Archive for the ‘ Survival ’ Category

Chicago police were questioning four African-Americans Wednesday evening over a Facebook Live video that showed a mentally disabled white man being tied up and tortured while someone yelled F— white people! and F— Donald Trump!

Source: Four arrested after Facebook Live video shows man being tied up, beaten

World’s Oldest PersonBorn on 29 November 1899, Emma Morano is 116 years old and is currently the world’s oldest living person. She is believed to be the last person living born in the 19th century. So, what’s her secret to longevity? Well, she has been following the same diet for around 90 years. She has three eggs per day (two raw, one cooked), fresh Italian pasta and a dish of raw meat.

Source: 50 Unique Women Who Deserve The Spotlight – Page 24 of 50 – Viral Scoop

Ten years ago, Shinya Yamanaka revolutionized biological research with his discovery of how to turn ordinary skin cells into stem cells with just four key genes.

Source: Reflecting on the Discovery of the Decade: Induced Pluripotent Stem Cells | Gladstone Institutes

Mice were rejuvenated through a four-gene cocktail that allowed them to repair aging signs including loss of hair and organs malfunction. There were no signs of cancer and compared to untreated mice, the reprogrammed mice looked younger, with better organ function, improved cardiovascular performance and lived 30 percent longer.

Source: Study shows aging might be reversible thanks to cells group

No, your pubic hair cannot prevent STDs.

Source: Myths about pubic hair you must stop believing t1216 | Photo Galleries of Weight Loss, Diet Plan, Healthy Recipes, Sexual Health | TheHealthSite.com

For decades, neuroscientists and physicians have tried to get to the bottom of the age-old mystery of post-traumatic stress disorder, to explain why only some people are vulnerable and why they experience so many symptoms and so much disability.

All experts in the field now agree that PTSD indeed has its roots in very real, physical processes within the brain — and not in some sort of psychological “weakness.” But no clear consensus has emerged about what exactly has gone “wrong” in the brain.

In a Perspective article published this week in Neuron, a pair of University of Michigan Medical School professors — who have studied PTSD from many angles for many years — put forth a theory of PTSD that draws from and integrates decades of prior research. They hope to stimulate interest in the theory and invite others in the field to test it.

The bottom line, they say, is that people with PTSD appear to suffer from disrupted context processing. That’s a core brain function that allows people and animals to recognize that a particular stimulus may require different responses depending on the context in which it is encountered. It’s what allows us to call upon the “right” emotional or physical response to the current encounter.

A simple example, they write, is recognizing that a mountain lion seen in the zoo does not require a fear or “flight” response, while the same lion unexpectedly encountered in the backyard probably does.

For someone with PTSD, a stimulus associated with the trauma they previously experienced — such as a loud noise or a particular smell — triggers a fear response even when the context is very safe. That’s why they react even if the noise came from the front door being slammed, or the smell comes from dinner being accidentally burned on the stove.

Context processing involves a brain region called the hippocampus, and its connections to two other regions called the prefrontal cortex and the amygdala. Research has shown that activity in these brain areas is disrupted in PTSD patients. The U-M team thinks their theory can unify wide-ranging evidence by showing how a disruption in this circuit can interfere with context processing and can explain most of the symptoms and much of the biology of PTSD.

“We hope to put some order to all the information that’s been gathered about PTSD from studies of human patients, and of animal models of the condition,” says Israel Liberzon, M.D., a professor of psychiatry at U-M and a researcher at the VA Ann Arbor Healthcare System who also treats veterans with PTSD. “We hope to create a testable hypothesis, which isn’t as common in mental health research as it should be. If this hypothesis proves true, maybe we can unravel some of the underlying pathophysiological processes, and offer better treatments.”

Liberzon and his colleague, James Abelson, M.D., Ph.D., describe in their piece models of PTSD that have emerged in recent years, and lay out the evidence for each. The problem, they say, is that none of these models sufficiently explains the various symptoms seen in patients, nor all of the complex neurobiological changes seen in PTSD and in animal models of this disorder.

The first model, abnormal fear learning, is rooted in the amygdala — the brain’s ‘fight or flight’ center that focuses on response to threats or safe environments. This model emerged from work on fear conditioning, fear extinction and fear generalization.

The second, exaggerated threat detection, is rooted in the brain regions that figure out what signals from the environment are “salient,” or important to take note of and react to. This model focuses on vigilance and disproportionate responses to perceived threats.

The third, involving executive function and regulation of emotions, is mainly rooted in the prefrontal cortex — the brain’s center for keeping emotions in check and planning or switching between tasks.

By focusing only on the evidence bolstering one of these theories, researchers may be “searching under the streetlight,” says Liberzon. “But if we look at all of it in the light of context processing disruption, we can explain why different teams have seen different things. They’re not mutually exclusive.”

The main thing, says Liberzon, is that “context is not only information about your surroundings — it’s pulling out the correct emotion and memories for the context you are in.”

A deficit in context processing would lead PTSD patients to feel “unmoored” from the world around them, unable to shape their responses to fit their current contexts. Instead, their brains would impose an “internalized context” — one that always expects danger — on every situation.

This type of deficit, arising in the brain from a combination of genetics and life experiences, may create vulnerability to PTSD in the first place, they say. After trauma, this would generate symptoms of hypervigilance, sleeplessness, intrusive thoughts and dreams, and inappropriate emotional and physical outbursts.

Liberzon and Abelson think that testing the context processing theory will enhance understanding of PTSD, even if all of its details are not verified. They hope the PTSD community will help them pursue the needed research, in PTSD patients and in animal models. They put forth specific ideas in the Neuron paper to encourage that, and are embarking on such research themselves.

The U-M/VA team is currently recruiting people with PTSD — whether veterans or not — for studies involving brain imaging and other tests.

In the meantime, they note that there is a growing set of therapeutic tools that can help patients with PTSD, such as cognitive behavioral therapy mindfulness training and pharmacological approaches. These may work by helping to anchor PTSD patients in their current environment, and may prove more effective as researchers learn how to specifically strengthen context processing capacities in the brain.

Source: What’s really going on in PTSD brains? Experts suggest new theory — ScienceDaily

February 13, 2013

Shocking Alien Fears Force Pope From Office

By: Sorcha Faal, and as reported to her Western Subscribers

 

A stunning Ministry of Foreign Affairs (MFA) report prepared for President Putin, which is circulating in the Kremlin today, states that Pope Benedict XVI was forced to resign this past week over Catholic Church fears that this 85-year-old leader of over 1 billion Christians was “mentally and physically unprepared” to deal with the coming revelation about the truth of alien beings.

In our 22 January report, Russia Orders Obama: Tell World About Aliens, Or We Will, we detailed how the issue of extraterrestrial beings was brought to the forefront of the World Economic Forum (WEF) with the naming in their 2013 Executive Summary of the danger posed to our world over the discovery of alien life with their stating: “Proof of life elsewhere in the universe could have profound psychological implications for human belief systems.”

Also noted in our previous report were Prime Minister Medvedev’s 7 December 2012 off-air comments to reporters which were recorded and wherein he stated: “Along with the briefcase with nuclear codes, the president of the country is given a special ‘top secret’ folder. This folder in its entirety contains information about aliens who visited our planet… Along with this, you are given a report of the absolutely secret special service that exercises control over aliens on the territory of our country… More detailed information on this topic you can get from a well-known movie called Men In Black… I will not tell you how many of them are among us because it may cause panic.”

Spurring Pope Benedict XVI to become the first leader of the Catholic Church to resign in nearly 600 years, this MFA report says, was the appearance over Los Cristianos, Spain on 21 August 2011 of the long prophesized “bird of prey” interplanetary spacecraft, and which was followed nearly 3 weeks ago with a fleet of them appearing in the skies over Mexico City.

To fully understand the significance of these “bird of prey” UFO’s, this report continues, files relating to the 27 September 1989 Voronezh Incident must be studied in length, especially as it relates to the “messages” delivered to eyewitnesses from the “giants”.

In an 11 October 1989 New York Times article about the Voronezh Incident titled U.F.O. Landing Is Fact, Not Fantasy, the Russians Insist it says:

“It is not a joke, nor a hoax, nor a sign of mental instability, nor an attempt to drum up local tourism by drawing the curious, the Soviet press agency Tass insisted today in discussions of what it called an extraterrestrial visit to southern Russia.

Residents of the city of Voronezh insisted today that lanky, three-eyed extraterrestrial creatures had indeed landed in a local park and gone for a stroll and that a seemingly fantastic report about the event carried Monday by the official press agency Tass was absolutely true.

The three-eyed creature, about nine feet tall and fashionably dressed in silvery overalls and bronze boots and with a disk on its chest, disappeared, then landed and came out for a promenade with a companion and a robot.

The aliens seemed to communicate with each other, producing the mysterious appearance of a shining triangle, and activated the robot with a touch.”

Regarding these “messages” from the Voronezh “giants”, this MFA report says, was the warning to human beings that when these “bird of prey” UFO’s descend upon Earth the whole planet will be in peril.

The Voronezh “giants” further related, this report says, that the alien beings associated with these “bird of prey” UFO’s were the cause of the 14 April 1561 massive “sky battle” over Nuremberg, Germany which was depicted in a famous 16th century woodcut by Hans Glaser [photo 3rd left] and described by the residents as: “A very frightful spectacle.” “The sky appeared to fill with cylindrical objects from which red, black, orange and blue white disks and globes emerged. Crosses and tubes resembling cannon barrels also appeared whereupon the objects promptly began to fight one another.”

Important to note is that the Catholic Christian faith headed by Pope Benedict XVI, as well as nearly every other religion on Earth, all prophesize in their teachings a time when the “gods” will return to our planet and engage in a battle that could very well bring our entire planet to the brink of destruction.

Equally important to note about Pope Benedict XVI’s shock resignation is how it eerily compares with Saint Malachy, who as an Irish saint and Archbishop of Armagh, in the 12th Century, received a vision of 112 Popes later attributed to the apocalyptic list of Prophecy of the Popes. He was the first Irish saint to be canonized by Pope Clement III in 1199.

American authors Tom Horn and Cris Putnam in their 2012 book “Petrus Romanus: The Final Pope is Here” about Saint Malachy’s prophecies told interviewers last Spring that Pope Benedict XVI would resign by late 2012, or early 2013, and described the next Pope to follow as “Petrus Romanus,” or “Peter the Roman,” writing: “In the final persecution of the Holy Roman Church there will reign Peter the Roman, who will feed his flock among many tribulations; after which the seven-hilled city will be destroyed and the dreadful Judge will judge the people.”

Though the masses of people reading of the things this report contains will, undoubtedly, ridicule them, the same cannot be said of the elite moneyed classes who, even at this writing, are protecting themselves from “something” at such a fever-pitched pace it is destabilizing the entire global economy, and as exampled by the highly respected Zero Hedge news service in their article titled “What Do They Know That We Don’t?” and which, in part, says:

“Friday evening when no one was supposed to pay attention, Google announced that Executive Chairman Eric Schmidt would sell 3.2 million of his Google shares in 2013, 42% of the 7.6 million shares he owned at the end of last year—after having already sold 1.8 million shares in 2012. But why would he sell 5 million shares, about 53% of his holdings, with Google stock trading near its all-time high?

“Part of his long-term strategy for individual asset diversification and liquidity,” Google mollified us, according to the Wall Street Journal. Soothing words. Nothing but “a routine diversification of assets.”

Routine? He didn’t sell any in 2008 as the market was crashing. He didn’t sell at the bottom in early 2009. And he didn’t sell during the rest of 2009 as Google shares were soaring, nor in 2010, as they continued to soar. In 2011, he eased out of about 300,000 shares, a mere rounding error in his holdings. But in 2012, he opened the valves, and in 2013, he’d open the floodgates. So it’s not “routine.”

Mr. Schmidt isn’t alone. Corporate insiders were “aggressively selling their shares,” reported Mark Hulbert. And they were doing so “at an alarming pace.” The buy sell-to-buy ratio had risen to 9.2-to-1; insiders had sold over 9 times as many shares as they’d bought. They’d been aggressive sellers for weeks.

Instantly, soothing voices were heard: “don’t be alarmed,” they said. But Mr. Schmidt and his colleagues at the top of corporate America, multi-billionaires many of them, are immensely well connected, not only to each other but also to the Fed, whose twelve regional Federal Reserve Banks they own and control.”

To why Google Chairman Schmidt did not attend this years World Economic Forum, where the danger of aliens was being discussed, opting instead for a visit to North Korea (who announced yesterday that they had exploded another nuclear weapon) and when coupled with the information contained in this MFA report, is far from being “soothing”, and is, instead, something well all should be very alarmed about as the end is much nearer than the beginning as those with “eyes to see” and “ears to hear” already know.

February 13, 2012 © EU and US all rights reserved. Permission to use this report in its entirety is granted under the condition it is linked back to its original source at WhatDoesItMean.Com. Freebase content licensed under CC-BY and GFDL.

[Ed. Note: Western governments and their intelligence services actively campaign against the information found in these reports so as not to alarm their citizens about the many catastrophic Earth changes and events to come, a stance that the Sisters of Sorcha Faal strongly disagrees with in believing that it is every human beings right to know the truth. Due to our missions conflicts with that of those governments, the responses of their ‘agents’ against us has been a longstanding misinformation/misdirection campaign designed to discredit and which is addressed in the report “Who Is Sorcha Faal?”.]

You May Already Be To Late…But It Has Begun!

They Are Going To Come For You…Why Are You Helping Them?

Source: Shocking Alien Fears Force Pope From Office

According to Daniel Sheehan, the Catholic Church is now actively preparing for the discovery of Alien contact with highly a advanced alien species. Speaking at contact in the desert, he told of a what will be a historic papal encyclical decree calling for nothing less than the disassembly of the power structures that are destroying our civilisation and preventing us from joining an enlightened galactic community.Pope Francis previously caused quite a stir last year when he announced that he would baptise Aliens, quite a statement and a timely one at that given the fact the Vatican owns the biggest telescope on the planet.Former Minsitry Of Defence Nick Pope Told Neon Nettle: “It’s no secret that the Catholic Church has been repositioning themselves on this issue over the past few years. Do they know something? I doubt it. I think they’re just trying to ensure that if the scientific community announces the discovery of extraterrestrial life, the church is prepared.”Sheehan’s talk began with a summary of his previous work as an advocate for alien disclosure which, he says, also included classified sections from Project Bluebook (a study into UFO’s by the American airforce). He went on to say that his access to Bluebook gave him exposure to photographic evidence of crashes UFO’s that had Alien symbols on them.daniel p sheehan a harvard college trained american government foreign policy scholar talks about alien disclosure through the vatican © pressDaniel P. Sheehan, a Harvard College trained American Government & Foreign Policy Scholar talks about alien disclosure through the vaticanhttp://www.neonnettle.com/news/1447-pope-francis-to-announce-church-prep…

Source: Pope Francis To Announce Church Preparing For Alien Contact This Week (their-we are already here billions of years – CNN iReport

Vatican Approves UFOs

Vatican officials affirm the existence of UFOs and calls the aliens brothers, interviews with Msgr. Corrado Balducci and Fr. Gabriel Funes, News reveal secret talks with the UN on aliens and UFOS and agreement of possibility of the existence of extraterrestial life

Vatican Approves UFOs

‘The Aliens Are Our Brothers’

Dear Atila,

Salve Maria!

I believe you and TIA readers will be interested to know that the Vatican now is supporting the UFOs, according to the news reports below. I made a little research on the Internet and found these documents, whose value you may judge for yourself.

I gave the links to the sources so that you or anyone else can check the original documents. I also added links to the two principal Youtube interviews on the topic: one by Msgr. Corrado Balducci, a Vatican consultant on these matters; another by Fr. Gabriel Funes, the Chief Vatican Astronomer, whose Observatory is in the papal palace of Castelgandolfo.

Receive my best regards,

In Jesu et Maria,

Manoel Ricardo Fiuza, Brazil

______________________

News report from 2000

Monsignor Balducci is a Vatican theologian and an insider close to the Pope. He has been featured on national Italian television numerous times stating that extraterrestrial contact is a real phenomenon and “not due to some psychological impairment.”

In this testimony he explains that not only the general populace but also highly credible, cultured and educated people of high status are increasingly acknowledging that this is a real phenomenon. He goes on to speak about the extraterrestrial people as part of God’s Creation and affirm that they are neither angels nor devils. However, he affirms, they are probably more spiritually evolved.

Source here

______________________

News reports from April 7, 2012

The Vatican tries to get a step ahead on Extraterrestrial issues before announcements by major world governments

The Vatican is playing a leading role preparing the world for disclosure about extraterrestrials.

There are few things that are sure bets in this life and one of them is that the Vatican would never have stepped out to tell the world that they believe extraterrestrials are real without emphatic proof or advance knowledge that some type of disclosure is imminent.

The Vatican is not a cutting edge group; it generally moves so slow that it is painful to much of the world’s congregation. After all, this is the same organization that to this day does not allow women to be priests or any form of contraception. This is the same organization that forced Galileo to recant his findings and put him under house arrest for the remainder of his life for telling the world that the earth is not at the center of the universe.

Msgr. Corrado Balducci 

Msgr. Corrado Balducci

For the most part, the Vatican is stodgy, archaic, slow to move on major issues and generally behind the times. So what prompted them to move at lightening speed on the difficult issue of extraterrestrials life and full disclosure?

Well, they have been receiving information from their embassies that is hard to deny and they have attended a series of secret meetings in NYC at the UN that changed everything. Shortly after that, the Vatican gave the “Aliens Are My Brothers Interview,” which should have made worldwide headlines, but it was typically played down by the mainstream media.

The Vatican’s new openness on extraterrestrial life is consistent with reports of secret discussions held at the United Nations that began in February 2008 and are still ongoing today. The Vatican’s permanent representative to the UN, Archbishop Celestino Migliore, was reported to have attended these meetings along with a number of other prominent government officials to discuss increasing UFO sightings and the implications of extraterrestrial visitations.

Significantly, Migliore’s position requires that he maintain close relations with the Vatican’s Pontifical Academy of Sciences. At the time of the secret UN discussions, Migliore made a presentation on moral issues associated with scientific problems such as climate change. Most importantly, the UN discussions reportedly led to a new policy of openness on UFOs that is being adopted by approximately 30 nations beginning in 2009 and culminating with a full disclosure of information to the world. This is extremely significant as there are approximately 22 nations that have begun full or partial disclosure!

For a full list of countries that have partially disclosed significant UFO or alien information, click here.

The meetings that the Vatican took part in with the UN in New York City were also attended by a host of US government agencies that downplayed the announcement. We can only speculate about the agencies involved and the content discussed. You can be sure it was blockbuster news because, shorty afterwards, both the UN and the Vatican came out with their startling announcements.

Source here

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Vatican Official Declares on National Television:
Extraterrestrial Contacts Are Real

Some things simply cannot be debunked as much as people would like, no matter how hard the debunkers try. Sometimes the truth just keeps rising to the surface, and this is one of those times.

Monsignor Corrado Balducci, a theologian member of the Vatican Curia, the governing body, and highly placed Vatican official who is close to the Pope, has been on Italian Television no less than five times stating that extraterrestrial contact is a real phenomena.

Balducci provided an analysis of extraterrestrials that he feels is consistent with the Catholic Church’s understanding of theology. Monsignor Balducci emphasized that extraterrestrial encounters “are not demonic. They are not due to some psychological impairment. They are not a case of entity attachment, but rather these encounters deserve to be studied carefully.” Since Monsignor Balducci is a demonology expert and consultant to the Vatican and since the Catholic Church has historically demonized many new phenomena that were poorly understood, his statement that the Church does not censure these encounters is all the more remarkable.

The bottom line is that the Vatican has moved lightening fast on the extremely difficult issue of extraterrestrials and religion; they have attended secret meetings at the UN on exactly this subject. They have also met in secret with a host of US officials, and, after evaluating all the information, they made their astounding announcement.

It really makes no difference if you believe that the Vatican and UN announcement is a prelude to a false flag event or that it is real. One thing is for certain, some type of disclosure (probably partial or limited) is imminent and coming soon. It will be up to each person to decide on the authenticity of the actual announcement. The question becomes: Are we paying attention or are we asleep at the switch? We are all in for a Galileo Moment and those only come along every 200 to 300 years. Are you ready?

Source here

______________________
Vatican States: ‘Aliens Are Our Brothers,’
Interview with Religious Leaders on Aliens

In an interview entitled “Aliens Are My Brother” granted to L’Osservatore Romano, the Vatican newspaper, Father Gabriel Funes, director of the Vatican Observatory, stated: “In my opinion this possibility (of life on other planets) exists.” He also stated that “intelligent beings, created by God may exist in outer space” and “some aliens could even be free from original sin,” concluding that “there could be (other beings) who remained in full friendship with their creator”.

Fr. Gabriel Funes, Vatican Astronomer

Speaking about the search for Earth-like worlds about to be embarked upon with the Kepler Space telescope, Jesuit Brother Guy Consolmagno, another astronomer working at the Vatican Observatory, told the BBC, “We Jesuits are actively involved in the search for Earth-like planets.”

He continued, “The idea that there could be other intelligent creatures made by God in a relationship with God is not contrary to traditional Judeo-Christian thought. The Bible has many references to, or descriptions of, non-human intelligent beings; after all, that’s what angels are. Our cousins on other planets may even have their own salvation story – including other examples of the incarnation of the second person of the Trinity. We are open to whatever the Universe has for us.”

Source here

_________________

Source: Vatican Approves UFOs

1. Your partner shows up unannounced

Showing up at work unexpectedly is one of the signs your partner doesn’t respect you Surprising you with flowers on a random Wednesday is a welcome treat; showing up unannounced when you’re clearly busy or have a lot going on is not. If you find your partner repeatedly popping up at inopportune times, at inconvenient places, there’s a problem. As mentioned in The Frisky, if he or she shows up at your work, class, or home unannounced and uninvited, causing a scene, they don’t respect you.

2. Your partner uses gaslighting techniques

If you often find your partner using sneaky techniques to keep you in check, he or she doesn’t respect you. According to Your Tango,

“Gaslighting is a phrase assigned to an emotional abuse technique that has one partner convincing the other that reality is an illusion.

If your partner is denying they said and did things or blaming you for saying and doing things you didn’t, it’s abusive.” Have you ever known a person who, no matter how at fault they may be, somehow seems to vaguely skate over the issue, turning around on you? Dealing with a person like this is infuriating. If this is your partner’s norm, it’s likely it will never change.

 

3. Your partner treats sex as a transaction

A partner should never use sex as a tool Anytime a person expects sex in exchange for something, the most basic form of respect is tossed out the window. Sex should never be used as a method of coercion or a form of payment. It’s your body, and it certainly doesn’t belong to anyone else, no matter how committed two partners may be. If your partner does the chores, is it your job to owe them a sexual favor? No. Sadly, though, not everyone takes the same stance on the issue. Case in point — this article from The Stir that calls out Pat Robertson, host of a call-in show, who has claimed that wives should thank their husbands with sex each time they do chores around the house. No, just no.

4. Your partner isn’t proud of you

As you’ve strived for your parents’ approval throughout your life, seeking those heavily-weighted words of acceptance, you want the same from your partner. To hear “I’m proud of you,” from someone you respect is a big deal, and it’s important that both partners take pride in the relationship. When your partner is proud of you, and proud to be with you, Bustle says, there’s a mutual respect for one another. Could you imagine being in a relationship in which your significant other doesn’t really think you’ve worked hard for your career? Without a partner who’s genuinely proud of you, your accomplishments, and your overall contributions to your relationship, they clearly don’t realize or value your worth, and you shouldn’t stand for that. Ever.

5. Your partner refuses to compromise or negotiate

It is only natural the person closest to you will get under your skin, and part of a relationship is being able to discuss life’s major challenges as a team. But when one person in a relationship isn’t willing to act as a team, there’s bound to be long-term issues. A big part of respecting someone is being able to reach a compromise in which both parties are satisfied with the outcome. The Centers for Family Change says, “Respect is established when you consistently: consider and value the feelings and opinions of your partner; talk to and treat your partner in ways that you would want to be treated; and compromise and negotiate with your partner.” If you and your partner aren’t doing this, you’re not getting the respect you deserve.

Source: 5 Signs That Your Partner Doesn’t Respect You

“Remember, our nonviolent ETI from the contiguous universe are helping us bring zero point energy to Earth,” Podesta was told. “They will not tolerate any forms of military violence on Earth or in space.” The reference to ETI – extraterrestrial intelligence – set off alarm bells. So did mention of zero point energy, which its fans claim could be harnessed as an inexhaustible power supply.

How aliens and Apollo astronaut Edgar Mitchell got tangled up in WikiLeaks emails

Edgar Mitchell and Alan Shepard
Edgar Mitchell and Alan Shepard
Galatians 1:8 (NKJV) 8 But even if we, or an angel from heaven, preach any other gospel to you than what we have preached to you, let him be accursed.
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WikiLeaks’ purloined emails cover a wide range of issues that were handled by Hillary Clinton’s campaign chairman, John Podesta, in them are clear references to issues that have to do with E.T., alien energy sources and Apollo 14 astronaut Edgar Mitchell’s efforts to educate the public (DISCLOSURE) about Aliens from outer space before he died.

While GOP presidential candidate Donald Trump focused his fire on what the WikiLeaks file had to say about Clinton’s Wall Street speeches as a way to distract the public from the larger issue, UFO fans dwelled on what Mitchell was telling Podesta as he made the transition from the Obama White House to the Clinton campaign in 2015.

In an email from January of that year, Mitchell asked for an urgent meeting with Podesta about “(DISCLOSURE) and zero point energy,” and promised that a colleague named Terri Mansfield would “bring us up to date on the Vatican’s awareness of ETI.”

Mitchell sent another plea via email that August.

“Remember, our nonviolent ETI from the contiguous universe are helping us bring zero point energy to Earth,” Podesta was told. “They will not tolerate any forms of military violence on Earth or in space.”

The reference to ETI – extraterrestrial intelligence – set off alarm bells. So did mention of zero point energy, which its fans claim could be harnessed as an inexhaustible power supply.

“Hillary Clinton Leaked E-Mails Reveal Shocking Discussions on SPACE WARS, UFOs and ETs,” one of the more breathless (and search-optimized) headlines read.

But in fact, Mitchell never met with Clinton – or with Podesta, for that matter. “The meeting with Podesta, sadly, never took place,” Carol Rosin, one of Mitchell’s longtime collaborators, told GeekWire today in an email.

Rosin and Mansfield confirmed that Mitchell was indeed the author of the two emails, even though they went out via Mansfield’s email address, terribillionairs@aol.com. They said they worked with an aide to Podesta in hopes of arranging a meeting with him to discuss a treaty to ban weapons in outer space.

Rosin noted that Mitchell and Podesta shared an interest in extraterrestrial (DISCLOSURE).

“As you know, Dr. Mitchell was courageously educating people about the fact that ‘we are not alone,’ that there is no evidence of there being any hostile ETs here or coming to control, intervene or harm us, that we can have zero point energy, that there are no weapons based in space and that this is the unique time in history when our leaders can sign and ratify the ‘Treaty on the Prevention of the Placement of Weapons in Outer Space’ that has been introduced by the leaders of Russia and China,” Rosin said.

So, what about Podesta? When he left the White House in February 2015, he said in a tweet that his biggest regret of the previous year was “once again not securing the disclosure of the UFO files.”

“I’ve talked to Hillary about that,” Podesta told KLAS-TV this March during a campaign stop in Las Vegas. “There are still classified files that could be declassified.”

