Fight Aging!

The nuclear DNA in our cells is surrounded by a panoply of exceedingly efficient quality control and repair machinery, but nonetheless damage occurs: individual cells suffer all sorts of mutations over time as molecules react with DNA or pieces are lost or reshuffled during replication. This is more pronounced in long-lived cells, such as those in the central nervous system, or the stem cell populations that support specific tissues.

Cancer spawns from nuclear DNA damage, and the risk of cancer grows greatly with age - not just because of growing damage to nuclear DNA, but also due to the decline of the immune system's watchdogs and other related consequences of aging. But aside from cancer, does the accumulation of various forms of nuclear DNA damage scattered across our cells contribute meaningfully to dysfunction and decline? There is some debate on this topic, and while the consensus position is more or less "yes, of course," there is at this point no experiment by which one can conclusively demonstrate that this is the case.

Today I'll point you to an open access study in which researchers compare DNA sequencing data from the blood of a pair of 40-year-old twins and a pair of 100-year old twins. Blood cells cycle into and out of circulation on a timescale of a few months, but we might take nuclear DNA damage in blood cells as being representative of the damage present in the population of hematopoietic stem cells that generated those blood cells.

Aging as Accelerated Accumulation of Somatic Variants: Whole-Genome Sequencing of Centenarian and Middle-Aged Monozygotic Twin Pairs

It has been postulated that aging is the consequence of an accelerated accumulation of somatic DNA mutations and that subsequent errors in the primary structure of proteins ultimately reach levels sufficient to affect organismal functions. The technical limitations of detecting somatic changes and the lack of insight about the minimum level of erroneous proteins to cause an error catastrophe hampered any firm conclusions on these theories.

In this study, we sequenced the whole genome of DNA in whole blood of two pairs of monozygotic (MZ) twins, 40 and 100 years old, by two independent next-generation sequencing (NGS) platforms (Illumina and Complete Genomics). Potentially discordant single-base substitutions supported by both platforms were validated extensively by Sanger, Roche 454, and Ion Torrent sequencing.

We demonstrate that the genomes of the two twin pairs are germ-line identical between co-twins, and that the genomes of the 100-year-old MZ twins are discerned by eight confirmed somatic single-base substitutions, five of which are within introns. Putative somatic variation between the 40-year-old twins was not confirmed in the validation phase.

We conclude from this systematic effort that by using two independent NGS platforms, somatic single nucleotide substitutions can be detected, and that a century of life did not result in a large number of detectable somatic mutations in blood.

I would have expected more differences and larger differences to turn up, but as the researchers note it is impossibly to detect mutations that have not spread to at least some degree (in this case that means spreading through the population of hematopoietic stem cells). A next step might be a survey of whole genome sequencing by tissue types in old twins, especially those with longer-lived cells, to see whether this low level of exhibited mutational damage is peculiar to blood or typical for most or all tissues.

The number of somatic variants may be substantially larger but those present in smaller fractions of cells go undetected. Consistent, detectable somatic variation likely includes somatic mosaicism in blood generated during development or clonal expansion of mutations generated at any point during the lifetime. The frequency of these variants is limited in blood even after 100 years of life.

In summary, this study shows that the number of detectable somatic variants in blood by using NGS is very low and that accumulation of somatic mutations is not necessarily a consequence of a century of life. Stochastic somatic variation occurring in less than 20% of cells will go undetected, however.

An improvement on current methods of creating pluripotent stem cells has been in the news the past few days. It involves stressing cells with simple mechanisms, and is straightforward enough that I hear numerous laboratories and individual researchers have started in on trying it out immediately, as well as revisiting other variants of stressing cells to see what the outcome might be. The methodology is something that diybio enthusiasts could carry out as a weekend project with minimal cost and equipment, which is a great improvement over prior standard methods involving delivery of genes or similar operations.

As with all such potential infrastructure improvements, one pillar of importance is the reduction in cost and difficulty of research. When someone figures out a much cheaper way of achieving any particular goal all further work that builds on that goal moves more rapidly: existing groups can do more, and new groups that previously couldn't afford to join in now start work. Cell pluripotency is near the base of regenerative medicine and tissue engineering: ways to better achieve it accelerate the whole field.

As you can see there are also other ramifications, however, such as for persistent reports of pluripotent stem cells isolated from adult tissues - VSELs and others - and the debate over difficulties in replicating that research.

In 2006, Japanese researchers reported a technique for creating cells that have the embryonic ability to turn into almost any cell type in the mammalian body - the now-famous induced pluripotent stem (iPS) cells. In papers published this week, another Japanese team says that it has come up with a surprisingly simple method - exposure to stress, including a low pH - that can make cells that are even more malleable than iPS cells, and do it faster and more efficiently.

