Fight Aging! Newsletter, June 22nd 2015

June 22nd 2015

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • Fight Aging! 2015 Fundraiser for SENS Rejuvenation Research: Seeking Matching Fund Founders
  • CGI Molecular Biochemistry Videos from the SENS Research Foundation
  • More on Efforts to Lobby the FDA to Accept Aging as a Medical Condition that Can and Should Be Treated
  • Sirtuin Research Continues Apace
  • Everyone Ages for the Same Reasons, and Many Age-Related Diseases Share the Same Roots
  • Latest Headlines from Fight Aging!
    • The Continuing Challenge of Selling Healthy Longevity
    • More People are Considering Radical Life Extension
    • In Some Senses 80 is Already the New 40
    • A Look at the Cryonics Community
    • The Solar Cycle and Autoimmunity
    • Hair Loss and MicroRNA 22
    • Vinculin in Heart Aging and Longevity
    • Mitochondrial Biogenesis and Mitophagy in Aging
    • Mining Stem Cell Exomes for Means to Spur Tissue Repair
    • An Update on Efforts to Develop Intermittent Fasting as an FDA-Approved Treatment


You will recall that last year we raised 150,000 to expand the work of the SENS Research Foundation on the biotechnologies needed to build a first generation of rejuvenation therapies. Aging is caused by cell and tissue damage and SENS research programs aim at the repair of that damage to bring frailty and age-related disease under medical control. Nine generous donors collaborated to provide a matching fund, and the community came together in response to that challenge. Those funds are already being put to good use by researchers.

Following on from that success Fight Aging! will run another grassroots fundraiser this year in collaboration with the SENS Research Foundation, with the main event beginning in October and running through to the end of the year. Again, all donations will go towards the early stage research needed to assure healthy longevity and an end to age-related disease. Between now and October we have the time to build a bigger and better matching fund than last year.

Accordingly: Fight Aging! is putting forward 25,000 to start this fund. I challenge those members of this community with the means to match some or all of this amount: step up and let's make a difference together.

But why do this, you might ask? Thousands of dollars is no small matter, for me just as much for you. I have made the call that a smaller bank account today is a fair trade for a better shot at health and longevity tomorrow, but why should you?

Because SENS Research Programs are of Great Importance

The SENS Research Foundation is perhaps the only organization presently focused on rescuing and speeding up all of the research programs necessary to produce human rejuvenation therapies. A few such fields are, thankfully, doing well today: we can all agree, I'm sure, that stem cell research is progressing at a good pace and there is little that we can do to help. There are a good number of other fields of research that are just as vital when it comes to the treatment of aging, however: clearance of cross-links, mitochondrial repair, senescent cell clearance, and more besides. Unlike stem cell medicine, there are few researchers in these lines of research, and they struggle to find funding and make progress. Yet without them even stem cell therapies will be limited in their benefits to health and longevity.

To bring an end to age-related disease all of the forms of damage that cause aging must be addressed, and it is vital that all of these research programs are brought into the mainstream and funded at a large scale. Few people other than the staff and allies of the SENS Research Foundation are working on this problem, and none of those are doing so in an organized way that allows you and I to make charitable donations to fund their work, confident that our money will go to one of the points of greatest impact.

Because Our Donations and Our Advocacy are Working

It takes time for research funding to make an impact, and few human endeavors are as slow to show progress as medical research. It is not unusual to wait five years or more to hear back on the next development in a long-running line of scientific inquiry. But groups like the Methuselah Foundation, the SENS Research Foundation, and their network of supporters have been at this for more than a decade now. The results of work and funding from earlier years are starting to emerge now, in the form of greater public support, in the form of new large initiatives like Calico, and in the form of meaningful progress in some of the laggard but vital lines of research.

This year, for example, saw publication of the first example of partial senescent cell clearance in normal mice, resulting in clear and impressive health benefits. SENS advocates have been calling for more funding for senescent cell clearance for more than a decade, and predicting that it should show significant benefits when realized, and it is a real shot in the arm to see solid progress emerging today. We are winning - let us not forget that. Past efforts are paying off, the wheel is beginning to turn, and this is exactly the time to pour it on and reinforce that success.

Because Our Donations Make an Immediate Difference to the Research Process

Donations that support grants for promising but poorly funded research have an immediate benefit for the labs involved, as they are frequently forced to delay follow-on work and new investigations. There is a large difference between what researchers want to work on and what they can raise funds for from the standard institutional sources. Philanthropy and organizations like the SENS Research Foundation are very necessary to bridge this divide. Noted researchers Michael and Irina Conboy at UC Berkeley had this to say about our 2014 fundraising:

In 2014 our lab hit a gap in funding and was in dire need of money to keep a postdoc for just a few more months, to finish up work on the rejuvenating effects of oxytocin. The SENS Research Foundation came through with the funds and we were able to finish and publish the work in Nature Communications. While maybe not the direct path to immortality, that project indicated an effective drug for muscle and bone regeneration (and probably other tissues as well), that is generally recognized as safe. Now the SENS Research Foundation funds our postdoc working on a mouse-sized blood-fraction exchange device project, and a cellular senescence collaboration. So we truly appreciate SENS and Fight Aging! and the donors; even a little support at the right time can make a huge difference in outcome.

Because We Light the Way for Larger Donations in the Future

Wealthy donors and large-scale philanthropy are always late to the party. These are the most conservative of funding sources, and do not step in until a field has well-established support. They wait for other people to lead the way by forming communities, raising seed funding, and carrying out proof of concept research programs. That means us. If you want to see more seven-figure donations to SENS research, the path to that outcome is through the small donations and day to day advocacy of a thousand individuals, through the discussion, persuasion, and growth of a community to support the goals of rejuvenation research.

If you have a vision for the future, if you can see more clearly than most, then it is your role to light the beacon, to point other groups towards the best and most promising research programs, those capable of bringing an end to the pain and suffering that accompanies aging. The more that we succeed in strengthening SENS research, the greater the number of new allies that will join in to reinforce our success. This is how change happens in medical research: every friend persuaded and every dollar donated makes a difference.


