Fight Aging! Newsletter, October 14th 2013

October 14th 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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  • Advocating the Longevity Dividend View
  • Looking Beyond Rapamycin at the Effects of Other Anti-Cancer Agents on Aging
  • Another Round of Speculation and Insider Rumor on Google's Calico Initiative
  • New Organ Prize Official Launch is December 4th at the World Stem Cell Summit
  • Persistent Viral Infections and Adaptive Immune System Aging
  • Latest Headlines from Fight Aging!
    • Creating Targeted Drug Factories From Stem Cells
    • Tissue Engineering of Secretory Gland Precursors
    • TAF-4 and HIF-1 Required for Life Extension Resulting From Several Different Mitochondrial Mutations
    • Population Logistics
    • More on Recent Advocacy for the Longevity Dividend
    • An Interesting Goal: Cryonics Without Repair
    • Towards the Use of Blood Vessel Cells to Repair and Regenerate Organs
    • Gene and Stem Cell Therapy That Might Reverse Some of the Loss of Healing Capacity in the Elderly
    • Exercise in Mice Extends Healthy But Not Average or Maximum Life Span
    • Dietary Studies Using Biomarkers Are a Better Proposition, But Still Require Care in Interpretation


The most conservative members of the aging research community don't believe that human life spans can be meaningfully extended any time soon, or that we should even make the attempt. Fortunately, they don't have much more to say on the matter, so don't contribute meaningfully to discussions on this topic within the scientific community. They are a part of the silent majority: researchers who only investigate aging, gathering data rather than attempting to do something about it.

Among scientists who do believe that lives can be lengthened, most - in public at least - adhere to the view that the only plausible goal is a gentle slowing of the pace of aging, and that even this is not going to happen any time soon. The proposed methodologies here generally involve ways to shift the operation of metabolism into more efficient states, such as that produced through the practice of calorie restriction, shown to extend healthy and maximum life spans in many different species. As the past few decades of research have demonstrated, this is an expensive and complex proposition. Despite billions of dollars in research funding, there is little to show yet beyond an increased understanding of the relationship between metabolism, genetics, and natural variations in longevity - and that present understanding is clearly just a starting point.

(Fortunately there is a much better way forward based on identifying and repairing the damage that causes aging. Such an approach doesn't require anywhere near as much new knowledge, and will lead to rejuvenation rather than just a slowing of aging. As yet this is a minority research program within longevity science, however, for all that it is the self-evidently better path forward. But that is not today's topic).

Among researchers who look with favor on work aimed at gently slowing aging, there is one group who have for some years promoted what they call the Longevity Dividend: a proposal for large-scale public funding to go towards methods of slowing aging. Their position is backed by models that show incrementally greater gains in health than can be achieved through the present modus operandi of trying to patch over age-related diseases in their late stages. At the highest level this is a matter of prevention versus cure: aging is the cause of age-related diseases, and thus efforts focused on treating aging should be far more efficient when it comes to raising quality of life and reducing the incidence and cost of frailty and disability in the old.

The Longevity Dividend camp has gathered supporters over the years, as open discussion of extending human life has become more acceptable within the scientific community, and this example of research and advocacy is their latest foray into the public funding arena:

The Pursuit Of Improved Physical And Mental Health

Medical advances, improved nutrition, and reductions in smoking have extended life expectancy and reduced the prevalence of diseases that stalk modern society. Paradoxically, though, for every success, an equally difficult challenge remains. As people age, they are less likely to suffer through a single disease but rather experience multiple maladies related to living longer. In this issue of Health Affairs we explore this paradox and many other subjects while conceding that humankind will never exhaust the quest for reducing mortality and relieving pain.

Are there other approaches to prolonging healthy living that could accompany these ongoing efforts? Dana Goldman, David Cutler, John Rowe, Pierre-Carl Michaud, Jeffrey Sullivan, Desi Peneva, and Jay Olshansky have developed a hypothetical alternative called "delayed aging." Their article reports that studies with animal models have shown real potential and concludes that greater investment in research on delaying aging appears to be an efficient way to forestall disease, extend healthy life, and improve public health.

Substantial Health And Economic Returns From Delayed Aging May Warrant A New Focus For Medical Research

Recent scientific advances suggest that slowing the aging process (senescence) is now a realistic goal. Yet most medical research remains focused on combating individual diseases. Using the Future Elderly Model - a microsimulation of the future health and spending of older Americans - we compared optimistic "disease specific" scenarios with a hypothetical "delayed aging" scenario in terms of the scenarios' impact on longevity, disability, and major entitlement program costs.

Delayed aging could increase life expectancy by an additional 2.2 years, most of which would be spent in good health. The economic value of delayed aging is estimated to be $7.1 trillion over fifty years. In contrast, addressing heart disease and cancer separately would yield diminishing improvements in health and longevity by 2060 - mainly due to competing risks. Delayed aging would greatly increase entitlement outlays, especially for Social Security. However, these changes could be offset by increasing the Medicare eligibility age and the normal retirement age for Social Security. Overall, greater investment in research to delay aging appears to be a highly efficient way to forestall disease, extend healthy life, and improve public health.

To live a longer, healthier life: delay aging, don't just cure disease, study concludes.

