Fight Aging! Newsletter, September 9th 2013

September 9th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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  • Extending Life By Gaining More Subjective Time
  • Methuselah Foundation Announces New Grants and Partnerships
  • More Life Extension in Flies By Manipulating Intestinal Tissue Gene Expression
  • A Programmed Aging View on the Mitochondrial Free Radical Theory of Aging
  • Aubrey de Grey Comments on the Hallmarks of Aging Paper
  • Latest Headlines from Fight Aging!
    • It's Never Too Late To Stop Shortening Your Life
    • SENS Research Report: Lysosomal Aggregates
    • Longevitize!: Essays on the Science, Philosophy and Politics of Longevity
    • On Genetic Variants and Human Exceptional Longevity
    • BRASTO Mice With Additional Sirt1 in the Brain Live Longer
    • Improved Prospects for Measuring Mitochondrial DNA Damage
    • Blocking the Action of Alzheimer's in Mice
    • A Look at Some of the Details of Past Gains in Life Expectancy
    • Caring About Baldness
    • An Example of Dietary Supplements Doing Nothing


The present development of means to extend life focuses on obtaining more objective time: lengthening the number of years spent alive and in good health. This is absolutely the right way to go, to my eyes. The most effective path ahead seems to be that of developing new medical technology to address the root causes of degenerative aging. But what about the path not taken? What could be done to extend subjective time spent alive and in good health?

As a topic this has cropped up here and there in the Fight Aging! archives in connection with suppressing the need for sleep. We spend a little more than a third of our lives unconscious and oblivious, as opposed to being up, around, and getting things done. Bypassing the need for sleep would be roughly the same thing as a 33% extension of healthy life from the point of view of subjective time.

Can sleep be removed from the human condition? With sufficiently advanced technology, sure. But at this point in the relentless advance of the life sciences it seems premature to make any statement about the feasibility of permanently removing sleep as a physiological necessity. There are a number of groups interested in short term elimination of the need to sleep, such as various military institutions, but I'm not aware of any researchers interested in permanent sleep suppression, nor do I know whether it is even possible to talk about the plausibility of that goal given the current state of knowledge. A worst case scenario would require near complete reverse engineering of the human brain in order to safely make the required alterations. A more likely scenario would involve gathering a better understanding of sleep physiology over the next 20-30 years and a resulting development of sleep-reducing drugs.

One thought with regard to sleep and subjective time is that eliminating sugars from your diet tends to result in the need for less sleep. If you, equipped with a better diet, an alarm clock, and sufficient willpower to skip your beauty sleep, find that you can get by just fine with an hour less of sleep each night, then you have extended your remaining subjective life span by 6% or so. For the record, that's in the same ballpark of additional time spent conscious as moderate regular exercise or calorie restriction are thought or expected to provide in humans - though of course without the health benefits created by either of those line items.

A 6% swing in life span is a drop in the ocean, of course. That we can do so little reliably is why we need better medical technologies.

Other means to gain more subjective time are probably just as far from implementation as the complete removal of the need to sleep, as they require a near-complete reverse-engineering and recreation of the human brain - but at least a great many more researchers are working on the foundations in this case. Once the human brain is fully reverse-engineered, it will be possible to run minds in machinery or software. Setting aside all of the caveats with regard to this (and there are a lot of them), this brings with it the possibility of running a mind much faster than real time: it's all just a matter of the level of processing power baked into the hardware or dedicated to run the emulation software. If you want more subjective time, just run faster.

Another option, one that also only becomes available with the capacity for substantial modification of the human brain and the physical structures that support it, is for multiple instances of consciousness to operate concurrently and with full real-time awareness of one another, all working within the same mind. So you are fully aware and in full conscious control of, say, (a) reading a book at the same time as (b) working at your job at the same time as (c) talking to a friend, and so on. This seems no less plausible than running one mind rapidly, given the necessary knowledge to recreate a human mind in machinery or software in the first place.

This is all a fair way in the future of course, and thus largely irrelevant to whether or not people in middle age today will have the opportunity to live far longer in good health. The first hurdle to a longer life is these failing bodies of ours - and so the first order of business should be building better medical technologies that can fix those failings.


Some news from the Methuselah Foundation arrived in my in-box today. The Foundation started a decade ago with the Methuselah Mouse Prize, or Mprize, a research prize for longevity science, and conducted the SENS rejuvenation research program before that initiative grew to need its own organization, the SENS Research Foundation. In the past few years Methuselah Foundation staff and volunteers have focused more on the tissue engineering side of longevity science: the Foundation is among the early investors in bioprinting company Organovo and runs the New Organ Prize, aiming to build a large enough crowdfunded research prize and community to speed the advent of complete functional replacement organs built from a patient's own cells.

Here's the latest update:

Here at Methuselah, we've been keeping busy over the last few months, and we have a lot of good news to share.

First, there's the official launch of our new partnership with Organovo to seed several of their 3D bioprinters into select university and medical research labs. We've also recently awarded two new grants to fund DNA sequencing research, both of which promise to advance the science of longevity. And last but not least, in order to finalize rules and structures for the launch of the New Organ Prize this winter, we've started working closely with the Institute of Competition Sciences, an organization focused around competition-based innovation that has previously worked with XPRIZE and NASA.

A New Partnership with Organovo

Organovo, a breakthrough biotech company that Methuselah has backed since its inception, continues to grow quickly. It was recently uplisted to the New York Stock Exchange (ONVO), and we're so optimistic about the potential impacts of its 3D tissue printing technology on cutting-edge biomedical research, we initiated a new partnership to help get more Organovo printers into prominent labs.