Modern computer-generated imagery has improved by leaps and bounds at the same pace as biotechnology, both driven by the same underlying trend towards ever-increasing and ever-cheaper processing power. This has led to something of a renaissance in the visualization of cellular biology, conveniently occurring at exactly the same time as researchers assemble far more accurate and complete data on the structures and processes involved. Popular science publications have been able to move far beyond static images, and nowadays high-quality video representations of organs, tissues, and cells are commonplace. Bear in mind that there is a still a great deal of interpretation and artistry involved in the creation of such things, however. They are built based on the best of today's knowledge, which is an ever-changing target these days, false colors are generously employed for clarity, and scenes may be greatly simplified so as to remove other elements that in reality exist but are not essential to the point being made. The map is not the territory.

That said, I think you'll find this selection of short videos interesting. They were commissioned by the SENS Research Foundation, and each gives a high level overview of the cellular biology relating to one particular ongoing research program aimed at producing treatments for the causes of degenerative aging.

Reversing Heart Disease

This video, narrated by actor Edward James Olmos, describes the process that causes heart disease and highlights a promising intervention that SENS Research Foundation is funding. The video begins with an explanation of cholesterol particles that can become trapped in blood vessels and the patrolling macrophages that normally remove them. However, the macrophages struggle to process oxidized cholesterol. This problem causes the macrophages to die, and the resulting foam cells form atherosclerotic plaques, which ultimately cause heart attacks and strokes. SRF is funding research into an enzyme that would enable macrophages to degrade these oxidized cholesterol particles, thereby rescuing the macrophages, preventing plaque buildup, and possibly even reversing the atherosclerotic process.

Stopping Cancer at the Starting Line

Narrated by actor Edward James Olmos, this video describes one of the body's critical anti-cancer defences - the telomeres. These caps on the ends of our chromosomes shorten each time a cell divides and, when they become too short, trigger the cell to self-destruct. When a cell grows too rapidly, it and all of its descendants normally suffer this fate. Such growths are sometimes called "pre-cancer". Since our stem cells need to be able to divide without this constraint in order to replace cells lost across the body, they produce the enzyme telomerase to re-extend their telomeres. Unfortunately, a small number of pre-cancerous cells manage to activate their own copies of the telomerase gene, escaping the limit on their growth. SENS Research Foundation is developing therapies to completely block telomere extension in pre-cancerous cells, ensuring the body's existing defences can function as intended.

Preventing Mitochondrial Aging

Actor Edward James Olmos narrates this short introduction to the mitochondria, the tiny organelles that 'burn' oxygen and nutrients to power our cells, before considering how during aging that same process can damage mitochondrial DNA - eventually causing the host cell to go into decline. Mitochondrial mutations are strongly implicated in several age-related conditions including Parkinson's disease and "sarcopenia", the gradual loss of muscle experienced even by active seniors. SENS Research Foundation is developing a therapy to prevent the failure of all such cells by placing backup copies of key mitochondrial genes in the cell's nucleus, where they are much better protected. With such a backup in place, damage to the mitochondrial DNA becomes irrelevant, and the cell can return to normal healthy function.


It seems that after some years of researchers feeling more comfortable talking in public about the goal of treating aging as a medical condition, the community is also beginning to feel constrained by the present regulatory and funding situations. Both are ridiculous. In the US the Food and Drug Administration (FDA) only approves treatments for specific uses and defined medical conditions. Aging is not a defined medical condition, therefore you can't legally deploy new technologies to treat it. That has a stifling effect on the ability to raise funds all the way along the development chain that leads from early stage research to commercialization.

Not that aging research receives anywhere near as much funding as it merits in the first place, regardless of the FDA situation: medical research is in general funded to a fraction of what even a moderately utilitarian view would suggest is a good plan. Aging research makes up a tiny fraction of that medical research funding, and efforts to actually treat rather than merely investigate aging garner a small portion of even that pittance. This is a society of beer and circuses, not one of respect for the sciences, at least if you look at the flows of money and other resources. The amounts spent on the above-board and regulated bribery of the last US presidential election summed to about twice the funding for the National Institute on Aging in that year, for example, and were probably roughly in the same ballpark as the sum of all aging research funding in the US that year, public and private.

In any case, those researchers who consider themselves stuck with working within the institutional funding system are of late gearing up to more seriously lobby the FDA to change the rules. This makes sense in their world: a change opens more doors in the future when it comes to seeking grants or establishing for-profit ventures based on their research. I am not optimistic that this is anything but the start of a very long, expensive, and distracting process for those who take on the lion's share of the responsibility for it, however. We have the example of sarcopenia to consider, this being the name given to the characteristic loss of muscle mass and strength that takes place with aging. Lobbying the FDA to consider this a medical condition and thus allow commercialization of treatments in the US has been underway for a long time indeed, with no sign that FDA bureaucrats are going to do anything more than continue to hold meetings, request expensive data, and waste time.

As I have long said, I think that the better road ahead is to commercialize treatments outside the US on the back of a strong medical tourism industry. The stem cell marketplace could grow into that, but has yet to organize to the point at which it can influence the research community sufficiently to close the funding circle. It absolutely should be any US researcher's expectation that their primary and best avenue for commercial application of medical research is outside the US. Further, a robust trade on that front is the only way to drive back the ever-increasing demands of the FDA. Regulatory competition with other regions is the only argument that bureaucrats reliably listen to: the point at which they look like fools for holding out further. I expect we'd still be waiting on legalization of stem cell treatments of any sort in the US if they hadn't been widely available for years in reliable clinics and hospitals across both land borders and the Pacific.

In any case, here is more on the topic of lobbying the FDA on approval for therapies that might treat aging. This is all some years in advance of anything that can actually effectively move the needle, so far as my view of the situation is concerned, but no harm in getting the groundwork laid early. Though, as noted above, I think they'll be at this for a while, and past the time at which initial treatments to partially treat some aspects of degenerative aging are available overseas via medical tourism.

Anti-ageing pill pushed as bona fide drug, regulators asked to consider ageing a treatable condition

Doctors and scientists want drug regulators and research funding agencies to consider medicines that delay ageing-related disease as legitimate drugs. Such treatments have a physiological basis, researchers say, and could extend a person's healthy years by slowing down the processes that underlie common diseases of ageing - making them worthy of government approval. On 24 June, researchers will meet with regulators from the US Food and Drug Administration (FDA) to make the case for a clinical trial designed to show the validity of the approach.