"When we treat someone with cancer, or heart disease, or stroke, we are treating a manifestation or byproduct of biological aging -- the underlying process marches on unaltered by this approach to disease," said Jay Olshansky, a professor at the University of Illinois School of Public Health in Chicago and a co-author of the study. "This means that even if we succeed for a time in extending life by treating disease, either that disease or another will emerge with time....Slowing aging alters the risk of all diseases simultaneously by attacking the origins of all of the things that go wrong with us as we grow older."

Delayed aging is better investment than cancer, heart disease

With even modest gains in our scientific understanding of how to slow the aging process, an additional 5 percent of adults over the age of 65 would be healthy rather than disabled every year from 2030 to 2060, reveals the forthcoming study. Put another way, an investment in delayed aging would mean 11.7 million more healthy adults over the age of 65 in 2060.

The analysis, from top scientists at USC, Harvard, Columbia, the University of Illinois at Chicago and other institutions, assumes research investment leading to a 1.25 percent reduction in the likelihood of age-related diseases. In contrast to treatments for fatal diseases, slowing aging would have no health returns initially, but would have significant benefits over the long term.

This is all very encouraging from the point of view that more public discussion of extended longevity through medical science is a good thing. A rising tide floats all boats. But attempting to slow aging is a great way to burn a lot of money and time with the expectation of very little to show for it at the end of the day. This isn't rejuvenation research of the sort advocated by the SENS Research Foundation, and only that type of repair-based strategies for treating aging have the possibility of producing the means of human rejuvenation soon enough to matter. The expected outcome for drug development to slow aging is that everyone in middle age today will age to death on much the same schedule as their parents: the emergence of treatments to slightly slow aging twenty years from now, produced at a vast cost, will do next to nothing to change that outcome.

Aging is damage, and only by repair of that damage can aging be reversed. So be appropriately pleased to see more discussion of extending healthy life in public, but recognize that only greater material support for SENS research and similar programs will help us live for decades longer in good health.


There is some debate over whether rapamycin, an immune suppressant agent that is presently being used in research to inhibit the activities of the protein produced by the mechanistic target of rapamycin (mTOR) gene, causes a slowing of aging or merely a reduction in cancer rates. The mTOR gene is a hot topic in research these days, as the extension of life in mice resulting from rapamycin is more reliable and easily replicated than is presently the case for any other line of longevity-enhancing drug development. The question of whether it actually slows aging or merely suppresses cancer is somewhat important for the future of this research, however. Both outcomes produce longer life in laboratory animals, but only one is of great interest to longevity science - if rapamycin is only a cancer suppressant, then its continued development will be picked up by the cancer research community, and the scientists aiming at aging will move on.

This runs the other way as well, of course. If there is debate over whether a cancer suppressant is slowing aging or not, then you will find researchers who think that perhaps it is time to take a closer look at how other known or suspected cancer suppressants work. Might they be slowing aging? This attitude is prevalent among researchers who subscribe to the programmed view of aging, seeing degenerative aging as something that might ultimately be stopped entirely through suitable alterations to genetic programming and protein levels. Digging through the enormous complexity of metabolism and its relationship with degenerative aging is much more attractive if you imagine that this sort of grail lies at the end of the road.

This research group advocates the hyperfunction theory of programmed aging, and its members see extension of life through inhibition of mTOR as supportive of that theory:

Selective anticancer agents suppress aging in Drosophila

According to our analysis of the literature more than 100 pharmaceutical substances that can prolong the lifespan of model organisms [have been discovered]. However, the increase of lifespan with aging-suppressor substances rarely exceeds 40%, which [is] greatly less than effects (up to 1000% or more) caused by mutations in the regulatory genes, which are the key switches of cell program to maintain growth or resist to stress, such as gene of PI3Ksubunit. We proceeded on the assumption that a more effective aging-suppressor drugs may be substances with specificity to the products of genes that control the evolutionarily conserved mechanisms of aging, mutations in which have the greatest effect on lifespan and the aging rate. In this regard, we investigated the aging-suppressive properties of specific pharmacological inhibitors of aging associated gene products TOR, PI3K, NF-κB and iNOS.

The aging process is associated with hyperactivation of TOR and PI3K, as well as NF-κB and iNOS, leading to cellular senescence, age-related pathologies, and oncogenesis. Therefore, many anticancer agents are inhibitors of the same enzymes as aging-suppressors, including TOR, PI3K, NF-κB and iNOS. This is entirely consistent with the theory that considers cellular senescence as age-dependent hyperactivation of pro-aging signaling pathways.

We studied the effects of inhibitors of PI3K (wortmannin), TOR (rapamycin), iNOS (1400W), NF-κB (pyrrolidin dithiocarbamate and QNZ), and the combined effects of inhibitors [on] Drosophila melanogaster lifespan and quality of life (locomotor activity and fertility). Our data demonstrate that pharmacological inhibition of PI3K, TOR, NF-κB, and iNOS increases lifespan of Drosophila without decreasing quality of life. The greatest lifespan expanding effect was achieved by a combination of rapamycin and wortmannin (by 23.4%). The bioinformatic analysis showed the greatest aging-suppressor activity of rapamycin, consistent with experimental data.