Under this program, Methuselah will donate at least $500,000 in direct funding for bioprinter research projects, to be divided among several institutions. This funding will cover budgeted bioprinter costs, as well as other aspects of project execution. Organovo will participate in selecting the best candidate institutions from all those that apply, and funding will commence as soon as selection is complete.

According to Organovo CEO Keith Murphy, "Organovo's technology has broad potential application in the life sciences. The opportunity to allow those working towards significant breakthroughs in organ bioprinting to use the NovoGen MMX bioprinter is exciting, and we're happy to be able to establish this joint effort with Methuselah Foundation to enable greater access to Organovo's powerful platform."

One expected outcome from the program is a greater set of preliminary results to justify the granting of additional government research grants in the 3D bioprinting space. Together, Methuselah and Organovo are confident that this can become a springboard for much broader productive use of bioprinting in regenerative medicine.

Two Grants for Promising Genetic Research

Given the declining costs of DNA sequencing, all kinds of research that used to be prohibitively expensive even a few years ago is now becoming possible, and we've been considering how best to take advantage of this. For example, we just awarded a $10,000 research grant to Dr. Joao Pedro de Magelhaes at the University of Liverpool to sequence the genome of the bowhead whale in order to study mechanisms for longevity in this warm-blooded mammal whose lifespan is estimated at over 200 years.

Not only are bowhead whales far longer-lived than humans, but their massive size means that they are likely to possess unique tumor suppression mechanisms. "These mechanisms for the longevity and resistance to aging-related diseases of bowhead whales are unknown," says Dr. de Magelhaes, "but it is clear that in order to live so long, these animals must possess aging prevention mechanisms related to cancer, immunosenescence, neurodegenerative diseases, and cardiovascular and metabolic diseases."

The bowhead whale study will be conducted at the state-of-the-art Liverpool Centre for Genomic Research, and results will be made available to the research community.

In July, Methuselah also awarded $5,000 to Dr. L. Stephen Coles, co-founder and Executive Director of the Gerontology Research Group and a prominent researcher on supercentenarians (people aged at least 110). This grant, in support of Dr. Coles's own pancreatic cancer treatment, will also provide for an accompanying study of new methods of personalized gene sequencing and pre-testing of potential chemotherapy courses in immunodeficient mouse models. The research is being carried out under the auspices of Champions Oncology of Baltimore, MD, and promises to shed light on the efficacy of individual DNA sequencing in guaranteeing effective chemotherapy outcomes for cancer patients.

Developing the New Organ Prize

The Institute of Competition Sciences, an exciting young organization dedicated to organizing the knowledge base of the prize competition industry, is "building a community of leaders and providing the resources they need for impactful, competition-based innovation." We're proud to now be working closely with the ICS team, alongside our growing body of illustrious scientific advisors, in structuring a New Organ Prize that will powerfully accelerate the field of tissue engineering in order to help solve the global organ crisis.

We're currently seeking feedback on our draft prize rules from experts in the fields of regenerative medicine, stem-cell science, and tissue engineering, and we'd like to invite you to submit your input as well in order to help ensure that New Organ's prize criteria, judging process, and award structure are as effective and impactful as possible.

To participate in this public comment period for the New Organ Prize, which runs through September 19, 2013, just complete our online questionnaire. And make sure to stay tuned for more information over the next few months as prize rules are finalized and we build toward our public launch this winter!

And as always, thank you for your continued interest in - and generous support of - the Methuselah Foundation. We couldn't do it without you!


A number of methods of life extension in flies involve altering the expression of specific genes in intestinal tissues only. For example, upregulating PGC-1 in intestinal stem cell populations makes flies live up to 50% longer, possible due to altered mitochondrial activity. The behavior of mitochondria shows up in many genetic and other manipulations of life span in laboratory animals, and mitochondrial damage is thought to be one of the root causes of degenerative aging. In flies the aging of the intestine appears to be very important in the context of overall aging and mortality, and is possibly the driving central organ failure that determines when most individuals die.

In the open access paper quoted below, researchers move on from PGC-1 to instead insert the yeast gene NDI1 into fly intestines, which also shows a resulting extension of life. This was done to confirm that PGC-1 manipulation works to extend life through alteration of mitochondrial function: NDI1 has been used in investigations of mitochondrial function for some years. To pick one example, scientists have in the past introduced NDI1 into mammalian cells to investigate its ability to improve mitochondrial function. So it's not at all surprising to see similar results in flies:

Increased longevity mediated by yeast NDI1 expression in Drosophila intestinal stem and progenitor cells

A decline in mitochondrial activity has been implicated in multiple degenerative diseases of aging. These findings raise the intriguing possibility that strategies to stimulate mitochondrial activity during aging may delay the onset of pathology and extend healthspan. In support of this idea, we recently reported that overexpression of the fly PGC-1 homolog, dPGC-1, in ISC lineages is sufficient to preserve intestinal homeostasis during aging and extend fly lifespan. However, due to the extensive interactions that PGC-1 has with multiple aspects of metabolism, the possibility persists that endogenous dPGC-1 interactions, other than its role as a regulator of mitochondrial activity, play a role in the cellular and/or organismal phenotypes that we observed.

Unlike dPGC-1, ndi1 is exogenous, from a different kingdom, with no known homologs in animals, so any changes that result from ndi1 expression can reasonably be expected to be from the function of ndi1 as an NADH dehydrogenase. A previous study reported that ubiquitous expression of ndi1 using a constitutive driver line can increase fly lifespan. However, studies of the genetics of aging and lifespan determination are prone to confounding effects due to uncontrolled differences in genetic background between test and control lines. Using an inducible gene expresion system, which eliminates this issue, we failed to observe lifespan extension upon ubiquitous expression, but instead observed that neuron-specific expression of ndi1 can extend lifespan.