Podesta hasn’t discussed what might be in those files, but Clinton has vowed to “get to the bottom” of any mystery that still surrounds the UFO phenomenon.

Two other emails in WikiLeaks’ Podesta file were sent by Tom DeLonge, a veteran of the rock band Blink-182. Those emails refer to a UFO-related documentary project – perhaps the “Sekret Machines” multimedia project that DeLonge kicked off this year.

In an email from last October, DeLonge told Podesta that he’s “the one who interviewed you for that special documentary,” relating to “our sensitive topic.” In the other email, sent this January, DeLonge referred to Air Force Maj. Gen. William McCasland in connection with the 1947 Roswell UFO incident.

Roswell was of interest to Mitchell as well. When I interviewed him in 2014, he acknowledged that he relied on the claims that others have made about Roswell and other UFO sightings. That secondhand perspective also probably applies to Mitchell’s reference to the Vatican connection.

Even if Clinton (or Trump) comes across new revelations, it’ll be too late for Mitchell. He passed away this February at the age of 85. Nevertheless, there may yet be more to come from the late moonwalker. “The book Edgar and I wrote decades ago will soon be published,” Rosin said in her email.

Remember when they come:

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More from GeekWire:

Source: How aliens and Apollo astronaut Edgar Mitchell got tangled up in WikiLeaks emails

A ‘sixth sense’ which goes beyond the basic five senses of taste, smell, touch, sight and hearing, has apparently been discovered in America

A ‘sixth sense’ really does exist, scientists claim – but it’s got nothing to do with being able to see dead people.

Researchers in America say they have discovered the ‘intuition’ gene , which goes beyond the basic five senses of taste, smell, touch, sight and hearing.

This apparent sixth sense affects ‘proprioception’ or body awareness.

The discovery was made with the help of two young patients with a rare genetic neurological disorder who have a mutation in the ‘Piezo2’ gene affecting their body awareness.

When blindfolded, the pair were completely unable to walk without falling.

They also couldn’t track the position of their arms and legs as researchers gently moved them – something most people can do without looking.

While they were insensitive to certain kinds of touch, the pair – aged nine and 19 – could still feel pain, itch, temperature and gentle brushing.

6th Sense
Haley Joel Osment’s character in The Sixth Sense was able to see ghosts, but scientists believe our real sixth sense relates to body awareness

Neurologist Dr Carsten Bonnemann, of the National Institutes of Health in Maryland, US, said: “Our study highlights the critical importance of Piezo2 and the senses it controls in our daily lives.

“The results establish Piezo2 is a touch and proprioception gene in humans.

“Understanding its role in these senses may provide clues to a variety of neurological disorders.”

The two unrelated patients both have difficulties walking, possessing hip, finger and foot deformities and abnormally curved spines diagnosed as progressive scoliosis.

Pea-sized ‘human lungs’ have been grown in a lab and could revolutionise treatments

Dr Bonnemann discovered the patients have mutations in Piezo2 which seem to block the normal production or activity of proteins in cells generating electrical nerve signals.

Co-author Dr Alexander Chesler said: “As someone who studies Piezo2 in mice working with these patients was humbling.

“Our results suggest they are touch-blind. The patient’s version of Piezo2 may not work so their neurons cannot detect touch or limb movements.”

Scientist examining test tube in laboratory
Scientists say the Piezo2 gene is linked to our ‘sixth sense’ and relates to body awareness (Photo: Getty)

The researchers found blindfolding made it harder for them to reliably reach for an object in front of their faces than it was for unaffected volunteers.

The patients were also less sensitive to certain forms of touch.

They could not feel vibrations from a buzzing tuning fork as well as the control subjects could.

Britain in major HIV cure breakthrough as NHS patient stuns doctors with ‘remarkable progress’

But the patients’ nervous systems appeared to be developing normally. They were able to feel pain, itch and temperature normally.

The nerves in their limbs conducted electricity rapidly and their brains and cognitive abilities were similar to healthy controls of their age.

Dr Bonnemann said: “What’s remarkable about these patients is how much their nervous systems compensate for their lack of touch and body awareness.”

The study was published in the New England Journal of Medicine .

Source: ‘Sixth sense does exist’ scientists claim – but it’s nothing to do with ghosts – Mirror Online

Solar Physicists finally get the message: Landscheidt was right after all Posted: June 14, 2011 by tallbloke in Astrophysics, climate, Solar physics, solar system dynamics After years of pooh poohing Theodor Landscheidt’s methods, work and predictions, mainstream solar physics has made an announcement of the strong possibility of a protracted solar minimum with consequences for Earth’s climate. At a workshop in New Mexico today, the AAS brought the work of Livingstone and Penn into the spotlight and

Source: Solar Physicists finally get the message: Landscheidt was right after all | Tallbloke’s Talkshop

“Having a plan could be the difference between life and death.”

An axe, life vest, and helmet…….

Source: Hurricane Matthew leaves 11 dead in destructive march toward U.S.

Driven by technological progress, human life expectancy has increased greatly since the nineteenth century. Demographic evidence has revealed an ongoing reduction in old-age mortality and a rise of the maximum age at death, which may gradually extend human longevity. Together with observations that lifespan in various animal species is flexible and can be increased by genetic or pharmaceutical intervention, these results have led to suggestions that longevity may not be subject to strict, species-specific genetic constraints. Here, by analysing global demographic data, we show that improvements in survival with age tend to decline after age 100, and that the age at death of the world’s oldest person has not increased since the 1990s. Our results strongly suggest that the maximum lifespan of humans is fixed and subject to natural constraints.

Source: Evidence for a limit to human lifespan : Nature : Nature Research

An estimated 180,890 American men will be diagnosed with prostate cancer this year. The disease will also take the lives of 26,120 patients. But according to a new 10-year study conducted on more than 1,500 men in the United Kingdom, those who are diagnosed may want to hold off on starting aggressive treatment right away.Typically, men who are diagnosed with prostate cancer are given several options: Have surgery to remove all or part of the gland, undergo radiotherapy to reduce any tumors, or take a “watch and wait” active monitoring approach, which involves additional screenings and biopsies but no treatment, as the cancer can grow so slowly that it often doesn’t present a medical problem for those who have it. The study, published Wednesday in the New England Journal of Medicine, found that men who received treatment ― either surgery or radiotherapy ― were better able to limit their cancer from spreading. But this didn’t necessarily mean immediate treatment led to better overall outcomes. Among the men who took a “watch and wait” approach, nearly half didn’t need any additional treatment. As a result, they avoided the negative side effects that come with surgery and radiation, such as bowel and urinary incontinence, sexual dysfunction and life-threatening cardiovascular issues. Indeed, no matter what approach the men were randomized to, they weren’t likely to die of either the cancer itself, cancer treatment or other causes after ten years. That said, the patients in this study are still being followed because deaths from prostate cancer are usually measured after 15 to 20 years. “This paper really underscores that an active surveillance approach is good for many patients, but there are some who still need upfront treatment,” said Dr. Timothy J. Daskivich, a urologic oncologist and director of health services research for the Cedars-Sinai department of surgery in Los Angeles. “Time will tell if we can sort these patients out in the future.”While some men will need immediate treatment, further developments that help urologists identify low-risk and high-risk patients will be key to making sure that only men who need it the most will have to undergo surgery or radiation.How outcomes differed according to the treatmentThe Prostate Testing for Cancer and Treatment (ProtecT) trial recruited U.K. men ages 50 to 69 from 1999 to 2009. Of 2,664 men who received a diagnosis of prostate cancer, 1,643 agreed to be randomized to any one of three of the most common prostate cancer treatments: active monitoring (545 men), radical prostatectomy (553 men) or radiotherapy (545 men).The men were not further classed into low- or high-risk groups based on the features of their tumor or the levels of prostate-specific antigens in their blood. This is what the researchers found: There was no difference in death rates. The scientists followed up with the men after a median of 10 years and found that while there were less prostate cancer-specific deaths in the groups that got radiation or surgery, the difference was not significant, and all groups had at least a 98.8 percent survival rate when it came to prostate cancer-specific deaths. In all, the death rate from prostate cancer across all groups was about one percent after a median of ten years.There was a difference in the rate of cancer spread. Of the men who were randomized to the active monitoring group, 112 experienced disease progression, including cancer spread, which was higher than in the surgery and radiation groups (46 and 46, respectively). While there appears to be a slight advantage to getting treated immediately after a prostate cancer diagnosis to avoid cancer progression, longer-term follow up is needed to see if these results are significant, the researchers wrote. What this means for U.S. menIn an opinion piece that accompanied the study, Dr. Anthony V. D’Amico of the Dana-Farber Cancer Institute concluded that when compared with surgery or radiation, active monitoring leads to increased cancer spread, and that active monitoring should only be an option for men who already have another life-shortening disease that is expected to result in death after less than 10 years. Daskivich, who was not involved with the study, was more optimistic about active monitoring’s place in prostate cancer care, and included “low-risk” men among those who should consider active monitoring instead of surgery or radiation, even though the study didn’t stratify men according to high or low risk cancers. However, doctors still need more tools that help them confidently sort patients according to risk.“It’s all about treatment selection ― picking out patients who have higher risk disease who should get treated upfront, and those who have lower risk features who don’t need to be treated and managed with active surveillance,” said Daskivich. “That’s going to be the challenge in the coming years.”The results of the study won’t change much for most middle-aged men in the U.S., Daskivich

Source: Treating Prostate Cancer Is Often No Better Than Doing Nothing | Huffington Post

Colombia’s Civil War is Finally Over

Colombia’s FARC rebel group voted unanimously to approve a peace deal with the government on Friday, declaring an end to the five-decade war.

Source: Colombia’s Civil War is Finally Over

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

If a restaurant charged you $40 for coffee. Surely you’d be upset. But you let hospitals do it to you all the time.

It turns out that hospitals inflate specific prices  in ways that aren’t transparent to the patient, according to a new study that appeared Sept. 7 2016 in the journal Health Affairs.

Researchers at Johns Hopkins University in Baltimore found that many hospitals charged more than 20 times the cost of some services, particularly for certain services like CT scans and anesthesiology. The researchers said that the pattern of charging suggests that hospitals strategically look for surreptitious ways to boost revenue.

“Hospitals apparently mark up higher in the departments with more complex services, because it is more difficult for patients to compare prices in these departments,” Ge Bai, who led the study and is an assistant professor at the Johns Hopkins Carey Business School, said in a statement. [7 Medical Myths Even Doctors Believe]

Other high-tech services with exorbitant markups include MRI, electrocardiology (tests of the heart’s electrical patterns) and electroencephalography (tests of the brain’s impulse patterns), according to the findings. The services that had fees that were more in line with their actual costs to hospitals included “old-school” physical therapy and nursing, the researchers found.

The markups occurred in all types of hospitals, both private and nonprofit, the researchers said. Yet hospitals with the highest markups, on average, tended to be for-profit hospitals with strong power within their markets, because of either their system affiliations or their dominance of regional markets. In other words, those hospitals that can mark up prices, do mark up prices, according to the researchers.

The pricing can have serious consequences for the payer, the researchers said. For example, hospitals whose costs for a CT scan run at about $100 may charge a patient $2,850 for a CT scan, the study found.

“[The markups] affect uninsured and out-of-network patients, auto insurers and casualty and workers’ compensation insurers,” said Gerard Anderson, a professor at the Johns Hopkins Bloomberg School of Public Health and a co-author on the study.

“The high charges have led to personal bankruptcy, avoidance of needed medical services and much higher insurance premiums.”

In their study, based on 2013 Medicare and other data from nearly 2,500 U.S. hospitals, the researchers compared a hospital’s overall charge-to-cost ratio, which is the ratio of what the hospital charged compared to the hospital’s actual medical expense. The charge is recorded on a document called a chargemaster, which is an exhaustive list of the prices for all hospital procedures and supplies.

In 2013, the average hospital with more than 50 beds had an overall charge-to-cost ratio of 4.32 that is, the hospital charged $4.32 for every $1 of its own costs. However, at most hospitals that they examined, the researchers found that the charge-to-cost ratio was far higher in departments that were technologically advanced. The highest was in the CT department, with an average ratio of 28.5. [5 Amazing Technologies That Are Revolutionizing Biotech]

While understanding that hospitals need to generate revenue, the researchers recommend a cap on markups and consistency from department to department. They also suggest more transparency, by requiring hospitals to provide patients with examples in clear language of rates from area hospitals or what Medicare would pay.

“There is no regulation that prohibits hospitals from increasing revenues,” Bai told Live Science. “The problem is when they raise rates on people that have no ability to say no because they have an emergency and cannot compare prices.” This includes uninsured and out-of-network patients, “because they don’t have bargaining power against hospitals,” Bai added.

“We realize that any policy proposal to limit hospital markups would face a very strong challenge from the hospital lobby,” Anderson said. “But we believe the markup should be held to a point that’s fair to all concerned ? hospitals, insurers and patients alike.”

The researchers noted that Johns Hopkins Hospital has a charge-to-cost ratio of 1.3, among the lowest 1 percent of the sample studied. Maryland, the state in which the hospital is located, in general has the lowest ratios of any other state, they said.

Some of the infections could be tied to increasing antibiotic resistance. The vast majority of what may be preventable infections, however, could be controlled with targeted disinfection and better surveillance of water systems, say researchers involved with the study.

Source: Infections linked to water supply increasing healthcare costs, study says – UPI.com

Now that Walmart and your dumbass has sent all our money to China.  Chinese and Russian naval forces began joint exercises in the South China Sea on Monday, adding a new twist to ongoing tensions over Chinese island-building in the region.

The eight-day exercises will highlight marine corps units in “live-fire drills, sea crossing and island landing operations, and island defense and offense exercises,” Chinese navy spokesperson Liang Yang said in a report from China’s official Xinhua News Agency.
Aside from the marines, Chinese and Russian surface ships, submarines, planes, helicopters and amphibious armored equipment would be used, Liang said.

The Russian destroyer Admiral Tributs arrives for exercises with the Chinese navy.

Russia has sent some of its best vessels, including the Ropucha-class landing ship, and the Udaloy-class destroyer” to participate in the exercises, according to Chinese state-run broadcaster CCTV.
The 7,500-ton Udaloy-class destroyers are designed for anti-submarine warfare, while the 4,000-ton Ropucha-class landing ships are designed to carry up to 24 armored vehicles directly onto beaches.

Contested waters

The China-Russia naval exercises are an annual event, with previous versions taking place in the Sea of Japan, the East China Sea and the Yellow Sea, among other locations.
But this year’s event in the South China Sea takes on new significance after a landmark ruling against China’s claims in the region.
The Permanent Court of Arbitration found China had unlawfully restricted fishing access around the Scarborough Shoal, a small but strategic reef and fertile fishing ground 130 miles (200 kilometers) west from the Philippine island of Luzon.
Then last week the Philippines military released images of Chinese ships it said were capable of dredging sand around the reef.
Beijing has denied it is reclaiming land, saying that while Chinese coast guard vessels patrol the waters around the shoal, which it calls Huangyandao, they were there for “law enforcement.”

Russian and Chinese officers greet each other at the beginning of eight days of military exercises.

Territorial hotspots

Scarborough Shoal is only one point of tension in the South China Sea.
China claims almost all of the sea, including islands more than 800 miles (1,200 kilometers) from the Chinese mainland, despite objections from neighbors including the Philippines, Malaysia, Brunei and Vietnam.
Tensions have ratcheted up in the past two years as China has reclaimed land in massive dredging operations in the Spratly Islands, turning sandbars into islands equipped with airfields, ports and lighthouses.
In recent months, Beijing has reacted angrily to US freedom of navigation operations in the region, scrambling fighter jets and boats and denouncing the nation’s navies as “threatening Chinese sovereignty.”
When China announced the current naval exercises in July, it said it “does not target any third party,” according to the Xinhua report.

An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease

  • Steve HorvathEmail authorView ORCID ID profile,
  • Michael Gurven,
  • Morgan E. Levine,
  • Benjamin C. Trumble,
  • Hillard Kaplan,
  • Hooman Allayee,
  • Beate R. Ritz,
  • Brian Chen,
  • Ake T. Lu,
  • Tammy M. Rickabaugh,
  • Beth D. Jamieson,
  • Dianjianyi Sun,
  • Shengxu Li,
  • Wei Chen,
  • Lluis Quintana-Murci,
  • Maud Fagny,
  • Michael S. Kobor,
  • Philip S. Tsao,
  • Alexander P. Reiner,
  • Kerstin L. Edlefsen,
  • Devin Absher and
  • Themistocles L. Assimes
Contributed equally
Genome Biology201617:171

DOI: 10.1186/s13059-016-1030-0

Received: 6 July 2016

Accepted: 18 July 2016

Published: 11 August 2016

Abstract

Background

Epigenetic biomarkers of aging (the “epigenetic clock”) have the potential to address puzzling findings surrounding mortality rates and incidence of cardio-metabolic disease such as: (1) women consistently exhibiting lower mortality than men despite having higher levels of morbidity; (2) racial/ethnic groups having different mortality rates even after adjusting for socioeconomic differences; (3) the black/white mortality cross-over effect in late adulthood; and (4) Hispanics in the United States having a longer life expectancy than Caucasians despite having a higher burden of traditional cardio-metabolic risk factors.

Results

We analyzed blood, saliva, and brain samples from seven different racial/ethnic groups. We assessed the intrinsic epigenetic age acceleration of blood (independent of blood cell counts) and the extrinsic epigenetic aging rates of blood (dependent on blood cell counts and tracks the age of the immune system). In blood, Hispanics and Tsimane Amerindians have lower intrinsic but higher extrinsic epigenetic aging rates than Caucasians. African-Americans have lower extrinsic epigenetic aging rates than Caucasians and Hispanics but no differences were found for the intrinsic measure. Men have higher epigenetic aging rates than women in blood, saliva, and brain tissue.

Conclusions

Epigenetic aging rates are significantly associated with sex, race/ethnicity, and to a lesser extent with CHD risk factors, but not with incident CHD outcomes. These results may help elucidate lower than expected mortality rates observed in Hispanics, older African-Americans, and women.

Keywords

DNA methylation Epigenetic clock Race Gender Aging Coronary heart disease Hispanic paradox Black/white mortality cross-over

Background

Many demographic and epidemiological studies explore the effects of chronological age, race/ethnicity, and sex on mortality rates and susceptibility to chronic disease [1, 2, 3, 4, 5], but it remains an open research question whether race/ethnicity and sex affect molecular markers of aging directly. To what extent clinical biomarkers of inflammation, dyslipidemia, and immune senescence relate to cellular markers of aging also remains an open question. One major challenge is the lack of agreement on how to define and measure biological aging rates [6]. Many biomarkers of aging have been proposed ranging from clinical markers (such as whole-body functional evaluations and gait speed) to molecular markers such as telomere length [7, 8]. Available biomarkers capture only particular aspects of aging. For example, African Americans have been shown to have longer telomere lengths than Caucasians [9], despite significantly higher levels of inflammation, lower average life expectancies, and higher disease incidence. To date, no studies have employed epigenetic measures to estimate and compare molecular aging rates among gender or racial/ethnic groups.

Measures incorporating DNA methylation levels have recently given rise to a new class of biomarkers that appear informative of aging given that age has a profound effect on DNA methylation levels in most human tissues and cell types [10, 11, 12, 13, 14, 15, 16, 17, 18]. Several recent studies have measured the epigenetic age of tissue samples by combining the DNA methylation levels of multiple dinucleotide markers, known as Cytosine phosphate Guanines or CpGs [19, 20, 21]. We recently developed the epigenetic clock (based on 353 CpGs) to measure the age, known as “DNA methylation age” or “epigenetic age,” of assorted human cell types (CD4+ T cells or neurons), tissues, and organs—including blood, brain, breast, kidney, liver, lung [20], and even prenatal brain samples [22]. The epigenetic clock is an attractive biomarker of aging because it applies to most human tissues and its accurate measurement of chronological age is unprecedented.

The following evidence shows that the epigenetic clock captures aspects of biological age. First, the epigenetic age of blood has been found to be predictive of all-cause mortality even after adjusting for chronological age and a variety of known risk factors [23, 24, 25]. Second, the blood of the offspring of Italian semi-supercentenarians (i.e. participants who reached an age of at least 105 years) has a lower epigenetic age than that of age-matched controls [26]. Third, the epigenetic age of blood relates to frailty [27] and cognitive/physical fitness in the elderly [28]. The utility of the epigenetic clock method has been demonstrated in applications surrounding obesity [29], Down’s syndrome [30], HIV infection [31], Parkinson’s disease [32], Alzheimer’s disease-related neuropathologies [33], lung cancer [34], and lifetime stress [35]. Here, we apply the epigenetic clock to explore relationships between epigenetic age and race/ethnicity, sex, risk factors of coronary heart disease (CHD), and the CHD outcome itself.

Results

Blood datasets and racial/ethnic groups

An overview of our DNA methylation datasets can be found in Table 1. We analyze multiple sources of DNA: mostly blood, saliva, and lymphoblastoid cell lines. In addition, brain datasets were used to compare men and women (Table 2). We considered the following racial/ethnic groups (Table 1): 1387 African Ancestry (African Americans and two groups from Central Africa), 2932 Caucasian (non-Hispanic whites), 657 Hispanic, 127 East Asians (mainly Han Chinese), and 59 Tsimane Amerindians.

Table 1

Overview of the DNA methylation datasets. The rows correspond to the datasets used in this article. Columns report the tissue source, DNA methylation platform, number of participants, access information, and citation and a reference to the use in this text

Tissue source

Array

Participants (n)

Women (n)

African Ancestry, Caucasian, Hispanic, Tsimane, East Asian (n)

Mean age (years) (range)

Available

Citation

Figure

1. Women’s Health Initiative (blood)

450

1462

1462

676, 353, 433, 0, 0

63 (50–80)

dbGAP, NHLBI

Current article

1

2. Bogalusa (blood)

450

969

547

288, 681, 0, 0, 0

43 (29–51)

dbGAP, NHLBI

Current article

1

3. PEG (blood)

450

335

138

0, 289, 46, 0, 0

70 (36–91)

GSE72775

Current article

1

4. Saliva from PEG

450

259

113

0, 166, 93, 0, 0

69 (36–88)

GSE78874

Current article

1

5. Older Tsimane and others

450

310

150

0, 235, 38, 37, 0

66 (35–92)

GSE72773

Current article

3

6. Younger Tsimane and Caucasians

450

46

31

0, 24, 0, 22, 0

15 (2–35)

GSE72777

Current article

3

7. East Asians vs. Caucasians (PSP samples removed)

450

312

132

0, 279, 0, 0, 33

68 (34–93)

GSE53740

Li, 2014 [73]

3

8. African populations

450

256

50

256, 0, 0, 0, 0

40 (16–90)

EGAS00001001066

Fagny, 2015 [42]

4

9. Cord blood

27

216

110

92, 70, 0, 0, 0

0 (0–0)

GSE27317

Adkins, 2011 [44]

10. Male saliva

27

91

0

0, 59, 32, 0, 0

29 (21–55)

GSE34035

Liu, 2010 [74]

11. Female saliva

27

42

42

0, 27, 15, 0, 0

27 (21–55)

GSE34035

Liu, 2010 [74]

12. Lymphoblastoid cell lines

450

237

154

75, 68, 0, 0, 94

34 (5–73)

GSE36369

Heyn, 2013 [88]

Additional file 1

Table 2

Description of brain datasets for evaluating the effect of gender. Additional details can be found in “Methods

Data

Participants (n)

Men (%)

Age mean ± SE [min, max]

Brain region

Brain tissue samples (n)

Study 1

117

41 %

84.0 ± 9.8 [40, 105]

CRBLM

112

EC

108

PFCTX

114

STG

117

Study 2

142

68 %

48.0 ± 23.2 [16, 96]

CRBLM

112

FCTX

133

PONS

125

TCTX

127

Study 3

147

63 %

44.3 ± 9.6 [19, 68]

CRLM

147

Study 4

37

62 %

64.4 ± 17.4 [25, 96]

CRBLM

36

PFCTX

36

Study 5

209

66 %

52.3 ± 29.8 [1, 102]

CRBLM

201

FCTX

201

Study 6

718

37 %

88.5 ± 6.6 [66, 108]

DLPFC

718

CRBLM cerebellum, DLPFC dorsolateral prefrontal cortex, EC entorhinal cortex, FCTX frontal cortex, PFCTX prefrontal cortex, PONS pons, STG superior temporal gyrus, TCTX temporal cortex

Accuracy of the epigenetic clock

DNAm age, also referred to as epigenetic age, was calculated in human samples profiled with the Illumina Infinium 450 K platform using a previously described method [20]. As expected, we found DNAm age to have a strong linear relationship with chronological age in blood and saliva (correlations in the range of 0.65–0.93, Figs. 1, 2, 3, 4, and 5) and in lymphoblastoid cell lines (r = 0.59; Additional file 1). Based on a spline regression line, we defined a “universal” measure of epigenetic age acceleration, denoted “Age Accel.” in our figures, as the difference between the observed DNAm age value and the value predicted by a spline regression model in Caucasians. The term “universal” refers to the fact that this measure can be defined in a vast majority of tissues and cell types with the notable exception of sperm [20]. A positive value of the universal age acceleration measure indicates that DNA methylation age is higher than that predicted from the regression model for Caucasian participants of the same age. Our intrinsic and extrinsic age acceleration measures (see “Methods”) only apply to blood data. A measure of intrinsic epigenetic age acceleration (IEAA) measures cell-intrinsic epigenetic aging effects that are not confounded by extra-cellular differences in blood cell counts. The measure of IEAA is an incomplete measure of the age-related functional decline of the immune system because it does not track age-related changes in blood cell composition, such as the decrease of naïve CD8+ T cells and the increase in memory or exhausted CD8+ T cells [36, 37, 38]. The measure of extrinsic epigenetic age acceleration (EEAA) only applies to whole blood and aims to measure epigenetic aging in immune-related components. It keeps track of both intrinsic epigenetic changes and age-related changes in blood cell composition (see “Methods”). The estimated blood cell counts, which are used in these measures, correlate strongly with corresponding flow cytometric measurements from the MACS study (Additional file 2): r = 0.63 for CD8 + T cells, r = 0.77 for CD4+ T, r = 0.67 B cell, r = 0.68 naïve CD8+ T cell, r = 0.86 for naïve CD4+ T, and r = 0.49 for exhausted CD8+ T cells.

