”
The LSU Health research team discovered that the stress sensor C/EBP-homologous protein (Chop) regulates the function of MDSCs. They learned how Chop is distributed within the tumor environment in different types of cancer. They also determined how Chop controls tumor growth. The team confirmed their findings by deleting Chop and studying the effect. They found that the absence of Chop not only reduced the ability of MDSCs to inhibit T cells and suppress immune response, but also boosted the effectiveness of treatment.
“Chop-deficient MDSCs displayed reduced signaling through CCAAT/enhancer-binding protein-β, leading to a decreased production of interleukin-6 (IL-6) and low expression of phospho-STAT3. IL-6 overexpression restored immune-suppressive activity of Chop-deficient MDSCs,” wrote the investigators. “These findings suggest the role of Chop in tumor-induced tolerance and the therapeutic potential of targeting Chop in MDSCs for cancer immunotherapy.”
NEW YORK (Reuters Health) – A new analysis of previous studies ties too much sitting at the computer or lying around watching TV to a greater risk of depression.
Based on dozens of studies covering hundreds of thousands of participants, Chinese researchers found that sedentary behavior was linked to a 25 percent higher likelihood of being depressed compared to people who were not sedentary.
The research has limitations, Long Zhai, of Qingdau University Medical College in Shangong, and his coauthors write, but it suggests that physical activity would be a good prescription for preventing depression.
“Although it was a thorough investigation of a relatively new research area, a number of unanswered questions still remain,” said Megan Teychenne from the Centre for Physical Activity and Nutrition Research at Deakin University in Melbourne, Australia.
Among these is “whether sedentary behavior increases the risk of depression; or whether it is that those with depression are just more likely to engage in sedentary behaviors such as computer use or television viewing,” said Teychenne, who wasn’t involved in the study.
For their report, published in the British Journal of Sports Medicine, Zhai and colleagues combined and re-analyzed the findings for a total of 193,166 participants from 24 previously published observational studies that looked at levels of sedentary behavior and risk of depression.
Two of the studies were conducted in Australia, four in Asia, seven in the Americas and 11 in Europe.
Across continents, the researchers found that people with the most sedentary behavior were 25 percent more likely to be depressed overall compared to those who were the least sedentary.
The study team also saw differences depending on people’s preferred type of inactivity. Those whose most frequent sedentary behavior was watching TV were 13 percent more likely to be depressed, while those who spent their sedentary time using the computer or Internet, had a 22 percent higher depression risk.
The analysis didn’t look at the reasons behind the links. And, the study team points out, most of the included studies accounted for other factors, like illnesses, that might explain the sedentary behavior, the depression, or both, but those studies may not have taken every possible factor into account.
The research team also notes that they cannot rule out the possibility that depression leads to sedentary behaviors rather than the other way around.
Nonetheless, that the two go hand in hand is enough to suggest that more activity might be the antidote, they conclude.
Teychenne also said that even though the study results are inconclusive regarding the connection between sedentary behavior and mental health, researchers do know that being sedentary is linked to other poor health outcomes like cardiovascular disease and type 2 diabetes.
“Therefore, the message we really need to get out to the public is ‘Move more and sit less,’” she said.
“I think it’s certainly an important study, and it shows that there are links but it does point out some issues that we need to think about,” Jennifer Brunet told Reuters Health.
Brunet is a researcher with the School of Human Kinetics at the University of Ottawa in Ontario Canada, who was not involved with the study.
She added that she doesn’t think all sedentary behavior is a bad thing, and it could provide some escape from the stress of a hard day.
“Sometimes people read; people go on the Internet, and unfortunately, the measures that were used in the reviewed studies didn’t always differentiate what we can call healthier sedentary behaviors versus unhealthy sedentary behaviors,” Brunet pointed out.
Still, she said, there’s clear evidence that physical activity is good for the management of depression symptoms as well as clinical levels of depression.
There’s not enough good evidence to suggest that any one specific form of physical activity is best, she added, but research indicates that moderate exercise is most effective.