In the present study, we have extended this approach and show that expression of ndi1 in adult intestinal stem and progenitor cells can reduce whole tissue ROS levels, improve tissue homeostasis, delay the onset of intestinal barrier dysfunction, and extend the lifespan of flies. Therefore, a major conclusion of this study is that an increase in mitochondial NADH dehydrogenase activity alone in [intestinal stem cells] can delay both tissue and organismal aging, possibly by limiting pro-proliferative ROS levels in the intestinal epithelium.

Interestingly this manipulation is about as far as you can get from calorie restriction and growth-hormone related longevity manipulations that lead to smaller individuals: these longer-lived flies eat more and are larger that their unmodified peers.

Long-lived flies expressing ndi1 in [intestinal stem cells] have behavioral, physiological, and biochemical correlates of increased nutrition, showing increased feeding, weight, metabolic stores, and decreased systemic activation of AMPK. Importantly, ndi1-mediated weight gain can be observed upon adult-onset expression in [intestinal stem cells]. Moreover, both increased sensitivity to elevated temperatures, and resistance to starvation of the long-lived flies are wholly consistent with larger flies (with lower surface-to-mass ratios) and improved nutrient absorption and storage. Further studies using radioactive tracers of specific nutrients may provide clues as to whether increased total caloric uptake or differential absorption of specific nutrients play a role in the increased longevity of ndi1 expressing flies. Regardless of whether total caloric intake or absorbed nutrient composition plays a bigger role, one indication that improved nutrition plays a role in increasing lifespan is the ability of flies expressing ndi1 in [intestinal stem cells] to retain body weight and metabolic stores with age.


The data that will eventually make up a complete understanding of how aging progresses in an entire organism - with full descriptions of the relevant processes running all the way down to cells, sub-cellular components such as mitochondria, and interactions between proteins - is still very early in the game of assembly. It's a vast jigsaw puzzle in which researchers have assembled some of the more interesting areas, and have a good idea of the overall shape of things, but lots of pieces have yet to be fitted and large gaps remain. One of the consequences of this state of affairs is that researchers with quite different and even mutually exclusive theories on how aging progresses can all marshal a decent argument and use the known assembled areas to support their view.

The most important difference between different theories of aging is, I think, that between programmed aging and aging as stochastic damage. Programmed aging suggests that aging is an evolved genetic program that enacts epigenetic changes that in turn cause harm, perhaps because evolution optimizes for early life success, and the resulting programs run awry in older age, after the point at which there is little to no selection pressure to correct the crumbling of old flesh. The view of aging as stochastic damage is the exact opposite: damage to cells and protein machinery accumulates as a side-effect of ordinary metabolic operation, and the characteristic epigenetic changes observed with age are evolved compensatory mechanisms that try - and ultimately fail - to adapt to growing levels of damage. Evolutionary pressures that lead to good damage resistance, compensatory, and repair mechanisms are strongest for young individuals and weakest for old individuals. Hence the result is aging, which is just wear and tear in an evolved self-repairing system, wherein evolution (to a first approximation) only cares about the young.

So we have programmed aging, in which epigenetic change causes damage, and then aging as stochastic damage, in which damage causes epigenetic change. This is an important division because theory drives research strategy: in the programmed aging world there can be no rejuvenation without rebuilding or resetting human metabolism, and periodic repair of damage is doomed to ultimate futility. In the aging as stochastic damage world, periodic repair of damage will produce rejuvenation of the old and is the best of all therapies, while attempts to rebuild human metabolism are futile, expensive, and doomed to produce little benefit. Based on my years of reading around the field, I think that the balance of evidence strongly points to our living in stochastic damage world, which is why I support SENS research - but people who think otherwise are going to advocate for research strategies such as manipulation of mTOR levels in adult tissues that I see as largely useless in terms of practical results on human life span.

Mitochondria are the power plants of the cell, and their role in aging currently spans a handful of semi-assembled sections of the jigsaw puzzle. There is enough empty space left in this area of the puzzle for various groups to field their own quite different interpretations on how exactly it is that mitochondria contribute to aging. The view I'm in favor of is essentially the mitochondrial free radical theory of aging - the DNA inside mitochondria becomes damaged, some damaged forms take over some cells because they are not destroyed as readily by quality control mechanisms, and then the cells malfunction to export lots of damaging oxidative compounds. This is very much a viewpoint of the aging as stochastic damage camp, but another good reason to favor it is that it is only a few years of decent funding away from being testable in mice, through one of the nascent methods of repairing or replacing mitochondria.

Here is a different take on the mitochondrial free radical theory of aging, however, one from the programmed aging camp, set out as an explanation for the layperson:

New Take on Free Radicals

In Barja's version [of the mitochondrial free radical theory], the leakage of free radicals [from mitochondria] is not unavoidable; rather toxic by-products are borrowed (co-opted) for a purposeful self-destruction. Thus he turns the weakness of MFRTA into a strength, noting that the rate of leakage is dramatically variable from one animal species to another, and in different tissues at different times. This must be purposeful, and the purpose (aging→ death) is modulated according to environmental cues.

Part of the problem with the MFRTA theory is that the damage is centered on the mitochondria, which are dynamic, "disposable" organelles within the cell. Barja wondered how might it come about that mitochondria inflict permanent damage on the cell? Three years ago he found a clue. Mitochondria retain a bit of their own DNA, a relic from their historic origins as independent bacteria. Mitochondrial DNA (abbreviated mtDNA) is exposed to the [free radical] products of oxidative chemistry at close range, and is easily damaged. Sometimes the mtDNA is broken by the [free radicals that the mitochondria produce].