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Fig. 1

Intrinsic epigenetic age acceleration in Caucasians and Hispanics. ad DNA methylation age (y-axis) versus chronological age (x-axis) in (a) Women’s Health Initiative, (b) blood data from PEG, (c) dataset 5, (d) saliva data from PEG. Dots corresponds to participants and are colored by ethnic group (gray = Caucasian, blue = Hispanic). The gray line depicts a spline regression line through Caucasians. We define two measures of age acceleration based on DNAm age. eg The bar plots relate the universal measure of epigenetic age acceleration to race/ethnicity, which is defined as residual to the spline regression line through Caucasians, i.e. the vertical distance of a point from the line. By definition, the mean age acceleration in Caucasians is zero. h, m Results after combining the three blood datasets using Stouffer’s meta-analysis method. i Age acceleration residual versus ethnicity in the saliva data from PEG. jm The y-axis reports the mean value of IEAA, which is defined as residual from a multivariate regression model that regresses DNAm age on age and several measures of blood cell counts. Each bar plot reports 1 standard error and the p value from a group comparison test (ANOVA). n Age acceleration in blood versus age acceleration in saliva for the subset of PEG participants for whom both data were available

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Fig. 2

Intrinsic epigenetic age acceleration in Tsimane, Hispanics, East Asians, and Caucasians. ac DNA methylation age (y-axis) versus chronological age (x-axis) in (a) dataset 5, (b) dataset 6, (c) dataset 7. Dots corresponds to participants and are colored by race/ethnicity (green = African American, gray = Caucasian, blue = Hispanic, red = Tsimane, orange = East Asians). The gray line depicts a spline regression line through Caucasians. We define two measures of age acceleration based on DNAm age. df The bar plots relate the universal measure of epigenetic age acceleration to race/ethnicity, which is defined as residual to the spline regression line through Caucasians, i.e. the vertical distance of a point from the line. gi The y-axis reports the mean value of IEAA, which is defined as residual from a multivariate regression model that regresses DNAm age on age and several measures of blood cell counts. Each bar plot reports 1 standard error and the p value from a group comparison test (ANOVA)

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Fig. 3

Intrinsic epigenetic age acceleration versus African or European Ancestry. ac DNA methylation age (y-axis) versus chronological age (x-axis) in (a) Women’s Health Initiative, (b) Bogalusa study. Dots corresponds to participants and are colored by race/ethnicity (green = African Ancestry, gray = Caucasian). The gray line depicts a spline regression line through Caucasians. We define two measures of age acceleration based on DNAm age. c, d The bar plots relate the universal measure of epigenetic age acceleration to race/ethnicity, which is defined as residual to the spline regression line through Caucasians. e, h Results after combining the two blood datasets using Stouffer’s meta-analysis method. f, g The y-axis reports the mean value of IEAA, which is defined as residual from a multivariate regression model that regresses DNAm age on age and several measures of blood cell counts. Each bar plot reports 1 standard error and the p value from a group comparison test (ANOVA)

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Fig. 4

Extrinsic epigenetic age acceleration and blood cell counts across groups. EEAA versus race/ethnicity in (a, q) Women’s Health Initiative, (b) blood data from PEG, (c, k) dataset 5, (l) dataset 6, (o) dataset 7, (r) Bogalusa study. Flow cytometric, age adjusted estimates (e, t) naïve CD8+ T and (j, x) naïve CD4+ T cell counts in the WHI LLS. Age adjusted estimates of naïve CD4 + T cells based on DNA methylation data from (f, u) Women’s Health Initiative, (g) blood data from PEG, (h, m) dataset 5, (n) dataset 6, (p) dataset 7, (v) Bogalusa study. (d, i, s, w) Meta-analysis across the respective datasets based on Stouffer’s method

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Fig. 5

Analysis of African rainforest hunter-gatherers and farmers. a DNAm age versus age using 256 blood samples from [42]. The points are colored as follows: magenta = AGR (urban setting), turquoise = AGR (forest), brown = RHG (forest). Group status versus (b) universal age acceleration, (d) intrinsic age acceleration, (f) extrinsic age acceleration. Habitat versus (c) universal age acceleration, (e) intrinsic age acceleration, (g) extrinsic age acceleration. (h, i) are analogous to (a, b) but the y-axis is based on a DNAm age estimate that excluded CpG that were located near SNPs. In this robustness analysis, we removed CpG probes containing genetic variants at a frequency higher than 1 % in the populations studied

Hispanics have a lower intrinsic aging rate than Caucasians

We find that Hispanics have a consistently lower IEAA compared to Caucasians (p = 7.1 × 10–10, Fig. 1m). An important question is whether the observed differences in blood can also be observed in other tissues. Using a novel saliva dataset (dataset 4, saliva from PEG) we find that Hispanics have a lower epigenetic aging rate than Caucasians (p = 0.042, Fig. 1i). The fact that our findings in blood can also be validated in saliva is consistent with the strong correlation between epigenetic age acceleration measures of the two sources of DNA (r = 0.70, p = 1.4 × 10–12, Fig. 1n). The lower value of IEAA in Hispanics unlikely reflects country of birth or of residence (at age 35 years) given the robust findings across samples and our detailed analysis in the WHI, where we find that Hispanics born outside US, but living in the US, have a higher IEAA than Hispanics born and raised in the US (p = 0.025, Additional file 3B).

CHD risk factors bear little or no relationship with IEAA

We related our measures of age acceleration to risk factors related to CHD since the latter are significant predictors of mortality. In postmenopausal women from the Women’s Health Initiative (WHI), we found no evidence that IEAA is associated with disparities in education, high density lipoprotein (HDL) or low density lipoprotein (LDL) cholesterol, insulin, glucose, C-reactive protein (CRP), creatinine, alcohol consumption, smoking, diabetes status, or hypertension (see Table 3).

Table 3

Multivariate model that regresses epigenetic age acceleration on participant characteristics in the WHI. Coefficients and p values from regressing measures of intrinsic and extrinsic epigenetic age acceleration on participant characteristics from dataset 1

Multivariate linear regression

Intrinsic EAA

Extrinsic EAA

Estimate (SE)

p

Estimate (SE)

p

Race/ethnicity

Hispanic vs. African American

–0.94 (0.35)

0.007

3.363 (0.439)

<10–15

White vs. African American

0.71 (0.295)

0.016

1.94 (0.37)

1.6 × 10–7

HDL-cholesterol

0.006 (0.01)

0.558

–0.003 (0.013)

0.799

Triglyceride

0.003 (0.002)

0.059

0.004 (0.002)

0.04

Insulin

0 (0.001)

0.664

0.001 (0.001)

0.337

Glucose

0.003 (0.004)

0.486

0.007 (0.005)

0.112

CRP

0.023 (0.018)

0.215

0.052 (0.023)

0.023

Creatinine

0.703 (0.594)

0.237

1.985 (0.745)

0.008

BMI

0.035 (0.021)

0.103

0.045 (0.027)

0.093

Education

High school (HS) vs. no HS

0.357 (0.426)

0.403

–0.784 (0.534)

0.142

Some college vs. no HS

0.469 (0.381)

0.219

–1.171 (0.478)

0.014

College vs. no HS

0.486 (0.519)

0.349

–2.253 (0.65)

0.001

Grad school vs. no HS

0.36 (0.424)

0.396

–1.648 (0.531)

0.002

Alcohol

Past drinker vs. Never

1.668 (1.1)

0.13

–0.598 (1.379)

0.665

Light drinker vs. Never

–0.101 (0.536)

0.85

–0.751 (0.672)

0.264

Moderate vs. Never

–0.416 (0.748)

0.578

–0.401 (0.937)

0.669

Heavy vs. Never

–0.354 (0.88)

0.687

–0.833 (1.103)

0.45

Smoking

Former vs. Current

–0.573 (1.039)

0.581

–0.104 (1.302)

0.936

Never vs. Current

–0.376 (1.039)

0.718

–0.122 (1.303)

0.925

Diabetes

0.216 (0.43)

0.616

–0.061 (0.539)

0.909

Hypertension

0.364 (0.241)

0.131

0.262 (0.302)

0.386

R-squared

0.029

0.069

Tsimane have a lower intrinsic aging rate than Caucasians

The Tsimane are an indigenous population (~15,000 inhabitants) of forager-horticulturalists who reside in the remote lowlands of Bolivia. They reside mostly in open-air thatch huts, and actively fish, hunt, and cultivate plantains, rice, and manioc through slash-and-burn horticulture [39]. Tsimane provide a unique contribution to aging researchers and epidemiologists because they experience high rates of inflammation due to repeated bacterial, viral, and parasitic infections, yet show minimal risk factors for heart disease or type 2 diabetes as they age; they have minimal hypertension and obesity, low LDL cholesterol and no evidence of peripheral arterial disease [39, 40, 41]. Since Hispanics share genetic ancestry with peoples indigenous to the Americas, we hypothesized that a slower intrinsic aging rate might also be observable by analyzing Tsimane blood samples [39]. Among participants who are older than 35 years, Tsimane have the lowest intrinsic age acceleration (Fig. 2d, g). While Tsimane have a significantly lower IEAA than Caucasians after the age of 35 years (p = 0.0061), no significant difference could be observed in younger participants (Fig. 2e, h). In this analysis, the threshold of 35 years was chosen so that a sufficient number of young participants would be included in dataset 6. We found no significant difference in IEAA between older Hispanics and Tsimane, which might reflect the relatively low group sizes of n = 37 Tsimane versus n = 38 Hispanics.

IEAA is not associated with CHD in the WHI

Based on our findings above showing little or no relationship between IEAA and CVD risk factors at baseline, we hypothesized that IEAA would not predict future onset of CHD. A multivariate logistic regression model shows that IEAA is not significantly associated with an increased risk of incident CHD (Table 4). However, as expected, current smoking, prior history of diabetes, hypertension, high insulin and glucose levels, and lower HDL predicted an increased risk of CHD (Table 4).

Table 4

Logistic model that regresses CHD status on epigenetic age acceleration and participant characteristics in the WHI. Coefficients, Wald Z statistics, and corresponding p values resulting from regressing CHD status on measures of epigenetic age acceleration and various participant characteristics. The results for the measure of IEAA and EEAA can be found in columns 2 and 3, respectively

Logistic model. Outcome CHD case status

Intrinsic EAA

Extrinsic EAA

Covariates

Estimate (SE)

Z

p

Estimate (SE)

Z

p

Epig. Age Accel

–0.017 (0.01)

–1.72

0.085

–0.006 (0.008)

–0.74

0.458

Age

0.027 (0.008)

3.44

0.001

0.028 (0.008)

3.52

4.3 × 10-4

Race/ethnicity

Hispanic vs. African American

0.083 (0.152)

0.55

0.584

0.118 (0.153)

0.77

0.443

White vs. African American

0.141 (0.135)

1.04

0.298

0.135 (0.135)

1.00

0.319

HDL-cholesterol

–0.02 (0.005)

–4.29

1.8 × 10–5

–0.02 (0.005)

–4.33

1.5 × 10-5

Triglyceride

0.001 (0.001)

1.43

0.153

0.001 (0.001)

1.38

0.169

Insulin

0.002 (0.001)

2.26

0.024

0.002 (0.001)

2.25

0.024

Glucose

0.005 (0.002)

2.64

0.008

0.005 (0.002)

2.64

0.008

CRP

0.013 (0.008)

1.61

0.107

0.013 (0.008)

1.61

0.108

Creatinine

0.518 (0.281)

1.84

0.065

0.515 (0.281)

1.84

0.067

BMI

–0.011 (0.01)

–1.19

0.235

–0.012 (0.01)

–1.22

0.223

Education

High school (HS) vs. no HS

–0.058 (0.183)

-0.32

0.753

–0.067 (0.183)

–0.37

0.715

Some College vs. no HS

0.008 (0.164)

0.05

0.96

–0.004 (0.165)

–0.03

0.979

College vs. no HS

–0.198 (0.223)

–0.89

0.373

–0.219 (0.223)

–0.98

0.327

Grad school vs. no HS

–0.237 (0.183)

–1.29

0.196

–0.251 (0.183)

–1.37

0.171

Alcohol

Past drinker vs. Never

–0.6 (0.514)

–1.17

0.243

–0.641 (0.513)

–1.25

0.212

Light drinker vs. Never

–0.34 (0.233)

–1.46

0.145

–0.343 (0.233)

–1.47

0.141

Moderate vs. Never

–0.1 (0.32)

–0.31

0.754

–0.096 (0.32)

–0.30

0.764

Heavy vs. Never

–0.34 (0.381)

–0.89

0.373

–0.337 (0.381)

–0.88

0.377

Smoking

Former vs. Current

–0.997 (0.467)

–2.13

0.033

–0.989 (0.467)

–2.12

0.034

Never vs. Current

–1.321 (0.468)

–2.82

0.005

–1.317 (0.468)

–2.81

0.005

Diabetes

0.706 (0.196)

3.61

3.0 × 10-4

0.699 (0.196)

3.58

3.4 × 10-4

Hypertension

0.565 (0.103)

5.46

4.8 × 10-8

0.559 (0.103)

5.41

6.3 × 10-8

Hispanics and Tsimane have a higher EEAA than Caucasians

According to our measure of EEAA, Hispanics have a significantly older extrinsic epigenetic age than Caucasians (meta-analysis p = 0.00012, Fig. 4a–d) and fewer naïve CD4+ T cells, based on cytometric data from the WHI LLS, the MACS study, and imputed blood cell counts (Fig. 4f–j, Additional file 2H, I). This pattern of fewer naïve CD4+ T cells is even more pronounced for Tsimane (Fig. 4m, n), who experience repeated acute infections and elevated, often chronic, inflammatory loads.

Epigenetic age analysis of East Asians

Because ancient Native American populations share common ancestral lineages with East Asians, we examined whether East Asians also differ from Caucasians in terms of epigenetic aging rates. We found no significant difference between Caucasians and East Asians in terms of IEAA (Fig. 2i), EEAA (Fig. 4o), or naïve CD4+ T cells (Fig. 4p). Similarly, we found no difference in lymphoblastoid cell lines (Additional file 1). However, these comparative analyses are limited by the relatively small number of samples and should be repeated in larger datasets.

Which risk factors for cardiometabolic disease are associated with EEAA?

Our multivariate model analysis in the WHI (Table 3) shows that EEAA tracks better than IEAA with risk factors for cardiometabolic disease; EEAA was positively associated (higher) with: triglyceride levels (multivariate model p = 0.04), CRP (p = 0.023), and creatinine (p = 0.008). EEAA was negatively associated (lower) with higher levels of education in all ethnic groups (p from 2.0 × 10–8 to 0.05, Additional file 4I–L). For each racial/ethnic group, we find that women who did not finish high school exhibit the highest levels of EEAA (leftmost bar in Additional file 4J–L).

Epigenetic aging rates of African Americans

In the following, we compare African Americans with European Americans in terms of IEAA and EEAA. Comparisons of African Americans with Caucasians in terms of IEAA yield contradictory findings across datasets that differ in age range: African American women have slightly lower IEAA than Caucasian women in the WHI (p = 0.017 Fig. 3f), but no significant difference can be observed for the younger participants of the Bogalusa study (Fig. 3g). Indeed, participants in the WHI (aged between 50 and 80 years) were older than those of the Bogalusa study (aged between 29 and 51 years). This failure to detect a significant racial/ethnic difference in IEAA in younger participants is consistent with our results from the comparison of younger Tsimane and Caucasians (Fig. 2h). A multivariate model analysis based on the Bogalusa study (comprising African Americans and Caucasians) confirms that IEAA does not differ between middle-aged African Americans and Caucasians but IEAA is higher among men (p = 0.025) and has a marginally significant association with hypertension (p = 0.064, Table 5). When relating individual variables to IEAA, we find significant associations for hypertension (p = 0.00035, Additional file 5D–F) but not for type II diabetes status or educational level.

Table 5

Multivariate model that regresses epigenetic age acceleration on participant characteristics in the Bogalusa study. Coefficients and p values from regressing measures of intrinsic and extrinsic epigenetic age acceleration on participant characteristics from dataset 2

Multivariate linear regression

Intrinsic EAA

Extrinsic EAA

Estimate (SE)

Z

p

Estimate (SE)

Z

p

Race

Caucasian vs. African American

–0.013 (0.316)

–0.04

0.97

0.843 (0.316)

2.67

0.0076

Gender

Female vs. Male

–0.622 (0.278)

–2.24

0.025

–0.718 (0.277)

–2.60

0.0093

Education

Grade 8–9 vs. < Grade 8

1.583 (1.468)

1.08

0.28

2.177 (1.465)

1.49

0.14

Grade 10–12 vs. < Grade 8

1.285 (1.27)

1.01

0.31

2.267 (1.267)

1.79

0.074

Vocat/Tech vs. < Grade 8

0.307 (1.299)

0.24

0.81

1.921 (1.295)

1.48

0.14

College vs. < Grade 8

0.85 (1.281)

0.66

0.51

2.375 (1.277)

1.86

0.062

Graduate vs. < Grade 8

0.147 (1.336)

0.11

0.91

1.53 (1.332)

1.15

0.25

Diabetes (II)

0.173 (0.485)

0.36

0.72

0.012 (0.483)

0.03

0.98

Hypertension

0.539 (0.291)

1.86

0.064

1.247 (0.29)

4.30

1.7 × 10-5

R-squared

0.025

0.043

Our findings for EEAA are highly consistent across the two studies and age groups: African Americans have lower EEAA than Caucasians in the WHI and in the Bogalusa study (p = 7.2 × 10–7, Fig. 4q, r, s). Our flow cytometric data from the WHI LLS show that African American women exhibit a higher abundance of naïve CD8+ T cells than Caucasian women (p = 1.7 × 10–9, Fig. 4t).

In multivariate regression analyses of EEAA, we find that African Americans have indications of a significantly younger immune system age than Caucasians (p =  0.0076) after controlling for gender, educational level, diabetes status, and hypertension. In the Bogalusa study, we find three significant predictors of EEAA: race/ethnicity, hypertension, and gender (p = 0.0093, Table 5). A marginal analysis in the Bogalusa study identifies a significant association between EEAA and hypertension (p = 8.0 × 10–5, Additional file 5G–I), type II diabetes status in Caucasians (p = 0.0085, Additional file 6H), but not in African Americans (Additional file 6I). Contrary to our findings in the WHI, no significant association can be observed between EEAA and educational level (Additional file 7).

African rainforest hunter-gatherers and farmers

To evaluate the effect of subsistence ecology and environment on epigenetic aging rates, we analyzed 256 blood samples from two different groups in Central Africa: rainforest hunter-gatherers (RHGs, traditionally known as “pygmies,” sampled from Baka and Batwa populations) and African populations that have adopted an agrarian lifestyle (AGRs, traditionally known as “Bantus,” sampled from the Nzebi, Fang, Bakiga, and Nzime populations) over the last 5000 years [42]. The ancestors of the RHGs and AGRs diverged ~60,000 years ago. These groups have historically occupied separate ecological habitats—the ancestors of RHGs in the equatorial rainforest while those of AGRs in drier, more open space savannahs and grasslands. Many RHG groups still live in the rainforest as mobile bands, whereas AGR populations now occupy primarily rural or urban deforested areas, though some AGR groups have settled in the rainforest over the last millennia.

We considered three groups: (1) RHG (n = 102); (2) AGR living in the forest (n = 60); and (3) AGR living in an urban setting (n = 94). The forest habitat was significantly associated with an increase in AgeAccel (p = 2.4 × 10–8, Fig. 5c) and EEAA (p = 5.9 × 10–11, Fig. 5g), but no difference was found for IEAA (p = 0.11, Fig. 5e). Further, no significant difference could be observed between AGR and RHG when focusing on participants living in the rainforest, suggesting greater importance of environment over genetic differences. These results are not affected by differences in genetic variants between RHG and AGR as can be seen from a robustness analysis where we removed CpG probes containing genetic variants at a frequency higher than 1 % in the populations studied (Fig. 5h, i).

Sex effects in blood and saliva

We explored whether differences exist between men and women in epigenetic aging rates. According to measures of IEAA, men are older than women in two racial/ethnic groups: African Americans (Additional file 8A, B) and Caucasians (Additional file 9A, B, N, Z).

Overall, men have higher IEAA and EEAA than women even when controlling for education, diabetes, and hypertension (Table 5). Using saliva data from PEG, we find that Hispanic men age faster than Hispanic women (p = 0.021, Fig. 6j). According to EEAA, Caucasian men are epigenetically older than Caucasian women (Additional file 9C, O, ZA), but we do not observe a significant difference in other groups such as African Americans (Additional file 8C) or central African populations (Fig. 6p, q). The results for EEAA are also consistent with significant sex differences in blood cell counts suggesting more rapid immunosenescence in men. Men have fewer naïve CD4+ T cells than women in three racial/ethnic groups: Caucasians (p = 0.0015 in the Bogalusa study, p = 0.051 in PEG, p = 4.2 × 10–5 in dataset 5); Tsimane (p = 0.0088 in older Tsimane); and African Americans (p = 0.011 in the Bogalusa study).

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Fig. 6

Sex effect on epigenetic age acceleration in blood and saliva. Panels of the first two rows (aj) and last two rows (ks) relate sex to intrinsic and extrinsic epigenetic age acceleration, respectively. Results are reported for blood tissue in all but one panel (j). The combined results across all blood studies can be found in panels (i) IEAA, (s) EEAA. Each bar plot reports 1 standard error and a Kruskal–Wallis test

Sex effects in brain tissue

We analyzed the effect of sex on the universal measure of age acceleration (Age Accel.) in six independent brain datasets (Table 2 and “Methods”). In total, we analyzed 2287 brain samples from 1370 participants. In our analysis, we distinguished the cerebellum from other brain regions because it is known to age more slowly than other brain regions according to the epigenetic clock [43]. While sex did not have a significant effect on the epigenetic age of the cerebellum (Fig. 7a), we found that other brain regions from men exhibit a significantly higher age acceleration than those from women (Fig. 7b, meta-analysis p = 3.1 × 10–5).

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Fig. 7

Effect of sex on the epigenetic age of brain tissue. Each panel depicts a forest plot resulting from the meta-analysis of sex effects. Each row in a forest plot shows the mean difference in epigenetic age between men and women and a 95 % confidence interval. To combine the coefficient estimates from the respective studies into a single estimate, we applied a fixed-effects model weighted by inverse variance, which is implemented in the metafor R package [89]. a Gender did not have a significant effect on the epigenetic age of the cerebellum, which is known to age more slowly than other brain regions according to the epigenetic clock [43]. b When excluding cerebellar samples from the analysis, we find that male brain regions exhibit a significantly higher age acceleration than female brain regions (mean difference = 0.82, meta-analysis p = 3.1 × 10–5). The difference remains significant even after adjusting for intra-subject correlations using a linear mixed effects model (mean difference = 0.77, p = 0.0034)

Studies of young participants

So far, our results have largely pertained to participants who are middle-aged or older (Table 1, column 6) as we only had access to two datasets involving newborns, infants, children, adolescents, and/or young adults. In dataset 6 (which involved participants between the ages of 2 and 35 years), we did not observe a significant difference epigenetic aging rates between Caucasians and Tsimane. In cord blood samples [44], we found no significant difference in the epigenetic ages of cord blood samples between African American and Caucasian newborns (p = 0.23).

Robustness analysis in the WHI

The epigenetic clock involves 47 CpGs whose broadly defined neighborhood includes a single nucleotide polymorphism (SNP) marker according to the probe annotation file from the Illumina 450 K array. Thus, genetic differences coupled with differences in hybridization efficiency could give rise to spurious differences between different racial/ethnic groups.

We addressed this concern in multiple ways. First, we re-analyzed the WHI data by removing the 47 CpGs (out of 353 epigenetic clock CpGs) from the analysis. The epigenetic clock software imputes the 47 missing CpGs using a constant value (the mean value observed in the original training set). Using the resulting modified epigenetic clock, we validate our findings of racial/ethnic differences in terms of IEAA and EEAA (Additional file 8A–C). However, this type of robustness analysis is limited because the removal of a subset of DNA methylation probes, potentially influenced by proximal genetic variation, is not as good a control as directly having matched genetic data. Second, we used a completely independent epigenetic biomarker based on a published signature of age-related CpGs from Teschendorff et al. [13]. Again, these results corroborate our findings (Additional file 8D, E). Third, we validated our findings using the original blood-based aging measure by Hannum [19] (Additional file 8F, G). Fourth, we highlight that both the Horvath and Hannum age estimators were developed based on training data from mixed populations. The training data underlying the Horvath clock involved four racial/ethnic groups (mainly Caucasians, Hispanics, African Americans, and to a lesser extent East Asians). The Hannum clock was trained on Caucasians and Hispanics. While race/ethnicity can lead to a significant offset between DNAm age and chronological age (which is interpreted as age acceleration), these two variables are highly correlated in all racial/ethnic groups.

Discussion

Our main findings are that: (1) Hispanics and Tsimane have a lower intrinsic but a higher extrinsic aging rate than Caucasians; (2) African Americans have a lower extrinsic epigenetic aging rate than Caucasians and Hispanics; (3) levels of education are associated with a decreased level of EEAA in each race/ethnic group (Additional file 4); (4) neither intrinsic nor extrinsic aging rates of blood tissue are predictive of incident CHD in the WHI even though EEAA is weakly associated with several cardiometabolic risk factors of CHD (such as hypertension, triglycerides, and CRP); (5) men exhibit higher epigenetic aging rates than women in blood, saliva, and brain samples, and (6) the rain forest habitat is significantly associated with extrinsic age acceleration but not with intrinsic age acceleration in African populations. Although precise understanding of the significance of epigenetic aging measures awaits further elaboration, our principal findings may provide additional context towards resolving several controversial, epidemiological paradoxes, including the Hispanic paradox, black–white mortality cross-over, the Tsimane inflammation paradox, and the sex morbidity–mortality paradox.

Hispanic paradox

The lower level of IEAA in Hispanics echo the finding that Hispanics in the US have a lower overall risk of mortality than Caucasians despite having a disadvantaged risk profile [45, 46, 47, 48]. Our findings stratified by country of birth suggest that the lower intrinsic aging rate of Hispanics does not reflect biases arising through immigration such as a “healthy immigrant effect” (Additional file 3). Our finding regarding higher levels of EEAA in Hispanics parallels the findings that Hispanics have higher levels of metabolic/inflammatory risk profiles [49] and that Hispanics have a lower relative CD4+ T cell percentage than Caucasians [50]. Several articles have explored the question of why the immune system of Hispanics might differ from that of Caucasians [51, 52, 53].

Black–white mortality cross-over

In the US, the black–white mortality cross-over refers to the reported pattern of lower mortality after the age of 85 years among black men and women, compared to whites, despite their higher observed mortality rates at younger ages [54, 55, 56, 57]. Although we find no differences in IEAA between African Americans and Caucasians at younger ages, older African American adults from the Bogalusa study had lower IEAA than their Caucasian counterparts. This finding might reflect selective survival of more robust individuals or other aspects of health and systemic risk given its independence from common risk factors for cardiovascular disease and type II diabetes mellitus. Our finding regarding the lower EEAA of African Americans, compared to Caucasians, is consistent with the longer leukocyte telomere lengths of African Americans relative to those of Caucasians [3, 9]. Lastly, our flow cytometric data show that African Americans have a larger number of naïve CD8+ T cells than Caucasians (Fig. 4t).

Tsimane inflammation paradox

Our results regarding the low intrinsic aging rate in Tsimane may help address another paradox (which we refer to as the Tsimane inflammation paradox), wherein high levels of inflammation and infection, and low HDL levels, are not associated with accelerated cardiovascular aging [39]. The finding that Tsimane have decreased levels of IEAA has parallels to the following clinical/epidemiological observations: even older Tsimane show little evidence of chronic diseases common in high-income countries, like diabetes, atherosclerosis, asthma, and other autoimmune disorders [39]. High levels of physical activity are maintained well into late adulthood [58].

The finding that Tsimane have increased levels of EEAA has parallels to the following observation: a lifetime of diverse pathogen stresses, elevated inflammation and extensive immune activation, seems to lead to more rapid depletion of naïve CD4+ T cells and greater expression of exhausted T cells, i.e. more rapid immunosenescence [39, 40, 59]. Infectious disease and high chronic inflammatory load contribute to the low life expectancy of Tsimane, 43.5 years at birth during the period 1950–1989, and 54.1 years during 1990–2002 [40, 60].