The programmed aging viewpoint must be contrasted with the view that aging is an accumulation of damage. We see changes in protein levels and epigenetic alterations with aging because metabolism reacts to that damage - damage causes change, the reverse of the programmed aging view of change leading to damage. If, as I believe from my reading around the field, aging is indeed largely a matter of a stochastic accumulation of unrepaired damage, then manipulation of genes and metabolism to try to slow down aging is a very poor way forward in comparison to just fixing the damage. Building methods of repair for the known forms of damage that cause aging should be a far easier and faster development program - which is why I support SENS over mainstream work on the development of longevity drugs. It is the more optimal path forward, and the only one likely to lead to radical life extension in our lifetimes.


I'm definitely not going to run up a quick post every time that a journalist thinks he or she has something new to say about Calico, Google's recently announced and only just underway initiative aimed at pushing forward the bounds of longevity science and extending human life. If I did that it would be Calico day and and day out until Google finally revealed the details of their research and funding agenda - which, frankly, I can't imagine is more than a long internal white paper at this point, and subject to change. But I'll indulge just this once, since it's been a couple of weeks, long enough for someone in the profession to actually have done some legwork and come up with something that we outsiders don't yet know.

New details on Google's anti-aging startup

Calico is considered the brainchild of Bill Maris, the Google Ventures managing partner who once was a biotech portfolio manager at Investor AB. Sources says that Maris looked at the life sciences landscape, and saw hundreds of companies all focused on curing or minimizing various diseases and conditions. In all cases, the goal was either to prolong life and/or improve the quality of life. What didn't exist, however, were companies focusing on the root cause of so much of this disease and death. Namely, that we all keep getting older. Or, put another way, that our bodies begin to fail on a cellular level - largely due to degradation of our genetic materials.

Now that the entire genome had been coded, Maris wondered if it was possible to actually study the genetic causes of aging and then create drugs to address them (a question that was heavily influenced by talks with futurist and Googler Ray Kurzweil). For example, what if you examined the genomes of thousands of healthy 90 year-olds from all parts of the world? What genetic similarities do they have? Or, perhaps, what happens to most of us that didn't happen to them. Even if this didn't result in longer life, it perhaps could at least lead to an improved quality of life for folks on the back nine.

One of those Maris called on was Google co-founder and director of special projects Sergey Brin, who expressed interest in investing. But as conversations progressed between Brin, Maris and Google CEO Larry Page, a consensus began to form that the best course of action would be to fund the entire project off of Google's balance sheet (the board would later agree). I have heard various numbers as to the exact Google commitment, but for now can only really say that we're talking about a minimum of hundreds of millions (tranched out, of course). The company itself still isn't commenting, although it's possible that there will be some specifics in its next quarterly earnings report (due next week).

You might recall that Maris made some interesting comments on the direction of Google Ventures late last year.

Maris said some of the areas he is interested in include businesses that are focused on radical life extension, cryogenics and nanotechnology.

At present some observers are joining the perhaps-too-obvious dots to suggest that Calico will fund programs focused on the data side of medical research, as Google is a Big Data company. If so, then I wouldn't expect Calico to directly contribute much to the bottom line of (a) the number of years of healthy life gained by you and I, and (b) just how long it takes to develop and deploy longevity-enhancing therapies. The obvious places to start with data are genetic studies of longevity or comparative studies of biology between long-lived and short-lived people and species - and that's all a sideshow, really, far removed from research programs capable of producing human rejuvenation.

Google Calico details emerge: Immortality, Obamacare, and millions of dollars

According to insiders familiar with Calico's formation, Maris was inspired by the work of the Human Genome Project, which had coded the entire DNA sequence. The combination of that, and an understanding of how Big Data crunching could be implemented, led to suggestions that Calico could compare the genome of healthy older people - such as those who had made it to their 90s without encountering any significant health issues - and see how, in aggregate, they differed from others.

Really this is all just more reading of tea leaves. It is very good that large sums of money are sliding towards longevity science: the avalanche that began ten years ago with a few advocates and small foundations has started in earnest. But it should be expected that Google will probably follow the present mainstream distribution of funding for longevity science, which is to say that most of it will go towards things like calorie restriction mimetic development, or the next drug candidate after rapamycin thought to slightly slow aging, or the study of centenarian genomes, and so on. None of these are paths to human rejuvenation, and only some of them are even slow, hard paths to slightly extending healthy human life.

So the arrival large-scale funding doesn't bypass the need to ensure that rejuvenation research (such as SENS, the Strategies for Engineered Negligible Senescence) dethrones slowing aging (such as rapamycin development) as the dominant strategy for the aging research community. That process is underway, and many noted researchers are SENS supporters, but it has a long way to go yet.

I don't spend my time advocating for the development of SENS-style repair therapies, ways to reverse the known root causes of degenerative aging, because I'm some kind of longevity science counter-culture hipster, supporting the minority view in the field because it's the minority view in the field. I advocate repair-based research aimed at reversal of aging because, based on my decade of reading research and observing the biotechnology community, I'm convinced that it's the only plausible and cost-effective way to produce large gains in healthy life span soon enough to matter to those of us in middle age today.

At this point any high-level strategy for longevity science will lead to some form of first generation therapies twenty years or so from now. If the present mainstream focus on drug development and gently slowing aging by metabolic manipulation continues to be the dominant approach, then the therapies of the 2030s will be weak medicine, and will do little for those of us who by then have become old, aging and dying on much the same schedule as our parents. What use is slowing the damage of aging when you are already old and damaged? But equally over those twenty years the research community could instead choose to work on repairing the root causes of aging - choose to produce rejuvenation therapies that reverse age-related frailty and effectively treat age-related disease, resulting in large gains in healthy life span even for people who are already old.