What Barja found (in collaboration with labs of Juan Sastre and Maria Jesus Pertas) is that mtDNA fragments are released into the cell and even into the bloodstream. Some of these fragments find their way into the cell nucleus, and they can insert themselves into the nuclear DNA, where they might do great damage. There are many redundant copies of mtDNA, but only two copies of the nuclear DNA. Barja was able to detect sequences associated with mtDNA in samples of the nuclear DNA taken from tissues of young and old rats. There was consistently more mtDNA in the old rats than the young, and up to four times as much in some samples. This suggests that [damage] occurring at the site of the mitochondria can transfer itself to the cell nucleus, and there it can persist and accumulate with age.

Though you should really read the open access paper for a better outline of this researcher's objections to the mitochondrial free radical theory of aging. It's much more of a casual read than the abstract might suggest:

Updating the Mitochondrial Free Radical Theory of Aging: An Integrated View, Key Aspects, and Confounding Concepts

An updated version of the mitochondrial free radical theory of aging (MFRTA) and longevity is reviewed. Key aspects of the theory are emphasized. Another main focus concerns common misconceptions that can mislead investigators from other specialties, even to wrongly discard the theory. Those different issues include (i) the main reactive oxygen species (ROS)-generating site in the respiratory chain in relation to aging and longevity: complex I; (ii) the close vicinity or even contact between that site and the mitochondrial DNA, in relation to the lack of local efficacy of antioxidants and to sub-cellular compartmentation; (iii) the relationship between mitochondrial ROS production and oxygen consumption; (iv) recent criticisms on the MFRTA; (v) the widespread assumption that ROS are simple "by-products" of the mitochondrial respiratory chain; (vi) the unnecessary postulation of "vicious cycle" hypotheses of mitochondrial ROS generation which are not central to the free radical theory of aging; and (vii) the role of DNA repair concerning endogenous versus exogenous damage. After considering the large body of data already available, two general characteristics responsible for the high maintenance degree of long-lived animals emerge: (i) a low generation rate of endogenous damage: and (ii) the possession of tissue macromolecules that are highly resistant to oxidative modification.

It is an interesting assembly of data, and as usual with publications one might disagree with at the high level there's plenty in there to agree with on other levels. I'm somewhat skeptical of the relevance of some of the points, however. For example, that antioxidant supplementation doesn't really do much to the pace of aging. That is a valid and good objection to the early and general free radical or oxidative theories of aging, but it is absolutely the case that suitably designed antioxidant compounds targeted to mitochondria improve health and extend life. What the general failure of all other antioxidant strategies tells us is that the biology here is complex: it matters exactly where those antioxidants go, and what chemical form they have. Near all forms of antioxidant won't find their way to the mitochondria where they might do some good, and will in fact tend to interfere in the role of oxidative compounds in hormetic processes, such as those involved in producing the health benefits of exercise.


The Hallmarks of Aging paper was published earlier this year. It is an outline by a group of noted researchers that divides up degenerative aging into what they believe are its fundamental causes, with extensive references to support their conclusions, and proposes research strategies aimed at building the means to address each of these causes. This is exactly what we want to see more of in the aging research community: deliberate, useful plans that follow the Strategies for Engineered Negligible Senescence (SENS) model of approaching aging.

Read through the Hallmarks of Aging and you'll see that it is essentially a more mild-mannered and conservative restatement of the SENS approach to aging - written after more than ten years of advocacy and publication and persuasion within the scientific community by SENS supporters. To my eyes, the appearance of such things shows that SENS is winning the battle of ideas within the scientific community, and it is only a matter of time before it and similar repair-based efforts aimed at human rejuvenation dominate the field. Rightly so, too, and it can't happen soon enough for my liking. SENS and SENS-like research is the only way we're likely to see meaningful life extension technologies emerge before those of us in middle age now die, so the more of it taking place the better.

Aubrey de Grey, author of the original SENS proposals and now Chief Science Officer of the SENS Research Foundation that funds and guides rejuvenation research programs, is justifiably pleased by the existence of the Hallmarks of Aging. See this editorial in the latest Rejuvenation Research, for example:

A Divide-and-Conquer Assault on Aging: Mainstream at Last

On June 6th, a review appeared concerning the state of aging research and the promising ways forward for the field. So far, so good. But this was not any old review. Here's why: (a) it appeared in Cell, one of the most influential journals in biology; (b) it is huge by Cell's standards - 24 pages, with well over 300 references; (c) all its five authors are exceptionally powerful opinion-formers - senior, hugely accomplished and respected scientists; (d) above all, it presents a dissection of aging into distinct (though inter-connected) processes and recommends a correspondingly multi-pronged ("divide and conquer") approach to intervention.

It will not escape those familiar with SENS that this last feature is not precisely original, and it may arouse some consternation that no reference is made in the paper to that prior work. But do I care? Well, maybe a little - but really, hardly at all. SENS is not about me, nor even about SENS as currently formulated (though a depressing number of commentators in the field persist in presuming that it is). Rather, it is about challenging a profound, entrenched, and insidious dogma that has consumed biogerontology for the past 20 years, and which this new review finally - finally! - challenges (albeit somewhat diplomatically) with far more authority than I could ever muster.


Aging has been shown, over several decades, to consist of a multiplicity of loosely linked processes, implying that robust postponement of age-related ill-health requires a divide-and-conquer approach consisting of a panel of interventions. Because such an approach is really difficult to implement, gerontologists initially adopted a position of such extreme pessimism that all talk of intervention became unfashionable. The discovery of genetic and pharmacological ways to mimic [calorie restriction], after a brief period of confused disbelief, was so seductive as a way to raise the field's profile that it was uncritically embraced as the fulcrum of translational gerontology for 20 years, but finally that particular emperor has been decisively shown to have no biomedically relevant clothes.