Sex morbidity–mortality paradox

The sex morbidity–mortality paradox was first described in the 1970s and refers to the observation that women possess a lower age-adjusted mortality rate compared to men despite a higher suffering from a higher burden of co-morbid conditions [61, 62]. Most explanations focus on differences in lifestyle behaviors or healthcare utilization. However, marked sex differences in health and disability remain after controlling for differences in work-related behavior, smoking, obesity, and other behaviors [63]. Whereas other explanations attest to sex differences in a variety of biomarkers, our epigenetic aging markers show robust and consistent male-biased vulnerability in multiple tissues (blood, brain, and saliva) in all racial groups. Similar sex differences in blood-based epigenetic aging rates have also been reported in minors and teenagers [64].

Strengths and limitations

Our study has several strengths including the analysis of 18 DNA methylation datasets (Tables 1 and 2), large sample sizes (almost 6000 samples), multiple tissues (blood, saliva, brain), access to unique populations (Tsimane Amerindians; rainforest hunter-gatherers and farmers), two flow cytometric studies, and robust epigenetic biomarkers of aging. Our analysis of race/ethnicity also spanned seven different racial/ethnic groups (African American, Caucasian, Hispanic, Tsimane, East Asian, RHGs, and AGRs from Central Africa). Another strength is that our analysis of race/ethnicity involved two sources of DNA: blood and saliva. Limitations include the use of some datasets that are cross-sectional as opposed to longitudinal datasets and the fact that both IEAA and EEAA rely on imputed blood cell counts based on DNA methylation levels. Fortunately, the imputed blood cell counts are quite accurate (Additional file 2). Our results reported here concerning ethnic/racial differences in blood cell counts are supported both by our two flow cytometric datasets and by the literature. However, these measured data are not fully reflective of the breakdown of blood cell types, representing only T and B cells.

Conclusion

Our exploratory study demonstrates that epigenetic aging rates differ between different racial/ethnic groups and between men and women. Further, intrinsic epigenetic aging rates tend to have insignificant associations with well-studied risk factors of CHD whereas extrinsic aging rates tend to have significant (but weak) associations with several pro-inflammatory risk factors. While racial/ethnic differences have previously been observed in DNA methylation levels [44], we are the first to directly compare epigenetic aging rates across different racial/ethnic groups. Our derived intrinsic and extrinsic epigenetic aging rates in blood offer an independent glimpse into biological aging that incorporates genetics and the environment and provides potential insight into a number of epidemiological paradoxes. The application of genome-wide DNAm-based epigenetic analysis to understand race/ethnic and sex disparities in biological aging is novel and offers an important perspective that complements existing approaches based on other biomarkers. Future studies will need to confirm our findings with longitudinal designs and to extend the epigenetic age analysis to other tissues and organs.

Methods

We differentiate groups according to “race/ethnicity,” mindful about existing controversies over rigid racial definitions. Our use of these terms reflects self-identified group membership based on macro-categories commonly employed in censuses, human genetics, demography, and epidemiology. The term race/ethnicity thus combines elements of genetic ancestry, population history, and culture.

DNA methylation age and epigenetic clock

All of the described epigenetic measures of aging and age acceleration are implemented in our freely available software. The epigenetic clock is defined as a prediction method of age based on the DNAm levels of 353 CpGs. Predicted age, referred to as DNAm age, correlates with chronological age in sorted cell types (CD4+ T cells, monocytes, B cells, glial cells, neurons), tissues, and organs, including: whole blood, brain, breast, kidney, liver, lung, saliva [20]. Mathematical details and software tutorials for the epigenetic clock can be found in the Additional files of [20]. An online age calculator can be found at our webpage (https://dnamage.genetics.ucla.edu).

Intrinsic versus extrinsic measures of epigenetic age acceleration in blood

Empirical studies show that DNAm has a relatively weak correlation with various measures of white blood cell counts [31], which probably reflects the fact that dozens of different tissue and blood cell types were used to define DNAm age. However, we find it useful to explicitly define another measure of age acceleration that is completely independent of blood cell counts as described in the following. We distinguish intrinsic from extrinsic measures of epigenetic age acceleration in whole blood according to their relationship with blood cell counts. A measure of intrinsic epigenetic age acceleration (IEAA) measures “pure” epigenetic aging effects that are not confounded by differences in blood cell counts. Our measure of IEAA is defined as the residual resulting from a multivariate regression model of DNAm age on chronological age and various blood immune cell counts (naïve CD8+ T cells, exhausted CD8+ T cells, plasma B cells, CD4+ T cells, natural killer cells, monocytes, and granulocytes). The measure of IEAA is an incomplete measure of the age-related functional decline of the immune system because it does not track age-related changes in blood cell composition, such as the decrease of naïve CD8+ T cells and the increase in memory or exhausted CD8+ T cells [36, 37, 38].

We defined a measure of EEAA that only applies to whole blood and aims to measure epigenetic aging in immune-related components in two steps. First, we formed a weighted average of the epigenetic age measure from Hannum et al. [19] and three estimated measures of blood cells for cell types that are known to change with age: naïve (CD45RA + CCR7+) cytotoxic T cells; exhausted (CD28-CD45RA-) cytotoxic T cells; and plasma B cells using the approach by Klemera Doubal [65]. Second, we defined the measure of EEAA as the residual resulting from a univariate model that regressed the weighted average on chronological age. By definition, our measure of EEAA has a positive correlation with the amount of exhausted CD8+ T cells and plasmablast cells and a negative correlation with the amount of naïve CD8+ T cells. Blood cell counts were estimated based on DNA methylation data. EEAA tracks both age-related changes in blood cell composition and intrinsic epigenetic changes. In most blood datasets, EEAA has a moderate correlation (r = 0.5) with IEAA. We note that, by definition, none of our three measures of epigenetic age acceleration are associated with the chronological age of the participant at the time of blood draw.

Relationship to mortality prediction

Although the epigenetic clock method was only published in 2013, there is already a rich body of literature that shows that it relates to biological age. Using four human cohort studies, we previously demonstrated that both the Horvath and Hannum epigenetic clocks are predictive of all-cause mortality [23]. Published results in Marioni et al. [23] show that DNAm age adjusted for blood cell counts (i.e. IEAA) is prognostic of mortality in four cohort studies. We recently expanded our original analysis by analyzing 13 different cohorts (including three racial/ethnic groups) and by evaluating the prognostic utility of both IEAA and EEAA. All considered measures of epigenetic age acceleration were predictive of age at death in univariate Cox models (pAgeAccel = 1.9 × 10–11, pIEAA = 8.2 × 10–9, pEEAA = 7.5 × 10–43) and multivariate Cox models adjusting for risk factors and pre-existing disease status (pAgeAccel = 5.4 × 10–5, pIEAA = 5.0 × 10–4, pEEAA = 3.4 × 10–19) where the latter adjusted for chronological age, body mass index, education, alcohol, smoking pack years, recreational physical activity, and prior history of disease (diabetes, cancer, hypertension). These results will be published elsewhere. Further, the offspring of centenarians age more slowly than age matched controls according to Age Accel and IEAA [26] which strongly suggests that these measures relate to heritable components of biological age. Two independent research groups have shown that epigenetic age acceleration predicts mortality [24, 25].

Description of the blood datasets listed in Table 1

All data presented in this article have been made publicly available as indicated in the column “Available” of Table 1.

Dataset 1: Women’s Health Initiative (WHI)

Participants included a subsample of participants of the WHI study, a national study that began in 1993 which enrolled postmenopausal women between the ages of 50 and 79 years into either one of two three randomized clinical trials [66]. None of these women had CHD at baseline but about half of these women had developed CHD by 2010. Women were selected from one of two WHI large subcohorts that had previously undergone genome-wide genotyping as well as profiling for seven cardiovascular disease related biomarkers including total cholesterol, HDL, LDL, triglycerides, CRP, creatinine, insulin, and glucose through two core WHI ancillary studies [67]. The first cohort is the WHI SNP Health Association Resource (SHARe) cohort of minorities that includes >8000 African American women and >3500 Hispanic women. These women were genotyped through WHI core study M5-SHARe (www.whi.org/researchers/data/WHIStudies/StudySites/M5) and underwent biomarker profile through WHI Core study W54-SHARe (…data/WHIStudies/StudySites/W54). The second cohort consists of a combination of European Americans from the two Hormonal Therapy trials selected for GWAS and biomarkers in core studies W58 (…/data /WHIStudies/StudySites/W58) and W63 (…/data/WHIStudies/StudySites/W63). From these two cohorts, two sample sets were formed. The first (sample set 1) is a sample set of 637 CHD cases and 631 non-CHD cases as of 30 September 2010. The second sample set (sample set 2) is a non-overlapping sample of 432 cases of CHD and 472 non-cases as of 17 September 2012. The ethnic groups differed in terms of the age distribution in the sense that Caucasian women tended to be older. Therefore, we randomly removed 80 % of the Caucasian women who were older than 65 years when it came to the direct comparisons reported in our figures. This resulted in a total sample size of 1462 women, comprising 673 African Americans, 353 Caucasians, and 433 Hispanics. There was no significant difference in age between the three ethnic groups. However, we kept all of the samples in our analysis of clinical characteristics, such as future CHD status and baseline characteristics such as education, hypertension, diabetes, and smoking, in order to ensure that sufficient sample sizes were available for these analyses. Our results are highly robust with respect to using the smaller or larger versions of the datasets. All results are qualitatively the same for the two versions of the datasets. We acknowledge a potential for selection bias using the above-described sampling scheme in WHI but suspect if such bias is present it is minimal. First, some selection bias is introduced by restricting our methylation profiling at baseline to women with GWAS and biomarker data from baseline as well, given the requirement that these participants must have signed the WHI supplemental consent for broad sharing of genetic data in 2005. However, we believe that selection bias at this stage is minimized by the inclusion of participants who died between the time of the start of the WHI study and the time of supplemental consent in 2005, which resulted in the exclusion of only ~6–8 % of all WHI participants. Nevertheless, participants unable or unwilling to sign consent in 2005 may not represent a random subset of all participants who survived to 2005. Second, some selection bias may also occur if similar gross differences exist in the characteristics of participants who consented to be followed in the two WHI extension studies beginning in 2005 and 2010 compared to non-participants at each stage. We believe these selection biases if present have minimal effects on our effect estimates. Data are available from the page https://www.whi.org/researchers/Stories/June%202015%20WHI%20Investigators’%20Datasets%20Released.aspx, see the link https://www.whi.org/researchers/data/Documents/WHI%20Data%20Preparation%20and%20Use.pdf.

Dataset 2: Bogalusa

We analyzed the blood DNA methylation levels of 968 participants (680 Caucasians, 288 African Americans; age range = 28–51.3 years) from the Bogalusa Heart study [68] who were examined in Bogalusa, Louisiana during 2006–2010 for cardiovascular risk factors. All participants in this study gave informed consent at each examination. Study protocols were approved by the Institutional Review Board (IRB reference no. 12-395283) of the Tulane University Health Sciences Center. DNA was extracted from 1106 whole blood samples using the PureLink Pro 96 Genomic DNA Kit (LifeTechnology, CA, USA) following the manufacturer’s instructions. The Infinium HumanMethylation450 BeadChip (Methy450K) was used for whole genome DNA methylation analysis.

All the samples were processed at the Microarray Core Facility, University of Texas Southwestern Medical Center at Dallas, Texas. For DNA methylation analysis, 750 ng genomic DNA from each participant was bisulphite converted using the EZ-96 DNA Methylation Kit (Zymo Research, CA, USA) and the efficiency of the bisulphite conversion was confirmed by built-in controls on the Methy450K array. The methylation profile of each individual was measured by processing 4 μL of bisulphite-converted DNA, at a concentration of 50 ng/μL, on a Methy450K array. The bisulphite-converted DNA was amplified, fragmented, and hybridized to the array. The arrays were scanned on an Illumina HiScan scanner and the raw methylation data were extracted using Illumina’s Genome Studio methylation module. Data cleaning procedures were undertaken using R package “minfi” [69], generating quality control report, finding sample outliers, cell counts estimation, and annotation accessing. The R package wateRmelon [70] was used for β-value normalization and quality control. For correction of systematic technical biases in the 450 K assay, β-value normalization was performed by the “dasen” function, in which type I and type II intensities and methylated and unmethylated intensities will be quantile normalized separately after backgrounds equalization of type I and type II. The R package ChAMP [71] was used for batch effect analysis and correction with “champ.SVD” and “champ.runCombat” functions. The clinical variables and participant characteristics are defined in the captions of the respective Additional files.

The are available from https://biolincc.nhlbi.nih.gov/studies/bhs/.

Dataset 3: blood from Hispanics and Caucasians of PEG

The Parkinson’s disease, Environment, and Genes (PEG) case-control study aims to identify environmental risk factors (e.g. neurotoxic pesticide exposures) for Parkinson’s disease.

The PEG study is a large population-based study of Parkinson’s disease of mostly rural and township residents of California’s central valley [72]. Here we only used diseased participants from wave 1 (PEG1). Since all participants of dataset 3 had Parkinson’s disease, disease status could not confound associations with epigenetic aging. Medication status was not associated with epigenetic age acceleration. The data are available from Gene Expression Omnibus.

Dataset 4: saliva samples from PEG

This novel dataset comes from the PEG study (described above). Since PD disease status did not relate to epigenetic age acceleration in these data, we ignored it in the analysis. However, our findings are unchanged after incorporating PD status in a multivariate model. About half of the samples overlapped with those of dataset 3, which is why we could correlate epigenetic age acceleration between blood and saliva.

Datasets 5 and 6: blood from Tsimane, Hispanics, and Caucasians

Datasets 5 and 6, which were collected and generated in the same way, only differ in terms of the chronological ages. All participants in dataset 5 are older than 35 years while those in dataset 6 are younger or equal to 35 years. The dataset involved three different ethnic groups: Tsimane Amerindians, Hispanics living in the US, and Caucasians living in the US. Fasting whole-blood samples were collected from Tsimane via venipuncture in field villages in the vicinity of San Borja, Bolivia as a part of the annual biomedical data collection for a longitudinal project on aging during 2004–2009 (Tsimane Health and Life History Project). Manual complete blood counts were conducted using a hemocytometer, erythrocyte sedimentation rate was calculated following the Westergren method, and hemoglobin was analyzed with a QBC Autoread Plus Dry Hematology System (Drucker Diagnostics, Port Matilda, PA, USA). Specimens were stored in liquid nitrogen until transfer to the US on dry ice, where they were stored at –80 °C. All participants provided written and informed consent; study protocols and procedures were approved at the individual, village, and Tsimane government level, as well as by the University of California, Santa Barbara and University of New Mexico Institutional Review Boards (IRB Reference numbers 14-0604 and 07-157, respectively). Specimens were shipped on dry ice to the University of Southern California for extraction. The same core facility provided blood samples that were collected at the same time and stored in the same condition as Hispanic participants living in the US. The DNA samples from all participants (Caucasians, Hispanics, Tsimane) were randomized across the Illumina chips to avoid confounding due to chip effects. For our age prediction analysis, we used background corrected beta values resulting from Genome Studio.

Hispanics for datasets 5 + 6: Participant recruitment: Participation in the BetaGene study was restricted to Mexican Americans from families of a proband with gestational diabetes mellitus (GDM) diagnosed within the previous 5 years. Probands were identified from the patient populations at Los Angeles County/USC Medical Center, OB/GYN clinics at local hospitals, and the Kaiser Permanente health plan membership in Southern California. Probands qualified for participation if they: (1) were of Mexican ancestry (defined as both parents and ≥3/4 of grandparents Mexican or of Mexican descent); (2) had a confirmed diagnosis of GDM within the previous 5 years; (3) had glucose levels associated with poor pancreatic β-cell function and a high risk of diabetes when not pregnant; and (4) had no evidence of β-cell autoimmunity by GAD-65 antibody testing. Recruitment targeted two general family structures using siblings and/or first cousins of GDM probands, all with fasting glucose levels <126 mg/dl (7 mM): (1) at least two siblings and three first cousins from a single nuclear family; or (2) at least five siblings available for study. Using information from the proband to determine preliminary eligibility, siblings and first cousins were invited to participate in screening and, if eligible, detailed phenotyping (below) and collection of DNA. Available parents and connecting uncles and aunts were asked to provide DNA and had a fasting glucose determination. In addition, women of Mexican ancestry who have gone through pregnancy without GDM, as evidenced by a plasma or serum glucose level <120 mg/dl after a 50 g oral glucose screen for GDM, were also collected. Recruitment criteria for control probands were similar to that of the GDM probands, but were also selected to be age, BMI, and parity-matched to the GDM probands. Unrelated samples for the present methylation analysis were selected randomly from all BetaGene participants. The BetaGene protocol (HS-06-00045) has been approved by the Institutional Review Boards of the USC Keck School of Medicine.

Dataset 7: blood from East Asians and Caucasians

Here we downloaded the publicly available DNA methylation data from GSE53740 [73]. Since we found that progressive supranuclear palsy (PSP) had a significant effect on epigenetic age acceleration, we removed PSP samples from the analysis. Further, we focused on comparing East Asians to Caucasians since other racial/ethnic groups were represented by fewer than 10 samples.

Dataset 8: blood from African populations

We used blood methylation data from [42]. We studied peripheral whole-blood DNA from a total of 256 samples (for which the chronological age at the time of blood draw was available).

As detailed in Fagny et al. [42], the samples come from seven populations located across the Central African belt. These populations can be divided into two main groups: RHG populations, historically known as “pygmies,” who have traditionally relied on the equatorial forest for subsistence and who live close to, or within, the forest; and AGR populations, living either in rural/urban deforested regions or in forested habitats in which they practice slash-and-burn agriculture. Informed consent was obtained from all participants and from both parents of any participants under the age of 18 years. Ethical approval for this study was obtained from the institutional review boards of Institut Pasteur, France (RBM 2008-06 and 2011-54/IRB/3).

Dataset 9: cord blood samples from African Americans and Caucasians

These 216 cord blood samples from 92 African American and 70 Caucasian participants come from a study that described racial differences in DNA methylation levels [44].

Datasets 10 and 11

Saliva samples from Caucasians and Hispanics. The data were generated by splitting the data from [74] by sex, which reflected the use of these data in the development of the epigenetic clock software [20]. Note that these data were generated on the older Illumina platform (27 K array). Some of the data were used as training data in the development of the epigenetic clock, which might bias the results. By contrast, the novel saliva data from PEG (dataset 4) provide an unbiased analysis.

Dataset 12: lymphoblastoid cell lines from Han Chinese, African Americans, and Caucasians

We clustered the samples based on the interarray correlation. Since 51 samples were very distinct from the remaining samples, they were removed as potential outliers. Disease status did not affect the estimates of DNAm age, which is why we ignored it.

Description of brain datasets

We collected brain datasets from six independent studies to assess gender effect on epigenetic age acceleration. We focused on Caucasian samples since there were insufficient numbers of other racial/ethnic groups.

  • Study 1: brain DNA methylation data from a study of Alzheimer’s disease study from [75], GEO accession GSE59685. DNA methylation profiles of the cerebellum, entorhinal cortex, prefrontal cortex, and superior temporal gyrus were available from 117 individuals. We ignored disease status since it was not associated with age acceleration.

  • Study 2: brain DNA methylation data from neurologically normal participants from [76], GEO accession GSE15745. DNA methylation data of the cerebellum, frontal cortex, pons, and temporal cortex regions from up to 148 neurologically normal participants of European ancestry [76].

  • Study 3: cerebellar DNA methylation data from [77], GEO GSE38873. DNA methylation data from the cerebellum of 147 participants from a case-control study (121 cases/32 controls) of psychiatric disorders. Since disease status did not affect DNAm age, we ignored it.

  • Study 4: prefrontal cortex samples from [78], GEO GSE61431. We analyzed 37 Caucasian participants (European ancestry).

  • Study 5: frontal cortex and cerebellum from neurologically normal Caucasian participants from [79]. The DNA methylation data and corresponding SNP data can be found in dbGAP, http://www.ncbi.nlm.nih.gov/gap (accession: phs000249.v2.p1). We only analyzed 209 Caucasian participants who met our stringent quality control criteria. We excluded several putative outliers from the original dataset including three individuals who were genotyped on a different platform, six participants who were outliers according to a genetic analysis (PC plot), and 13 participants who had the wrong gender according to the gender prediction algorithm of the epigenetic clock software.

  • Study 6: dorsolateral prefrontal cortex samples from 718 Caucasian participants from the Religious Order Study (ROS) and the Memory and Aging Project (MAP). The DNA methylation data are available at the following webpage https://www.synapse.org/#!Synapse:syn3168763. We focused on brain samples of Caucasian participants from these two prospective cohort studies of aging that include brain donation at the time of death [80]. Additional details on the DNA methylation data can be found in [81]. We were not able to evaluate the effect of race/ethnicity on epigenetic age acceleration since the dataset contained only 12 Hispanic samples (which did not differ significantly from Caucasians in terms of epigenetic age). Further, we found no association between disease status and epigenetic age acceleration, which is why we ignored disease status in our analysis.

Preprocessing of Illumina Infinium 450 K arrays

In brief, bisulfite conversion using the Zymo EZ DNA Methylation Kit (ZymoResearch, Orange, CA, USA) as well as subsequent hybridization of the HumanMethylation450k Bead Chip (Illumina, San Diego, CA, USA), and scanning (iScan, Illumina) were performed according to the manufacturers’ protocols by applying standard settings. DNA methylation levels (β values) were determined by calculating the ratio of intensities between methylated (signal A) and unmethylated (signal B) sites. Specifically, the β value was calculated from the intensity of the methylated (M corresponding to signal A) and unmethylated (U corresponding to signal B) sites, as the ratio of fluorescent signals β = Max(M,0)/[Max(M,0) + Max(U,0) + 100]. Thus, β values range from 0 (completely unmethylated) to 1 (completely methylated) [82]. The epigenetic clock software implements a data normalization step that repurposes the BMIQ normalization method from Teschendorff [83] so that it automatically references each sample to a gold standard based on type II probes as detailed in [20].

Estimating blood cell counts based on DNA methylation levels

We estimate blood cell proportions using two different software tools. Houseman’s estimation method [84], which is based on DNA methylation signatures from purified leukocyte samples, was used to estimate the proportions of cytotoxic (CD8+) T cells, helper (CD4+) T, natural killer, B cells, and granulocytes. The software does not allow us to identify the type of granulocytes in blood (neutrophil, eosinophil, or basophil) but we note that neutrophils tend to be the most abundant granulocyte (~60 % of all blood cells compared with 0.5–2.5 % for eosinophils and basophils). The advanced analysis option of the epigenetic clock software [20] was used to estimate the percentage of exhausted CD8+ T cells (defined as CD28-CD45RA-) and the number (count) of naïve CD8+ T cells (defined as (CD45RA + CCR7+) as described in [31].

Flow cytometric data from the Long Life Study of the WHI

While our DNA methylation data from the WHI were assessed at baseline, the flow cytometric data were measured 14.6 years after baseline. Between March 2012 and May 2013, a subset of WHI participants were enrolled in the Long Life Study (LLS) and additional biospecimens, physiometric, and questionnaire data were collected. All surviving Hormone Trial participants followed through 2010 and all African American and Hispanic/Latino participants from the SNP Health Association Resource (WHI-SHARe) sub-cohort were included if CVD biomarker from WHI baseline exam and genome-wide genotyping (GWAS) data were available and if they were at least 63 years old by 1 January 2012. Women who were either unable to provide informed consent (e.g. dementia) or those residing in an institution (e.g. skilled nursing facility) were excluded. Of a total of 14,081 eligible WHI participants, 9242 women consented to participate, 7875 were enrolled, and 7481 underwent successful blood draws. Blood was collected at locations across the US using a standardized protocol between March 2012 and May 2013 (Examination Management Services, Inc.) Fresh peripheral blood samples were packaged in Styrofoam with cold packs and were sent overnight to a central testing facility in Seattle.

A random sample of 600 residual fresh peripheral blood specimens (single tube, following CBC analysis) was transported to the University of Washington Medical Center’s (UWMC’s) flow cytometry laboratory and high-sensitivity, multi-parameter flow cytometry was performed utilizing a modified four-laser, multi-color Becton-Dickinson (BD; San Jose, CA, USA) LSRII flow cytometer. All of the flow cytometry studies were performed within 72 h of sample collection between June 2012 and February 2013. A single tube was used to evaluate T lymphocyte subsets: CD45 (KO), CD8 (BV), CD45RA (F), CCR7 (PE), CD5 (ECD), CD56 (PC5), CD3 (APC-H7), CD4 (A594), CD28 (APC), CD27 (PC7). A second tube evaluated B lymphocyte subsets: CD45 (APC-H7), CD20 (V450), kappa (F), lambda (PE), CD23 (ECD), CD5 (PC5.5), CD19 (BV650), CD38 (A594), CD10 (APC), CD27 (PC7), CD3 (APC-A700). Categories of circulating cells were quantified using a predefined population-based gating strategy based on established gating strategies for both T lymphocyte [85] and B lymphocyte [86] subsets.

Flow cytometric data from the MACS cohort

As part of Additional file 2, we validated imputed blood cell counts using flow cytometric data and DNA methylation data collected from men of the Multi-Center AIDS Cohort Study (MACS). The data were generated as described in [87]. Briefly, human peripheral blood mononuclear cell (PBMC) samples were isolated from fresh blood samples and either stained for flow cytometry analysis or used for genomic DNA isolation. DNA was isolated from 1 × 106 PBMC using Qiagen DNeasy blood and tissue mini spin columns. Quality of DNA samples was assessed using Nanodrop measurements and accurate DNA concentrations were measured using a Qubit assay kit (Life Technology). Cryopreserved PBMC obtained from the repository were thawed and assayed for viability using trypan blue. The mean viability of the samples was 88 %. Samples were stained for 30 min at 4 °C with the following antibody combinations of fluorescently conjugated monoclonal antibodies using the manufacturers recommended amounts for 1 million cells: tube 1: CD57 FITC (clone HNK-1), CD28 phycoerythrin (PE, L293), CD3 peridinin chlorophyll protein (PerCP,SK7), CD45RA phycoerythrin cyanine dye Cy7 tandem (PE-Cy7, L48), CCR7 Alexa Fluor 647 (AF647, 150503), CD8 allophycocyanin H7- tandem (APC-H7, SK1) and CD4 horizon V450 (V450, RPA-T4); tube 2: HLA-DR FITC (L243), CD38 PE (HB7), CD3 PercP, CD45RO PE-Cy7 (UCHL-1), CD95-APC(DXZ), CD8 APC-H7, and CD4 V450); tube 3: CD38 FITC (HB7), IgD PE (1A6–2), CD3 PerCP, CD10 PE-Cy7 (HI10a), CD27 APC (eBioscience, clone 0323, San Diego, CA), CD19 APC-H7 (SJ25C1) and CD20 V450 (L27). Antibodies were purchased from BD Biosciences, San Jose, CA (BD) except as noted. Stained samples were washed twice with staining buffer and run immediately on an LSR2 cytometer equipped with a UV laser (BD, San Jose, CA, USA) for the detection of 4′,6-diamidino-2-phenylindole dihydrochloride (DAPI) which was used as a viability marker at a final concentration of 0.1 ug/mL. Lineage gated isotype controls to measure non-specific binding were run and used CD3, CD4, and CD8 for T-cells or CD19 for B-cells. Fluorescence minus one controls (FMO) were also utilized to assist gating and cursor setting. A range of 20,000–100,000 lymphocytes were acquired and analyzed per sample using the FACSDiva software package (BD, San Jose, CA, USA).