"It's amazing. I would have never thought external stress could have this effect," says Yoshiki Sasai. It took Haruko Obokata, a young stem-cell biologist at the same centre, five years to develop the method and persuade Sasai and others that it works. "Everyone said it was an artefact - there were some really hard days."

The results could fuel a long-running debate. For years, various groups of scientists have reported finding pluripotent cells in the mammalian body. But others have had difficulty reproducing such findings. Obokata started the current project by looking at cells thought to be pluripotent cells isolated from the body. But her results suggested a different explanation: that pluripotent cells are created when the body's cells endure physical stress.

Obokata has already reprogrammed a dozen cell types, including those from the brain, skin, lung and liver, hinting that the method will work with most, if not all, cell types. On average, she says, 25% of the cells survive the stress and 30% of those convert to pluripotent cells - already a higher proportion than the roughly 1% conversion rate of iPS cells.

Link: http://www.nature.com/news/acid-bath-offers-easy-path-to-stem-cells-1.14600

SENS Research Foundation cofounder Aubrey de Grey has been in the European press of late - such as the interview quoted below. Automated translation of colloquial Spanish is almost as bad as that of Russian, so proceed with caution. Even so there is much to be said for living in an age in which I can complain about the quality of automated translation: its existence greatly lowers the barriers to ongoing communication between regions of the world.

Question: My daughter asked me why we die, what should I say?

Answer: You can say that the human body is a machine, a very complicated machine, but it should not surprise us that it stops working, because that happens to all machines, including cars. The good news is that cars can last much longer than was planned if given a really good and complete maintenance. That's why there are cars that are one hundred years old even if they were designed to only last ten or twenty. It should be the same for the human body and the only reason it does not happen is that our body is so complicated that we have not yet understood how to do that maintenance. But we're working on it.

Question: So I tell my daughter that she will live a thousand years?

Answer: Of course we do not know, but I think we have at least 50% chance of developing these maintenance technologies if we collect enough money to support research. In 20 or 25 years we will have therapies that affect people who are then 60 or 70 years old and rejuvenate them to the point of granting an additional 30 years of healthy life. That means they will have another 30 years in which we can build even better therapies and rejuvenate them once again. This is what I call the "escape velocity of aging" and is the reason I think the people who are born now may avoid the problems of being old. That means your longevity depends on the risk of dying from accidents, but not on the date you were born.

Link: http://translate.google.com/translate?u=noticias.lainformacion.com/ciencia-y-tecnologia/ciencias-general/aubrey-de-grey-la-gente-que-ha-nacido-ahora-podra-evitar-los-problemas-de-envejecer_o0vzCbXZynZgFkxvO2LUc/

SENS Research Foundation staff spend a fair amount of time analyzing new papers and talking with researchers in the broader community, looking for recent lines of work relevant to rejuvenation biotechnology. There is a lot going on, enough that digesting it would be a full time job: molecular biology is far too large a field for any one group to have a good idea as to what is going on in every last laboratory. Despite the fact that very little of the research community has any great interest in producing ways to treat aging, it is still the case that many scientists are working on technologies that can be adapted or will otherwise contribute to the end goal of repairing the root causes of aging.

Arriving in my in-box today is a new outcome of this ongoing research review, a joint effort between the Methuselah Foundation and SENS Research Foundation to publicize some of the more interesting and relevant research recently uncovered:

Rejuvenation Biotechnology Update

Dear Friends,

As one of The 300, your loyal support of the Methuselah Foundation make up the backbone of our mission. We hope to honor your trust in our shared vision with a curated, quarterly newsletter featuring some of the latest, most exciting developments in reversing or obviating the diseases of aging. We're always on the watch for high-impact efforts that show significant promise for extending healthy human life, and as always, we welcome your input and thoughts. Please let us know if you find this information valuable, readable, and informative. Hope you enjoy!

All the Best,
David Gobel

Dear Supporters,

At SENS Research Foundation, our CSO Team is a full time, internal research team that supports Aubrey de Grey in the work of keeping up-to-date on the most cutting edge science in rejuvenation biotechnology. Michael Rae, Ben Zealley, and Maximus Peto spend many, many hours reviewing the science literature, analyzing new papers, reporting on their findings, and offering suggestions for research priorities for SRF. We are delighted to draw on that work in partnership with Methuselah Foundation, to provide the members of its MF 300 with this newsletter highlighting a handful of the most notable scientific articles and advances, and some of the insights inspired by those advances.