This is the most important debate in medical research today, as the outcome will determine whether we die as did our parents, or whether we have the opportunity to live in good health for centuries. Yet the broader public are oblivious to it.


The New Organ Prize is an initiative of the Methuselah Foundation, and has been under development for a little while - an open beta for trying out crowdfunding strategies, building alliances, and so forth. This is an evolution of the organization's experience with research prizes and their use in spurring a scientific community to achieve greater and more rapid progress. The Foundation's past work on the Mprize for longevity science, and associated networking behind the scenes, helped to speed the transformation of aging research from a field in which any public discussion of life extension was likely to be career-threatening into a community that now embraces the quest for longer healthy lives. Much of the publicity for longevity science that you see today would never have happened even as recently as a decade ago, as back then researchers were much more circumspect and funding sources much more conservative.

The New Organ Prize exists in a different, more liberated, and openly ambitious scientific environment and has a different aim: to accelerate the development of whole organ tissue engineering, creating functional long-lasting organs just as good as the natural variety, built from a patient's own cells, and to make this happen far sooner than it otherwise would. The Methuselah Foundation staff have already built a range of important alliances, such as with tissue printing company Organovo, and the arrangement outlined in the announcement that I found in my in-box today:

We're thrilled to announce that Methuselah has now secured an official launch date and partner for the New Organ Prize - the World Stem Cell Summit (WSCS), taking place in San Diego, CA on December 4-6, 2013. As the premier annual forum for regenerative medicine, there's no better place than WSCS to unveil New Organ to the scientific community and the world. And we'd love for you to join us.

WSCS and Methuselah Foundation aspire to build an enduring partnership that will contribute to the realization of whole organ engineering, preservation, and regeneration for the benefit of millions. With attendees from more than 40 countries, the Summit's interdisciplinary agenda for the global stem cell community explores everything from disease updates and new research directions to cell standardization, regulatory pathways, and economic development.

This year, New Organ will be an integral part of WSCS. During this three-and-a-half day event that includes a variety of speaker presentations, ongoing exhibitions, small group events, and social opportunities, WSCS chairman Bernie Siegel will join Methuselah CEO Dave Gobel on stage in a joint announcement celebrating the official launch of the New Organ Prize.

Our whole team will be there ... and we wouldn't be here without you. Just like the leaders of the World Stem Cell Summit, you're committed to New Organ's success, and we'd be honored to mark this milestone together. To learn more about WSCS and register, visit

Thanks again for your ongoing support. Here's to the upcoming launch of New Organ!


The immune system can be broadly divided into adaptive and innate components, both of which decline with age. A failing immune system is one of the most serious aspects of frailty in the elderly, leaving them vulnerable to pathogens that a young person would shrug off, and suffering from reduced monitoring activities aimed at the destruction of potentially cancerous, senescent, and other harmful cells.

Focusing just on the adaptive immune system, there are a range of contributing causes identified by researchers to date. Firstly, new T cells, the workers and killers of the immune system, are only created in large numbers when an individual is young. The thymus, where these immune cells mature, atrophies early in adult life, its evolved task of setting up the immune cell population done. The supply of new immune cells diminishes to a trickle thereafter, a fraction of what it was. This effectively caps the T cell population associated with the active immune system: the body only supports so many.

This soft limit on the number of T cells leads to the second cause of immune system decline, which is structural, inherent in the nature of the immune system's organization and mode of operation. The adaptive immune system remembers threats, and it does do by maintaining a converted population of memory cells, one for each threat. Unfortunately some threats, like herpesviruses, cannot be cleared from the body: they keep coming back, again and again, each time leading to more cells becoming specialized to remember them. The main culprit here appears to be cytomegalovirus (CMV), which the majority of people have been exposed to by the time they are old: aside from its effects on the immune system's memory cell contingent it is largely harmless, and you probably didn't even notice your initial infection. But ultimately your immune system becomes overpopulated by memory cells dedicated to CMV, with too few naive T cells left to do its other jobs.

These outlines are simplifications of a complex set of issues, and omit any discussion of how the array of cellular and molecular damage that accumulates with aging also impacts the immune system negatively. The important point to take away from this is that the research community has near-term options available to reverse these contributions to immune system frailty. For example: the use of tissue engineering to restore thymic tissue to the role of generating a flow of new T cells; regular infusions of fresh T cells created from the patient's own stem cells; the use of new cancer therapy technologies to target and kill memory T cells specialized to CMV, freeing up space for new T cells. None of these are beyond the capacity of today's technology - as is so often the case, it's just a matter of devoting research and development resources to the problem for a few years, in a world in which funding sources lack the vision to support even the obvious bold advances.

Here is a good, conservative, and very readable open access review of the role of CMV in immune system decline:

Human T cell aging and the impact of persistent viral infections

Aging is associated with a dysregulation of the immune response, loosely termed "immunosenescence." Each part of the immune system is influenced to some extent by the aging process. However, adaptive immunity seems more extensively affected and among all participating cells it is the T cells that are most altered. There is a large body of experimental work devoted to the investigation of age-associated differences in T cell phenotypes and functions in young and old individuals, but few longitudinal studies in humans actually delineating changes at the level of the individual.