Current treatments for diseases related to ageing "just exchange one disease for another", says physician Nir Barzilai of the Albert Einstein College of Medicine in New York. That is because people treated for one age-related disease often go on to die from another relatively soon thereafter. "What we want to show is that if we delay ageing, that's the best way to delay disease."

Barzilai and other researchers plan to test that notion in a clinical trial called Targeting Aging with Metformin, or TAME. They will give the drug metformin to thousands of people who already have one or two of three conditions - cancer, heart disease or cognitive impairment - or are at risk of them. People with type 2 diabetes cannot be enrolled because metformin is already used to treat that disease. The participants will then be monitored to see whether the medication forestalls the illnesses they do not already have, as well as diabetes and death.

On 24 June, researchers will try to convince FDA officials that if the trial succeeds, they will have proved that a drug can delay ageing. That would set a precedent that ageing is a disorder that can be treated with medicines, and perhaps spur progress and funding for ageing research.

To be clear, I don't think metformin is going to do much for anyone when it comes to aging. The evidence in human and animal studies for metformin to slow aging is all over the map, and pretty weak overall if you ask me. Even if the best outcomes observed in these studies actually happened in all humans, which they won't, this isn't anything to write home about. It's not even as good as exercise or calorie restriction, both of which are free and backed by the gold standard of weight of evidence when it comes to benefits to health. But you might consider this as an example of reaching for the tools immediately to hand in order to make inroads into the regulatory process.


A lot of time and money has gone into the study of sirtuins, a class of a few proteins that participate in numerous cellular processes that influence natural variations in aging and longevity. There was something of a big hype cycle over this back a few years, and like all hype cycles centered on alleged approaches to modestly slowing aging through drugs that alter the operation of metabolism, it all came to nothing exciting in the end. A fair chunk of new cellular biochemistry was mapped, a chunk that it has to be said is in fact a tiny, minuscule slice of the overall space of proteins and genes, something like a few billion was spent, and no reliable demonstrations of extended life in higher animals or viable therapies for age-related disease resulted. It is perhaps worth bearing in mind here that the primary goal of the scientific endeavor in the broader field of cell biology is in fact to map every last complex interaction of cellular biochemistry, and applications of that knowledge are secondary at best, a nagging concern that comes up when writing grants, since the rest of the world has an interest in new technologies and better medicines. I exaggerate, but not greatly.

Large research initiatives have inertia once they are underway and established, and so a broad range of investigations into sirtuin biochemistry continue apace today. Even a brief search of published papers on sirtuins and aging turns up more than a dozen publications in the last couple of months, which is a sizable number for any one narrow subtopic in the life sciences. It is all very interesting, but I think we should continue to assume that there is next to nothing here of any real relevance to the treatment of aging as a medical condition. At the very best this is a long, hard road to drugs that make slight adjustments to the course of aging in any given individual, probably not as large as the adjustments you can make yourself via exercise and calorie restriction. Of course the scientific community should continue along the path of gathering complete understanding of cellular biochemistry, all knowledge will be useful eventually, but we should maintain a realistic view of what various portions of that venture can in fact achieve in the near future.

Here are a selection of recent sirtuin-related papers for you to peruse at your leisure, things that I wouldn't normally take any time to point out. But there is always more going on than is individually newsworthy in my eyes.

Reversing stem cell aging (PDF)

SIRT3 and SIRT7 converge at mitochondrial protection to ensure hematopoietic stem cell maintenance. These protective programs are repressed in aged hematopoietic stem cells and reintroduction of SIRT3 or SIRT7 improves the functional capacity of aged hematopoietic stem cells. Thus, SIRT3 and SIRT7 may modulate the aging process by regulating stem cell quiescence and tissue maintenance. It will be of particular interest to establish whether other tissues use the same mechanism for maintaining stem cell quiescence. It will also be important to identify other genes that mediate mitochondrial protein folding stress to regulate stem cell quiescence.

Sirtuins and Proteolytic Systems: Implications for Pathogenesis of Synucleinopathies

Loss of proteostasis associated with a burden and an impairment of the proteolytic pathways is one of the hallmarks of α-synuclein-induced toxicity. Therefore, modulation of the proteolytic molecular pathways that are deregulated appears as a rational strategy to fight against the harmful effects promoted by α-synuclein. Sirtuins are a family of highly conserved NAD+ dependent histone deacetylases that have emerged as central players in several biological processes, such as transcription, apoptosis, DNA repair, stress cellular response and energetic metabolism. The interest in sirtuins, in the context of proteostasis, emerged with the discoveries that sirtuins have the ability to modulate proteostasis, particularly the autophagy degradation pathway, and aging.

Sirtuin function in aging heart and vessels

Age is the most important risk factor for metabolic alterations and cardiovascular accidents. Although class III histone deacetylases, alias Sirtuins, have been appealed as "the fountain of youth" their role in longevity control and prevention of aging-associated disease is still under debate. Indeed, several lines of evidence indicate that sirtuin activity is strictly linked to metabolism and dependent on NAD+ synthesis both often altered as aging progresses.

SIRTain regulators of premature senescence and accelerated aging

Amongst the seven known mammalian sirtuin proteins, SIRT1 has gained much attention due to its widely acknowledged roles in promoting longevity and ameliorating age-associated pathologies. The contributions of other sirtuins in the field of aging are also gradually emerging. Here, we summarize some of the recent discoveries in sirtuins biology which clearly implicate the functions of sirtuin proteins in the regulation of premature cellular senescence and accelerated aging.

Depletion of SIRT6 causes cellular senescence, DNA damage, and telomere dysfunction in human chondrocytes

SIRT6, a member of the sirtuin family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases, has been implicated as a key factor in aging-related diseases. However, the role of SIRT6 in chondrocytes has not been fully explored. The purpose of this study was to examine the role of SIRT6 in human chondrocytes by inhibiting SIRT6 in vitro. Depletion of SIRT6 in human chondrocytes caused increased DNA damage and telomere dysfunction, and subsequent premature senescence. These findings suggest that SIRT6 plays an important role in the regulation of senescence of human chondrocytes.