Best,
Mike Kope

The Methuselah Foundation is thrilled to partner with SENS Research Foundation in order to bring out the most recent advancements in tissue engineering, regeneration, and rejuvenation research for members of The 300. It doesn't take a scientist to understand the vital importance of investing in healthy life extension, so our newsletters will frame these developments as accessibly and approachably as possible. We'll focus on the relevance of three recent studies (within the past 3-6 months) and describe how each one fits into the broader landscape of longevity research.

This first edition of what will hopefully be a regular feature offers commentary on the following papers, and as you can see once you start to delve into the details very little is clear cut. It is rarely easy to see after only a few months whether new and interesting research will turn out to be game-changing, irrelevant, or merely the foundation of an incrementally better treatment that reaches clinical availability five to ten years from now. The forest of science has very thick undergrowth indeed.

You might look back in the Fight Aging! archives to see references to the work on GDF-11 and the C1q paper. I am nowhere near as cautious in my expectations as an actual researcher in the field, and you should bear that in mind: note the differences between my comments and those of the SENS Research Foundation folk.

Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy

These results are exciting, but further testing is needed, and there is good reason to be cautious. First, the observation that GDF-11 usually declines with age suggests that the real problem to be addressed is whatever causes its decline in aging. Second, GDF-11 is known to inhibit neurogenesis, and therefore human supplementation with this protein may cause problems. As with any therapeutic, adequate testing will need to be done to ensure safety and efficacy in humans.

A final noteworthy aspect of this study is that GDF-11 was able to reverse cardiac hypertrophy in "wild-type" (non-mutant) mice. A great many studies in aging research use mutant mice to model diseases of aging, and most humans do not have single-gene mutations that cause age-related disease. Thus, research on wild-type mice may more accurately model human diseases associated with advanced age, and lead to more promising therapeutic strategies.

Therapeutic and preventive effects of methylene blue on Alzheimer's disease pathology in a transgenic mouse model

There has been considerable interest in the use of MB as a treatment for human brain diseases in which proteins form toxic aggregates, such as Alzheimer's disease, >Parkinson's Disease, and "tauopathies," wherein mutant forms of the protein Tau aggregate. Aggregation and accumulation of substances in body tissues, particularly the brain, is also a theme in research on aging.

The mechanism of MB's potentially beneficial effects on AD is not known, but it has been speculated to act by assisting the function of mitochondria in the brain. Declining mitochondrial function is another phenomenon which may be associated with diseases of aging, and is an active topic in rejuvenation biotechnology research. It's also important to be aware of the possibility that MB may not represent a cure for AD. It may turn out to be a treatment whose beneficial effects would wear off if it were discontinued, particularly if it functions via mitochondrial antioxidant activity.

A Dramatic Increase of C1q Protein in the CNS during Normal Aging

We find it important to always be careful when considering whether some scientific observation is a cause or a consequence of aging. The present paper, with its notable 300-fold increase in C1q, can easily tempt one to conclude: "high levels of C1q need to be removed." This may be the case, but not necessarily. Before coming to this kind of conclusion, we strive to ask questions such as: "Is there some aspect of the immune system, related to C1q, which is recruited more highly in aging? If we ameliorate this activation of the immune system, will C1q levels no longer rise so much?"

Finally, the authors noted that while mouse C1q was ~300 fold higher in aging, it was only 8-fold higher in human brains: a noteworthy difference. We hope that further experiments will answer these questions, and others, to inform us about the exact role of C1q in aging dysfunction.

Researchers here investigate another easy measure that correlates with mortality rates, confirming results seen in earlier studies. Insofar as reaction time is a function of rising levels of damage in brain and nervous system tissue the correlation seems plausible, but as the researchers point out there is no good understanding of the exact mechanisms involved.

In a representative sample of adults, slower and more variable performance on a simple reaction time task was associated with increased rates of both all-cause and cardiovascular disease mortality over a follow-up period of approximately 15 years. The association between reaction time variability and mortality remained after adjustment for reaction time mean, and was therefore not accounted for by the tendency for people with more variable reaction times to have slower responses.

Mechanisms underlying the association between slower and more variable reaction times and mortality risk are not known. One hypothesis concerns 'system integrity', which suggests that since bodily systems deteriorate with age, slower and more variable reaction times reflect a central nervous system that is deteriorating in parallel with other bodily systems. Given the correlated heterogeneity in the aging of these systems, slower and more variable reaction times in adulthood might indicate poor physiological functioning across several bodily systems, any of which might increase risk of death in turn.