In most studies, the number and proportion of late-differentiated T cells, especially CD8+ T cells, is reported to be higher in the elderly than in the young. Limited longitudinal studies suggest that accumulation of these cells is a dynamic process and does indeed represent an age-associated change. Accumulations of such late-stage cells may contribute to the enhanced systemic pro-inflammatory milieu commonly seen in older people.

We do not know exactly what causes these observed changes, but an understanding of the possible causes is now beginning to emerge. A favored hypothesis is that these events are at least partly due to the effects of the maintenance of essential immune surveillance against persistent viral infections, notably Cytomegalovirus (CMV), which may exhaust the immune system over time. It is still a matter of debate as to whether these changes are compensatory and beneficial or pathological and detrimental to the proper functioning of the immune system and whether they impact longevity.

Dissecting the effects on immune alterations in elderly individuals with respect to age, low grade-inflammation, disease and CMV seropositivity remains a big challenge. We are currently approaching this challenge by assessing individual variations in responses to CMV, namely antibody titer, specificity, and neutralizing activity and determination of the specific CMV cell reservoirs (e.g., monocytes) rather than just "infected vs. not infected." This approach appears to us more likely to yield informative data in populations where almost all subjects are infected with the virus, for instance elderly individuals even in industrialized countries and essentially everyone in developing countries. Furthermore, longitudinal studies are needed including young and elderly healthy individuals to dissect the effects of age vs. CMV infection.

This is the sort of data gathering exercise that I would like to see augmented in medical research by more aggressive experiments in intervention, an area in which I think the research community is far less active than it could be. In the past you could argue costs, but costs are plummeting in the life sciences as biotechnology advances rapidly. It seems to me that just as much could be learned by augmenting T cell numbers or destroying memory T cells in animal studies as by exploring human data in more detail - and moreover it would also move the world closer to working therapies should the results be positive, which won't happen in the data gathering default mode of modern research.


Monday, October 7, 2013

One emerging strategy in medical research is to set up factories in the body to manufacture proteins and drugs in situ as needed. Taking advantage of existing cellular machinery to do this make sense, and so we see the production of technology demonstrations like this one:

The researchers inserted modified strands of messenger RNA into connective tissue stem cells - called mesenchymal stem cells - which stimulated the cells to produce adhesive surface proteins and secrete interleukin-10, an anti-inflammatory molecule. When injected into the bloodstream of a mouse, these modified human stem cells were able to target and stick to sites of inflammation and release biological agents that successfully reduced the swelling. "If you think of a cell as a drug factory, what we're doing is targeting cell-based, drug factories to damaged or diseased tissues, where the cells can produce drugs at high enough levels to have a therapeutic effect."

Mesenchymal stem cells have become cell therapy researchers' tool of choice because they can evade the immune system, and thus are safe to use even if they are derived from another person. [The messenger RNA] technique to program cells is harmless, as it does not modify the cells' genome, which can be a problem when DNA is used (via viruses) to manipulate gene expression. "This opens the door to thinking of messenger RNA transfection of cell populations as next generation therapeutics in the clinic, as they get around some of the delivery challenges that have been encountered with biological agents."

Monday, October 7, 2013

Researchers make progress in growing another tissue type from cells:

[Researchers have] created precursors to salivary and lacrimal glands that, when transplanted into mice, successfully connected to the host ducts and nervous system. Once connected, these lab-grown secretory glands helped to restore the production of saliva and tears in animals from which healthy salivary or lacrimal glands had previously been excised.

To create the secretory glands, [the researchers] built on previous work that used a bioengineering technique they developed to reconstitute organ germs from teeth and hair follicles via a 3-D cell processing method. First, they created the glandular precursors - or "germs" - in vitro using single epithelial and mesenchymal cells isolated from embryonic glands. After three days in organ culture, the bioengineered glands had undergone branching morphogenesis, followed by stalk elongation and cleft formation - three tell-tale signs of organogenesis. By that time, the researchers also observed an accumulation of saliva in the ducts of the bioengineered salivary gland germs.

[The researchers] next engrafted these secretory gland germs in mice - from which healthy salivary or lacrimal glands had been removed - using a nylon thread-guided, interepithelial tissue-connecting plastic method it published [last year]. Not only did the precursor secretory glands innervate, but in response to stimulation by the nervous system, they began to secrete saliva and tears, moistening dry mouths and eyes in the animal models.

Tuesday, October 8, 2013

Much of present research into longevity-enhancing genetic alterations is a matter of following the chains of association in protein machinery, looking for common mechanisms shared by different mutations. Since any given metabolic alteration that extends life can be induced or influenced by changing the levels of numerous different proteins, it is expected that (a) researchers will find many different longevity mutations beyond those already known, and (b) most of these will act through a much smaller number of common mechanisms. Identifying those common mechanisms is one path towards greater understanding of the way in which natural variations in longevity are determined by genes and the operation of metabolism.

While numerous life-extending manipulations have been discovered in the nematode Caenorhabditis elegans, one that remains most enigmatic is disruption of oxidative phosphorylation. In order to unravel how such an ostensibly deleterious manipulation can extend lifespan, we sought to identify the ensemble of nuclear transcription factors that are activated in response to defective mitochondrial electron transport chain (ETC) function.