The publication of so authoritative a commentary adopting the "paleogerontological" position, that aging is indeed chaotic and complex and intervention will indeed require a panel of therapies, but now combined with evidence-based optimism as to the prospects for implementing such a panel, is a key step in the elevation of translational gerontology to a truly mature field.

In essence, as de Grey points out, work on aging has been following the wrong, slow, expensive, low-yield path for a couple of decades: the path of deciphering the mechanisms of calorie restriction and altering genes and metabolism to slightly slow down aging. This path cannot result in large gains in life expectancy and long-term health, and it cannot result in therapies that will greatly help people who are already old. What use is slowing down the accumulation of the damage of aging if you are already just a little more damage removed from death, and frail and suffering because of it, and the treatment will meaningfully alter none of that? If we want to add decades or more to our healthy life spans before we die, then rejuvenation and repair of damage are what is needed: ways to reverse frailty, remove suffering, and restore youthful function.


Monday, September 2, 2013

A lot of self-harm takes place when it comes to individual life expectancy. Smoking, eating too many calories, and being sedentary top the list in wealthier populations these days. Ignorance is also very important at the present time because of the prospects for the development of rejuvenation biotechnology: if you don't know that reversal of aging might be accomplished in future decades, then you can't make a choice to support that progress. Yet new therapies to impact aging will have a much larger effect on life span than any lifestyle choice. If they arrive in time, that is, which requires widespread public support and far greater funding than presently exists.

But people, as a general rule, don't tend to put a great deal of value on the distant years of their own personal future. We know this because there are so many who smoke, get fat, and don't exercise, and who choose to remain fairly ignorant of the workings of their own body vis a vis long-term maintenance.

Despite recent declines in the numbers of people smoking and tar yields of cigarettes, smoking remains the leading preventable cause of death in Europe. Previous studies had demonstrated that prolonged cigarette smoking from early adult life was associated with about 10 years loss of life expectancy, with about one quarter of smokers killed by their habit before the age of 70. Stopping at ages 60, 50, 40 or 30 years gained back about 3, 6, 9 or the full 10 years. However, the hazards of continuing to smoke and the benefits of stopping in older people had not been widely studied.

In the current study, scientists tracked the health of 7,000 older men (mean age 77 years, range 66 to 97) from 1997 to 2012 who took part in the Whitehall study of London civil servants. Hazard ratios (HRs) for overall mortality and various causes of death in relation to smoking habits were calculated after adjustment for age, last known employment grade and previous diagnoses of vascular disease or cancer. During the 15-year study 5,000 of the 7,000 men died. Deaths in current smokers were about 50% higher than in never smokers, due chiefly to vascular disease, cancer and respiratory disease. Deaths in former smokers were 15% higher than in never smokers, due chiefly to cancer and respiratory disease.

Smokers who survive to 70 still lose an average of 4 years of life. Average life expectancy from age 70 was about 18 years in men who had never regularly smoked, 16 years for men who gave up smoking before age 70 but only about 14 years in men still smoking at age 70. Two-thirds of never smokers (65%), but only half of current smokers (48%), survived from age 70 to age 85.

Monday, September 2, 2013

The SENS Research Foundation works on a new paradigm for medicine and aging: the goal is to repair the known underlying causes of degenerative aging so as to prevent and reverse its effects, creating actual rejuvenation in patients, and ultimately removing age-related disease and frailty from the world.

At present new biotechnologies needed for rejuvenation therapies are in the early stages of development. One line of this research involves removing accumulated metabolic waste products from the lysosome. Lysosomes are the recycling units of the cell, breaking down unwanted proteins and broken cellular machinery so that the parts can be reused. But they fail with age, largely because they become bloated with hardy waste products that they are incapable of breaking down. This leads to reduced cell maintenance, more damaged cells, and the consequent progressive failure of the biological systems and organs that those cells belong to.

All of this sizable contribution to degenerative aging could be prevented via the periodic application of suitable medical technologies, which is to say a means to break down and remove the compounds that the lysosome struggles with:

Cells are equipped with specialized "incinerators" called lysosomes, where they send damaged or unwanted material for destruction. Some cellular wastes, however, are so chemically snarled that even the lysosome is unable to shred them. With no way to eliminate these compounds, the cellular garbage simply builds up over time, progressively interfering with cell function. The disabling of specific cell types by their characteristic waste products drives numerous age-related pathologies. For instance, age-related macular degeneration (AMD) - the primary cause of blindness in persons over the age of 65 - is believed to be primarily caused by the progressive disabling of retinal pigment epithelial (RPE) cells in the eye, resulting from their accumulation of A2E, a kind of waste specific to RPE cells. Currently, there is no effective treatment for this form of AMD .

At the SENS Research Foundation Research Center (SRF-RC), our Lysosomal Aggregates team is working to efficiently deliver novel enzymes into the lysosome to degrade A2E . Extensive protocols have been developed which employ RPE cells derived from humans to be used as cell lines for the study of AMD. In our prior research, we identified many enzymes (e.g., manganese peroxidase) capable of degrading A2E in vitro, but were unable to efficiently deliver most of them to the lysosome. We are now working to develop ways to efficiently deliver the most promising identified enzymes into the lysosome of cells. One in particular (which we are calling SENS20) has demonstrated efficacy in degrading A2E not only in vitro but in A2E-loaded RPE cells.

In 2013, the SRF-RC team is in the process of putting SENS20 to the test, assessing its ability to degrade A2E in vitro and in RPE cells. We are also performing a variety of tests to assure ourselves that the enzyme and its activity are not toxic to the cell . The studies will build toward eventual testing of candidate enzymes in animals that develop A2E-driven blindness and - if successful - eventually towards human clinical trials. We are advancing toward preventing or curing macular degeneration with the first- of-class regenerative therapy for this debilitating disease.