Our results demonstrate that slower and more variable reaction times are predictors of mortality risk in a representative population sample. Priorities for future research should include identifying the mechanisms underlying these associations. Since reaction time can be measured at low cost relatively quickly, it should be measured routinely in epidemiological studies.

Link: http://dx.doi.org/10.1371/journal.pone.0082959.t004

Generating the network of blood and lymph vessels needed to sustain tissue is the hardest part of tissue engineering, or at least it is the largest obstacle at the moment. Some inroads have been made, and workarounds such as the use of decellularized donor tissue are promising. This research suggesting that researchers may be close to good solutions to the challenge of creating vessel networks in tissue grown from stem cells, however:

[Researchers] have engineered skin cells for the very first time containing blood and lymphatic capillaries. They succeeded in isolating all the necessary types of skin cells from human skin tissue and engineering a skin graft that is similar to full-thickness skin.

Tissue fluid is excreted from a wound which accumulates in a cavity on the skin's surface and can impede wound healing. Lymphatic vessels drain off this fluid. The researchers isolated lymphatic capillary cells from the human dermis. Together with the blood capillaries that were also engineered, this guarantees rapid, efficient vesicular supply of the skin graft. Up to now, this had been a major unsolved problem in molecular tissue biology and regenerative medicine.

The individual lymphatic cells spontaneously arranged themselves into lymphatic capillaries with all the characteristics of lymphatic vessels. In preclinical trials both the human lymphatic capillaries and the blood capillaries engineered in the laboratory connected with those of the laboratory animals. "What's novel is that the lymphatic capillaries collected and transported tissue fluid; hence they were functional. We assume that skin grafts with lymphatic and blood capillaries will, in future, both prevent the accumulation of tissue fluid and ensure rapid blood supply of the graft". This could markedly improve the healing process and the typical organ structure of this type of skin graft.

Link: http://www.mediadesk.uzh.ch/articles/2014/erstmals-im-labor-haut-mit-blut-und-lymphgefaessen-erzeugt_en.html

SENS stands for the Strategies for Engineered Negligible Senescence, a research and development plan first assembled more than a decade ago by biomedical gerontologist Aubrey de Grey. This was a work of vision and synthesis: taking decades of research results from many diverse fields of medical research whose scientists had comparatively little contact with one another, and little interest in working on ways to treat aging, and pulling these results together into a convincing argument as to (a) which forms of cellular and molecular damage cause aging, and (b) how to go about developing the means of repair for this damage.

Aging is damage, and repair is rejuvenation. Sufficiently comprehensive implementations of SENS should not only prevent aging and age-related disease, but also reverse the effects of aging in the old. This isn't a matter of hand-waving: the capabilities in molecular biology and research plans to build therapies are outlined in considerable detail at the SENS Research Foundation website and in related scientific papers. You should take a look if you haven't recently. The estimated cost of developing this to the point of demonstration in mice is on a par with the total cost of development of a single drug: perhaps $1-2 billion over 10-20 years.

It is pleasing to chart the changing character of press coverage over the years for SENS rejuvenation research and its figurehead advocate and organizer Aubrey de Grey. In the past ten years of increasing support within the scientific community and an influx of millions of dollars in philanthropic funding for research, it has become ever harder for journalists to stick their heads in the sand and pretend that SENS is either fringe or not real science. The gatekeepers of the establishment are never kind to any form of change or progress in the early days.

Measured by budget the SENS Research Foundation is a presently a tenth of the size of the well-established and mainstream Buck Institute for Aging Research. This is still larger than a good many labs in the field, and funding for SENS research has grown considerably over the past few years. Skilled molecular biologists in numerous laboratories are working on aspects of the SENS program of development for rejuvenation therapies. This work is still at the level of building tools and foundations for later progress but is very much real, tangible medical research. This is a new and upcoming field, the future of medical science and aging.

Aubrey de Grey: Out to Defy Death

Spend a moment asking yourself, "What is the world's worst problem?"

Biomedical gerontologist Aubrey de Grey, Ph.D., has an answer that may be radically different from yours. For him, it's aging, and he not only makes a convincing case for why this is so, but he's devoting his life to doing something about it. Dr. de Grey is the founder of SENS, a research foundation that aims to help build the regenerative medicine industry, an industry that arguably has the best chance for curing the diseases of aging. Surprisingly, he's having more success than the people who were calling him a maverick and a heretic five years ago ever imagined.