“I often tell people to pick activities that are enjoyable, and that’s the key to it,” she said. “We don’t want to pressure people to do physical activity, we want them to choose it and one way of choosing it is if they feel it’s an enjoyable activity.”
How pneumonia bacteria can compromise heart health
September 18, 2014
Bacterial pneumonia in adults carries an elevated risk for adverse cardiac events (such as heart failure, arrhythmias, and heart attacks) that contribute substantially to mortality — but how the heart is compromised has been unclear. A study now demonstrates that Streptococcus pneumoniae, the bacterium responsible for most cases of bacterial pneumonia, can invade the heart and cause the death of heart muscle cells.
Bacterial pneumonia in adults carries an elevated risk for adverse cardiac events (such as heart failure, arrhythmias, and heart attacks) that contribute substantially to mortality — but how the heart is compromised has been unclear. A study published on September 18th in PLOS Pathogens now demonstrates that Streptococcus pneumoniae, the bacterium responsible for most cases of bacterial pneumonia, can invade the heart and cause the death of heart muscle cells.
Carlos Orihuela, from the University of Texas Health Science Center in San Antonio, USA, and colleagues initially studied the reasons for heart failure during invasive pneumococcal disease (when S. pneumoniae bacteria infect major organs such as the lungs, bloodstream, and brain) in mice, and subsequently confirmed some of their main findings in rhesus macaques and in heart tissue from deceased human patients.
Mice with severe invasive pneumococcal disease showed elevated levels of troponin, a marker for heart injury, in their blood. They also had abnormal EKGs. When the researchers examined the hearts of the mice, they found microscopic sites of injury (called microlesions) in the heart muscle. S. pneumoniae were found within these microlesions, indicating the bacteria were able to invade and multiply within the heart. Looking in more detail, the researchers identified dying heart muscle cells in the tissue surrounding microlesions.
At the molecular level, the researchers found that the S. pneumoniae toxin pneumolysin was present within the microlesions and responsible for heart muscle cell death. They also showed that S. pneumoniae requires a molecule called CbpA to exit the bloodstream and invade the heart. Moreover, an experimental vaccine formulation composed of CbpA and a non-toxic version of pneumolysin generated antibodies that protected mice against cardiac invasion and heart damage.
Having obtained tissues from three rhesus macaques that had died from pneumococcal pneumonia, the researchers found cardiac microlesions that were similar in size and appearance to those seen in mice, but without the presence of S. pneumoniae bacteria. The situation was similar in cardiac samples from human patients who had died from invasive pneumococcal disease. Two of the samples (they looked at a total of nine) showed microlesions, but the lesions did not contain bacteria.
As the macaques and the human patients had been treated with antibiotics, the researchers wondered whether the bacteria had caused the lesions but subsequently been killed by the treatment. To test this, they infected mice with S. pneumoniae and treated them with a high-dose antibiotic (ampicillin) when the lesions were first apparent. The hearts of these mice looked similar to the macaques and human samples, with clear presence of microlesions but devoid of bacteria. As the researchers discuss, ampicillin acts by breaking bacteria apart and releasing their contents, including pneumolysin, and this could exacerbate the death of heart muscle cells. Alternative antibiotics that do not spill their bacterial targets’ contents exist and might be advantageous.
Having shown for the first time that S. pneumoniae can directly damage the heart — which could help explain the link between pneumonia and adverse heart events — the researchers conclude that “research is merited to determine the true frequency of cardiac microlesions in patients hospitalized with invasive pneumococcal disease, if modifications in antibiotic therapy improve long-term outcomes, and if prevention of cardiac damage is an indication for vaccination.”
The above story is based on materials provided by PLOS. Note: Materials may be edited for content and length.