Differential expression of sirtuins in the aging rat brain

Although there are seven mammalian sirtuins (SIRT1-7), little is known about their expression in the aging brain. We tested mRNA and protein expression levels of rat SIRT1-7, and the levels of associated proteins in the brain. Our data shows that SIRT1 expression increases with age, concurrently with increased acetylated p53 levels in all brain regions investigated. SIRT2 and FOXO3a protein levels increased only in the occipital lobe. SIRT3-5 expression declined significantly in the hippocampus and frontal lobe, associated with increases in superoxide and fatty acid oxidation levels, and acetylated CPS-1 protein expression, and a reduction in MnSOD level. While SIRT6 expression declines significantly with age acetylated H3K9 protein expression is increased throughout the brain. SIRT7 and Pol I protein expression increased in the frontal lobe. This study identifies previously unknown roles for sirtuins in regulating cellular homeostasis and healthy aging.

Expression of SIRT1 and SIRT3 varies according to age in mice

Sirtuins (SIRTs) are involved in multiple cellular processes including those related to aging, cancer, and a variety of cellular functions including cell cycle progression, DNA repair, and cellular proliferation. SIRTs have been shown to extend the yeast life span, although there is presently little known about SIRT expression in the organs of mice. In the present study, we were especially interested in identifying differences in SIRT expression between young mice and aged mice. Specifically, we investigated the expression of SIRT1 and SIRT3 in the kidney, lung, skin, adipose tissue, and spleens of 6-month-old and 24-month-old mice using immunohistochemical staining. Compared with that in younger mice, the expression of SIRT1 in 24-month-old rats was increased in kidney, lung, and spleen tissue, while that of SIRT3 was decreased in adipose, kidney, and lung tissue. The results of our study suggest that aging is associated with altered patterns of expression of SIRT1 and SIRT3. In addition, we noted that the expression patterns of SIRT1 and SIRT3 varied by organ. Taken together, the results of this study suggest the possibility that SIRTs may be involved in diseases associated with aging.

SIRT1 in the brain - connections with aging-associated disorders and lifespan

SIRT1, the best studied member of the mammalian sirtuins, has a myriad of roles in multiple tissues and organs. However, a significant part of SIRT1's role that impinges on aging and lifespan may lie in its activities in the central nervous system (CNS) neurons. Systemically, SIRT1 influences energy metabolism and circadian rhythm through its activity in the hypothalamic nuclei. From a cell biological perspective, SIRT1 is a crucial component of multiple interconnected regulatory networks that modulate dendritic and axonal growth, as well as survival against stress. This neuronal activity of SIRT1 is also important for neuronal plasticity, cognitive functions, as well as protection against aging-associated neuronal degeneration and cognitive decline.

SIRT1 Deficiency in Microglia Contributes to Cognitive Decline in Aging and Neurodegeneration via Epigenetic Regulation of IL-1β

Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as the brain ages is an aberrant innate immune response characterized by proinflammation. However, the molecular mechanisms underlying aging-associated proinflammation are poorly defined. Whether chronic inflammation plays a causal role in cognitive decline in aging and neurodegeneration has not been established. Here we report a mechanistic link between chronic inflammation and aging microglia and a causal role of aging microglia in neurodegenerative cognitive deficits. We showed that SIRT1 is reduced with the aging of microglia and that microglial SIRT1 deficiency has a causative role in aging - or tau-mediated memory deficits via IL-1β upregulation in mice. Interestingly, the selective activation of IL-1β transcription by SIRT1 deficiency is likely mediated through hypomethylating the specific CpG sites on IL-1β proximal promoter. In humans, hypomethylation of IL-1β is strongly associated with chronological age and with elevated IL-1β transcription. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in aging and neurodegenerative diseases.


Mechanically speaking, degenerative aging happens for the same underlying reasons in all of us. We all share the same operation of cellular metabolism, generating the same lingering waste products, the same forms of biochemical wear and tear that slowly slip past otherwise comprehensive repair mechanisms. It's all damage, and aging is in effect just a process of damage accumulation. Our organs and tissues react to that damage and waste in the same ways, so much so that you can use patterns of epigenetic markers of cell state to identify age, pulling that out from all of the thousands of changes in cell state that are distinct to a person's unique environment and circumstances.

There is a lot of interest today in identifying the genetic differences and metabolic processes that react to environmental circumstances to determine natural variations in aging and longevity in our species. Some people think that this is the way to produce therapies to extend healthy life spans: figure out what makes some people more likely to live to 100, say a 1% chance rather than a next to 0% chance, and implement some kind of drug that affects similar changes in ordinary people. Take Human Longevity Inc., for example, as representative of the viewpoint of a sizable research contingent. This all seems like a short-sighted approach to me. You're tinkering around in the reaction to the underlying cause of aging, while failing to address the actual problem - which is the damage that causes these reactions. It's like trying to make cars fall apart less frequently by working on oil formulations. There's a much better approach to making cars fall apart less frequently, and that's to repair them every so often. If you don't carry out periodic repair, you aren't going to get much out of better oil. It all seems backwards in a way.

You can make a bunch of money mining, analyzing, and selling genetic data. Human Longevity Inc. will no doubt do just fine as a business, and along the way add to human knowledge in a useful way that incrementally advances the general state of medicine. This just isn't the path to near term meaningful extension of human life spans. It's heading off in entirely the wrong direction for that, missing the forest for the trees, and the same can be said for much of the rest of the research community. They are very focused on mapping aging and its biochemistry in all of its present variations, and largely disinterested in fixing the damage that causes all of this glorious biological complexity. And pain, and suffering, and death. It's the pain and suffering and death on a vast scale that makes this something other than an academic matter in which the research community can be indulged in their desire to produce a complete map of the situation.

In any case, here is an example of the point that aging has root causes, and many age-related conditions spring from the same root causes. There are thousands of failure modes for damaged tissues, but back down the chain of cause and consequence only a handful of those root causes. This is written from the perspective of those who see intervention in the reactions to damage as the way forward, rather than those who look to repair of damage as the way forward - which is to say it is written from the present mainstream view, not the view that needs to supplant it if we are to see meaningful progress in the near future.