Using a feeding RNAi approach, we targeted over 400 transcription factors and identified 15 that, when reduced in function, reproducibly and differentially altered the development, stress response, and/or fecundity of isp-1(qm150) Mit mutants relative to wild-type animals. Seven of these transcription factors - [including HIF-1 and] the CREB homolog-1 (CRH-1)-interacting protein TAF-4 - were also essential for isp-1 life extension.

When we tested the involvement of these seven transcription factors in the life extension of two other Mit mutants, namely clk-1(qm30) and tpk-1(qm162), TAF-4 and HIF-1 were consistently required. Our findings suggest that the Mit phenotype is under the control of multiple transcriptional responses, and that TAF-4 and HIF-1 may be part of a general signaling axis that specifies Mit mutant life extension.

Tuesday, October 8, 2013

Many people believe that greatly increased population levels are the inevitable result of increased human longevity. Separately, many people believe that overpopulation is presently happening, and will lead to catastrophe in the near future. I and many others have noted in the past that overpopulation doesn't exist today, that many multiples of today's population could exist on this one planet with a high standard of living using no more than today's technology, and that population models show that even radical life extension doesn't greatly increase the population size. Supporting any level of population is simply another engineering challenge, one well within our capabilities today for any plausible near future population size, never mind using the improved technologies of tomorrow.

What people point to today as overpopulation is more accurately labeled as poverty caused and maintained by bad governance: resources squandered, persistent war, kleptocracies, regulation, serfdom, and so on. It is not a matter of counting heads, but of greed and inhumanity. So little of the light and noise put out on the topic of overpopulation seems particularly rational to me, but here is a generally sensible piece from a pro-longevity author:

By far the most predominant criticism made against indefinite longevity is overpopulation. It is the first "potential problem" that comes to mind. But fortunately it seems that halting the global mortality rate would not cause an immediate drastic increase in global population; in fact, if the mortality rate dropped to zero tomorrow then the doubling rate for the global population would only be increased by a factor of 1.75, which is smaller than the population growth rate during the post-WWII baby-boom.

Finding innovative solutions to new and old problems is what humanity does. Thus while overpopulation is the most prominent and most credible criticism against continually-increasing lifespans, and the one that needs to be planned-for the most (because it will eventually happen, but it will lead to sustainability, resource and living space problems only if we do nothing about it), it is in no way insoluble, nor particularly pressing in terms of the time available to plan and implement solutions to shrinking living-space and resource-space (i.e. the space occupied by resources such as food, energy-production, workplaces, etc.). We have a host of potential solutions today, ones we can use to increase available living space without regulating the global birthrate, and decades following the achievement of indefinite lifespans to consider the advantages and disadvantages of the various possible solutions, to develop them and to implement them.

So then: wherefore from here? Overpopulation is still the most prominent criticism raised against indefinite longevity, and if combated, it could lead to an increase in public support for the longevity movement. You might think that the widespread concern with overpopulation due to increasing longevity won't really matter, if they turn out to be wrong, and overpopulation isn't so insoluble a problem as one is inclined to first presume. But this misses a crucial point: that the time it takes to achieve longevity is determined by and large by how widespread and strongly society and the members constituting it desire and demand it. If we can convince people today that overpopulation isn't an insoluble problem, then continually-increasing longevity might happen much sooner than otherwise. At the cost of 100,000 deaths due to age-correlated causes per day, I think hastening the arrival of indefinite longevity therapies by even a modest amount is somewhat imperative. Hastening its arrival by one month will save 3 million lives, and achieving it one year sooner than otherwise will save an astounding 36.5 million real, human lives.

Wednesday, October 9, 2013

Here is a better article covering recent advocacy for the Longevity Dividend. A group of researchers have been seeking large-scale public funding of ways to slow aging for some years now, aiming for a sweeping alteration in the strategy for research into aging and age-related disease, and this is one of their periodic calls to action:

Slowing aging is no fantasy. Researchers can delay how rapidly lab animals such as mice and roundworms grow old with a variety of measures, from genetic tinkering to extremely low-calorie diets. So far, however, nobody has shown that any drug or diet can postpone human senescence. But some scientists, including demographer S. Jay Olshansky of the University of Illinois, Chicago, argue that we now know enough about aging to start an intensive, multiyear search for ways to delay it in people - a sort-of Manhattan Project for longevity. "Aging is the underlying risk factor for most of the things that go wrong with us" as we grow older, he says. That means slowing the process would not just add years to our lives, but it would also postpone illnesses such as cancer, diabetes, and heart disease that primarily strike the elderly.

An extra couple of years might not be very attractive if you're going to be sick and decrepit. But slowing aging would also allow about 5% more seniors to avoid infirmity between 2030 and 2060 than would reductions in cancer or heart disease alone. "To my friends who want to live forever, I say it makes for great science fiction," Olshansky says. "Our goal is to extend healthy life, not necessarily life itself."

Olshansky belongs to the Longevity Dividend Initiative (LDI), a group of researchers and organizations that has been talking up the payoffs of postponing human aging. [He] and his colleagues are ready to take the next step, he says. In 2014, the LDI plans to start raising money, mainly from nongovernmental organizations and private individuals, to fund research to develop age-fighting measures, Olshansky says. Although researchers are already studying many potential options, the LDI's goal is to usher them into human studies and possible use.