Armand O. Brown, Beth Mann, Geli Gao, Jane S. Hankins, Jessica Humann, Jonathan Giardina, Paola Faverio, Marcos I. Restrepo, Ganesh V. Halade, Eric M. Mortensen, Merry L. Lindsey, Martha Hanes, Kyle I. Happel, Steve Nelson, Gregory J. Bagby, Jose A. Lorent, Pablo Cardinal, Rosario Granados, Andres Esteban, Claude J. LeSaux, Elaine I. Tuomanen, Carlos J. Orihuela. Streptococcus pneumoniae Translocates into the Myocardium and Forms Unique Microlesions That Disrupt Cardiac Function. PLoS Pathogens, 2014; 10 (9): e1004383 DOI: 10.1371/journal.ppat.1004383
growing body of evidence suggests that environmental stresses can cause changes in gene expression that are transmitted from parents to their offspring, making “epigenetics” a hot topic. Epigenetic modifications do not affect the DNA sequence of genes, but change how the DNA is packaged and how genes are expressed. Now, a study by scientists at UC Santa Cruz shows how epigenetic memory can be passed across generations and from cell to cell during development.
The study, published September 19 in Science, focused on one well studied epigenetic modification–the methylation of a DNA packaging protein called histone H3. Methylation of a particular amino acid (lysine 27) in histone H3 is known to turn off or “repress” genes, and this epigenetic mark is found in all multicellular animals, from humans to the tiny roundworm C. elegans that was used in this study.
“There has been ongoing debate about whether the methylation mark can be passed on through cell divisions and across generations, and we’ve now shown that it is,” said corresponding author Susan Strome, a professor of molecular, cell and developmental biology at UC Santa Cruz.
Strome’s lab created worms with a mutation that knocks out the enzyme responsible for making the methylation mark, then bred them with normal worms. Using fluorescent labels, they were able to track the fates of marked and unmarked chromosomes under the microscope, from egg cells and sperm to the dividing cells of embryos after fertilization. Embryos from mutant egg cells fertilized by normal sperm had six methylated chromosomes (from the sperm) and six unmarked or “naked” chromosomes (from the egg).
As embryos develop, the cells replicate their chromosomes and divide. The researchers found that when a marked chromosome replicates, the two daughter chromosomes are both marked. But without the enzyme needed for histone methylation, the marks become progressively diluted with each cell division.
“The mark stays on the chromosomes derived from the initial chromosome that had the mark, but there’s not enough mark for both daughter chromosomes to be fully loaded,” Strome said. “So the mark is bright in a one-cell embryo, less bright after the cell divides, dimmer still in a four-cell embryo, and by about 24 to 48 cells we can’t see it anymore.”
The researchers then did the converse experiment, fertilizing normal egg cells with mutant sperm. The methylation enzyme (called PRC2) is normally present in egg cells but not in sperm, which don’t contribute much more than their chromosomes to the embryo. So the embryos in the new experiment still had six naked chromosomes (this time from the sperm) and six marked chromosomes, but now they also had the enzyme.
“Remarkably, when we watch the chromosomes through cell divisions, the marked chromosomes remain marked and stay bright, because the enzyme keeps restoring the mark, but the naked chromosomes stay naked, division after division,” Strome said. “That shows that the pattern of marks that was inherited is being transmitted through multiple cell divisions.”
Strome noted that the findings in this study of transmission of histone methylation in C. elegans have important implications in other organisms, even though different organisms use the repressive marker that was studied to regulate different genes during different aspects of development. All animals use the same enzyme to create the same methylation mark as a signal for gene repression, and her colleagues who study epigenetics in mice and humans are excited about the new findings, Strome said.
“Transgenerational epigenetic inheritance is not a solved field–it’s very much in flux,” she said. “There are dozens of potential epigenetic markers. In studies that document parent-to-child epigenetic inheritance, it’s not clear what’s being passed on, and understanding it molecularly is very complicated. We have a specific example of epigenetic memory that is passed on, and we can see it in the microscope. It’s one piece of the puzzle.”