Declarations

Acknowledgements

We would like to acknowledge the following WHI investigators. Program Office (National Heart, Lung, and Blood Institute, Bethesda, MD, USA): Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford, and Nancy Geller. Clinical Coordinating Center (Fred Hutchinson Cancer Research Center, Seattle, WA, USA): Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg. Investigators and Academic Centers: JoAnn E. Manson (Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA); Barbara V. Howard (MedStar Health Research Institute/Howard University, Washington, DC, USA); Marcia L. Stefanick (Stanford Prevention Research Center, Stanford, CA, USA); Rebecca Jackson (The Ohio State University, Columbus, OH, USA); Cynthia A. Thomson (University of Arizona, Tucson/Phoenix, AZ, USA); Jean Wactawski-Wende (University at Buffalo, Buffalo, NY, USA); Marian Limacher (University of Florida, Gainesville/Jacksonville, FL, USA); Robert Wallace (University of Iowa, Iowa City/Davenport, IA, USA); Lewis Kuller (University of Pittsburgh, Pittsburgh, PA, USA); Sally Shumaker (Wake Forest University School of Medicine, Winston-Salem, NC, USA). Women’s Health Initiative Memory Study (Wake Forest University School of Medicine, Winston-Salem, NC): Sally Shumaker.

Funding

This study was supported by NIH/NHLBI 60442456 BAA23 (Assimes, Absher, Horvath), National Institutes of Health NIH/NIA 1U34AG051425-01 (Horvath). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. The PEG data were supported by NIEHS RO1ES10544 (Ritz) and NIEHS R21 ES024356 (Horvath, Ritz). Gurven and Trumble were funded by NIH/NIA R01AG024119 and R56AG02411. The Religious Order study and Rush Memory and Aging Project (brain dataset 6) were funded by P30AG10161, R01AG17917, RF1AG15819, and R01AG36042.

One of our flow datasets was collected by the Multicenter AIDS Cohort Study (MACS) at UCLA (Principal Investigators, Roger Detels and Otoniel Martinez-Maza), U01-AI35040. The MACS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID) with additional co-funding from the National Cancer Institute (NCI P30 CA016042), the National Institute on Drug Abuse (NIDA 5P30 AI028697), the National Institute of Mental Health (NIMH), the National Institute on Aging (NIA Grant 1RO1-AG-030327 by BDJ), and UL1-TR000424 (JHU CTSA). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or donors to the David Geffen School of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Availability of data and materials

Our DNA methylation data are publicly available through gene expression omnibus (GEO) accession numbers: GSE72775, GSE78874, GSE72773, and GSE72777. Further, the WHI and Bogalusa datasets are available through dbGAP (http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000200.v10.p3 and https://biolincc.nhlbi.nih.gov/studies/bhs/).

African Populations: The genotyping data generated in this study have been deposited in the European Genome-Phenome Archive under accession codes EGAS00001000605, EGAS00001000908 and EGAS00001001066. The DNA methylation data generated in this study have been deposited in the European Genome-Phenome Archive under accession code EGAS00001001066.

The GSE numbers for the brain datasets are as follows: GSE59685, GSE15745, GEO GSE38873, and GEO GSE61431. Brain data 5 can be found at http://www.ncbi.nlm.nih.gov/gap (accession: phs000249.v2.p1) and brain data 6 at https://www.synapse.org/#!Synapse:syn3168763.

Authors’ contributions

SH conceived of the study, developed the methods, analyzed the data, and wrote the first draft of the article. MG, BT, HK, and HA contributed the DNA from the Tsimane Amerindians and interpreted the findings. ML, BR, and BC helped to interpret the data and edited the article. BR and SH contributed the PEG DNA methylation data. AL analyzed the brain datasets. DS, SL, and WC contributed the DNA methylation data from the Bogalusa Heart Study. SH, PT, DA, and TA contributed the DNA methylation data from the WHI. KE and AR contributed flow cytometric data from the WHI LLS. BJ and TR contributed flow data from the MACS. LQM, MF and MSK contributed DNAm data from African hunter gatherers. All authors helped interpret the data and edited the manuscript. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Ethics approval and consent to participate

This study was reviewed by the UCLA institutional review board (IRB#13-000671 and IRB#14-000061) as well as the University of California Santa Barbara and University of New Mexico Institutional Review Boards (IRB Reference numbers 14-0604 and 07-157 respectively).

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease Steve Horvath†Email authorView ORCID ID profile, Michael Gurven†, Morgan E. Levine, Benjamin C. Trumble, Hillard Kaplan, Hooman Allayee, Beate R. Ritz, Brian Chen, Ake T. Lu, Tammy M. Rickabaugh, Beth D. Jamieson, Dianjianyi Sun, Shengxu Li, Wei Chen, Lluis Quintana-Murci, Maud Fagny, Michael S. Kobor, Philip S. Tsao, Alexander P. Reiner, Kerstin L. Edlefsen, Devin Absher† and Themistocles L. Assimes††Contributed equa

Source: An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease | Genome Biology | Full Text

On the off-chance you’re alive in 150 years, you could be in for a very bad day, when the asteroid Bennu collides with Earth, unleashing a blast 200 times more powerful than that of the bomb that destroyed Hiroshima. OK, the odds are pretty good you won’t be around in 150 years, and they’re only 1 in 2,700 at the very likeliest that Bennu will pay us such a nasty house call. But the space rock is making a lot of news and getting a lot of attention from NASA all the same—and it should.

Discovered in 1999, Bennu measures 1,614 ft. (492 m) across and checks two worrisome boxes on the asteroid danger list. It is what astronomers all a near-Earth object (NEO), which is any comet or asteroid that approaches the sun at 1.3 Earth’s distance or closer. Bennu not only gets that close but actually crosses Earth’s orbit every six years as it makes its own circuit through the solar system. It is also what is known as a potentially hazardous asteroid (PHA), which is any asteroid that measures 460 ft. (140 m) or more, is close enough to be an NEO and poses a risk of doing serious global or regional damage if it strikes Earth. A blast equivalent to 200 Hiroshimas is serious indeed.

But Bennu is less worrisome than it seems too. Here’s why.

For starters, in order to reach that 1 in 2,700 risk level in 150 years or so, the asteroid first has to be gravitationally nudged from its current course when it passes between Earth and the moon on an earlier approach it will make in 2135. That could happen: Gravity plays unpredictable tricks on moving bodies, and a body that passes between the gravitational fields of both Earth and the moon can be jostled in innumerable ways. Of course that also means Bennu might be pushed in a direction that makes it less rather than more likely to hit Earth in the future.

What’s more, asteroid tracking has become a very precise science—one that is led by NASA’s Near-Earth Objects Program Office at the Jet Propulsion Laboratory (JPL) in Pasadena. With the help of astronomers around the world, the JPL team has identified and mapped the route of 95% of the dangerous rocks in the solar system measuring 0.62 miles (1 km) or more, and 40% of those in the 460-ft. class. With the help of a bump in funding from Congress that was approved in 2012, JPL expects to get that second number up to 90%.

Knowing the course the space rocks take as they make their periodic swings through our cosmic neighborhood does a lot more than just let us know how long our species has to live before an incoming bit of ordnance sends us the way of the dinosaurs. It also means we can do something to prevent the disaster from happening at all.

Both NASA and the European Space Agency have gotten very good at visiting asteroids and comets. The ESA’s Rosetta spacecraft and Philae lander arrived at comet 67P in 2014 and NASA’s Dawn spacecraft is currently orbiting the dwarf planet Ceres after having already orbited the asteroid Vesta. Similar navigational skills could be used to launch interceptors to asteroids when they are still years away from reaching Earth. Once the spacecraft arrived at the target it could either break it apart with an explosive or, more prudently, simply push it off course either with an engine or simply by crashing into it.

NASA will get some practice soon with Bennu itself when it launches the OSIRIS-REx spacecraft on Sept. 8. Over the course of its seven-year mission, the probe will fly to Bennu, map its surface and return a small sample of its dust and other material to Earth for study. The mission should reveal more about the chemistry, history and the organic potential of the solar system generally and about Bennu’s composition specifically. The precise makeup of the asteroid could help scientists determine what it would take to destroy or deflect it if the need ever arises.

Until then though, as you were. Bennu may or may not be coming our way, but if it is, we’ve got plenty of time to prepare our hello.

At least not much

Source: No, You Don’t Have to Worry (Much) About Getting Clobbered by an Asteroid | TIME

It was 23 years ago that Charl Van Wyk was sitting peacefully in the congregation at St. James Church in Cape Town, South Africa, when terror struck.

As Van Wyk has told WND, “The moment of chaos and carnage unfurled is forever etched in my mind.”

On July 25, 1993, while young people were singing in front of the congregation, Van Wyk heard a noise at a front door leading into the sanctuary. A group of attackers stepped through the doorway and lobbed grenades affixed with nails at the congregation. Then they opened fire with their assault rifles.

It took a few seconds to grasp what was happening, but when Van Wyk realized what danger the church was in, he dropped to his knees and drew his .38 special revolver from his ankle holster. Although he was in the fourth row from the back of the large sanctuary, he aimed as best he could and fired two rounds at the attackers.

He then crawled to the aisle and dashed for a back door, hoping to get behind the attackers and shoot them at close range to prevent further bloodshed.

But as he rounded the corner outside the building, he saw the terrorists already at their getaway car. He fired his last three rounds, and the terrorists jumped into their vehicle and raced off.

The attackers, who were members of the Azanian People’s Liberation Army, killed 11 people and wounded 58. They had also planned to lob petrol bombs into the sanctuary, where there were an estimated 1,000 people.

However, they abandoned that phase of the attack when they realized someone in the congregation was shooting back at them.

It may be a cliché, but Charl Van Wyk has proven it true – the only thing that can stop a bad guy with a gun (and grenades and petrol bombs) is a good guy with a gun.

Van Wyk chronicled his harrowing ordeal, as well as the aftermath and implications, in the book and DVD versions of “Shooting Back: The Right and Duty of Self-Defense.”

Today, gun rights are under attack in America and around the world. Van Wyk, whose Christian mission work focuses on Africa, argues Christians have a duty to resist anti-gun laws and those who pass them.

“If a thug in government, or on the streets, wants to take my life or someone else’s, or rape my wife or daughter, he needs to dodge my bullets!” Van Wyk told WND. “In Africa we often see the rape of women and children by rebel and government soldiers. The Christian man does not only have a right, but also a duty, to resist these wicked men with lethal force.

“To protect our families is to honor God. Basically, God’s laws trump human laws!”

Can Christians use guns to defend themselves? Yes, they can — and they must. Get your copy of “Shooting Back: The Right and Duty of Self-Defense” from the WND Superstore today.

Van Wyk remarked more Christian men should pray, “Lord, make me fast and accurate!” instead of being “spineless cowards who make the working environment of the bad guy safer.”

He said historically Christians believed not only were murderers guilty of law breaking, but also those who did not protect the lives of victims of violence as best they could. He wonders where that doctrine would leave most of today’s Christian men.

“We are to help the suffering with our resources; how can we stand by and watch the murder of the innocent?” he asked rhetorically. “In the Christian life, cowardice is a crime!”

The hero said resisting the wicked is actually part of a Christian’s God-ordained witness to them.

“During the war between Northern and Southern Sudan, Northern Muslim soldiers defected to the Southern Christian army because of their fighting tenacity and the godly manner in which they treated their POWs,” Van Wyk revealed. “Have we ever considered that the way in which we fight, and how we treat our enemies, can be a witness to them?”

He stressed the importance of teaching one’s children these ideas about self-defense, because public education systems and the media bombard young minds with commands not to offend anyone, but to “endure evil and be a doormat for the wicked.”

Van Wyk did his part to educate the public by helping to found Gun Owners of South Africa. He noted crime is out of control in South Africa, but the South African government is bent on disarming the population, thus taking away the ability of citizens to defend themselves from criminals.

image: http://www.wnd.com/files/2012/01/bc_shooting_back.jpg

bc_shooting_back“Women in South Africa are feeling particularly vulnerable because of the extremely high incidence of rape and murder,” Van Wyk stated. “They have started a division of GOSA called ‘Girls on Fire,’ through which they are educating women on the advantages and rights of female firearm ownership in South Africa.”He said “Girls on Fire” launched in 2015 with a “16 Days of Action for No Violence Against Women and Children” education campaign. The goal is to enable and empower women to stop being victims who have to protest the current state of affairs and start protecting themselves and their families.

Ultimately, women face the same reality as men, according to Van Wyk.

“When a bad guy has a gun, only a good guy with a gun can resist him,” he said. “Not much else will do the job.”

Can Christians use guns to defend themselves? Yes, they can — and they must. Get your copy of “Shooting Back: The Right and Duty of Self-Defense” from the WND Superstore today.
Read more at http://www.wnd.com/2016/07/dodge-my-bullets-st-james-massacre-hero-pushes-self-defense/#0qSZByPohbMbuF6T.99

Video: Pope demands protection for Christians after Pakistan attack

Read more at http://www.wnd.com/2016/07/dodge-my-bullets-st-james-massacre-hero-pushes-self-defense/#0qSZByPohbMbuF6T.99

Read more at http://www.wnd.com/2016/07/dodge-my-bullets-st-james-massacre-hero-pushes-self-defense/#0qSZByPohbMbuF6T.99

It was 23 years ago that Charl Van Wyk was sitting peacefully in the congregation at St. James Church in Cape Town, South Africa, when terror struck. As Van Wyk has told WND, “The moment of chaos and carnage unfurled is forever etched in my mind.” On July 25, 1993, while young people were singing […]

Source: ‘Dodge my bullets!’ Church-massacre hero pushes self-defense

INFLAMMATION: The Cardiac Killer

Citations

Willerson JT, Ridker PM. Inflammation as a Cardiovascular Risk Factor. Circulation. 2004; 109: II-2-II-10 [Link]

Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, Kastelein JJ, Bittner V, Fruchart JC; Treating to New Targets Investigators. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007 Sep 27;357(13):1301-10. [Link]

Cabrera MAS, de Andrade SM, Dip RM. Lipids and All-Cause Mortality among Older Adults: A 12-Year Follow-Up Study. The Scientific World Journal. 2012;2012:930139. doi:10.1100/2012/930139. [Link]

Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008 Nov 20;359(21):2195-207. [Link]

C-Reactive Protein, Fibrinogen, and Cardiovascular Disease Prediction The Emerging Risk Factors Collaboration. N Engl J Med 2012; 367:1310-1320October 4, 2012DOI: 10.1056/NEJMoa1107477 [Link]

Rucker R, Chowanadisai W, Nakano M. Potential physiological importance of pyrroloquinoline quinone. Altern Med Rev. 2009 Sep;14(3):268-77. [Link]

W, Bauerly K, Tchaparian E, Rucker RB. Pyrroloquinoline quinone (PQQ) stimulates mitochondrial biogenesis. FASEB J 2007;21:854 [Link]

Ohwada K, Takeda H, Yamazaki M, et al. Pyrroloquinoline quinone (PQQ) prevents cognitive deficit caused by oxidative stress in rats. J Clin Biochem Nutr 2008;42:29-34. [Link]

Bauerly K, Harris C, Chowanadisai W, et al. Altering Pyrroloquinoline Quinone Nutritional Status Modulates Mitochondrial, Lipid, and Energy Metabolism in Rats. Hansen IA, ed. PLoS ONE. 2011;6(7):e21779. doi:10.1371/journal.pone.0021779. [Link]

Harris, Calliandra B. et al. Dietary pyrroloquinoline quinone (PQQ) alters indicators of inflammation and mitochondrial-related metabolism in human subjects. Journal of Nutritional Biochemistry , Volume 24 , Issue 12 , 2076 – 2084 [Link]

Windler E, Schöffauer M, Zyriax BC. The significance of low HDL-cholesterol levels in an ageing society at increased risk for cardiovascular disease. Diab Vasc Dis Res. 2007 Jun;4(2):136-42. [Link]

Lee S Gross, Li Li, Earl S Ford, and Simin Liu. Increased consumption of refined carbohydrates and the epidemic of type 2 diabetes in the United States: an ecologic assessment. Am J Clin Nutr May 2004 vol. 79 no. 5 774-779 [Link]

López-Alarcón M, Perichart-Perera O, Flores-Huerta S, et al. Excessive Refined Carbohydrates and Scarce Micronutrients Intakes Increase Inflammatory Mediators and Insulin Resistance in Prepubertal and Pubertal Obese Children Independently of Obesity. Mediators of Inflammation. 2014;2014:849031. doi:10.1155/2014/849031. [Link]

Siri-Tarino PW, Sun Q, Hu FB, Krauss RM. Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease. The American Journal of Clinical Nutrition. 2010;91(3):535-546. doi:10.3945/ajcn.2009.27725. [Link]

Robert H Knopp, Barbara M Retzlaff. Saturated fat prevents coronary artery disease? An American paradox. Am J Clin Nutr November 2004 vol. 80 no. 5 1102-1103 [Link]

Koh AS, Simmons-Willis TA, Pritchard JB, Grassl SM, Ballatori N. Identification of a mechanism by which the methylmercury antidotes N-acetylcysteine and dimercaptopropanesulfonate enhance urinary metal excretion: transport by the renal organic anion transporter-1. Mol Pharmacol 2002 Oct;62(4):921-6 [Link]

Kerksick C, Willoughby D. The Antioxidant Role of Glutathione and N-Acetyl-Cysteine Supplements and Exercise-Induced Oxidative Stress. Journal of the International Society of Sports Nutrition. 2005;2(2):38-44. doi:10.1186/1550-2783-2-2-38. [Link]

Langsjoen H1, Langsjoen P, Langsjoen P, Willis R, Folkers K. . Usefulness of coenzyme Q10 in clinical cardiology: a long-term study. Mol Aspects Med. 1994;15 Suppl:s165-75. [Link]

Chowanadisai W, Bauerly KA, Tchaparian E, Wong A, Cortopassi GA, Rucker RB. Pyrroloquinoline Quinone Stimulates Mitochondrial Biogenesis through cAMP Response Element-binding Protein Phosphorylation and Increased PGC-1α Expression. The Journal of Biological Chemistry. 2010;285(1):142-152. doi:10.1074/jbc.M109.030130. [Link]

Miquel J. Can antioxidant diet supplementation protect against age-related mitochondrial damage? Ann N Y Acad Sci 2002 Apr;959:508-16. Xu D, Finkel T. A role for mitochondria as potential regulators of cellular life span. Biochem Biophys Res Commun 2002 Jun 7;294(2):245-8. [Link]

Ho PI, Collins SC, Dhitavat S, Ortiz D, Ashline D, Rogers E, Shea TB. Homocysteine potentiates beta-amyloid neurotoxicity: role of oxidative stress. J Neurochem 2001 Jul;78(2):249-53 [Link]

Zhang P, Xu Y, Sun J, et al. Protection of pyrroloquinoline quinone against methylmercury- induced neurotoxicity via reducing oxidative stress. Free Radic Res 2009;43:224-233 [Link]

Chowanadisai W, Bauerly KA, Tchaparian E, Wong A, Cortopassi GA, Rucker RB. Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1 alpha expression. J Biol Chem. 2010 Jan 1;285:142-52 [Link]

Nakano M, Ubukata K, Yamamoto T, Yamaguchi H. Effect of pyrroloquinoline quinone (PQQ) on mental status of middle-aged and elderly persons. FOOD Style. 2009;21:13(7):50-3. [Link]

Rucker R, Chowanadisai W, Nakano M. Potential physiological importance of pyrroloquinoline quinone. Altern Med Rev. 2009 Sep;14(3):268-77. [Link]

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Source: The Cardiac Killer

High blood pressure is the most important controllable risk factor

The researchers looked at the proportion of strokes caused by specific risk factors to determine the extent to which eliminating each risk would reduce the impact of stroke. Eliminating high blood pressure was estimated to reduce risk by nearly 48 percent, the findings showed.

The investigators also calculated potential reductions for eliminating other risk factors:

  • Physical inactivity: 36 percent,
  • Poor diet: 23 percent,
  • Obesity: 19 percent,
  • Smoking: 12 percent,
  • Heart causes: 9 percent,
  • Diabetes: 4 percent,
  • Alcohol use: 6 percent,
  • Stress: 6 percent,
  • Lipids (blood fats): 27 percent.
The combined reduction for all 10 risk factors was 90.7 percent across all regions, age groups and among both men and women. The study authors noted, however, that the importance of various risk factors vary in different regions. For example, high blood pressure causes about 39 percent of strokes in North America, Australia and western Europe, but nearly 60 percent in Southeast Asia.

Source: 9 Out of 10 Strokes Could Be Prevented, Study Finds | Health Care | US News

If you want to get into shape, you might decide to eat more vegetables and go to the work out more. But what if you want to have more energy, improve your mood, and sleep better? Welcome to “biohacking,” where practitioners use data about themselves and their environment to perfect their daily routine of eating, sleeping, working, and exercising for optimal performance.

Biohacking has been around for a while—but is now making its way into the workplace. Well, the Silicon Valley workplace, at least.

At Nootrobox, a San Francisco company that makes brain supplements, the entire company collectively fasts for 36 hours every week. “It was hard for the first couple of weeks, but now it’s like the company culture,” says co-founder Geoffrey Woo. “A weekly ritual if you will.” Some members of the nine-person company, all aged from mid-twenties to mid-thirties, even start early and do a 60-hour weekly fast.

Woo defines biohacking as treating your body like a computer system. “That means being experimental and rigorous about inputs in the system,” he says. “Measuring, quantifying and optimizing those inputs for specific outputs.”

Woo and his co-founder, Michael Brandt, have used data to solve larger problems since they met as computer science majors at Stanford. While in college, this took the form of Brandt using a journal to track all his conversations, in a bid to get better at talking to women. “It shows that mindset of being very rigorous, of measuring and quantifying one’s schedule to optimize for an outcome,” says Woo.

This same methodical approach is behind the company’s weekly staff fasts. And the method is working, says Woo—Tuesday fast days are “one of our most productive days of the week.”

Dave Asprey, 42, one of the first biohackers and an advocate for the practice, has spent $300,000 and two decades on hacking his own body and says he plans to live to 180 years old.

He says there’s considerable interest among various Silicon Valley companies in the work produced by his biohacking company, Bulletproof. Yahoo’s CEO, Marissa Mayer, for example, invited him to speak to her company’s whole workforce, he says, and Yahoo owns a “Bulletproof Vibe,” a machine that vibrates the whole body and is intended to replicate some of the benefits of exercise.

Among Asprey’s own employees, executives use a heart rate variability sensor before big meetings to try to take themselves out of fight-or-flight mode. The result, Asprey says, is “we’ll have meetings that are more cooperative and creative.” He has also asked neuroscientists to hook his senior leadership team up with electrodes so they can monitor brainwaves and try to control their minds better.

“When you’re in control of your biology, you’re in control of your mind and you can make better decisions,” he says. “You’re actually a better person.”

Asprey’s employees regularly fast and, though he wouldn’t force the company to collectively fast—“that’d be incredibly odd and dysfunctional,”—he says he’d like to introduce an optional staff fasting day.
The downsides to tracking your body at work

Though there’s a great deal of excitement over biohacking, the idea of weekly staff fasts likely sounds a little daunting to all but the uber-committed. What if a friend invites you to a dinner party on fast Tuesday? If it’s your birthday and you’d like to bring in cake? Or if you have your period and just really want a piece of chocolate?

Until recently, Nootrobox didn’t have to worry about that last problem. The two co-founders and first six employees were all men, and the Nootrobox only hired its first woman this month.

Inevitably, there are ethical and human resources concerns that come with staff fasting, and some of them are gender-related. Even if a fast is optional, employees may feel pressured to take part. If they can’t, perhaps because of an illness or pregnancy, the employee could be forced to reveal private medical information to the employer.

Asprey also says that fasting is “definitely” not a good idea for people with eating disorders—which tend to affect women more than men. And of course, he says, “there are certain times of the month for women when fasting is much harder.”

There are also questions about whether it’s even right for bosses to see exactly what makes employees stressed or unhappy, and how employers could use health data about their staff.

Brandon Smith, a therapist who focuses on workplace culture, says measuring employees’ heart rates and brain waves raises serious questions. “Will it be used in assessing people’s performance and determining rewards and promotions?” he asks. “For example, ‘Brad clearly handles pressure better than Sanchit. Look at his brain waves.’ Unless this practice is purely voluntary and the data can only be accessed by the participating employee, it is a dangerous idea to implement.”

Smith says biohacking can be a valuable tool for self-discovery, and a means for employees to gain greater self-awareness and control over their emotions. But it should not go further than that.

“When biohacking becomes a tool used by the organization to control and manipulate employees’ emotions, moods and physical reactions to various situations, the company has crossed an ethical line,” he says. “Our journey as human beings is one of self-discovery. To that end, biohacking can be a value. Beyond that, it is a damaging Orwellian control tactic.”

Asprey acknowledges that there can be downsides to biohacking, but that “there’s a much bigger downside to ignoring your environment and letting it tell your biology to get weak and die after you’re too old to have kids.”

For his part, Woo admits that biohacking and staff fasts are a rather specific taste. “Everyone can benefit from the work we’re doing at Nootrobox, but not everyone should work at Nootrobox,” he says. Given the nature of the company’s work, it attracts employees who are already involved or interested in biohacking, he says.

“It’s not a job requirement to fast or biohack but it’s an activity that predicates why we exist as an organization,” he says. “We think biohacking can help people become better versions of themselves, and in turn create a better, more productive society.”
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Neuroscientists say multitasking literally drains the energy reserves of your brain
THE INEVITABLE
The future of tech really is an Uber for everything
Just the beginning.(Reuters/Kacper Pempel)
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Written by
Kevin Kelly
Co-founder, Wired Magazine
July 05, 2016

After living online for the past three decades, first as a pioneer in a rather wild empty quarter, and then later as a builder who constructed parts of this new continent, my confidence in inevitability is based on the depth of these technological changes. The daily glitter of high-tech novelty rides upon slow currents. The roots of the digital world are anchored in the physical needs and natural tendencies of bits, information, and networks. No matter what geography, no matter what companies, no matter what politics, these fundamental ingredients of bits and networks will hatch similar results again and again. Their inevitability stems from their basic physics. I endeavor to expose these roots of digital technology because from them will issue the enduring trends in the next three decades.

Our first impulse when we confront extreme technology surging forward in this digital sphere may be to push back. Not all of this shift will be welcomed. Established industries will topple because their old business models no longer work. Entire occupations will disappear, together with some people’s livelihoods. New occupations will be born and they will prosper unequally, causing envy. The continuation and extension of the trends I outline will challenge current legal assumptions and tread on the edge of outlaw—a hurdle for law abiding citizens. By its nature, digital network technology rattles international borders because it is borderless. There will be heartbreak, conflict and confusion.

Our first impulse when we confront extreme technology surging forward in this digital sphere may be to push back. To stop it, prohibit it, deny it, or at least make it hard to use. (As one example, when the internet made it easy to copy music and movies, Hollywood and the music industry did everything they could to stop the copying. To no avail. They only succeeded in making enemies of their customers.) Banning the inevitable usually backfires. Prohibition is at best temporary, and in the long counter productive.