Tuesday, September 3, 2013

A new e-book of collected essays from the longevity science advocacy community is available, an effort organized by the folk at the Center for Transhumanity:

Containing more than 160 essays from over 40 contributors, this edited volume of essays on the science, philosophy and politics of longevity considers the project of ending aging and abolishing involuntary death-by-disease from a variety of viewpoints: scientific, technological, philosophical, pragmatic, artistic. In it you will find not only information on the ways in which science and medicine are bringing about the potential to reverse aging and defeat death within many of our own lifetimes, as well as the ways that you can increase your own longevity today in order to be there for tomorrow's promise, but also a glimpse at the art, philosophy and politics of longevity as well - areas that will become increasingly important as we realize that advocacy, lobbying and activism can play as large a part in the hastening of progress in indefinite lifespans as science and technology.

The collection is edited by Franco Cortese. Its contributing authors include William H. Andrews, Ph.D., Rachel Armstrong, Ph.D., Jonathan Betchtel, Yaniv Chen, Clyde DeSouza, Freija van Diujne, Ph.D., John Ellis, Ph.D., Linda Gamble, Roen Horn, the International Longevity Alliance (ILA), Zoltan Istvan, David Kekich (President & C.E.O of Maximum Life Foundation), Randal A. Koene, Ph.D., Maria Konovalenko, M.Sc. (Program Coordinator for the Science for Life Extension Foundation), Marios Kyriazis, MD, M.Sc MIBiol, CBiol (Founder of the ELPIs Foundation for Indefinite Lifespans and the medical advisor for the British Longevity Society), John R. Leonard (Director of Japan Longevity Alliance), Alex Lightman, Movement for Indefinite Life Extension (MILE), Josh Mitteldorf, Ph.D., Tom Mooney (Executive Director of the Coalition to Extend Life), Max More, Ph.D. , B.J. Murphy, Joern Pallensen, Dick Pelletier, Hank Pellissier (Founder of Brighter Brains Institute), Giulio Prisco, Marc Ransford, Jameson Rohrer, Martine Rothblatt, Ph.D., MBA, JD., Peter Rothman (editor-in-chief of H+ Magazine), Giovanni Santostasi, Ph.D (Director of Immortal Life Magazine), Eric Schulke, Jason Silva , R.U. Sirius, Ilia Stambler, Ph.D (activist at the International Longevity Alliance), G. Stolyarov II (editor-in-chief of The Rational Argumentator), Winslow Strong, Jason Sussberg, Violetta Karkucinska, David Westmorland, Peter Wicks, Ph.D, and Jason Xu (director of Longevity Party China and Longevity Party Taiwan).

Tuesday, September 3, 2013

It is generally thought that genetic influences on natural variations in human longevity are less important than environmental factors and lifestyle choices: 25% genes versus 75% everything else are the ballpark figures often mentioned. However it is also generally thought that the importance of genetic variations increases greatly in older age: people are more likely to reach the age of 100 if they bear certain gene variants. Though it should be noted that "more likely" here is still a very low chance overall. At the present time regardless of genes most people die before reaching 90, let alone 100. This is why we need the research community to focus on better medical technology for treating and reversing degenerative aging for everyone, rather than conduct a great deal of introspection on the nature of the few percent who make it to exceptional old age.

Here is an open access paper that provides some insight into current work on the genetics of exceptional human longevity - really a matter of interest and knowledge rather than something that will lead to any sort of meaningful advance in medicine. I think that the authors are optimistic in their view that anything other than very marginal treatments can result from identifying characteristic genetic differences in centenarians. It's still the case that the vast majority of people with those differences die without living that long: the improvement in mortality rate in old age due to these longevity-associated genetic variants is not large.

Despite evidence from family studies that there is a strong genetic influence upon exceptional longevity, relatively few genetic variants have been associated with this trait. One reason could be that many genes individually have such weak effects that they cannot meet standard thresholds of genome wide significance, but as a group in specific combinations of genetic variations, they can have a strong influence. Previously we reported that such genetic signatures of 281 genetic markers associated with about 130 genes can do a relatively good job of differentiating centenarians from non-centenarians particularly if the centenarians are 106 years and older. This would support our hypothesis that the genetic influence upon exceptional longevity increases with older and older (and rarer) ages.

We investigated this list of markers using similar genetic data from 5 studies of centenarians from the USA, Europe and Japan. The results from the meta-analysis show that many of these variants are associated with survival to these extreme ages in other studies. Since many centenarians compress morbidity and disability towards the end of their lives, these results could point to biological pathways and therefore new therapeutics to increase years of healthy lives in the general population.

Wednesday, September 4, 2013

BRASTO mice have raised levels of SIRT1 in the brain. Researchers are finding that altering levels of this sirtuin in brain tissues seems to have more of an impact than other manipulations, which to date haven't shown reliable extension of healthy life. At this point any result like the one below will have to be replicated before it can be taken seriously, however, given the contradictory data for sirtuins and life extension from the past decade.

Among scientists, the role of proteins called sirtuins in enhancing longevity has been hotly debated, driven by contradictory results from many different scientists. [Researchers have now] identified the mechanism by which a specific sirtuin protein called Sirt1 operates in the brain to bring about a significant delay in aging and an increase in longevity. Both have been associated with a low-calorie diet.

Sirt1 prompts neural activity in specific areas of the hypothalamus of the brain, which triggers dramatic physical changes in skeletal muscle and increases in vigor and longevity. "In our studies of mice that express Sirt1 in the brain, we found that the skeletal muscular structures of old mice resemble young muscle tissue. Twenty-month-old mice (the equivalent of 70-year-old humans) look as active as five-month-olds."