The first author of the Science paper is Laura Gaydos, a graduate student in Strome’s lab at UC Santa Cruz who led the study for her Ph.D. thesis and is now a postdoctoral researcher at Fred Hutchinson Cancer Research Center in Seattle. The other coauthor is Wenchao Wang, who did one of the initial experiments as a graduate student in Strome’s lab several years ago when she was at Indiana University. This research was supported by the National Institutes of Health, a UCSC Dissertation Year Fellowship, and the ARCS Foundation.
“[In our paper] we also review the evidence for alternative explanations for cravings and unhealthy eating behavior,” the investigators wrote. “Because microbiota are easily manipulatable by prebiotics, probiotics, antibiotics, fecal transplants, and dietary changes, altering our microbiota offers a tractable approach to otherwise intractable problems of obesity and unhealthy eating.”
Scientists from the University of California–San Francisco, Arizona State University, and the University of New Mexico concluded from a literature review that gut microbes influence human eating behavior and dietary choices to favor consumption of the particular nutrients they grow best on instead of simply passively living off whatever nutrients we choose to send their way.
While it is unclear exactly how this occurs, the researchers believe the gut microbiome may influence our decisions by releasing signaling molecules into our gut. Because the gut is linked to the immune system, the endocrine system, and the nervous system, those signals could influence our physiologic and behavioral responses.
“Bacteria within the gut are manipulative,” said Carlo Maley, Ph.D., director of the UCSF Center for Evolution and Cancer and corresponding author on the team’s paper (“Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms”), which appears in BioEssays. “There is a diversity of interests represented in the microbiome, some aligned with our own dietary goals, and others not.”
However, it turns out that we can influence the compatibility of these microscopic, single-celled microbes by deliberating altering what we ingest, added Dr. Maley, with measurable changes in the microbiome within 24 hours of diet change.
“Our diets have a huge impact on microbial populations in the gut,” he continued. “It’s a whole ecosystem, and it’s evolving on the time scale of minutes.:
There are even specialized bacteria that digest seaweed, found in humans in Japan, where seaweed is popular in the diet.
Research suggests that gut bacteria may be affecting our eating decisions in part by acting through the vagus nerve, which connects 100 million nerve cells from the digestive tract to the base of the brain.
“Microbes have the capacity to manipulate behavior and mood through altering the neural signals in the vagus nerve, changing taste receptors, producing toxins to make us feel bad, and releasing chemical rewards to make us feel good,” noted Athena Aktipis, Ph.D., co-founder of the Center for Evolution and Cancer with the Helen Diller Family Comprehensive Cancer Center at UCSF and who is currently in Arizona State University’s department of psychology.
In mice, certain strains of bacteria increase anxious behavior. In humans, one clinical trial found that drinking a probiotic containing Lactobacillus casei improved mood in those who were feeling the lowest. The researchers proposed further research to test the sway microbes hold over us. For example, would transplantation into the gut of the bacteria requiring a nutrient from seaweed lead the human host to eat more seaweed?
The speed with which the microbiome can change may be encouraging to those who seek to improve health by altering microbial populations. This may be accomplished through food and supplement choices, by ingesting specific bacterial species in the form of probiotics, or by killing targeted species with antibiotics. Optimizing the balance of power among bacterial species in our gut might allow us to lead less obese and healthier lives, according to the authors.
We are simply at the end of this era.
The Printing press, libraries, mass education, fax machines, internet, youtube, blogs,…….
companies like Microsoft or Oracle or Hewlett-Packard as fundamentally bets against technology. They keep throwing off profits as long as nothing changes. Microsoft was a technology company in the ’80s and ’90s; in this decade you invest because you’re betting on the world not changing. Pharma companies are bets against innovation because they’re mostly just figuring out ways to extend the lifetime of patents and block small companies.