We now appreciate that everything is undergoing change, even though much of this alteration is imperceptible. A vigilant eyes-wide-open embrace works much better. My intent is to uncover the roots of digital change so that we can embrace them. Once seen, we can work with their nature, rather than struggle against it. Massive copying is here to stay. Massive tracking and total surveillance is here to stay. Ownership is shifting. Virtual reality is becoming real. We can’t stop artificial intelligences and robots from improving, creating new businesses and taking our current jobs. It may be against our initial impulse, but we should embrace the perpetual remixing of these technologies. Only by working with these technologies, rather than trying to thwart them, can we gain the best of what they have to offer. I don’t mean to keep our hands off. We need to regulate these emerging inventions to prevent actual (vs. hypothetical) harms, both by legal and technological means. We need to civilize and tame them in their particulars. But we can only do that with deep engagement, first-hand experience, and a vigilant acceptance. These technologies are not going away.

Change is inevitable. We now appreciate that everything is mutable and undergoing change, even though much of this alteration is imperceptible. The highest mountains are slowly wearing away under our feet, while every animal and plant species on the planet is morphing into something different in ultra slow motion. Even the eternal shining sun is fading on an astronomical schedule, though we will be long gone when it does. Human culture, and biology, too, are part of this imperceptible slide towards something new.
(Kevin Kelly/Viking)

At the center of every significant change in our lives today is a technology of some sort. Technology is humanity’s accelerant. Because of technology everything we make is always in the process of becoming. Every kind of thing is becoming something else, while it churns from “might” to “is.” All is flux. Nothing is finished. Nothing is done. This never-ending change is the pivotal axis of the modern world.

Constant flux means more than simply “things will be different.” It means processes—the engines of flux—are now more important than products. Our greatest invention in the past 200 years was not a particular gadget or tool but the invention of the scientific process itself. Once we invented the scientific method, we could immediately create thousands of other amazing things we could have never discovered any other way. This methodical process of constant change and improvement was a million times better than inventing any particular product because the process generated a million new products over the centuries since we invented it. Get the ongoing process right and it will keep generating ongoing benefits. In our new era, processes trump products. Constant flux means processes—the engines of flux—are now more important than products.

This shift towards processes also means ceaseless change is the fate for everything we make. We are moving away from the world of fixed nouns and towards a world of fluid verbs. In the next thirty years we will continue to take solid things—an automobile, a shoe—and turn them into intangible verbs. Products will become services and processes. Embedded with high doses of technology, an automobile becomes a transportation service, a continually updated sequence of materials, rapidly adapting to customer usage, feedback, competition, innovation, and wear. Whether it is a driverless car, or one you drive, this transportation service is packed with flexibility, customization, upgrades, connections, and new benefits. A shoe, too, is no longer a finished product, but an endless process of reimagining our extended feet, perhaps with disposable covers, sandals that morph as you walk, treads that shift, or floors that act as shoes. “Shoe-ing” becomes a service and not a noun. In the intangible digital realm, nothing is static or fixed. Everything is becoming.

Upon this relentless change all the disruptions of modernity ride.

Source: The future of tech really is an Uber for everything — Quartz

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™

BOCA RATON, FL–(Marketwired – May 12, 2016) – Cubic Pharmaceuticals, a company based in the UK that focuses on developing and distributing high-quality, unique medicines and supplements, announced its Cubicole D3 is more available in the US Market than ever, on Amazon.com and the supplement can help people manage depression.

“It is incredible that research has found Vitamin D to be effective with anti-depressants and to help manage the disorder. It is unbelievably important in this day and age to have more effective treatments for depression when millions of people worldwide are diagnosed with it,” said Saumil Bhatt, CEO of Cubic Pharmaceuticals.

An international study has discovered taking Vitamin D can have a potential impact on mental health and clinical depression according to a recent article on dailymail.co.uk. Vitamin D had been found to increase the effectiveness of antidepressants and Dr. Jerome Sarris, who led a study by ARCADIA Mental Health Research Group at the University of Melbourne, described the results as significant.

Sarris discovered Vitamin D, also known as the sunshine vitamin, has been found to boost mood in combination with anti-depressants. These results were determined after researchers examined 40 clinical trials worldwide, where participants were prescribed with Vitamin D, some other nutraceuticals and placebo pills. Participants who took the Vitamin D supplement experienced less symptoms of depression than those taking the placebo.

Results of the trial is linked to certain receptors in the brain for vitamin D and these receptors are found in the areas of the brain that are linked to the development of depression. For this reason, vitamin D has been linked with depression, according to the Vitamin D Council, and the supplement may increase the amount of monoamines, which can help treat depression.

“People with depression now have a Vitamin D supplement to try in combination with medication to bring results and better treat their condition. I hope with Cubicole D3 more people can treat depression than ever,” Bhatt said.

Cubic Pharmaceuticals Ltd was founded in 2008 and by two pharmacists, Mr. Arun Jangra and Mr. Anwar Ali, who brought in their substantial experience of pharmacy and formulations whilst working with NHS. Since its inception, Cubic Pharmaceuticals Ltd has distributed and traded Ethical, Generics, OTC and Unlicensed Medicinal Products (SPECIALS) sharing knowledge and experiences. For more about the brand, visit: http://www.cubicpharmaceuticals.co.uk.

*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.

Source: Cubicole D3 Vitamin D Supplement May Help Treat Depression

Carl Smith Provides the Rosetta Stone of Solar Science?

Carl is no longer with us, but he has certainly left us with a legacy. Back in 1965 Paul Jose was one of the first to link solar modulation with planetary movements. He discovered that the planets roughly returned to the same position every 178.8 years (My research suggests 172 yrs). Jose’s paper included a very rough solar radius graph which showed some modulation but was difficult to draw from. Later Theodor Landscheidt wrote many papers using a similar principle but mainly relied on solar torque graphs which ranged over long time periods. Theodor also focused on the zero crossings  or when the Sun returns to the centre of the solar system, which in my opinion is not the crucial stage but happens close to grand minima. Landscheidt predicted a Grand Minimum to start at 1990, peak around 2030 (the latter 2030 might be late, if the current trend continues) and extend out to 2070…Those dates are derived from the zero crossing method which incorporates an extreme in solar torque measurements.

Then Carl Smith in 2007 using JPL data and his own programming skills plotted the Angular Momentum of the Sun. This graph I believe is the Rosetta stone of solar science.

Carl’s original graph did not have the green arrows, but instead he displayed red arrows when the curve reached zero. (both Carl & Landscheidt concentrated on the negative angular momentum as the graph goes through zero). Link to Carl’s original article HERE.. The solar disturbances occurring at the green arrows is a new discovery quite different to the Landscheidt theory.

Carbon 14 graph from Wiki showing correlation with Carl’s graph. Green squares corresponding with the green arrows.

Carl’s Graph was produced in 2007. Around 12 months later I stumbled on his graph while doing some ENSO research and noticed the “camel shaped humps” at the green arrows (green arrows added later), this is the point of divergence and the beginning of my research.

The humps or disturbance to the normal pattern also looked to line up very accurately with prior slowdowns of the Sun for the last 400 years. I later discovered this to be true for the last 6000 years. By studying the shape of the hump and measuring the Saturn angle we can now also quantify the severity of the solar downturn which lines up with the 11000 yr 14C (solar proxy) records in timing and strength, I call these humps the AMP event which stands for Angular Momentum Perturbation. Further research established another correlation, I checked the planetary position at the point of disturbance and noticed a recurring pattern. Every time there is a disturbance on Carl’s graph we have the same planetary position. This position is Neptune, Uranus and Jupiter together with Saturn opposing, this only happens on a cycle around 172 years average, which now laid the foundation for solar modulation planning. In addition it also became obvious that Angular Momentum (AM) was responsible for the strength of the solar cycle, the AM curve very closely matches the sunspot curve which now allows us easily to predict modulation strength for the next 200 years and more. The AM graphs serve as a marker and AM is not a driver in itself, the background forces are gravity, rotation, torque and velocity. There is one fact that cannot be argued against, the position of the planets as just described radically changes the path of the Sun around the Solar System Barycenter (SSB), this also coincides with all solar slowdowns. Only this planetary position can cause this radical path change.

The oncoming Grand Minimum will prove Carl’s graph is the key to solar activity, which will radically change the solar scientific arena. It will take time for Angular Momentum Theory (AMT) to take hold, but the house of cards of the last 50 years of solar science will eventually crumble, showing us all how little we really know.

Below is a new version of Carl’s graph that uses different data that slightly enhances the AMP events at the green arrows. Click on the image for a full size view.

Be sure to visit our sister site that has more new research in the Planetary Realm along with a full archive of Dr. Landscheidt’s & Carl Smith’s work  http://landscheidt.wordpress.com/

Dont forget to vote on “who’s name should be on the next grand minimum” in the poll link at the top.

___________________________________________________________________________________________________

Addition Keystone graphs produced after paper publication:

solar powerwave

3 prongs grand minima

Source: Beyond Landscheidt…. | Planetary Theory Moves to the Next Level

Holy Crap! Global cooling is coming.

If you have no Idea what this means start with Landscheidt cycles…..

Beyond Landscheidt…. | Planetary Theory Moves to the Next …

www.landscheidt.info/
Jul 23, 2009 – Landscheidt predicted a Grand Minimum to start at 1990, peak … Momentum (AM) was responsible for the strength of the solar cycle, the AM …

A Cycles Based Approach to Understanding Solar Activity & Climate.

Stupid PILLS

From the Aging Brain Care folks:

What drugs make you stupid….

Source: ACB_scale_-_legal_size.pdf

LSD: Distortions of Vision and Pain

This paper is a manually-entered copy of the complete published text of the 1979paper. The author thanks the editors of erstwhile Perceptual and Motor Skillsfor thisspecial permission. The published text pagination has been preserver, except thathyphenated words and REFERENCES crossing page boundaries have been gathered tothe page on which they were begun.In addition to this Preface, one minor change has been made to correct a newly-founderror on the published p. 518, an error which is explained the

Around 12% of US women will develop invasive breast cancer over the course of their life, according to statistics released by the US Breast Cancer Statistics.

The idea that breast cancer risk could be determined through DNA tests is not necessarily a new one, but studies focusing on this concept have been more or less inconclusive. But a recent analysis conducted at the University College London has shown that this type of test could potentially become a new way of determining predisposition towards cancer.

Breast cancer has become an increasing threat to women worldwide, not only in the US. Even if scientific parties are still in contradiction with one another regarding what exactly triggers cancer, the fact that the patient’s body undergoes certain changes when the disease actually appears still remains true.

Said study was based on the analysis of 600 breast tissue samples from both healthy women and ones which have been diagnosed with breast cancer. In regards to the latter group, DNA tests showed that 30% of specific genes undergo certain alterations when cancer actually develops in the patient’s system.

True, this study is still somewhat inconclusive as the ones before it when focusing on exact tell-tale hints of cancer risk. But scientists were able to identify specific reprogramming cells that switch from normal behavior to cancerous. By conducting further analysis on the matter, the research team could potentially identify the exact triggers of cancer, stemming from genetic inheritance to factors related to menopause entry.

The importance of this study is based on the fact that epigenetic alterations are completely reversible through immediate treatment and gene therapy. Once higher risk cells are identified, therapies could potentially force them to go back to normal, effectively circumventing breast cancer. But this idea is not limited to this type of cancer if further inquiries show that every cancer type, be it prostate or others, alters the genetic make-up of the patient before it actually starts appearing in higher numbers.

The current move towards gene therapy through genetic alteration has gained an increase in popularity among medical parties worldwide. Several cures for various diseases are currently being developed at several pharmaceutical companies across the globe. If breast cancer risk is proven to stem from epigenetic modifications, this will undergo thorough analysis with the hopes of finding a potential cure or prevention method as well.

But the concept that breast cancer risk could be determined through DNA tests still needs more work to be done in order to prove its conclusiveness. Only time will tell if research teams will be able to isolate the specific genes that can cause a normal healthy woman to have an increase in risk towards cancer development.

Source: Breast Cancer Risk Could Be Determined Through DNA Tests

A possible asteroid flyby in March has enthusiasts on their toes as NASA announced that near-Earth object 2013 TX68 will zip past us soon enough.

2013 TX68 was first spotted in 2013. Estimated to be approximately 100 feet in diameters, the near-Earth object is certainly a massive one. However, with several scenarios plotted by NASA scientists, the results indicate that there is really no danger embedded in the March 5th flyby.

The best case scenario for the March 5th flyby is that 2013 TX68 approaches Earth at a distance of only 11,000 miles. In this case, the massive asteroid could be spotted with the naked eyes as it zips right past our planet. The worst case scenario for those anxious to catch a glimpse of 2013 TX68 is that the asteroid follows a course keeping it at 9 million miles away from Earth. Under these circumstances, the near-Earth object will remain an elusive presence.

On Wednesday, NASA released a statement announcing the March 5th flyby. However, the same statement reads:

“The variation in possible closest-approach distances is due to the wide range of possible trajectories for this object”.

Since 2013 TX68 was only discovered a couple of years ago, tracking it hasn’t bought sufficient conclusive data to plot an exact flyby trajectory. Nonetheless, the possible asteroid flyby in March has enthusiasts on their toes. The good news is that the near-Earth-object isn’t heading for our planet in any of the NASA scenarios. A possible collision is fully excluded with the March 5th flyby.

Nonetheless, according to the manager of the Center for NEO studies with NASA’s Jet Propulsion Laboratory, there are under 1 in 250 million chances that 2013 TX68 will impact Earth in September 2017. There’s even less than a collision chance for upcoming flyby in 2046 or 2097.

Paul Chodas, the manager of the Center for NEO Studies reassured everyone that the likelihood of a collision is so small that no real concern is sparked.

Asteroid 2013 TX68 was spotted as it flew by Earth almost two years ago. At the time, the asteroid remained at a distance of 1.3 million miles from Earth. A possible asteroid flyby in March has enthusiasts on their toes.

In anticipation, let’s remember the near-Earth-object which made the headlines when it exploded over Chelyabinsk. This event was caused by an asteroid approximately 65 feet in diameter. The damage to the nearby region was immense. Buildings, infrastructure and 1,000 people suffered the consequences. There is no telling of the impact results if 2013 TX68 asteroid would enter a collision track at any point in the future.

 

Source: A Possible Asteroid Flyby in March Has Enthusiasts on Their Toes

But many of the women she met on the streets and through harm reduction organizations were smart, self-aware, and independent. Evie took on more responsibility and became an active participant in the sex worker rights movement, presenting about sex work and drugs at conferences, summits, workshops, and trainings across the country. She advocates for visibility and acceptance of sex work and the repeal of laws against drugs and prostitution. She argues that sex work is just that—work.

E

vie* introduced herself with a little wave to a woman in black cutoff shorts. “Hey, hon, are you working tonight? Do you need supplies?”

It was a misty evening in May and Evie was handing out kits, carefully packed and folded brown paper bags of condoms and syringes for women out doing sex work or using drugs. When a woman lingering on the street recognizes her or makes eye contact, it’s important to approach politely, but not too formally.

“Cops call you ‘ma’am’ and ‘miss,’ but ‘hon’ and ‘sweetheart’? We know what ‘sweetheart’ means,” she explained.

ADVERTISING

Evie started doing outreach to sex workers five years ago, when she was 22. Some friends were volunteering, and Evie was attracted to the pragmatism of harm reduction, which argues that people shouldn’t go to jail for crimes that don’t harm others, that they shouldn’t die just because they do self-destructive things. At the time she thought trading sex for money was something only the “absolutely desperate” did. As a white college grad, she never imagined it could be a job.

But many of the women she met on the streets and through harm reduction organizations were smart, self-aware, and independent. Evie took on more responsibility and became an active participant in the sex worker rights movement, presenting about sex work and drugs at conferences, summits, workshops, and trainings across the country. She advocates for visibility and acceptance of sex work and the repeal of laws against drugs and prostitution. She argues that sex work is just that—work.

The majority of the sex workers Evie knows who are “out” haven’t gone public by choice.

When she talks to groups of college students or presents at a conference, she explains that even though society frames sex work as either a last resort or the result of a celebratory, sex-positive choice, people who have sex for money do so in a variety of ways and for many different reasons. Some don’t consider themselves sex workers or identify with a larger movement for sex workers’ rights. Others might be personally comfortable with the decisions they’ve made, but the threat of arrest or a widespread attitude of pity and disdain keep them closeted.

The thing is, Evie’s not just advocating for other people. Even as she rails against the stigma of sex work, she also lives with it.

 

Someone you know is a sex worker,” announced a 2011 media campaign by the St. James Infirmary in San Francisco, the first health clinic established for and by sex workers. Though it’s a powerful suggestion, the term “sex worker” is still fraught. Evie and the other women interviewed for this article share some fundamental beliefs about the practice of trading sex for money: It should be legal, it should be safe, it should not be shameful or stigmatized. But because trading sex for money is stigmatized, illegal, and sometimes unsafe, the circumstances of someone’s life determine how and if she publicly acknowledges having done sex work or calls herself a sex worker and whether she tells her friends and family what she does for money.

Evie started working in restaurants when she was 16. By her early twenties she felt “terribly exploited.” The hours were long, the pay was bad, and “I could just be fired for any reason,” she says. In 2012, after a customer left a negative Yelp review, that’s what happened. A friend she knew from doing outreach worked at a strip club and suggested Evie try dancing there. Five hours at the club paid more than an entire week of waiting tables, so she gave it a try.

A few months in, Evie began offering some customers “extras”—oral sex in the champagne room. Thanks to an ad in the erotic services section of backpage.com, she started making up to $400 for a date. Backpage and the club have become her only sources of income; she does all her sex work advocacy for free. Evie doesn’t particularly enjoy sex work, but while she’s in college, it beats waitressing.

Most people in Evie’s life don’t know any of this. The majority of the sex workers Evie knows who are “out” haven’t gone public by choice—they’ve been exposed online or by law enforcement. Those who disclose, get arrested, or are outed, can lose housing, savings, financial aid, government assistance, and custody of their children. If they have a legit job, they can lose that as well and might fail a background check in the future. This kind of profiling and arrest happens much more frequently to women of color and trans women—something casually referred to as being arrested for “walking while trans.”

Some sex worker rights activists say that white women like Evie should come out as an act of solidarity. If everyone who’s had sex for money were open about it, would the public accept that sex work defies stereotypes and is more prevalent than most imagine? The answer is a Catch-22. Stigma and severe criminal penalties keep people from openly fighting laws and cultural attitudes.

Even for someone like Evie, disclosing that she does sex work requires a careful assessment of all that could go wrong. When she was worried that an inflamed open sore in her mouth might be herpes, her visit to the doctor meant choosing between her health and her privacy. She was nervous enough to admit she worked as an “escort,” and when she did, he told her, “well, this is what you should expect.” Had Evie tried to call the police when a coked-up client threw her onto the floor and kicked her, she doesn’t think they would have arrested her, but they likely “would have laughed at me and asked why I was in the room,” she says. Other than a few people who know about her job, Evie didn’t feel comfortable telling most friends about the assault.

What Evie’s friends do know is that she’s a committed advocate. She likes that they come to her with questions about drugs or safer sex. Still, if friends or acquaintances find out she works in a club, she says, they treat her like “this curious object where people can ask you all of these personal questions”—about body hair, outfits, customers. And most of them still assume she’s only stripping. “They’ll ask me if extras go on—not realizing they’re talking about me,” she says.

Evie’s parents think she’s a bartender in a strip club. She says it’s a pretty common pretext: “If you talk to the families of every girl who works in a strip club,” Evie says, “98 percent of them think their daughter is a bartender.” Evie would like to tell them, but her mom got so angry even thinking about Evie tending bar there. “How are they gonna treat you?” Evie says her mother asked her.

Plenty of people who have sex for money will never even consider themselves sex workers.

Though cops occasionally try to bust people in the club, Evie knows that because she’s white and reads as a middle-class woman who doesn’t use drugs, and works at a club rather than on the street, it’s unlikely she’ll ever be arrested for prostitution. In Brooklyn, for example, most prostitution arrests occur outdoors and in 2014, 94% of the people charged with loitering for the purpose of prostitution were black.

Earlier this year, an Arizona woman named Monica Jones spoke at the United Nations about being profiled by police because she is a sex worker and a trans woman of color. Jones was arrested in 2013 while she was walking down the street in Phoenix. She says she wasn’t working that night and refused to attend a diversion program called Project ROSE, which offers a sentence of education or rehabilitation instead of jail time. “I’m proud to be a sex worker,” she says she told authorities. Jones was then charged with “manifesting prostitution,” a broadly-defined law that makes it a crime to stop and talk with people on the street or wave at a motor vehicle. She pleaded “not guilty.”

To fight a charge on principle “comes at a cost, and not everyone can bear that cost,” says Penelope Saunders, coordinator of the Best Practices Policy Project, an organization that advocates for policy change around sex work and the sex trade. Monica Jones is pursuing a degree in social work from the University of Arizona and says her “schooling suffered tremendously” during the case. “I don’t know if I’m going to make it to next semester,” she says. She was found guilty of manifesting prostitution in 2014. The prosecution had relied heavily on her past arrests and her activism as an out sex worker to secure the verdict, and for that reason, an appeals court overturned Jones’ conviction the following year. Her case may be retried. Monica Jones says she knows many people who want to be outspoken, “but they’re afraid of being outed and profiled by police.”

“Once you have a prostitution charge, [coming out] is kind of irrelevant,” says Sarah Patterson, the Deputy Director of Red Umbrella Project, an advocacy organization for sex workers. Because black, Latina, and transgender women are much more likely to be profiled and arrested, Patterson says that white women who have stable lives, education, and access to resources “have little to lose by being out.”

“As a white woman, I think that white sex worker advocates have a lot more work to do with being in solidarity with those who can’t choose whether or not they are outed,” she says.

But whether or not they’re outed because of an arrest, plenty of people who have sex for money will never even consider themselves sex workers. And those are precisely the ones who could help the movement.

 

Sophie* says that when she was 17, she started thinking about becoming “a prostitute.”

“I don’t really know why, but I thought it sounded like a really good idea,” Sophie, who is 24, white and grew up working class, told me. When she moved to New York City at 21, she had $150 and was crashing on a friend’s couch. Craigslist seemed like an easy way to make money. Today she enjoys her steady jobs as a waitress and a barista, and sees a couple of regular clients for sex.

Her friends know that she sometimes dates and her mother even knows that she’s worked as a dominatrix in the past. But Sophie does not identify as a sex worker. “I do it really casually and I don’t like doing it when I need money,” Sophie says, acknowledging that her attitude towards trading sex is different than many self-professed sex workers. “I know plenty of people that identify as sex workers and that’s not how I do my work.”

“People view sex work as me on the corner with a stranger in a car…but if you look at what the law says, prostitution is exchanging sex for any goods.”

In other words, for Sophie, having sex with her clients for money doesn’t feel like work. “I don’t like doing anything out of desperation,” she says. “I have done it out of desperation, I guess, but usually I like to do it ‘cause it’s fun for me.”

People who have been hurt or arrested while doing sex work or who disliked doing it often tell her this attitude is “a little too casual” when, for them, sex work is a “serious thing,” she says. Why have sex for money and call it a hobby? they wonder. Why not just have sex for pleasure?

But because you’re not desperate for money doesn’t mean you don’t want it. “Money is absolutely part of why I enjoy it,” says Sophie. But even with monetary gain, “it’s a hobby.”

Rather than narrowing the definition of sex work to exclude women like Sophie who aren’t having sex to support themselves, Monica Jones, who was arrested in Arizona, wants to broaden it. She knows that not everyone can disclose, but she thinks that lots of people who’d never consider themselves sex workers have done some sort of sex work. “It is more common than people would admit,” says Jones. Women who have sex with their husbands for allowances, women with sugar daddies, people who trade sex for rides or places to stay—“some people don’t identify as sex workers because to them what they’re doing is [considered] normal,” says Jones. “People view sex work as me on the corner with a stranger in a car…but if you look at what the law says, prostitution is exchanging sex for any goods.”

 

In early 2014, a friend and fellow Duke student exposed 18-year-old Belle Knox as “the Duke Porn Star.” Knox, whose real name is Miriam Weeks, had starred in more than 30 porn scenes and films in order to pay her $4,300 a month tuition bill from Duke. On the TV show The View, she described her experience in the porn industry as “supportive, exciting, thrilling and empowering.” It was other students, who threatened her life and threw garbage on her, who made her feel unsafe.

Later that year, Rolling Stone magazine reported that Knox’s family had stopped speaking to her after she was outed. Belle Knox hadn’t even broken the law, but her story confirmed Evie’s fears about what could happen if her work became public. A woman who dares to admit without shame that she’s done something illegal and disreputable is tiptoeing across a minefield of legal and personal risk—even a white, cisgender, middle-class woman. In Evie’s progressive community it’s socially acceptable, even cool, to support sex worker rights or hand out needles and condoms in dangerous neighborhoods, but to actually do sex work openly would mean rejection, gossip, and awkward questions.

Unlike Sophie, Evie says she accepts her identity as a sex worker in order to “emphasize that I’m part of an unregulated exploited labor force.” Even though she’s a white, cisgender woman who works indoors, Evie does miss out on rights and privileges that come with a recognized, legit job. Most people take the freedom to vent after a bad day at work for granted. Sex workers who are closeted can’t do this. “I deserve to complain about work to my friends, too,” says Evie.

How many straight guys would be OK with dating someone who has sex for money?

Regardless of how a person feels about the act of trading sex for money, secrecy brings “anxiety, stress, and pressure to constantly be aware of what you’re saying, your surroundings, people’s perceptions of you,” says Rena McDaniel, a psychologist who treats sexual minorities and has several patients who work in the sex trade. According to McDaniel, shame and anxiety can leave people with a sense of invisibility, “feeling like they can’t be their authentic selves.”

Being honest inevitably affects romantic relationships, too. Evie and Jonathan (not his real name) met through a mutual friend. They would go hiking, see bands, or search out hole-in-the-wall restaurants. He knew she worked as a dancer in a club and he says he thought it was hot. “So, do you sleep with these guys? Do you have sex for money?” he asked Evie after they’d been dating for a few months. It was the first relationship she’d had since she’d started working. She was caught off-guard and told him, “no.”

They broke up after less than six months, but stayed friends. Evie wanted to sleep with him again, and so she decided that he should know the truth about her work. One night over a bottle of wine she brought up their earlier conversation. “Remember when you asked me if I have sex for money and I said, ‘no’?” She took a deep breath. “Well the answer’s actually ‘yes.’”

Jonathan says his meltdown “happened really fast. Like when you get too mad in a fight.” He doesn’t remember what he said. According to Evie, he told her “I would never go out with a prostitute,” and says he’d have broken up with her if he’d known.

As soon as Jonathan sobered up he started texting apologies. He hadn’t meant to lash out, but his discomfort was real. “I don’t want to think people you could fall in love with can be bought—it just triggers this primal insecurity in me,” he said. She forgave him and they remained friends. Still, his reaction has left her reluctant to tell other people she dates. How many straight guys would be OK with dating someone who has sex for money?

“People malign sex workers without realizing that they’re talking to one.”

Not coming out has an extra incentive for activists like Evie: It makes it easier for them to meet with officials and policymakers. Jessica*, a longtime advocate with a salaried position at an NGO, says that while “it doesn’t feel great” to keep her experience doing sex work private, “I’m not willing to sacrifice the work that I could do for a personal decision.”

Jessica is often in the room for policy conversations around anti-prostitution laws and sex trafficking. As she works to convince people with power or money not to further criminalize sex work, she is constantly wrestling with the question of whether to come out. She has a good job and a masters’ degree. She knows that she has a choice, while some other people do not. Am I making it harder for someone with less privilege to come out? she asks herself.

Prominent white activists like Sarah Patterson have come out as an act of solidarity, but Jessica thinks the people she works with wouldn’t respect or collaborate with her if they knew the truth. Often during meetings, she says “people malign sex workers without realizing that they’re talking to one.”