As you can see, this is the position taken by researchers who think that some modest gains can be made, but who - for whatever reason - don't see repair of the root causes of aging leading to rejuvenation per the SENS model as a viable path forward. In many ways this is a competition for attention and funding: work on rejuvenation and its backers versus work on modestly slowing aging and its backers. That said, funding isn't a fixed bucket, and the more that aging, longevity, and medical research are discussed in public the larger that bucket might become.

Wednesday, October 9, 2013

Cryonics as presently practiced is the low-temperature storage of a patient on death, so as to preserve the structure of the mind and offer a chance at being revived by a future medical community capable of rejuvenation, repair, and restoration to life. Cryonics as a medical technology has been under development at a slow pace since the early 1970s, with a steady delivery of improvements in process and methodologies. This piece from a recent issue of Cryonics Magazine discusses strategies and goals for future improvements in the cryopreservation process:

Let's start with the following definition of cryonics: "Cryonics is the stabilization of critically ill patients at ultra-low temperatures to allow resuscitation in the future." As you can see, nothing in this definition says that repair is an intrinsic feature of cryonics. But is this a reasonable perspective? Yes, cryonics patients will require a second look at their condition by a future doctor who will have more advanced medical technologies at his/her disposal. This could conceivably be called "repair." Most cryonics patients will also require rejuvenation biotechnologies. After all, it makes little sense to cure the patient's disease but leave him/her in a fragile, debilitated state. This could be called "repair" too, in particular if you believe that aging is the progressive accumulation of damage.

The repair that I want to discuss here is repair of the damage that is associated with the cryopreservation process itself. If we can eliminate this kind of damage, and the associated requirement of repair in the future, we will make the idea of cryonics a whole lot more attractive. Perhaps the most obvious advantage is that cryonics could not be dismissed solely by pointing to the (irreversible) damage caused by the cryopreservation process itself. In essence, such a form of cryonics would be akin to putting a critically ill patient in a state of true suspended animation. This would strengthen the legal position of cryonics patients because a decision to abandon a patient in such a condition would be more akin to murder (or at least serious neglect).

Another advantage would be that the absence of cryopreservation damage would increase the likelihood of the patient being restored to good health in the future. Less damage is also likely to translate into lower costs, too, and it is rather obvious that such an advantage can mean more security for the patient. Reversible cryopreservation may also lead to earlier treatment and resuscitation attempts, which may reduce challenges associated with re-integration [into society]. Cryonics without repair also matters in the here-and-now. Without the goal of reversible cryopreservation there are no objective, empirical criteria to evaluate the quality of care in a cryonics case. Last, but not least, we should do no harm. Allowing unnecessary injury of the patient because future advanced technologies should be able to fix it is a morally suspect gamble with a person's life.

Thursday, October 10, 2013

Investigations continue into what can be done with comparatively simple transplantation of various different types of stem cell:

Damaged or diseased organs may someday be healed with an injection of blood vessel cells, eliminating the need for donated organs and transplants, according to scientists. Researchers show that endothelial cells - the cells that make up the structure of blood vessels - are powerful biological machines that drive regeneration in organ tissues by releasing beneficial, organ-specific molecules. They discovered this by decoding the entirety of active genes in endothelial cells, revealing hundreds of known genes that had never been associated with these cells. The researchers also found that organs dictate the structure and function of their own blood vessels, including the repair molecules they secrete.

"Our work suggests that that an infusion of engineered endothelial cells could engraft into injured tissue and acquire the capacity to repair the organ. These studies - along with the first molecular atlas of organ-specific blood vessel cells - will open up a whole new chapter in translational vascular medicine and will have major therapeutic application. Scientists had thought blood vessels in each organ are the same, that they exist to deliver oxygen and nutrients. But they are very different." Each organ is endowed with blood vessels with unique shape and function and delegated with the difficult task of complying with the metabolic demands of that organ.

The scientists postulated that endothelial cells derived from embryonic stem cells [are] able to be taught how to act like an organ-specific blood vessel, [and the] team generated endothelial cells from mouse embryonic stem cells that were functional, transplantable and responsive to microenvironmental signals. These embryonic-derived endothelial cells "are versatile, so they can be transplanted into different tissues, become educated by the tissue, and acquire the characteristics of the native endothelial cells."

Researchers can propagate these cells in large numbers in the laboratory. "We now know what it takes to keep these cells healthy, stable and viable for transplantation." The researchers transplanted these generic endothelial cells [into] the liver of a mouse and found that [they] became indistinguishable from native endothelial cells. This also occurred when cells were grafted into kidneys. "These naive endothelial cells acquire the phenotype - the molecular profile and signature - of the native pre-existing endothelial cells due to the unique microenvironment in the organ. These transplanted endothelial cells are being educated by the unique biophysical microenvironment organ in which they are placed. They morph into endothelial cells that belong in the organ, and that can repair it. If you have a heart injury and you need to reform some of your cardiomyocytes, the endothelial cells that are around the heart secrete factors that are specific for helping a heart repair itself."

Thursday, October 10, 2013

One aspect of the frailty of being old is the loss of healing capacity. Stem cell activity diminishes, probably as a part of an evolved response to accumulated cellular damage that minimizes cancer risk, and even minor injuries become troubling. Researchers are investigating the details of this process with the intent of reversing the signaling systems involved, restoring some of the youthful ability to heal. This, unfortunately, doesn't do anything to address the underlying damage of aging - it is in some ways like removing the safety features that prevent overuse of a worn engine - but the end result is better than not having the ability to do this.