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For hundreds of years it has been known that a plant extract from the French lilac (Galega officinalis) improved the intense urination seen in diabetes patients. From this plant guanidine was extracted but it was too toxic for human use. In the 1920s another extract – galegine – of the French liliac was briefly used followed by synthetic analogs – Synthalin A and B. In the 1950s artificial drugs – phenformin, butformin and metformin – with a chemical similarity to guanidine became available for clinical use. In the 1970s however phenformin and buformin were withdrawn from the market because of the increased risk for lactic acidosis (1,2), a severe disease with a mortality rate of about 50% (3). A safer analog of these drugs, metformin, is now probably the most widely prescribed antidiabetic drug in the US (1). It is also used to treat polycystic ovary syndrome (PCOS), an endocrine disorder, leading to anovulation (failure to release the egg cell from the ovaries) (4).
Calorie restriction (CR) is the best investigated experimental technique to extend lifespan of a wide range of organisms from yeast to rats (5). Metformin has been suspected for quite a while to be a CR mimetic – a drug that mimics the effects of a CR diet. Indeed, Stephen Spindler found that short-term (8 weeks) of metformin supplementation mimicked 75% of the gene expression changes observed in long-term CR. In contrast, short-term (8 weeks) CR only mimicked 71% of gene expression changes (6). Thus the metabolic effects of metformin supplementation and CR are very similar and suggest that metformin will, like CR, extend the lifespan and reduce the incidence of many degenerative diseases.
Buformin, phenformin, and metformin have been shown to extend the mean and maximal lifespan in mice, rats, and C. elegans – a tiny round worm and one of the most popular model organisms in biological research (4,7,8). It also reduces spontaneous and carcinogen-induced tumor incidence in normal and cancer susceptible mice, rats and hamsters (9,10). Recently it was found that injection of metformin decreased tumor burden by a remarkable 72%, tumor volume by 50%, and multiplicity by 66% in a toxin-induced mice model for lung cancer (11). Epidemiological studies have shown that diabetes patients treated with metformin have a lower risk for cancer compared to those treated with other anti-diabetic drugs (12,13). The use of metformin as an adjuvant therapy in the treatment of cancer is currently under investigation. Finally, metformin also has a positive effect on a wide range of risk factors for coronary heart disease (CVD) such as decreases in plasma triglycerides, total cholesterol, LDL, Lp(a), free fatty acids, and CRP while slightly increasing HDL (4). However, a recent meta-analysis found no significant harm nor benefits of metformin therapy on cardiovascular events (14).
Fig. 1 Pathways influenced by metformin that explain its life extension properties. The blunt ending arrows indicate inhibition while the arrows indicate activation.
The mechanisms for lifespan extension by metformin are not completely understood yet but probably involve AMPK and its downstream target mTOR (fig. 1) (4). mTOR is also the target of the famous life extension drug rapamycin that increases lifespan in mice both when administered early and during middle life (15,16). mTOR inhibits autophagy thus metformin activates autophagy by inhibiting mTOR. Autophagy clears cells from dysfunctional organelles – such as mitochondria – and other junk that can impair normal cellular functions and thereby extends lifespan. mTOR stimulates protein synthesis and for still very incomplete understood reasons protein synthesis reduces lifespan. Therefore again metformin is expected to retard aging. If the cell cycle is arrested – that is the cell temporally stops dividing – and the cell continues to receive growth signals (mTOR stays active), it can lead to cell senescence – a state of permanent cell cycle arrest (4). Senescent cells secrete proinflammatory molecules, this has been termed the senescence-associated secretory phenotype, and can locally stimulate tumor growth (17). Metformin is expected to prevent cell senescence by removing the growth signal pressure. AMPK inhibits NAD(P)H oxidase, an enzyme whose action produces superoxide – a free radical. Metformin thus decreases free radical production (4). Free radicals are molecules that have an unpaired electron, they desperately try to find an extra electron to stabilize their configuration and in the process destroy other molecules by stealing their electrons. The free radical theory of aging is without doubt the most well known mechanistic aging theory. It was first proposed by Denham Harman in 1956 (18). Since then the failure of antioxidants to extend the lifespan has cast doubt on the validity of the free radical theory but still most biogerontologists think that free radicals do play a certain role. In fact some even suggest that the failure of antioxidants is expected because they undermine the bodies stress response (19). AMPK can be activated by: (i) binding of AMP, and (ii) phosphorylation by other enzymes. Metformin has clearly been shown to increase the phosphorylation of AMPK but the effects on AMP are disputed. Phenformin and buformin inhibits complex I of the respiratory chain, so maybe metformin does so too. Such an inhibition would decrease ATP – the universal energy currency for life – production and thereby increase AMP levels.