“I think they assume that [a sex worker] would have dressed up for that conversation like Erin Brockovich. They don’t realize I can go buy a gray suit too,” she says.

Of course, there’s one instance where being out actually helps a sex work activist: outreach on the street. Once, while doing outreach with a friend, Evie gave some kits to a woman who she’d seen several times before. “It was summer [and] the street was hopping,” Evie recalls. “Why are you guys out here doing this? What do you do outside of this?” she says the woman asked them. Evie told her she danced at a club and the woman immediately seemed more comfortable. “We were already getting along,” he says. “[T]here definitely was a change in her expression. She said she thought that was so great.”

It’s cathartic for Evie, too. Outreach is one of the few times she can talk openly about her job. It’s the one moment where “you’re actually able to have a conversation with someone and stand on the street for five minutes and just be a person.”

Source: The dangerous Catch-22 of coming out as a sex worker | Fusion

A comprehensive review, which has sifted through data from 70 trials of the most popular drugs for the treatment of depression, shows that antidepressants may up risk of suicide, aggression. Study authors also found that big pharmas often fail to report critical side-effects of their products along with drug-related deaths.

The review found that antidepressants may make underage patients more prone to adopt an aggressive behavior. Still, no such side-effect was found in adults, though researchers suspect that some trial data may be misreported.

Nevertheless, researchers have suspected for years that antidepressants may boost risk of suicide as families have often complained that the drugs were behind their loved ones’ tragic end. But antidepressant makers and doctors have dismissed such claims because no comprehensive study has ever found a link between the two.

The research review which comprises data on more than 18,000 patients is considered the largest to date. It was carried out by a team at the Nordic Cochrane Center in Denmark, and reviewed by University College London in the U.K.

After analyzing trial data and comparing it to reports submitted by families of people who committed suicide, researchers found that the companies who funded the trials have often misclassified the deaths to their products’ benefit.

Study authors were startled and ‘deeply worried’ by the unprecedented situation.

“It is absolutely horrendous that they have such disregard for human lives.”

said Prof. Peter Gotzsche, lead author of the research and mental heart expert with the Copenhagen-based Nordic Cochrane Center.

In the U.S., antidepressant use saw a tremendous rise in just two decades. Currently, one in ten people take antidepressants on prescription, while one in four middle-aged women take the drugs.

But this doesn’t mean that the U.S. was hit by a tidal wave of depression in recent years. In fact, doctors often prescribe the drugs for off-label uses such as dependence, ADHD and autism in children, anxiety, and eating disorders.

Nordic Cochrane Centre researchers found that at least four deaths by suicide were misreported by a pharmaceutical company. In one case, a patient tried to kill himself after taking venlafaxine, but since he died days later in a hospital his death was no longer considered to having occured during the trial. Suicidal attempts were often mislabeled as a sign of either emotional instability or depression.

The review also found that though antidepressants do not seem to work on children they do boost their risk of suicide. This is why, study authors believe that it is better to follow alternative courses of actions including psychotherapy, art therapy, and exercise before resorting to medications.

Source: Antidepressants May Up Risk of Suicide, Aggression

Six Foods Bill Marler Never Eats

Bill Marler B-W headshotUnpasteurized (“raw”) milk and packaged juices. Unpasteurized milk, sometimes called “raw” milk, can be contaminated with bacteria, viruses and parasites. Between 1998 and 2011, there were 148 food poisoning outbreaks linked to raw milk and raw milk products in the US—and keep in mind that comparatively few people in the country ever consume these products, so 148 outbreaks is nothing to ignore. As for unpasteurized packaged juices, one of Marler’s earliest cases was the 1996 E. coli outbreak from unpasteurized Odwalla apple juice. As a result, he won’t go near raw milk or juice. There’s no benefit big enough to take away the risk of drinking products that can be made safe by pasteurization,” he says.

Raw sprouts. Uncooked and lightly cooked sprouts have been linked to more than 30 bacterial outbreaks (mostly of salmonella and E. coli) in the US since mid-1990s. As recently as 2014, salmonella from bean sprouts sent 19 people to the hospital. All types of sprouts—including alfalfa, mung bean, clover and radish sprouts—can spread infection, which is caused by bacterial contamination of their seeds. “There have been too many outbreaks to not pay attention to the risk of sprout contamination,” Marler says. “Those are products that I just don’t eat at all.” He did add that he does eat them if they’re cooked.

Meat that isn’t well-done. Marler orders his burgers well-done. “The reason ground products are more problematic and need to be cooked more thoroughly is that any bacteria that’s on the surface of the meat can be ground inside of it,” Marler says. “If it’s not cooked thoroughly to 160°F throughout, it can cause poisoning by E. coli and salmonella and other bacterial illnesses.” As for steaks, needle tenderizing—a common restaurant practice in which the steak is pierced with needles or sliced with knives to break down the muscle fibers and make it more tender—can also transfer bugs from the surface to the interior of the meat. If a restaurant does this (Marler asks), he orders his steak well-done. If the restaurant doesn’t, he’ll opt for medium-well.

Prewashed or precut fruits and vegetables. “I avoid these like the plague,” Marler says. Why? The more a food is handled and processed, the more likely it is to become tainted. “We’ve gotten so used to the convenience of mass-produced food—bagged salad and boxed salads and precut this and precut that,” Marler says. “Convenience is great but sometimes I think it isn’t worth the risk.” He buys unwashed, uncut produce in small amounts and eats it within three to four days to reduce the risk for listeria, a deadly bug that grows at refrigerator temps.

Raw or undercooked eggs. You may remember the salmonella epidemic of the 1980s and early ’90s that was linked mainly to eggs. If you swore off raw eggs back then, you might as well stick with it. The most recent salmonella outbreak from eggs, in 2010, caused roughly 2,000 reported cases of illness. “I think the risk of egg contamination is much lower today than it was 20 years ago for salmonella, but I still eat my eggs well-cooked,” Marler says.

Raw oysters and other raw shellfish. Marler says that raw shellfish—especially oysters—have been causing more foodborne illness lately. He links this to warming waters, which produce more microbial growth. “Oysters are filter feeders, so they pick up everything that’s in the water,” he explains. “If there’s bacteria in the water it’ll get into their system, and if you eat it you could have trouble. I’ve seen a lot more of that over the last five years than I saw in the last 20 years. It’s simply not worth the risk.”

First published at http://bottomlinehealth.com/health-insider/6-things-this-food-safety-expert-wont-eatand-one-surprising-food-he-will/ Copyright © 2016 by Boardroom Inc., 281 Tresser Blvd., Stamford, Connecticut 06901-3229. www.BottomLineHealth.com

2015 – Profile in Obsession: Bill Marler, By Naomi Tomky March 24, 2015

2015 – The New Yorker – A Bug in the System
The New Yorker, Wil S. Hylton, February 2, 2015.

2014 – Q&A: Food Safety Lawyer Bill Marler on What Not to Eat
The National Law Journal, Interview with Jenna Greene, November 3, 2014.

2012 – Bill Marler, Attorney, Blogger, and Food Safety Advocate, Talks Turkey (Or Spinach, Rather)
Miami New Times, Interview with Ily Goyanes, November 2.

2012 – Bill Marler Interview, Part Two: His Most Difficult Cases and Lobbying Congress
Miami New Times, Interview with Ily Goyanes, November 14.

2012 – Profiles in Public Health Law: Interview with William “Bill” Marler CDC Public Health Law News, July.

2012 – Food Safety Lawyer Bill Marler On Sprouts, Raw Milk, and Why “Local” Isn’t Always Safer Blisstree.com, Hanna Brooks Olsen, March 5.

2011 – Listeria outbreak draws Seattle lawyer to battle
Associated Press, Shannon Dininny, October 9.

2011 – Food-Borne Illness Attorney: Top Foods to Avoid
ABC News, Neal Karlinsky, September 29.

2011 – How to Keep Food Free of Salmonella: Lawsuits
The Atlantic, Barry Estabrook, August 31.

2011 – More Stomach-Churning Facts about the E. Coli Outbreak
New York Times, Mark Bittman, June 8.

2011 – Bill Marler: A Personal Injury Attorney and More
The Xemplar, Nicole Black, June 1.

2011 – Good Food Hero: Bill Marler, Food Safety Attorney
Good Food World, Gail Nickel-Kailing, May 23.

2011- Poisoned: The True Story of the Deadly E. coli Outbreak that Changed the Way Americans Eat.
Inspire Books, Jeff Benedict, May 15

2011 – New Book Chronicles Islander Marler’s Work.
Bainbride Island Review, Connie Mears, May 13.

2010 – Food Safety Lawyer Puts His Money Where Your Mouth Is
AOL News, Andrew Schneider, September 29

2009 – Food Safety Lawyer’s Wish: Put Me Out of Business
Seattle Times, Maureen O’Hagan, November 23

2009 – WSU Discourse on Food Safety, Courtesy Seattle Lawyer
Kitsap Sun, Tristan Baurick,  August 29

2009 – When Food Sickens, He Heads for Courthouse
Minneapolis Star-Tribune, Matt McKinney, June 24

2009 –  Bill Marler, The Food-Safety Litigator
Culinate, Miriam Wolf, April

2009 – Food Fight:Bill Marler’s Beef (PDF)
Washington Law & Politics, David Volk, May

2009 – Candidate for Top FSIS Job talks E. coli Testing, Irradiation, Education
The Meating Place, Ann Bagel Storck, February 6

2009 – Five Minutes with Bill Marler, Well Known Lawyer, Food Safety Activist
CattleNetwork, Chuck Jolley, February 5

2009 – Heath Surveillance the Key to Fresh Produce
The Packer, Tom Karst, February 3

2008 – Seattle Food Contamination Expert in China as Tainted Milk Sickens Thousands of Kids
Seattle Health Examiner, September 23

2008 –  E. Coli Lawyer Is Busier Than Ever
Associated Press, February 4

2007 –  Legally Speaking: The Food Poisoning Lawyer
The Southeast Texas Record, John G. Browning, November 20

2007 –  The Nation’s Leading Food-borne Illness Attorney Tells All
Washington State Magazine, Hannelore Sudermann, August

2007 –  Back to Court: Burst of E. coli Cases Returns Jack in the Box Litigator to the Scene
Meat and Poultry News, Steve Bjerklie, June 8

2007 – Food Fight
Portland Oregonian, Alex Pulaski, March

2007 –  Mr. Food Illness Esquire
QSR Magazine, Fred Minnick, February

2006 –  Seattle Attorney Dominates Food-Borne Illness Litigation
KPLU, October 20

2006 –  How a Tiny Law Firm Made Hay Out of Tainted Spinach
The Wall Street Journal, Heather Won Tesoriero and Peter Lattman, September 27

2005 – Bill Marler – Education Holds Key in Tainted Food Fight
King County Bar Association Bar Bulletin, Ross Anderson, November

2001 –  THE INSIDE STORY: How 11 Schoolkids Got $4.75 Million in E. coli Lawsuit
MeatingPlace.com, Bryan Salvage, March 7

2001 –  Hammer Time: Preparation Pays When Disputes Escalate to Lawsuits
Meat & Poultry Magazine, David Hendee

2001 –  For Seattle Attorney, A Bacterium Brings Riches—and Enemies
The Wall Street Journal, Rachel Zimmerman

2001 –  The Bug That Ate The Burger
Los Angeles Times, Emily Green, June

1999 –  Courting Publicity, Attorney Makes Safe Food His Business
Seattle Post, Maggie Leung, September 7

Source: 6 Things A Food Poisoning Expert Refuses To Eat

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

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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  • 7 reasons why you’re working out and still not losing weight

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

The mosquito-borne Zika virus, which has been linked to brain damage in thousands of babies in Brazil, is likely to spread to all countries in the Americas except for Canada and Chile, the World Health Organization said on Monday.

Zika transmission has not yet been reported in the continental United States, although a woman who fell ill with the virus in Brazil later gave birth to a brain-damaged baby in Hawaii.

Brazil’s Health Ministry said in November that Zika was linked to a fetal deformation known as microcephaly, in which infants are born with smaller-than-usual brains.

Brazil has reported 3,893 suspected cases of microcephaly, the WHO said last Friday, over 30 times more than in any year since 2010 and equivalent to 1-2 percent of all newborns in the state of Pernambuco, one of the worst-hit areas.

The Zika outbreak comes hard on the heels of the Ebola epidemic in West Africa, demonstrating once again how little-understood diseases can rapidly emerge as global threats.

“We’ve got no drugs and we’ve got no vaccines. It’s a case of deja vu because that’s exactly what we were saying with Ebola,” said Trudie Lang, a professor of global health at the University of Oxford. “It’s really important to develop a vaccine as quickly as possible.”

Large drugmakers’ investment in tropical disease vaccines with uncertain commercial prospects has so far been patchy, prompting health experts to call for a new system of incentives following the Ebola experience.

“We need to have some kind of a plan that makes (companies) feel there is a sustainable solution and not just a one-shot deal over and over again,” Francis Collins, director of the U.S. National Institutes of Health, said last week.

The Sao Paulo-based Butantan Institute is currently leading the research charge on Zika and said last week it planned to develop a vaccine “in record time”, although its director warned this was still likely to take three to five years.

British drugmaker GlaxoSmithKline said on Monday it was studying the feasibility of using its vaccine technology on Zika, while France’s Sanofi said it was reviewing possibilities.

RIO CONCERNS

The virus was first found in a monkey in the Zika forest near Lake Victoria, Uganda, in 1947, and has historically occurred in parts of Africa, Southeast Asia and the Pacific Islands. But there is little scientific data on it and it is unclear why it might be causing microcephaly in Brazil.

Laura Rodrigues of the London School of Hygiene and Tropical Medicine said it was possible the disease could be evolving.

If the epidemic was still going on in August, when Brazil is due to host the Olympic Games in Rio de Janeiro, then pregnant women should either stay away or be obsessive about covering up against mosquito bites, she said.

The WHO advised pregnant women planning to travel to areas where Zika is circulating to consult a healthcare provider before traveling and on return.

The clinical symptoms of Zika are usually mild and often similar to dengue, a fever which is transmitted by the same Aedes aegypti mosquito, leading to fears that Zika will spread into all parts of the world where dengue is commonplace.

More than one-third of the world’s population lives in areas at risk of dengue infection, in a band stretching through Africa, India, Southeast Asia and Latin America.

Zika’s rapid spread, to 21 countries and territories in the Americas since May 2015, is due to the prevalence of Aedes aegypti and a lack of immunity among the population, the WHO said in a statement.

RISK TO GIRLS

Like rubella, which also causes mild symptoms but can lead to birth defects, health experts believe a vaccine is needed to protect girls before they reach child-bearing age.

Evidence about other transmission routes, apart from mosquito bites, is limited.

“Zika has been isolated in human semen, and one case of possible person-to-person sexual transmission has been described. However, more evidence is needed to confirm whether sexual contact is a means of Zika transmission,” the WHO said.

While a causal link between Zika and microcephaly has not yet been definitively proven, WHO Director-General Margaret Chan said the circumstantial evidence was “suggestive and extremely worrisome”.

In addition to finding a vaccine and potential drugs to fight Zika, some scientists are also planning to take the fight to the mosquitoes that carry the disease.

Oxitec, the UK subsidiary of U.S. synthetic biology company Intrexon, hopes to deploy a self-limiting genetically modified strain of insects to compete with normal Aedes aegypti.

Oxitec says its proprietary OX513A mosquito succeeded in reducing wild larvae of the Aedes mosquito by 82 percent in an area of Brazil where 25 million of the transgenic insects were released between April and November. Authorities reported a big drop in dengue cases in the area

The mosquito-borne Zika virus, which has been linked to brain damage in thousands of babies in Brazil, is likely to spread to all countries in the Americas except for Canada and Chile, the World Health Organization said on Monday.

Source: Zika virus set to spread across Americas, spurring vaccine hunt | Reuters

Getting too little sleep during the week can increase some risk factors for diabetes, but sleeping late on weekends might help improve the picture, a small U.S. study suggests.

Researchers conducted a sleep experiment with 19 healthy young men and found just four nights of sleep deprivation were linked to changes in their blood suggesting their bodies weren’t handling sugar as well as usual.

But then, when they let the men get extra sleep for the next two nights, their blood tests returned to normal, countering the effect of the short-term sleep deprivation.

“It gives us some hope that if there is no way to extend sleep during the week, people should try very hard to protect their sleep when they do get an opportunity to sleep in and sleep as much as possible to pay back the sleep debt,” said lead study author Josaine Broussard of the University of Colorado Boulder.

The study doesn’t prove sleeping late every weekend can counter the ill effects of insufficient rest every other night of the week, Broussard cautioned.

And it doesn’t prove that catching up on sleep will prevent diabetes.

“We don’t know if people can recover if the behavior is repeated every week,” Broussard added by email. “It is likely though that if any group of people suffer from sleep loss, getting extra sleep will be beneficial.”

To assess the impact of sleep on diabetes risk, Broussard and colleagues focused on what’s known as insulin sensitivity, or the body’s ability to use the hormone insulin to regulate blood sugar. Impaired insulin sensitivity is one risk factor for type 2 diabetes, which is associated with age and obesity and happens when the body can’t properly convert blood sugar into energy.

The researchers did two brief sleep experiments. On one occasion, the volunteers were permitted just 4.5 hours of rest for four nights, followed by two evenings of extended sleep that amounted to 9.7 hours on average. On another occasion, the same men were allowed to sleep 8.5 hours for four nights.

After the four nights of sleep deprivation, the volunteers’ insulin sensitivity had fallen by 23 percent and their bodies had started to produce extra insulin. But when researchers checked again after two nights of extended rest, the men’s insulin sensitivity, and the amount of insulin their bodies produced, had returned to normal, mirroring what was seen during the portion of the experiment when the volunteers consistently got a good nights’ rest.

The volunteers were given a calorie-controlled diet to limit the potential for their food and drink choices to influence the outcomes. In the real world, when people don’t get enough sleep they tend to overeat, which may limit how much results from this lab experiment might happen in reality, the authors note in a report scheduled for publication in the journal Diabetes Care.

“The results from the present study are unlikely to be fully reflective of what may occur in persons who are older, overweight or obese, or have other potent risk factors for diabetes,” said James Gangwisch, a researcher at Columbia University who wasn’t involved in the study.

Chronically sleep-deprived people are more likely to develop other health problems, though, ranging from obesity to high blood pressure to cognitive deficits, the study authors point out.

“By catching up on sleep on the weekends, people are reducing average extent and severity of the effects of sleep deprivation,” Gangwisch added by email. “Ideally, we would all get sufficient sleep on a nightly basis.”

Getting too little sleep during the week can increase some risk factors for diabetes, but sleeping late on weekends might help improve the picture, a small U.S. study suggests.

Source: Sleeping in on weekends may help reduce diabetes risk | Reuters

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

A team of researchers plans to figure out why this happens

In recent years, scientists have made small steps towards understanding the relationship between sleep and Alzheimer’s disease. Now, researchers from Oregon Health & Science University in Portland may soon illuminate the connection—they are launching the first experiment of its kind that will study a key process in the brains of sleeping humans, as NPR reports.

Disrupted sleep patterns have long been a common complaint for patients in the early stages of Alzheimer’s disease, sometimes decades before they develop cognitive problems or noticeable memory loss. The reason, researchers have discovered, is likely the buildup of beta amyloid plaque, a sticky amalgamation of proteins that collects in synapses and is characteristic of Alzheimer’s disease. A number of studies published in the last five years have found that people (and mice) with disrupted sleep patterns had more beta amyloid plaque in their brains.

Researchers are starting to get a sense for why this is the case—sleep may sweep toxins from the brain, preventing beta amyloid from collecting in synapses. But scientists are still not sure what comes first—does the beta amyloid buildup cause the disrupted sleep, or the other way around? “It may be a vicious cycle,” Miroslaw Mackiewicz of the National Institute on Aging told the AP in July.

In order to better understand the brain’s “sweeping” mechanism that may be key to the Alzheimer’s puzzle, the Oregon team plans to observe people’s brains while they sleep. To do it, they’ll use a super-sensitive MRI machine to monitor just how and when the sweeping occurs during a participant’s sleep cycle. Though the researchers know it may be challenging to get volunteers to sleep in a noisy, confined MRI machine, they hope their findings could illuminate the relationship between sleep and Alzheimer’s disease. If they can figure that out, new treatments and preventative measures for the disease may soon follow

Source: Not Enough Sleep May Help Alzheimer’s Take Hold | Popular Science

small study suggests that for adolescents, their number of Facebook friends may be related to their stress levels, with more than 300 friends associated with higher levels of the stress hormone cortisol.

 

The study only included 88 participants at one point in time, so it can’t indicate whether changes in Facebook metrics cause an increase in stress, or vice versa.

Other important external factors are also responsible for cortisol levels, but Facebook involvement may have its own effect, senior author Sonia Lupien of Montreal Mental Health University Institute said in a statement.

“We were able to show that beyond 300 Facebook friends, adolescents showed higher cortisol levels; we can therefore imagine that those who have 1,000 or 2,000 friends on Facebook may be subjected to even greater stress,” she said.

The 88 teens in the study, age 12-17, answered questions about their Facebook use frequency, number of friends, self-promoting behavior and supporting behavior of friends. The researchers measured the teens’ cortisol levels four times a day for three days.

Kids who had more than 300 Facebook friends tended to have higher cortisol levels than those with fewer friends, the researchers reported in Psychoneuroendocrinology.

With more peer interaction on Facebook, however, cortisol levels tended to be lower. Neither depression nor self-esteem were related to cortisol levels.

Cortisol levels in early adolescence may influence risk of depression years later, the authors wrote.

Wenhong Chen of the department of Radio-TV-Film and the department of Sociology at the University of Texas at Austin, who was not part of the new study, points out that the research is about Facebook, and so the findings can’t necessarily be generalized to other forms of social media use.

It may also not be generalizable to other age groups, Chen said.

“The preliminary nature of our findings will require refined measurement of Facebook behaviors in relation to physiological functioning and we will need to undertake future studies to determine whether these effects exist in younger children and adults,” Lupien said. “Developmental analysis could also reveal whether virtual stress is indeed ‘getting over the screen and under the skin’ to modulate neurobiological processes related to adaptation.”

Offline friend network size was also related to cortisol levels.

“It may not be about the number of friends either online or offline, it may be more about potential communication overload,” Chen said by email.

Larger networks may mean more peers and more drama, she said.

Rather than using the overall number of friends online or offline it may be more revealing to examine network composition, strong ties and weak ties, as well as individuals’ position in their networks, she said.

ource: Facebook network and stress levels may be tied together | Duluth News Tribune

Powered by radios in trees, homegrown network serves 50 houses on Orcas Island

When you live somewhere with slow and unreliable Internet access, it usually seems like there’s nothing to do but complain. And that’s exactly what residents of Orcas Island, one of the San Juan Islands in Washington state, were doing in late 2013. Faced with CenturyLink service that was slow and outage-prone, residents gathered at a community potluck and lamented their current connectivity.

“Everyone was asking, ‘what can we do?’” resident Chris Brems recalls. “Then [Chris] Sutton stands up and says, ‘Well, we can do it ourselves.’”

Doe Bay is a rural environment. It’s a place where people judge others by “what you can do,” according to Brems. The area’s residents, many farmers or ranchers, are largely accustomed to doing things for themselves. Sutton’s idea struck a chord. “A bunch of us finally just got fed up with waiting for CenturyLink or anybody else to come to our rescue,” Sutton told Ars.

Around that time, CenturyLink service went out for 10 days, a problem caused by a severed underwater fiber cable. Outages lasting a day or two were also common, Sutton said.

Faced with a local ISP that couldn’t provide modern broadband, Orcas Island residents designed their own network and built it themselves. The nonprofit Doe Bay Internet Users Association (DBIUA), founded by Sutton, Brems, and a few friends, now provide Internet service to a portion of the island. It’s a wireless network with radios installed on trees and houses in the Doe Bay portion of Orcas Island. Those radios get signals from radios on top of a water tower, which in turn receive a signal from a microwave tower across the water in Mount Vernon, Washington.

“I think people were leery whether we could be able to actually do it, seeing as nobody else could get better Internet out here,” Sutton said.

But the founders believed in the project, and the network went live in September 2014. DBIUA has grown gradually, now serving about 50 homes.
“It wasn’t that hard”

Erin Bennett

Sutton holds a drone he used to analyze potential radio locations.

Back in 2013, CenturyLink service was supposed to provide up to 1.5Mbps downloads speeds, but in reality we “had 700kbps sometimes, and nothing at others,” Brems told Ars. When everyone came home in the evening, “you would get 100kbps down and almost nothing up, and the whole thing would just collapse. It’s totally oversubscribed,” Sutton said.

That 10-day outage in November 2013 wasn’t a fluke. At various times, CenturyLink service would go out for a couple of days until the company sent someone out to fix it, Sutton said. But since equipping the island with DBIUA’s wireless Internet, outages have been less frequent and “there are times we’re doing 30Mbps down and 40Mbps up,” Brems said. “It’s never been below 20 or 25 unless we had a problem.”

Unlike many satellite and cellular networks, there is no monthly data cap for DBIUA users.

Sutton, a software developer who has experience in server and network management, says he’s amazed how rare projects like DBIUA are, claiming “it wasn’t that hard.” But from what he and Brems told Ars, it seems like it took a lot of work and creative thinking to get DBIUA off the ground.

“The part of Orcas Island we’re on looks back toward the mainland,” Sutton said. “We can see these towers that are 10 miles away, and you realize, ‘hey, can’t we just get our own microwave link up here to us from down there, and then do this little hop from house to house to house via wireless stuff?’”
One of StarTouch’s microwave backhaul towers.

The DBIUA paid StarTouch Broadband Services about $11,000 to supply a microwave link from a tower on the mainland to a radio on top of Doe Bay’s water tower. The water tank, at about 50 feet, is the only structure that’s high enough to create a point-to-point link to the mainland. It is owned by the Doe Bay Water Users Association, which let DBIUA install the radios and other equipment.

Sutton and friends set up Ubiquiti radios throughout the area, on trees and on top of people’s houses, to get people online. Sutton used Google Earth to map out the paths over which wireless signals would travel, and then the team conducted on-the-ground surveys to determine whether one point could reach another.
Flight of the drones

The rural Orcas Island has a lot of hills and obstacles that could disrupt the wireless signals, and it would have been “prohibitively expensive” for DBIUA to install its own towers. As such, many of the radios had to be installed in trees. Sutton had a solution for this as well—DBIUA would use a drone to determine whether a radio on a treetop could reach other points of the network.

Initially, the drone was equipped with a camera to determine whether the treetop could “see” the next radio in the network. Later, Sutton added radios to the drone itself so he could test the wireless signal at the treetop. When they confirmed a tree would work, “we hired the person to climb up the tree and install the radios,” Sutton said.

Most homes in the network have a radio on the roof or the side of the house that points to one of about 10 relay points, which have multiple radios for receiving and distributing signals. Relay points themselves can be on a tree, a pole, or on the side of a house.

“For some people, like me, the signal comes to my tree, and then down into my house to service me,” Sutton said.

A relay point has one radio to receive a signal and a couple more radios to send it in different directions. Each relay point is similar to the setup on top of the water tank.

DBIUA

Network status map.

A tree will generally have a box with DBIUA equipment, and Power over Ethernet (POE) cables going up the tree to the radios. POE cable also goes from the box “back to the closest power source, usually in someone’s home, and we can then provide that home a connection to the network,” Sutton explained. “In the person’s home is the power brick that puts power into the Ethernet cable,” providing electricity to the outdoor equipment. The system uses low-voltage power, with each radio requiring about eight watts.