Genetic evidence for common pathways in human age-related diseases

It is widely accepted among gerontologists that common processes mechanistically underlie both aging and the pathogenesis of multiple age-related diseases and that targeting common factors in aging will have a significant benefit to human health. A wealth of experimental data from lower organism studies supports this concept, and human progeroid syndromes indicate that disruption of key biological processes can result in the premature onset of multiple age-related pathologies. There has, however, been little direct evidence that this is true in normal human aging and age-related disease, and the role of canonical aging pathways in human age-related pathologies has not been established.

Our gene-based findings suggest that while inflammation, immune regulation, and cholesterol metabolism are all broadly important in human aging, cholesterol metabolism genes alone are strikingly enriched among multiple age-related diseases. Multiple apolipoproteins have been associated with disease, and APOE is a particularly notable genetic loci in human health, as discussed. Consistent with these prior findings, our data suggest that apolipoprotein metabolism is a key underlying pathway in multiple human age-related diseases. Our findings suggest that apolipoprotein metabolism may represent a mammalian-specific underlying pathway in aging and age-related disease, supporting the notion that interventions in lipoprotein metabolism will provide significant benefits to human health. Epidemiological studies already support the adoption of earlier and more widespread statin use, and least one study has suggested that statins broadly affect the aging process. Clearly, apolipoprotein metabolism warrants continued attention as a safe and efficacious clinical target in aging.

In addition to providing further evidence supporting the critical importance of apolipoprotein metabolism in human age-related disease, here, we provide evidence supporting for the model that common, evolutionarily conserved pathways influence many age-related diseases. The data presented here provide new evidence supporting the continued pursuit of interventions designed to combat age-related disease based on genetic pathways of aging discovered in lower organisms. While many of these pathways, such as genome maintenance and IIS/mTOR signaling, have already been implicated in human health, our study provides the first evidence that genome-wide association studies of age-related diseases show a signature of conserved pathways of aging. Finally, while our study focused on age-related disease, our novel pathway-based approach provides a new method for identifying shared pathways of disease. We anticipate that this approach can be applied to traits that are mechanistically poorly defined to provide novel insight into the pathogenesis of human diseases.


Monday, June 15, 2015

It remains the case that most people are instinctively opposed to the idea of treating aging as a medical condition, bringing an end to age-related disease, and lengthening healthy life spans. No doubt our descendants will look upon this as a sort of transitory mania of the times, but it does make life much harder here and now for those aiming to raise funding and make progress towards that better world of the future. We don't need to persuade everyone, but we do need to persuade enough people to ensure the establishment of a scientific community as well funded and active as the present cancer or stem cell research establishments:

"A 20-year-old male today has a better chance of having a living grandmother than a 20-year-old in 1900 had of having a living mother." That's according to Lauren Carstensen, director of Stanford's Center on Longevity, who spoke during a panel on longevity at FORBES' third annual Women's Summit. The panel also included Longevity Fund partner Laura Deming, AARP CEO Jo Ann Jenkins and Robert Wood Johnson Foundation president Risa Lavizzo-Mourey, were varied: How have our lifespans changed in just a few generations? What's happening in longevity research right now? How can we use technology and policy not only to extend the lives we have, but also to make our golden years more, well, golden?

The panel's title, though, "The Longevity Paradox: Is Living Longer Really Better?", posed a question that was never really on the table. "I think the people on this panel will answer with a resounding yes when you consider the alternative," joked moderator Soledad O'Brien. Yet the fact remains that one of the biggest obstacles to improving longevity is convincing people it's worth the effort. Deming, who says she has been interested in longevity research since she was eight years old, gets plenty of skepticism when she tells people she funds it for a living. "People would be like, 'That is the stupidest thing I've ever heard. Why would you want to live longer?'" she said. "It was this visceral reaction to the idea that you could live a longer life."

All of the women on the panel have seen similar reactions to their work. To Lavizzo-Mourey, it's a question of "how we keep people functional their whole life." Carstensen suspects that when it comes to the years that have been added to average life expectancy, we mentally "tacked it on at the end made old age longer and nothing else." It's changing that culture that poses the biggest problem. "I think that our beliefs have not kept up with the way we are aging," explained Jenkins. "We continue to perpetuate these negative stereotypes of aging when we're not living that way every day."

Monday, June 15, 2015

Despite the fact that the public is largely indifferent or even hostile to the prospects for extended healthy longevity in the near future, there has been considerable progress in advocacy and awareness for this cause in recent years. It is now the case that more people than ever outside the scientific community are thinking seriously about this topic. Of course many will have important facts wrong, or misunderstand aspects of published research, or disagree with positions such as support for SENS research being the best way forward, or feel that there is little hope for meaningful progress in the next few decades, but all in all a broader public conversation on aging can only be a good thing. The more often that people encounter these ideas, the more supportive they will be towards research and development in this field:

I am very optimistic regarding my kids. In forty years, they are likely to be still healthy and relatively young. So they should probably plan for a very, very long life. At least 150 years, but possibly a lot more. If you believe that my prediction is silly and unlikely to come true, I am willing to grant you that it is highly speculative. However, from what I can see, lots of highly regarded biologists do take seriously the possibility that we could defeat aging in a few decades. So it is not entirely unreasonable. And the more decades I add to my prediction, the more likely it becomes. I would argue that the probably that I am correct grows exponentially with each decade I add. I have a really hard time imagining that we will still grow old 500 years from now. I do not have a lot of faith in biologists, but there are many of them and they have better and better tools.

But here is something interesting: we never imagine a future where people do not grow old. In Star Trek, James T Kirk grew old. Even the fierce vulcans grow old. In Star Wars, people grow old. Moreover, we still grant public employees pension plans based on limited longevities. There is a very serious risk that we are grossly underestimating the life expectancy of 20-year-old employees. I believe that it is because defeating aging is a taboo. Not even science-fiction writers want to consider it. In a sense, it is not surprising that only a few outliers like de Grey and Kurzweil talk about it. Sure, they are probably wrong in many important ways, but they are not wrong in the way that matters: aging can and will be defeated.