[The] team studied mice that had been genetically modified to overproduce Sirt1 protein. Some of the mice had been engineered to overproduce Sirt1 in body tissues, while others were engineered to produce more of the Sirt1 protein only in the brain. "We found that only the mice that overexpressed Sirt1 in the brain (called BRASTO) had significant lifespan extension and delay in aging, just like normal mice reared under dietary restriction regimens." The median life span of BRASTO mice in the study was extended by 16 percent for females and 9 percent for males. Delay in cancer-dependent death also was observed in the BRASTO mice relative to control mice.

It is unclear from the publicity materials whether this might be a result of inadvertent calorie restriction due to mice choosing to eat less under ad libitum conditions - it isn't enough just to let them eat what they want, you also have to measure the amount that they actually eat.

Wednesday, September 4, 2013

Higher levels of mitochondrial DNA (mtDNA) damage is one of the characteristic differences between old tissue and young tissue. It is thought to be a major contribution to degenerative aging, via a complex process that causes a small but significant fraction of cells to become overtaken by damaged mitochondria, malfunction, and export large quantities of damaging oxidative waste compounds into the surrounding tissue.

There are still a fair number of scientists who argue against the mitochondrial free radical theory of aging, however. Given the present state of research, my impression has been that the fastest way to prove beyond all doubt that mitochondrial DNA damage is a root cause of aging is to finish up one of the means to repair or replace mitochondria or mitochondrial DNA, and then try it out in mice. Given optimal funding that is only a couple of years distant, as the work is fairly advanced - but that optimal funding doesn't exist yet. Mitochondrial repair isn't a well-funded line of research, more is the pity, and as is the case for most of the best and most promising ways to intervene in the aging process.

Here, however, is a new technology that might have the potential to validate mitochondrial DNA damage as a direct cause of aging, or at least provide much better hard evidence than presently exists:

The accumulation of mtDNA mutations is associated with aging, neuromuscular disorders, and cancer. However, methods to probe the underlying mechanisms behind this mutagenesis have been limited by their inability to accurately quantify and characterize new deletion events, which may occur at a frequency as low as one deletion event per 100 million mitochondrial genomes in normal tissue. To address these limitations, [researchers] developed a ddPCR-based assay known as "Digital Deletion Detection" (3D) that allows for the high-resolution analysis of these rare deletions.

"It is incredibly difficult to study mtDNA mutations, let alone deletions, within the genome. Our 3D assay shows significant improvement in specificity, sensitivity, and accuracy over conventional methods such as those that rely on real-time PCR. The increase in throughput afforded by droplet digital PCR shortened the analysis of deletion events to days compared to months using previous digital PCR methods. Without the technology, we could not have made this discovery."

[The researchers] analyzed eight billion human brain mtDNA genomes and identified more than 100,000 genomes with a deletion. They discovered that, contrary to popular belief, the majority of the increase in mtDNA deletions was not caused by new deletions but rather by the expansion of previous deletions. They hypothesized that the expansion of pre-existing mutations should be considered as the primary factor contributing to age-related accumulation of mtDNA deletions.

Thursday, September 5, 2013

The best cure for Alzheimer's disease would be to revert all of the changes in brain tissue characteristic of the disease. This is in general the best approach to age-related degeneration overall. A lot of research falls outside this paradigm, however, looking for ways to work around these changes, or block the mechanisms by which the changes cause specific forms of damage. This can produce good therapies, but is usually the worse approach as there are potentially very many ways in which the underlying changes can cause harm - striking at the root should always be more cost-effective.

Here is news of a potential path to block the main destructive action of Alzheimer's:

Researchers have discovered a protein that is the missing link in the complicated chain of events that lead to Alzheimer's disease. Researchers also found that blocking the protein with an existing drug can restore memory in mice with brain damage that mimics the disease. "What is very exciting is that of all the links in this molecular chain, this is the protein that may be most easily targeted by drugs. This gives us strong hope that we can find a drug that will work to lessen the burden of Alzheimer's."

Scientists have already provided a partial molecular map of how Alzheimer's disease destroys brain cells. In earlier work, [researchers] showed that the amyloid-beta peptides, which are a hallmark of Alzheimer's, couple with prion proteins on the surface of neurons. By an unknown process, the coupling activates a molecular messenger within the cell called Fyn. [This latest research] reveals the missing link in the chain, a protein within the cell membrane called metabotropic glutamate receptor 5 or mGluR5. When the protein is blocked by a drug similar to one being developed for Fragile X syndrome, the deficits in memory, learning, and synapse density were restored in a mouse model of Alzheimer's.

New drugs may have to be designed to precisely target the amyloid-prion disruption of mGluR5 in human cases of Alzheimer's and [the researchers are] exploring new ways to achieve this.

Thursday, September 5, 2013

Life expectancy at birth has doubled in the past two centuries. This is largely due to advances in reducing childhood mortality: public health measures, control of infectious disease, and so forth. Adult life expectancy has increased more slowly, and remaining life expectancy in old age more slowly still - these are driven by new and more effective treatments for age-related disease, producing an incidental extension of adult life. The research community is only just now starting on the project of deliberately trying to slow or reverse the causes of degenerative aging, rather than focusing entirely on ways to fix the worst and most visible consequences of aging after they occur. This is why projecting past trends in life span into the future is not likely to produce accurate results - the entire approach to human medicine is presently shifting.

This article goes into some detail on the historical roots of modern gains in life expectancy at birth, much of which were a matter of better organization and sanitation rather than medical technology per se:

The most important difference between the world today and 150 years ago isn't airplane flight or nuclear weapons or the Internet. It's lifespan. We used to live 35 or 40 years on average in the United States, but now we live almost 80. We used to get one life. Now we get two. When I first started looking into why average lifespan has increased so much so rapidly, I assumed there would be a few simple answers, a stepwise series of advances that each added a few years: clean water, sewage treatment, vaccines, various medical procedures. But it turns out the question of who or what gets credit for the doubling of life expectancy in the past few centuries is surprisingly contentious. The data are sparse before 1900, and there are rivalries between biomedicine and public health, obstetricians and midwives, people who say life expectancy will rise indefinitely and those who say it's starting to plateau.