Researchers working with elderly mice have determined that combining gene therapy with an extra boost of the same stem cells the body already uses to repair itself leads to faster healing of burns and greater blood flow to the site of the wound. Their findings offer insight into why older people with burns fail to heal as well as younger patients, and how to potentially harness the power of the body's own bone marrow stem cells to reverse this age-related discrepancy.

To heal burns or other wounds, stem cells from the bone marrow rush into action, homing to the wound where they can become blood vessels, skin and other reparative tissue. The migration and homing of the stem cells is organized by a protein called Hypoxia-Inducible Factor-1 (HIF-1). In older people [fewer] of these stem cells are released from the bone marrow and there is a deficiency of HIF-1.

[Researchers] first attempted to boost the healing process in mice with burn wounds by increasing levels of HIF-1 using gene therapy, a process that included injecting the rodents with a better working copy of the gene that codes for the protein. That had worked to improve healing of wounds in diabetic animals, but the burn wound is particularly difficult to heal, and that approach was insufficient. So they supplemented the gene therapy by removing bone marrow from a young mouse and growing out the needed stem cells in the lab. When they had enough, they injected those supercharged cells back into the mice. After 17 days, there were significantly more mice with completely healed burns in the group treated with the combination therapy than in the other groups. The animals that got the combination therapy also showed better blood flow and more blood vessels supplying the wounds.

Friday, October 11, 2013

Here are the results of an analysis of the effects of exercise on aging and longevity in mice: it is expected to slow the onset of age-related frailty, but unlike the practice of calorie restriction it fails to extend either average or maximum life span.

Exercise has been unequivocally associated with a slowing of age-specific mortality increases in rats and with an increased median lifespan. However, the results in mice [to date] are not that clear.

Male C57Bl/6J mice, individually caged, were randomly assigned to one of two groups: sedentary (n = 72) or spontaneous wheel-runners (n = 72). We evaluated longevity and several health parameters including grip strength, motor coordination, exercise capacity (VO2max) and skeletal muscle mitochondrial biogenesis. We also measured the cortical levels of the brain-derived neurotrophic factor (BDNF), a neurotrophin associated with brain plasticity. In addition, we measured systemic oxidative stress and the expression and activity of two genes involved in antioxidant defense in the liver (that is, glutathione peroxidase (GPx) and manganese superoxide dismutase (Mn-SOD)). Genes that encode antioxidant enzymes are considered longevity genes because their over-expression may modulate lifespan.

Exercise does not cause an increase in either average lifespan or maximal lifespan. Maximal lifespan was defined as the age at which the longer-lived animal died. In our mice it was 950 days. Average lifespan was defined as the age at which 50% of the animals died. It was 750 days for sedentary mice and 770 for wheel-runners. Aging was associated with an increase in oxidative stress biomarkers and in the activity of the antioxidant enzymes, GPx and Mn-SOD, in the liver in mice. Life-long spontaneous exercise did not prolong longevity but prevented several signs of frailty (that is, decrease in strength, endurance and motor coordination). This improvement was accompanied by a significant increase in the mitochondrial biogenesis in skeletal muscle and in the cortical BDNF levels.

Friday, October 11, 2013

Most human dietary studies gather data via participant self-reporting, which has its limitations. Using biomarkers to examine levels of specific dietary components is a step up from that, but it doesn't remove the core issues inherent in looking at specific dietary components in isolation. For example, we know that overall calorie intake level is enormously important in determining health and longevity, and that correlates with levels of different dietary components. Also, people who make better efforts to take care of their health tend to have better diets, but that effort extends beyond just diet. So levels of specific dietary components in human studies are going to correlate with all sorts of other line items that can impact health and longevity, such as exercise, calorie intake, amount of visceral fat tissue, conscientiousness in use of medical resources, and so on.

Correlation is not causation, but invariably when it comes to diet there are all sorts of vested interests willing to sell you the idea that you should believe otherwise. This study reports a large enough result to awake that contingent:

Polyphenols are naturally occurring compounds found largely in fruits, vegetables, coffee, tea, nuts, legumes and cereals. More than 8,000 different phenolic compounds have been identified in plants. Polyphenols have antioxidant, antiinflammatory, anticarcinogenic, etc. effects.

Polyphenols might have a role in the prevention of several chronic diseases, but evaluating total dietary polyphenol (TDP) intake from self-reported questionnaires is inaccurate and unreliable. A promising alternative is to use total urinary polyphenol (TUP) concentration as a proxy measure of intake. The current study evaluated the relationship between TUPs and TDPs and all-cause mortality during a 12-y period among older adult participants. The study population included 807 men and women aged 65 y and older from the Invecchiare in Chianti study, a population-based cohort study of older adults living in the Chianti region of Tuscany, Italy.

In conclusion, the research proves that overall mortality was reduced by 30% in participants who had rich-polyphenol diets (greater than 650 mg/day) in comparison with the participants who had low-polyphenol intakes (less than 500 mg/day). "[The] results corroborate scientific evidence suggesting that people consuming diets rich in fruit and vegetables are at lower risk of several chronic diseases and overall mortality." Moreover, the research stresses the importance of evaluating - if possible - food intake by using nutritional biomarkers, not only food frequency questionnaires.


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