Tuesday, June 16, 2015

If you look back far enough for a point of comparison, technological progress has produced astounding results. Life expectancy at birth has in fact more or less doubled since ancient times. This is largely a result of reduced infant mortality and control of infectious disease, however, not any direct strategy of effectively tackling age-related disease. Life expectancy at 60 has climbed much more slowly than overall life expectancy, but it is nonetheless increasing at about a year every decade at the moment. This is an incidental increase, a side effect of general improvements in medicine; the clinical community is still not in any meaningful way trying to treat the actual causes of aging, the reasons why we become frail and diseased in old age. That will change shortly, is changing now in the laboratory, and past trends will shift radically to the upside in the decades ahead.

For thousands of years, the average lifespan of a human being was around 40 years. Evolution holds the explanation: it takes about two decades to grow up and be fully ready to reproduce. Then the offspring come along, and it takes another 20 years to get them ready to leave the nest and repeat the cycle.

"Biologically, we are programmed to live for 40 years, and if we had not been able to do so, the human species would have perished." The improvement in life expectancy over the past two centuries comes from the combined effect of a number of factors. "Sewage systems got better and limited the spread of diseases. Drinking water became cleaner. The industrial revolution provided more people with paid jobs and more money to spend on food and shelter. Housing got better. We got vaccination programmes and managed to limit the number of children dying. Deaths from violence also dropped dramatically as societies became better at organizing social order and protection."

"The importance of medical intervention has been generally overrated when it comes to past increases in longevity. To say that the invention of antibiotics is the reason we've expand­ed our life spans dramatically is false. Of course I am not blind to the enormous impact medical care and treatment can have had. There's no doubt that the decrease in cardiac deaths has significantly contributed to our increased longevity, but there's no consensus on the contribution of specific factors. Nonetheless, the development of human lifespan is an unprecedented story of success on a societal level, and we need to stop being pessimistic about people becoming older. We will live longer and better than ever, and we should each make it our mission to make the most of it."

Tuesday, June 16, 2015

The small, four decades old cryonics industry provides long-term low temperature storage for the body and brain immediately following death. Vitrification rather than straight freezing preserves tissues. Provided that the fine structure of the brain is preserved, and evidence to date strongly suggests it is, then the self and memory is preserved along with it. At some point the necessary molecular nanotechnologies will exist to revive a cryopreserved individual, repair their tissue damage, and restore them to a new life. The odds of success are unknown in this endeavor, but infinitely better than all of the other options open to those who will age to death prior to the advent of working rejuvenation therapies. It should be a great mark of shame upon our culture today that cryonics remains a small industry, and that most people reject it out of hand. Billions vanish into the grave and oblivion over the decades, where in a better world they could have been saved.

Max More has heard all of the criticisms. More is the president and CEO of Alcor, the largest of the world's cryonics organizations, which counts 1,033 members - those who have committed, legally and financially, to freezing themselves - and 134 "patients" frozen in aluminum casks at its Scottsdale headquarters. As a 5-year-old, More sat awestruck in front of the TV watching the first moon landing, dreaming of different worlds. While pursuing his doctorate in philosophy at Oxford in the 1980s, he fell in with a group of futurists who believed that humanity's best days lie ahead, courtesy of technology. They introduced him to cryonics, and the idea appealed to him immediately. "It's not about the fear of death," he says, "but the enjoyment of life - and wanting more of it."

More comes across as a reasonable man who is acutely aware that most people think his ideas are insane, or repugnant, or both. Like most of the cryonicists I spoke to, he frames his points as appeals to logic, not emotion. His confidence is infectious. Eventually, he says, the emerging field of nanotechnology will allow us to fix pretty much everything that ails us. He adds that the freezing process itself has evolved from the early haphazard model into rigorous protocols aimed at doing as little damage to the patient as possible. "It really will come to seem crazy to do anything else," he says cheerily. "People will look back on these days and say, 'What was wrong with us? We used to stick people into the ground or shove them into ovens!'"

Then and now, cryonics tended to attract a certain type of seeker: numerically minded males, sci-fi fans, and those with a distinctly non-abstract view of the afterlife. Ralph Merkle, a Xerox PARC alumnus, inventor of computer encryption algorithms, and nanotechnology theorist, is representative of the tribe. Merkle, also a Berkeley alum, says there is no bright line between life and death; science has cured dozens of illnesses that meant certain death a century ago. He reasons that it's just a matter of time before death can be delayed indefinitely. "What we refer to as 'death' is just a set of symptoms that have proven resistant to treatment."

Most cryonicists are impatient with talk of the soul. They believe that the traits that make us unique reside in the brain, so the key is to preserve that organ with as much fidelity as possible. (This approach has led to "neuro" cryopreservations, in which just the brain is frozen in expectation of one day placing it on a cloned body. Half of Alcor members choose neuro, which costs significantly less.) "You are nothing more than the signals flitting through your brain," says Robin Hanson, an economics professor at George Mason University who was a UC Berkeley health policy fellow and researcher at NASA's Ames facility in Silicon Valley. "And if we can preserve that, we can save you."

Wednesday, June 17, 2015

A number of studies propose associations between the solar cycle and aging, or for specific age-related conditions. The mechanisms involved are not clear at all, but it is possible to theorize about levels of radiation damage during embryonic development, for example, or the influence of small variations in solar radiation on the operation of metabolism over the long term. Many forms of autoimmune disease are not age-related conditions, but they can be considered forms of damage, so it is interesting to see even speculative data suggesting a correlation with the solar cycle:

Data shows a "highly significant" correlation between periodic solar storms and incidences of rheumatoid arthritis (RA) and giant cell arteritis (GCA), two potentially debilitating autoimmune diseases. The findings by a rare collaboration of physicists and medical researchers suggest a relationship between the solar outbursts and the incidence of these diseases. RA and GCA are autoimmune conditions in which the body mistakenly attacks its own organs and tissues. RA inflames and swells joints and can cause crippling damage if left untreated. In GCA, the autoimmune disease results in inflammation of the wall of arteries, leading to headaches, jaw pain, vision problems and even blindness in severe cases.

Researchers initially spotted data showing that cases of RA and GCA followed close to 10-year cycles. "That got me curious. Only a few things in nature have a periodicity of about 10-11 years and the solar cycle is one of them." When physicists tracked the incidence of RA and GCA cases, the results suggested more than a coincidental connection. The research, which tracked correlations of the diseases with both geomagnetic activity and extreme ultraviolet (EUV) solar radiation, focused on cases recorded in Olmsted County, Minnesota, over more than five decades. The physicists compared the data with indices of EUV radiation for the years 1950 through 2007 and indices of geomagnetic activity from 1966 through 2007. Included were all 207 cases of GCA and all 1,179 cases of RA occurring in Olmsted County during the periods. Correlations proved to be strongest between the diseases and geomagnetic activity.