There's nothing like looking back at the history of death and dying in the United States to dispel any romantic notions you may have that people used to live in harmony with the land or be more in touch with their bodies. Life was miserable - full of contagious disease, spoiled food, malnutrition, exposure, and injuries. But disease was the worst. The vast majority of deaths before the mid-20th century were caused by microbes -bacteria, amoebas, protozoans, or viruses that ruled the Earth and to a lesser extent still do.

How did we go from the miseries of the past to our current expectation of long and healthy lives? "Most people credit medical advances," says David Jones, a medical historian at Harvard - "but most historians would not." One problem is the timing. Most of the effective medical treatments we recognize as saving our lives today have been available only since World War II: antibiotics, chemotherapy, drugs to treat high blood pressure. But the steepest increase in life expectancy occurred from the late 1800s to the mid-1900s.

Friday, September 6, 2013

The superficial aspects of regenerative medicine and attempts to revert portions of the aging process attract far more attention than the meaningful aspects. People seem much more interested in evading baldness and making skin look good than in restoring youthful function to the inner organs whose failure will kill them. You can live with baldness, and not with a age-damaged heart, but you wouldn't know that if going just by the level of discussion devoted to these topics. This is far from the only area of life in which observed priorities fail to match up to the best course for personal self-interest, of course.

The ultimate victory, when it comes to the long-fought battle against baldness, would be to find a way to trick the body into creating brand-new hair follicles. Researchers first raised the possibility in the 1950s, when they observed new hair follicles forming during wound healing in rabbits and mice, but the work was later discredited. Then, in 2007, George Cotsarelis, a dermatologist at the University of Pennsylvania's Perelman School of Medicine, spotted hairs growing in the middle of small cuts they'd made in the skin of adult mice. "We figured out they were de novo hair follicles formed in a process that looked a lot like embryogenesis," says Cotsarelis.

It turns out that the wound-healing process causes skin cells to dedifferentiate, providing a limited time window during which those cells can be persuaded to form new hair follicles. Even more intriguingly, the researchers also found that inhibiting Wnt signaling during this window reduced follicle neogenesis, while overexpressing Wnt molecules in the skin increased the number of new follicles. In 2006, Cotsarelis, Zohar, Steinberg, Olle, and several other scientists cofounded a company called Follica to develop new combination therapies to induce follicle neogenesis. Although Follica has released few details on their proprietary procedure, the general idea is clear: their patented minimally invasive "skin perturbation" device removes the top layers of skin, causing the underlying skin cells to revert to a stem-like state, after which a molecule is applied topically to direct the formation of new hair follicles.

Indeed, Follica has already done preclinical and clinical trials, says Olle, "all of which confirm that we can consistently create new hair follicles in mice and in humans. As far as I know, no other approach has been able to achieve that." News of the progress has attracted strong interest from the public, with comments piling up below online articles about Follica and serving as de facto message boards for the science-savvy bald community to exchange expressions of hope and skepticism - and to speculate about when the "cure" might hit the market. Earlier this year, Cotsarelis's group sparked another comment frenzy by demonstrating that a protein called fibroblast growth factor 9 (Fgf9), which is secreted by gamma delta (γδ) T cells in the dermis, plays a key role in the formation of new follicles during wound healing in adult mice.

Friday, September 6, 2013

Dietary supplements of the sort sold in stores are largely useless, and those that do provide benefits have a far smaller effect than either exercise or calorie restriction. Past the point of maintaining something along the lines of the Reference Daily Intake, such as is provided by a multivitamin produce, the balance of evidence suggests that most of these supplements do little for long term health and longevity. In many cases modest extension of life observed in some animal studies (not not in others) can be explained away by inadvertent calorie restriction or other artifacts. In the case of antioxidant supplements the current consensus is that these in fact harm beneficial processes that depend upon the use of low levels of oxidants as signals.

Here is a study to show that a range of currently popular supplements do absolutely nothing to various measures of human metabolism:

Dietary supplements are widely used for health purposes. However, little is known about the metabolic and cardiovascular effects of combinations of popular over-the-counter supplements, each of which has been shown to have anti-oxidant, anti-inflammatory and pro-longevity properties in cell culture or animal studies. This study was a 6-month randomized, single-blind controlled trial, in which 56 non-obese men and women, aged 38 to 55 yr, were assigned to a dietary supplement (SUP) group or control (CON) group, with a 6-month follow-up.

The SUP group took 10 dietary supplements each day (100 mg of resveratrol, a complex of 800 mg each of green, black, and white tea extract, 250 mg of pomegranate extract, 650 mg of quercetin, 500 mg of acetyl-l-carnitine, 600 mg of lipoic acid, 900 mg of curcumin, 1 g of sesamin, 1.7 g of cinnamon bark extract, and 1.0 g fish oil). Both the SUP and CON groups took a daily multivitamin/mineral supplement.

The main outcome measures were arterial stiffness, endothelial function, biomarkers of inflammation and oxidative stress, and cardiometabolic risk factors. Twenty-four weeks of daily supplementation with 10 dietary supplements did not affect arterial stiffness or endothelial function in nonobese individuals. These compounds also did not alter body fat measured by DEXA, blood pressure, plasma lipids, glucose, insulin, IGF-1, and markers of inflammation and oxidative stress. In summary, supplementation with a combination of popular dietary supplements has no cardiovascular or metabolic effects in non-obese relatively healthy individuals.


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