The network uses 5.8GHz and 900MHz frequencies, and a little bit of 3.65GHz, mostly avoiding the crowded 2.4GHz band. All the connections need line-of-sight, “especially for 5.8GHz,” since the higher frequencies are more easily blocked, Sutton said.

There are now about 200 radios spread throughout the coverage area, and each homeowner who pays for service has a Wi-Fi router in the home to access the Internet.

Listing image by Chris Sutton
It can be done

Though DBIUA’s Internet service is a rarity, there are similar projects elsewhere. Brooklyn Fiber in New York was founded by two brothers to sell Internet access to the community. A volunteer project called the Red Hook Initiative buys Internet service from Brooklyn Fiber in order to provide free Wi-Fi.

In Germany, residents of a small town called Löwenstedt built their own Internet service. One Ars reader who lives in Norway personally installed fiber lines to his own property.
Further Reading
Want fiber Internet? That’ll be $383,500, ISP tells farm owner

Good news, though: Small ISP promises to do the same work for just $42,000.

“There’s actually a thriving global network of community wireless initiatives—many of whom stay in regular touch and swap information on recent software advances, promising hardware, and innovative business models,” Sascha Meinrath, X-Lab founder and Penn State telecommunications professor, told Ars. There are such projects in Austria, Spain, and Greece, and another that serves tribal reservations outside San Diego, he noted.

Just like on Orcas Island, these projects came into being because residents were frustrated with Internet access options from private companies.

Private ISPs have demanded as much as $383,500 from residents who want service and live in sparsely populated areas. Some cities and towns have built their own Internet services, but laws in numerous states make that difficult. A law in Washington state “authorizes some municipalities to provide communications services but prohibits public utility districts from providing communications services directly to customers,” according to attorney James Baller of the Baller Herbst Law Group, who has been fighting attempts to restrict municipal broadband projects for years.

While CenturyLink is the main ISP on Orcas Island, a company owned by Orcas Power & Light Co-op (OPALCO) is building out a fiber network in the San Juan County islands. That company says construction will cost “$1,500 to $6,000 on average” for each home, and residents would be responsible for anything beyond the first $1,500.

DBIUA charges much less, but even its low prices “can be significant depending on your income,” Brems said. The DBIUA customers include “lots of retired people and people living off the land. We had to convince people we knew what we were doing,” he said.
StarTouch installing a microwave link at the water tower.
DBIUA

DBIUA spent about $25,000 in total to build the network, and an anonymous resident provided the money in a 3-year, interest-free loan. Residents paid $150 to become members of the DBIUA and $75 a month for Internet service, which goes toward paying down the loan. The monthly fees also cover the $900 a month DBIUA pays StarTouch for bandwidth.
Further Reading
One big reason we lack Internet competition: Starting an ISP is really hard

Creating an ISP? You’ll need millions of dollars, patience, and lots of lawyers.

DBIUA needed 25 customers to pay the bills and stay afloat. At 50 now, the organization is paying the loan off a bit more quickly. Sutton hopes to lower the monthly price residents pay after the loan is paid off.

“We’re not making any money here, we’re just covering our costs,” Sutton said. Besides residents, DBIUA also provides Internet access to the water plant and the Doe Bay Resort. The water plant uses very little bandwidth, and the resort also has a fiber connection to OPALCO, he said. (DBIUA talked to OPALCO about purchasing fiber backhaul, but was unable to get wholesale rates, making it more economical to go with StarTouch, Sutton said.)
To prevent Internet slowdown, DBIUA builds slowly

DBIUA isn’t adding customers as fast as it can. Customers who signed up from the beginning got first priority.

“You had people who committed up front to say, ‘we’re going to help you jump start this,’” Sutton said. “The system is up and it’s really great and it’s fast and then you get a whole bunch of people who come in later and say, ‘oh, I wanted to wait and see if this is going to work and now I want on.’”

Sutton and friends don’t want to oversell the network and go down the same path as CenturyLink, which wasn’t able to provide even the meager 1.5Mbps download speeds it promised. They decided to take their time to add capacity before connecting everyone who wants service, but they expect to get up to 60 homes served by the end of the year.

The network port on the mainland that DBIUA connects to provides 100Mbps. Tests at the water tank show that the DBIUA network has real-world bandwidth of about 70Mbps down and up across the whole system.

There are no specific speed limits for each home, but the system automatically manages the load to prevent one person from hogging all the bandwidth.

“We monitor all the connections and if someone is using a lot of bandwidth for a long period of time, we talk to them and figure out what they are doing,” Sutton said. “Often times it’s people watching Netflix and then falling asleep and then it keep auto-playing things all night long.”

In practice, customers get the speed they need—at peak usage times, total bandwidth usage across the entire network is 30Mbps or so, well within the 70Mbps available.

“It’s really those teenagers that consume all the bandwidth,” Sutton said, describing his two kids “in the living room, and both of them are on their screens watching YouTube with a big smile on their face.”

The microwave connection to the mainland is strong enough to handle more subscribers, but adding homes to the network requires bolstering capacity in specific areas, Sutton explained.

No “waiting around for corporate America”

Capacity can be boosted by adding radios—or with some tree trimming. If there’s “a location where there was a tree in the way,” Sutton said, they’d “trim the tree so now we have better throughput there to manage more people.” The StarTouch link uses burstable billing, with prices going up the more they use.
CenturyLink’s promises “never came to fruition”

Sutton grew up on Orcas Island before living in Seattle for a while. He moved back to Orcas about eight years ago, telecommuting to his job in Seattle. “When the Internet connection was crappy I couldn’t do my job,” he said. “So this is personal.”

CenturyLink promised better speeds over the years “but that never came to fruition,” Sutton said. “Just waiting around for corporate America to come save us, we realized no one is going to come out here and make the kind of investment that’s needed for 200 people max.”

When contacted by Ars, CenturyLink said it upgraded its fiber backbone on Orcas Island in May and provides “up to 20Mbps” speeds “depending on where you reside in the island.”

But in the Doe Bay area, CenturyLink confirmed to Ars that it offers speeds only up to 1.5Mbps. The company also confirmed to Ars that “we are not currently adding broadband customers in Doe Bay.”

Doe Bay residents still buy home phone service from CenturyLink since DBIUA provides only Internet access. And a few DBIUA customers have even kept their CenturyLink DSL Internet as a backup in case DBIUA goes down.

But overall, CenturyLink’s poor infrastructure in Doe Bay is reminiscent of AT&T, which has refused to hook up homes in certain DSL areas where it hasn’t invested sufficiently in network. CenturyLink has gone so far as to tell customers who cancel their DSL service that they will not be able to start it up again, Brems said. “CenturyLink said, ‘we’ll take it off, but you’re never going to get back on.’”
The rest of the team

Brems, who works in advertising and marketing and is now mostly retired, lived in Seattle for more than 20 years before moving to Orcas Island about 15 years ago. He has been struck by the “can-do” spirit of the community, which in the past built its own water plant and fire station, he said.

“They didn’t wait for someone else to come along and say, ‘I can come and save you guys if you want,’” he said.
Further Reading
500Mbps broadband for $55 a month offered by wireless ISP

You’ve probably never heard of Webpass—and you probably won’t get its service.

While Sutton spearheaded the DBIUA project, others provided important expertise. Brems, for example, used his marketing knowledge to help convince people that the project could work and get the word out by writing press releases.

The other founders are Orcas Island airport manager Tony Simpson, who previously worked for the Air Force and Boeing; lawyer Shawn Alexander, who specializes in real estate, land use, and contracts; and Tom Tillman, co-owner of a sporting goods store and a former CenturyLink installer.

Alexander’s legal expertise helped in drafting contracts the members of DBIUA need to sign. The agreements require homeowners to keep hosting and supplying power to DBIUA equipment even if they stop buying the Internet service later on. (The power costs are only about $12 a year, Brems said.)

“We needed agreements in place that if you were to sell [the house], that the person who bought it knew there was a responsibility to keep the service going whether they chose to take advantage of it or not,” he said.
A smooth ride—most of the time

The network has run perfectly for long stretches of time, requiring little more than basic maintenance. But there have been occasional glitches.
Enlarge / Chris Sutton.
Erin Bennett

Early in the network’s life, Sutton got an alert at 2 am that a relay point was down. An in-person investigation determined that a sheep had disconnected an extension cord that was sitting in the middle of a field. Battery backup kept the radio running for about six hours; the 2 am alert arrived when the battery ran out.

To make sure the cord would be weather- and animal-proof, “we decided to just dig a trench through the field” to bury the line, Sutton said.

Another, more serious problem came just a few weeks ago. The radio installed by StarTouch on the mainland broke late on a Friday, and no one could fix it until the next week.

That meant there was no Internet service from DBIUA, but a backup plan was cobbled together. On Saturday, Sutton climbed the water tank and pointed a Ubiquiti radio at a different StarTouch tower on the mainland. The Ubiquiti radio only provided about 10Mbps, “which got us back going, but it was obviously limping along.”

On Monday, StarTouch replaced the radios at both ends, on the mainland and on top of the water tower. But Sutton was on a business trip and couldn’t get back to the water tower until Wednesday to switch the network over to the new connection.

During outages, customers can call a help line number to hear a message with the latest information on the network status. People on the island understand that this is all a volunteer effort and that there will be occasional problems.

“They really appreciated us just being up front with what was going on,” Sutton said.

The weekend outage was a learning experience, and now Sutton is considering leaving the backup radio on the water tower permanently in case the system needs to fail over to the second radio on the mainland. The router that DBIUA has at the water tower could then automatically switch to the second radio if the primary link goes down.
A true patriot

This past summer, Sutton was named the Doe Bay Community Association Patriot of the Year at the Fourth of July celebration. “In the past 18 months, he has literally driven every back road, climbed countless tall trees and run hundreds of sight lines…,” Brems said on his friend’s behalf. “He has unpacked, inventoried, programmed, and installed dozens of pieces of equipment. He has scaled the Doe Bay water tank multiple times.”

While Sutton has been the driving force of DBIUA, he is looking to impart some of his knowledge to other members of the association so they can fix problems when he can’t. Using Slack, they set up a training channel where Sutton is teaching them how the system works. He’s given members limited access to the monitoring system so they can get familiar with it, and he will eventually provide administrative rights so they can manage the network.

The group is also thinking up new ways to troubleshoot the network. One idea is to “put a Raspberry Pi at the different relay points to do speed tests [to the water tank] and log that over time,” Sutton said. That way, if people call and say Internet access is slow, DBIUA can check to see whether the problem is within its own network or in the connection to StarTouch.

Raspberry Pis could also monitor voltage on batteries to determine whether a radio has switched to backup power. That information could provide several hours of warning before a radio goes out completely.

While there’s room for growth and improvement, the current benefits have been obvious for service members. In mid-August, a few weeks before the DBIUA outage outlined above, there was a major outage affecting both wired and wireless broadband providers caused by a car crashing into a major utility pole on the island.

“I think so many other communities could do this themselves.”

Just about everyone was down for nearly an entire day—but not DBIUA.

The crash “took out a major fiber line,” Sutton said. “Almost all Internet in San Juan County (Orcas, Lopez, and San Juan Island) went out. AT&T, T-Mobile, [and] Sprint cell phone service went out. The only Internet that continued to work was the school, library, and the DBIUA, all of which were using StarTouch microwave for their backhaul. I did a little bit of gloating for sure.”

With all the success, people in other parts of Orcas have since asked Sutton to set up networks for them. “I’m like, ‘no, but I can tell you how to do it,’’’ he said. So although networks like DBIUA’s remain rare for now, Sutton believes it can be duplicated in more places than you’d expect.

“I think so many other communities could do this themselves,” he said. “There does require a little bit of technical expertise but it’s not something that people can’t learn. I think relying on corporate America to come save us all is just not going to happen, but if we all get together and share our resources, communities can do this themselves and be more resilient.”

.

Source: How a group of neighbors created their own Internet service | Ars Technica

We’re social animals — it’s just the way the cookie crumbled. For the most part, even the most introverted of human beings need some sort of human contact every once in a while, and face-to-face interactions may still be better than sending an email or a text. Despite what we may think about staying connected via technological advances, a new study suggests that when it comes to staving off depression, actually seeing your friends does a whole lot more good than sending them an emoji. The effects of actually seeing your friends in person are particularly salient in older individuals, and according to the Oregon Health and Science University study, those who reported “regular interactions with family and friends” were 5 percent less likely to face depression when compared to peers who only maintained phone, text, or email relationships. “We see a dose dependent effect with in-person contact,” says Dr. Alan Teo, a professor of psychiatry at OHSU. “The more face-to-face meetings, the lower the [depression] rates go.” Related: Apple’s newest iPhone isn’t as popular as its predecessors In conducting their study, researchers examined the interpersonal interactions of more than 11,000 Americans aged 50 years and older. Study participants were then monitored for two years for risks and signs of depression (other factors including health status, distance from family members, and mental health history were also taken into account). Ultimately, doctors found that respondents who had regular face-to-face interactions with their friends and family (at least three times a week), faced only a 6.5 percent chance of developing depression. On the other hand, those who only saw their friends or family once every few months or even more infrequently had an 11.3 percent risk of developing depression. Overall, some 9.5 percent of American adults suffer from depression at some point in their lives, so study results would suggest that having these in-person meetings with loved ones more frequently actually helps with overall psychological health. Of course, this isn’t to say that emails, texts, and other digital forms of communication are bad for us as a society. Indeed, an increase in messaging devices and mediums certainly allows human beings to stay more connected to one another. But at the end of the day, Teo says, emails, texts, and even phone calls, “are no substitute for face-to face contact.” While the study only examined older Americans, researchers believe that similar results may be extrapolated to millennials as well. However, with young adults’ widespread adoption of various social media outlets, Teo is curious as to the effects of Facebook, Twitter, and other platforms on feelings of depression, anxiety, and isolation. “In one of my next studies,” he said, “I am now trying to measure all different types of social media use to see how that plays out with mental health outcomes, particularly in younger adults.” So take note, friends. The next time you’re sharing a laugh or a gif via text or email, consider actually sharing some time in person. You may just put yourself in a better mood by doing so.

Source: In-Person Interactions Shown To Lessen Depression Risk | Digital Trends

Woman Says She Endured 8 Days In Psych Ward Because Cops Didn’t Believe BMW Was Hers”I do think race played a part in this.”Headshot of Christopher MathiasChristopher MathiasNational Reporter, The Huffington PostPosted: 09/11/2015 04:02 PM EDT | Edited: 09/11/2015 05:57 PM EDTPIX11NEW YORK — Kamilah Brock says the New York City police sent her to a mental hospital for a hellish eight days, where she was forcefully injected with powerful drugs, essentially because they couldn’t believe a black woman owned a BMW. In her first on-camera interview about her ordeal, which aired Thursday, the 32-year-old told PIX11 that it was all a “nightmare.”It’s a nightmare, Brock’s lawyer told The Huffington Post, that never would have happened if she weren’t African-American. Brock sued the city earlier this year in the U.S. District Court for the Southern District of New York. She contends that her constitutional rights under the Fourth and 14th Amendments were violated and that she suffered “unwanted and unwarranted intrusion of her personal integrity, loss of liberty [and] mental anguish.” The suit details how Brock pulled up to a traffic light in Harlem on Sept. 12, 2014, the music on her car stereo playing loudly. An NYPD officer approached her and asked why she was driving without her hands on the steering wheel, according to the suit. “I said I was dancing, I am at a light,” Brock told PIX11. “He asked me to get out of the car.”For unclear reason, Brock contends, she was taken into custody and transported to the NYPD’s 30th Precinct, where she was held for a few hours before being released without being charged with any crime. She said she was told to come back the next day to pick up her car, a 2003 BMW 325Ci.When she showed up at a police substation to get the car the next day, Brock said, “I just felt like from the moment I said I owned a BMW, I was looked at as a liar. They put me in handcuffs and said they just need to put me in handcuffs to take me to my car. And I said OK, whatever it’s gonna take to get to my car.””Then EMS approached me,” she continued. “And they said we’re gonna take you to your car. And I’m like, in an ambulance? I’m going to my car in an ambulance? I’m going to my car in an ambulance? I was just so confused.”Brock was taken instead to Harlem Hospital, where medical records obtained by her attorney, Michael Lamonsoff, show she was injected with powerful sedatives and forced to take doses of lithium.”He held onto me and then the doctor stuck me in the arm and I was on a stretcher and I woke up to them taking my clothes off, specifically my underwear,” Brock tearfully recalled for PIX11’s Nicole Johnson. “Then I went back out again. When I woke up the next day, I felt like I was in a nightmare. I didn’t understand why that was happening to me.” Medical records also show that over the course of her eight-day stay, personnel at the hospital repeatedly tried to get Brock to deny three things before she could be released: that she owned the BMW, that she was a professional banker, and that President Barack Obama followed her on Twitter. The lawsuit says it was these three assertions that were the basis for the city determining that Brock was delusional and to diagnose her with bipolar disorder. But according to Lamonsoff, Brock had no history of mental illness. She did own the BMW. At the time, she was employed as a banker and had worked at Citibank, Chase and Astoria Bank. And Obama does follow Brock on Twitter, just as he follows 640,000 other people. When Brock was finally released from the hospital, the lawsuit states, she was slapped with a $13,000 medical bill.A white woman would not have been treated like that, Lamonsoff argues.Courtesy of Michael Lamonsoff”If a white woman was trying to reclaim her BMW impounded by police, would she have been made a victim?” he said to HuffPost. “Would she have been questioned? Would she have been subject to sarcastic comments? Would she be made to justify who she was in order to ask for help? I don’t think so. I do think race played a part in this.”Institutional bias against African-Americans is well-documented and contributes to the racial disparities in how laws are enforced. Just this week, James Blake, formerly the fourth-ranked men’s tennis player in the world, was tackled and handcuffed at a midtown Manhattan hotel by police officers who confused him for a suspect in a crime. Blake, who is black, suffered cuts and bruises and was detained for about 15 minutes, until officers realized who he was. “In my mind, there’s probably a race factor involved, but no matter what, there’s no reason for anybody to do that to anybody,” Blake said after the incident.Responding to Brock’s lawsuit earlier this summer, the city claimed in court filings that she had been “acting irrational, she spoke incoherently and inconsistently, and she ran into the middle of traffic on Eighth Ave” during her encounter with police.Lamonsoff told HuffPost that “those allegations

Source: Woman Says She Endured 8 Days In Psych Ward Because Cops Didn’t Believe BMW Was Hers

Mixing a brew of biblical prophecies, the Hebrew calendar, a volatile economy, world politics, a reported near-death experience and astronomical occurrences, hordes of Utahns have become convinced that calamitous events are imminent — maybe by month’s end — and are taking every precaution.They are called “preppers” and are buying up food-storage kits, flashlights, blankets and tents. Some are even bracing to leave their homes — if need be.At American Fork’s Thrive Life, which sells mostly freeze-dried food, sales have shot up by “500 percent or more in the past couple of months,” says customer- service representative Ricardo Aranda. “There is a sense of urgency, like something is up. A lot of people are mentioning things about September, like a financial collapse.”TOP JOBS3 From3form Recruits Talented And Committed …Check out all the Trib TopJobsVIDEOSJordan Jensen, a salesman at Emergency Essentials, said his Bountiful store has been “crazy busy, sales up by definitely a large amount.”Those 72-hour emergency kits are “almost impossible to keep on the shelves,” Jensen says, “and we get a shipment every day.”A lot of customers, he says, believe “this is the month it will all happen — with a ‘blood moon’ and a currency collapse and everything.”Here’s how the doomsday scenario plays out: History, some preppers believe, is divided into seven-year periods — like the Hebrew notion of “shemitah” or Sabbath. In 2008, seven years after 9/11, the stock market crashed, a harbinger of a devastating recession. It’s been seven years since then, and Wall Street has fluctuated wildly in recent weeks in the wake of China devaluing its currency.Thus, they believe, starting Sept. 13, the beginning of the Jewish High Holy Days, there will be another, even larger financial crisis, based on the United States’ “wickedness.” That would launch the “days of tribulation” — as described in the Bible.They say Sept. 28 will see a full, red or “blood moon” and a major earthquake in or near Utah. Some anticipate an invasion by U.N. troops, technological disruptions and decline, chaos and hysteria.Some of these speculations stem from Julie Rowe’s books, “A Greater Tomorrow: My Journey Beyond the Veil” and “The Time Is Now.”Rowe, a Mormon mother of three, published the books in 2014 to detail a “near-death experience” in 2004, when the author says she visited the afterlife and was shown visions of the past and future.Though Rowe rarely gives specific dates for predicted events, she did describe in a Fox News Radio interview “cities of light,” including scores of white tents where people will live in the mountains and sometimes be fed heavenly “manna.” She saw a “bomb from Libya landing in Israel, but Iran will take credit.”And “Gadianton robbers” of Book of Mormon infamy, meaning secret and corrupt leaders, are “already here.”Her purpose in speaking out, Rowe told interviewer Kate Dalley, was “to wake more of us up. … We need each other as we unify in righteousness and continue to build a righteous army. When we need to defend the [U.S.] Constitution, we will be ready.”For the past year, the popular writer has been sharing her experience and visions at Mormon venues nationwide, drawing crowds of eager — and worried — listeners. Her two books have sold more than 20,000 copies apiece.In a rare move, officials with The Church of Jesus Christ of Latter-day Saints sent a memo to administrators and teachers in the Church Educational System, saying, “Although Sister Rowe is an active member of the [LDS Church], her book is not endorsed by the church and should not be recommended to students or used as a resource in teaching them. The experiences … do not necessarily reflect church doctrine, or they may distort doctrine.”The late Mormon apostle Boyd K. Packer said in the October 2011 LDS General Conference that the “end” was not near and urged young Latter-day Saints to plan to live long, productive lives.”You can look forward to doing it right: getting married, having a family, seeing your children and grandchildren, maybe even great-grandchildren,” Packer said.

Source: Some Mormons stocking up amid fears that doomsday could come this month | The Salt Lake Tribune

Earlier this year, TIME explored the promise of precision medicine in treating cancer patients. We featured one woman who was taking a drug typically used for melanoma to treat her brain tumor. Here’s an update on how she’s doing

In November 2013, MaryAnn Anselmo—who was on the cover of TIME in March—heard the words that most of us dread the most: she had cancer. Worse, it was stage 4 glioblastoma, a particularly aggressive brain tumor that often takes a patient’s life in a matter of months. Having just recovered from a devastating car accident, Anselmo thought, “Somebody wants me dead here.”

Nearly two years later, the New Jersey resident is receiving some completely different, and more welcome news. “The latest scan doesn’t show any tumor any more,” her physician, Dr. David Hyman, acting director of Developmental Therapeutics ad Memorial Sloan Kettering Cancer Center (MSKCC), tells TIME. The results from Hyman’s most recent study, which Anselmo participated in, is published in the latest issue of the New England Journal of Medicine (NEJM).

“I’m tired all the time,” she says, “but I’m dealing with it, living with it. I feel awesome compared to what this tumor could have done to me.”

MORE: The Cancer Gap

Hyman is reluctant to call it a “cure” for certain cancers—the burden of proof is higher than this one study or this one patient—but Anselmo’s cancer is gone. And for that, Anselmo can thank something called a basket trial, a new way for doctors to test promising cancer treatments that more precisely target the right therapies to the right patients at the right time. This is the first such trial of its kind.

The trial puts the idea of precision medicine to the test. At 23 cancer centers around the world, 122 patients with advanced cancer signed up for a last-resort treatment covered in the new study. All had their tumor genomes sequenced, so doctors could get a better sense of which mutations were driving the cancers, and whether there were any targeted therapies for those mutations.

Anselmo had three mutations fueling the growth in her brain, but she and her doctors at MSKCC decided to focus on one, called BRAF. A recently approved drug to treat BRAF mutations in melanoma helped shrink or halt tumor growth in half of treated patients, so doctors wanted to know whether the drug could help patients with the same mutation but with different kinds of cancer, like Anselmo. But while BRAF mutations occur in about 50% of melanoma cases, they are much rarer in other types of cancers. So creating a trial for patients like Anselmo would take both time and money that researchers couldn’t justify.

A basket trial, however, capitalizes on the growing understanding that cancers should be characterized by not just where they start (in the breast, colon or lung, for example) but also by how they grow — which mutations are driving them. A basket trial collects patients, all of whom have BRAF mutations, for instance, but who might have different types of cancer.

In the NEJM study, patients with non small cell lung cancer, colon cancer, thyroid cancer, multiple myeloma and, glioblastomas, among others, were included. By studying them as a group, Hyman says it’s possible to get a better idea of how feasible it is to target mutations like BRAF among those who don’t have melanoma.

So far, the results are encouraging. Patients with non small cell lung cancer seemed to have the best response rate to vemurafenib, 42%, after a year. More than 70% of the patients with this cancer saw their tumors shrink by at least 30% in length. There were promising signs that patients with the other, untreatable cancers also responded and took longer before their tumors progressed than they would have without the experimental therapy.

Anselmo was among the extraordinary responders. “It is unusual,” says Hyman of the apparent shrinkage of her tumor. “She really is an outlier in any way you measure it.”

NEJM 373; 8; 2015. Courtesy Dr. David Hyman: Anselmo’s brain tumor at the start of the study in 2014 (left) and on Aug. 11, 2015 (right)

But it’s precisely for patients like Anselmo that basket trials are being considered — the possibility that there may be one, two or however many patients who, rather than facing a poor prognosis with existing or non-existent options for treating their disease, may have a chance, however small, of living longer and even controlling their cancer.

“One of the things that gets lost when we talk averages and medians is how many patients benefit and for how long,” says Hyman. “There is a tremendous range and a concern that promoting the best successes sets the bar very high. But it also lets people know that things are not entirely hopeless, that there are people who have tremendous benefit from therapies and not get completely caught up in medians and averages.”

That being said, Hyman cautions that more work needs to be done to better apply the principles of precision medicine to improve patients’ outcomes. Since most tumors have many mutations, how can doctors determine which one, or ones, to target with drugs? Why do some patients respond very well, while others do not?

Another looming question has to do with how cancer doctors can start to incorporate what they are learning about mutations and cancer-causing pathways with their more traditional knowledge based on where tumors start. In the study, for example, patients with BRAF colon cancers did not respond to vemurafenib; but some started to show responses when vemurafenib was combined with another drug, cetuximab. That suggests that knowing where the cancer originates may still be an important part of the puzzle in figuring out which treatments might work best for which types of cancers.

In an editorial accompanying the study, researchers at the T.H. Chan Harvard School of Public Health and Boston University note that basket trials may be just the first step in a precision medicine approach to cancer. Once doctors figure out which types of cancers might respond best to, for example, a BRAF-focused drug, they might conduct additional trials on each of these cancers to determine which patients, like Anselmo, would benefit most.

For her, the trail has provided the chance to sing again. A jazz vocalist, she performed at a friend’s birthday party and attended a song-writing retreat in upstate New York. She makes weekly visits to her doctors — to the dermatologist to monitor any side effects from the drug, to Hyman every two months for a brain scan, and to get lab tests done to check on her immune system. And she’s tired all the time. “But that’s par for the course,” she says. “I’m just lucky to be alive at a time when cancer care is so different than it was years ago. Who would have known that treatments could be so customized? It’s so amazing, and I’m very thankful to be a part of it.”

 

How Doctors Cured This Woman’s Brain Cancer | TIME.