The findings were consistent with previous studies of the geographic distribution of RA cases in the United States. Such research found a greater incidence of the disease in sections of the country that are more likely to be affected by geomagnetic activity. Although the authors make no claim to a causal explanation for their findings, they identify five characteristics of the disease occurrence that are not obviously explained by any of the currently leading hypotheses. These include the east-west asymmetries of the RA and GCA outbreaks and the periodicities of the incidences in concert with the solar cycle. Among the possible causal pathways the authors consider are reduced production of the hormone melatonin, an anti-inflammatory mediator with immune-enhancing effects, and increased formation of free radicals in susceptible individuals.

Wednesday, June 17, 2015

A fair number of research groups are involved in investigations of the fine details of age-related hair loss. As in most research related to aging, scientists are for the most part much more interested in mapping the chain of change and consequence in cellular biochemistry than in seeking out first causes. The outcome here is that later attempts to build therapies based on new knowledge tend to involve prevention or alteration of downstream consequences of cellular and molecular damage rather than trying to repair or prevent that damage. All other things being equal, this is never going to be the best path forward. For one the consequences of a given form of damage will always be more numerous and more complex than the damage itself: much more effort is involved in chasing down all the loose ends. Secondly messing with the consequences of damage does nothing about the damage itself, which remains to continue causing harm.

During the active phase of the hair growth cycle, stem cell activity sustains an actively dividing population of epithelial cells at the base of the hair follicle called matrix cells. As progeny of the matrix cells move upward from the follicle base (or bulb), they differentiate into a hardened hair shaft, which emerges above the skin surface. Fully differentiated hair shafts consist of dead, but mechanically sound and highly cross-linked, keratin-filled cells. After a period of active hair shaft production, follicles activate an involution program, during which a large portion of epithelial cells die, and the remaining stem cells are reduced to a tight cluster underneath the skin surface. These follicles then remain dormant for some time; however, they can undergo activation and restart active hair shaft production.

The growth, regression, and resting phases together constitute the hair growth cycle, and this cycling can be influenced by a variety of local and systemic signaling factors. Consequently defects in hair cycling can arise from changes in the normal signaling milieu due to disease, aging, or injury. Commonly, in humans, scalp hair follicles enter resting phase prematurely, and hairs shafts become shorter and fall out, resulting in visible baldness. Therefore, identifying new signaling regulators of hair follicle regression will provide a better understanding of the hair loss pathogenesis mechanism and will likely identify novel therapeutic targets.

To test the function of miR-22, we generated a genetic tool to induce miR-22 overexpression in mouse hair follicles, and interestingly, found that increasing miR-22 results in hair loss in mice due to the premature regression of actively growing follicles. Surprisingly, our data reveal that the expression of over 50 distinct keratin genes are markedly reduced by miR-22 and that silencing of keratin-mediated hair shaft assembly by miR-22 is a prerequisite for follicle regression. In the future, our findings are likely to benefit human hair loss research efforts. Androgenic alopecia, where premature regression of scalp hair follicles is induced by increasing androgen levels, is the most common hair loss disorder in humans. Our unpublished data show that two binding sites for an androgen receptor are located in the promoter of both human and mouse miR-22. These findings support the hypothesis that miR-22 functions in the pathogenesis of Androgenic Alopecia, warranting future studies of miR-22 inhibitors as potential anti-hair loss drugs.

Thursday, June 18, 2015

Researchers have found a single gene intervention that improves heart function and extends life significantly, at least in flies. While looking at the results here, it is worth bearing in mind that a large extension of life in short-lived species via methods used to date, altering the operation of metabolism, does not seems to translate to a large extension of life in long-lived species. This is the case even when the actual mechanism is the same, works well, and seems to produce similar benefits in short term measures of health. Consider calorie restriction, for example. We certainly don't live 40% longer via that method, but mice do.

"More than 80 percent of protein groups found in flies, including vinculin network proteins, are similar to those found in rats and monkeys. We chose to focus on the proteins that naturally increase in expression in the aging hearts of flies, rats and monkeys. Since deletion or mutation of these proteins can lead to cardiomyopathy in patients, we wondered if their age-related upregulation was beneficial to the heart. Moreover, would overexpressing them improve heart function?"

Researchers found that the contractile function of the hearts of fruit flies is greatly improved in flies that overexpress the protein vinculin, which also accumulates at higher levels in the hearts of aging rats, monkeys and humans. In addition, flies genetically programmed to express elevated levels of vinculin lived significantly longer than normal fruit flies. The new study attributes the longer life of the flies to the improved contractile function of the heart due to the presence of more vinculin, which helps with the structure of the heart and connects heart muscle cells. In the study, 50 percent of vinculin-overexpressing flies lived past 11 weeks, to a maximum of 13 weeks. In contrast, 50 percent of control flies only made it to 4 weeks old and none lived past 8 weeks.

"With the average age being projected to increase dramatically in the coming decades, it is more important than ever that we understand and develop therapies for age-related heart failure. The results of this study implicate vinculin as a future candidate for therapy for people at risk of age-related heart failure." For example, if additional research supports these new findings, targeted gene or drug therapies related to vinculin and its network of proteins could be developed to strengthen the hearts of patients suffering from age-related heart failure.

Thursday, June 18, 2015

Mitochondria, the power plants of the cell, are implicated as a cause of degenerative aging. Each cell has a herd of mitochondria, dividing like bacteria (mitochondrial biogenesis) and removed by quality control mechanisms when damaged (mitophagy). In an increasing number of cells with advancing age, all mitochondria are damaged, however, fallen into a state that slips past quality control and quickly overtakes the mitochondrial population. This appears to be a fairly rapid transition for an individual cell, but otherwise a rare event. Still, this growing population of dysfunctional cells causes significant harm, such as by exporting reactive molecules that damage lipids and contribute to atherosclerosis.