ADP + Pi ⇔ ATP
ADP + ADP ⇔ AMP + ATP
AMP acts as an activator for AMP and thus complex I inhibition would activate AMPK. This one year study found that metformin inhibits complex I (20) while another one found no such inhibition (21). This is good and bad news. The inhibition of complex I is responsible for lactic acidosis induced by phenformin and buformin and since metformin does not inhibit complex I it is much safer. Indeed, in a meta-analysis of published reports and controlled trials for a total of 36000 patient years of metformin exposure, Salpeter et al. found no cases of metformin-induced lactic acidosis (22). However, several case reports have been published in the literature (23). A common factor among all cases is that the patients have contra-indicators for the use of metformin such as renal problems and heart failure. Of the 47 patients with confirmed metformin-induced lactic acidosis by 1998 only 4 did not have any contra-indications for its use and all 4 recovered (24). The bad news is that complex I inhibition is expected to decrease free radical leakage (4). Metformin has been shown to prevent protein cross-linking (4).
Chemically metformin is very similar to aminoguanidine (fig. 2), one of the most researched inhibitors of glycation (for a review on glycation and protein cross-linking see 25). AGEs activate RAGE – a cell membrane receptor – leading to inflammation. Metformin has been shown to reduce inflammation in cells exposed to AGEs (26). Metformin reduces IGF-1 – a peptide hormone that stimulates growth. Mice with mutations in the growth hormone signaling pathway have lover IGF-1 levels and life 25-60% longer than control mice (27,28). Based on research in C. elegans and some suggestive evidence in mice (lower IGF-1 in the growth hormone pathway mutant mice) it has been concluded that decreasing IGF-1 will probably extend lifespan (29). Recently it was shown that metformin protects against replicative stress (30).
Fig. 2 Structural relationship between metformin and aminoguanidine. Both contain a guaninium-group (as is also found in the side chain of arginine).
In my recent review (4) I have suggested that AMPK might not be involved in life span extension by CR because of the inconsistent results of several studies on how CR influences AMPK (activation, no-activation, or inhibition). AMPK might however ’intersect’ with the ‘CR-pathway’ and thus I’ve termed metformin an ‘indirect CR mimetic’ (fig. 3). This model also explains why CR and metformin have some different metabolic effects.
Fig. 3 Metformin as an indirect CR mimetic. The blue dots represent different steps (protein cascade) in the ‘CR pathway’. Note that even though for simplicity the pathway is represented as a linear series of steps, in reality it will be a complex network that intersects with many other pathways. The double arrow between AMPK and ‘other signaling pathways’ illustrates that other signaling pathways can activate AMPK and thus influence the ‘CR pathway’ but that activation of AMPK, for example by metformin, can also activate other pathways that are independent of the ‘CR pathway’ (idem dito for the other double arrow) (see: ref. 4).
Rapamycin is a very expensive drug, about 500 USD a month for a daily dose of 2mg. Metformin, on the other hand, is extremely cheap and its side effects are more moderate. Metformin does inhibit vitamin B12 absorption in about 10% (but in some studies up to 30%) of treated patients (31,32). Thus blood levels vitamin B12 should be regularly tested. In conclusion we can say that metformin is an interesting candidate for a cheap and safe CR mimetic.
NOTE:Statements herein have not been evaluated by the FDA or any regulatory body. LongeCity does not promote the off-label use of any drug without appropriate medical supervision.
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