There are numerous schools of thought on how best to fix this problem, even if very few researchers are actually working on it - the usual state of affairs for anything likely to prove effective in the treatment of aging, sad to say. Gene therapies to deliver replacements for damaged mitochondrial genes, or drug treatments to provide a regular delivery of the proteins those genes produce, for example. Some researchers consider it worth looking into enhanced quality control, or otherwise tinkering with mitochondrial dynamics, but this seems like a comparative poor approach, likely to just slow things down rather than reverse the damage.

Maintenance of mitochondrial function and energy homeostasis requires both generation of newly synthesized and elimination of dysfunctional mitochondria. Impaired mitochondrial function and excessive mitochondrial content are major characteristics of ageing and several human pathophysiological conditions, highlighting the pivotal role of the coordination between mitochondrial biogenesis and mitophagy. However, the cellular and molecular underpinnings of mitochondrial mass homeostasis remain obscure.

In our recent study, we demonstrate that DCT-1, the Caenorhabditis elegans homolog of mammalian BNIP3 and BNIP3L/NIX, is a key mediator of mitophagy promoting longevity under stress. DCT-1 acts downstream of the PINK-1-PDR-1/Parkin pathway and is ubiquitinated upon mitophagy-inducing conditions to mediate the removal of damaged mitochondria. Accumulation of damaged mitochondria triggers SKN-1 activation, which initiates a bipartite retrograde signaling pathway stimulating the coordinated induction of both mitochondrial biogenesis and mitophagy genes.

Taken together, our results unravel a homeostatic feedback loop that allows cells to adjust their mitochondrial population in response to environmental and intracellular cues. Age-dependent decline of mitophagy both inhibits removal of dysfunctional or superfluous mitochondria and impairs mitochondrial biogenesis resulting in progressive mitochondrial accretion and consequently, deterioration of cell function.

Friday, June 19, 2015

Researchers are digging into various ways in which stem cells signal other cells to change their behavior, as this this one of the means by which stem cell therapies produce benefits. Identifying the important signalsn would mean that at least some forms of stem cell transplant could be replaced with delivery of the signal molecules instead, probably an easier and cheaper approach to treatment:

The heart, for all its metronomic dependability, has little ability for self-repair. When heart muscle is damaged in a heart attack, the organ cannot replace the dead tissue and grow new. Instead, it must compensate for its lost pumping ability. That compensation comes with a high price: the heart grows large and flabby, and heart contraction weakens. From the start, heart damage seemed a problem custom-made for the burgeoning field of stem cell therapy. As knowledge about stem cells grew, several scientific teams conducted clinical trials on human heart attack victims, injecting damaged hearts with stem cells hoping the cells would take root and make new heart muscle. But results were disappointing.

A little more than a decade ago, researchers discovered that all cells secrete tiny communications modules jammed with an entire work crew of messages for other cells. Researchers renamed these vesicles exosomes. In the current study, researchers used a mouse model of myocardial infarction - heart attack. After infarct, mice received exosomes from either embryonic stem cells or exosomes from another type of cell called a fibroblast; mice receiving the fibroblast exosome served as the control group. The results were unmistakable. Mice that received exosomes from embryonic stem cells showed improved heart function after a heart attack compared to the control group. More heart muscle cells survived after infarct, and the heart exhibited less scar tissue. Fewer heart cells committed suicide - a process known as programmed cell death, or apoptosis. There was greater capillary development around the area of injury in the stem cell exosome group, which improved circulation and oxygen supply to the heart muscle. Further, there was a marked increase in cardiac progenitor cells - that is, the heart's own stem cells - and these survived and created new heart cells. The heartbeat was more powerful in the experimental group compared to the control group, and the kind of unhealthy enlargement that compensates for tissue damage was minimized.

The researchers then tested the effect of one of the most abundant gene-regulating molecules, or microRNAs, found in the stem cell exosome called miR-294. When miR-294 alone was introduced to cardiac stem cells in the laboratory, it mimicked many of the effects seen when the entire exosome was delivered. "To a large extent, this micro-RNA alone can recapitulate the activity of the exosome."

Friday, June 19, 2015

Like calorie restriction, the practice of intermittent fasting has been shown to improve measures of health in humans and extend healthy life spans in mice. One research group has in recent years been working on taking a specific implementation of intermittent fasting and running it through the expensive hurdles needed for FDA approval, for instance as an adjuvant therapy for cancer patients. Needless to say, this involves commercialization of a medical diet and industry participation, as otherwise where else will the funding come from for all this work? Arguably despite the long history of calorie restriction research there has been little effort to push approaches like this through the regulatory gauntlet because it requires some ingenuity to link "just eat less" with "some entity can charge lots of money for this." Here is an update on some of that work:

In a new study, researchers show that cycles of a four-day low-calorie diet that mimics fasting (FMD) cut visceral belly fat and elevated the number of progenitor and stem cells in several organs of old mice - including the brain, where it boosted neural regeneration and improved learning and memory. The mouse tests were part of a three-tiered study on periodic fasting's effects - testing yeast, mice and humans. Mice, which have relatively short life spans, provided details about fasting's lifelong effects. Yeast, which are simpler organisms, allowed researchers to uncover the biological mechanisms that fasting triggers at a cellular level. And a pilot study in humans found evidence that the mouse and yeast studies were, indeed, applicable to humans.

Bimonthly cycles that lasted four days of an FMD which started at middle age extended life span, reduced the incidence of cancer, boosted the immune system, reduced inflammatory diseases, slowed bone mineral density loss and improved the cognitive abilities of older mice tracked in the study. The total monthly calorie intake was the same for the FMD and control diet groups, indicating that the effects were not the result of an overall dietary restriction. In a pilot human trial, three cycles of a similar diet given to 19 subjects once a month for five days decreased risk factors and biomarkers for aging, diabetes, cardiovascular disease and cancer with no major adverse side effects.

The diet slashed the individual's caloric intake down to 34 to 54 percent of normal, with a specific composition of proteins, carbohydrates, fats and micronutrients. It decreased amounts of the hormone IGF-I, which is required during development to grow, but it is a promoter of aging and has been linked to cancer susceptibility. It also increased the amount of the hormone IGFBP, and reduced biomarkers/risk factors linked to diabetes and cardiovascular disease, including glucose, trunk fat and C-reactive protein without negatively affecting muscle and bone mass.


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