First they ignore you, then they laugh at you, then they fight you, then you win. To my eyes things have made it to the early stages of the winning part of that saying these days, certainly insofar as the scientific community is concerned. (Much more remains to be done in order to sell the public on the idea that radical life extension is a real possibility and that the relevant research is important and should be supported). SENS is far more than Aubrey de Grey nowadays: it's his vision, but has grown to be shared quite widely. There are dozens of influential allied scientists and laboratories, a number of high net worth philanthropists providing support, many advocates, a SENS Research Foundation staff, fundraisers, and of course the numerous researchers working to build the tools needed for future rejuvenation treatments.

The SENS Foundation is a public charity based in California, and its purpose is to fill a niche in the research funding chain. Private sector research, particularly in the drug industry, has funds to drive important research, but only after it's clear that the odds of success are good, the time frame is reasonably short, and the potential for profit large. At the other end of the research spectrum, public sector research funding is available for basic research that doesn't have an immediate commercial purpose.

However, in Dr. de Grey's view, and his colleagues as well, there's a midway point between the private sector funding and the public sector, and this midpoint is often neglected. Research that may yield incalculable commercial success (and public benefit as well), may be at such an early stage of development that it doesn't yet attract commercial funders. "We exist to make sure that this kind of intermediate research is not neglected," he says.

People no longer refer to Aubrey de Grey as a "maverick" or "heretic." "These days, I'm more often called 'controversial,'" he says, sounding pleased with this new characterization.

"Controversial," after all can be translated as, "might be right."

Judging by actions and the amount of noise generated, there is much more enthusiasm for hair regeneration than for regeneration of internal organs. But it's not news that people exhibit terrible prioritization when it comes to health, aging, and supporting research. If we lived in a rational world, the development of rejuvenation biotechnologies would be massively funded now that it is a plausible goal, and restoration of hair wouldn't be high on the list of priorities, given that it doesn't kill you, and there are all too many other forms of actually fatal degeneration to reverse:

One potential approach to reversing hair loss uses stem cells to regenerate the missing or dying hair follicles. But it hasn't been possible to generate sufficient number of hair-follicle-generating stem cells - until now. [Researchers demonstrated] a method for converting adult cells into epithelial stem cells, the first time anyone has achieved this in either humans or mice. The epithelial stem cells, when implanted into immunocompromised mice, regenerated the different cell types of human skin and hair follicles, and even produced structurally recognizable hair shaft, raising the possibility that they may eventually enable hair regeneration in people.

"This is the first time anyone has made scalable amounts of epithelial stem cells that are capable of generating the epithelial component of hair follicles." Those cells have many potential applications, including wound healing, cosmetics, and hair regeneration. [They] are not yet ready for use in human subjects, [however]. A hair follicle contains epithelial cells - a cell type that lines the body's vessels and cavities - as well as a specific kind of adult stem cell called dermal papillae. "When a person loses hair, they lose both types of cells. We have solved one major problem, the epithelial component of the hair follicle. We need to figure out a way to also make new dermal papillae cells, and no one has figured that part out yet."

Link: http://www.newswise.com/articles/converting-adult-human-cells-to-hair-follicle-generating-stem-cells

English is the language of computing, and hence increasingly the language of science these days. This is one of the reasons why there is much less coverage of cutting edge work on aging and related advocacy for longevity science in other languages, but here is a (translated) French language interview with Aubrey de Grey of the SENS Research Foundation:

Paris Match: Do you really think that human beings can live five hundred or a thousand years?

Aubrey de Grey: Yes. Anything that does not work in a body that ages and eventually makes us sick can potentially be cured by medicine. Without the accumulation of damage over the years, we could live hundreds of years. It is only a matter of time. My dream is that every adult, regardless of age, can remain all his or her life as healthy as when young.

Paris Match: What are the chances that aging becomes a distant memory?

Aubrey de Grey: Medicines designed to regenerate humans are all in development, although some are still in their infancy. I think we have a 50% chance to develop essential knowledge to understand the diseases of old age and therefore apply a range of therapies to eradicate these diseases. In twenty to twenty-five coming years, it will be possible.

Paris Match: Has tangible progress been made already?

Aubrey de Grey: Of course. Researchers have made significant progress in this area. For example, we know how to protect cells against high levels of damaged, toxic cholesterol. To achieve this, we inject an enzyme into these cells - a protein found in a bacterium - that makes them very resistant. This enzyme can alter chemical reactions within the cell without altering its balance.

Paris Match: Do you think that even the elderly have an opportunity to become young?

Aubrey de Grey: Yes, absolutely. The strategy of my SENS Research Foundation is based on the theory that it is much easier to periodically treat the causes of diseases associated with old age than stop the aging process itself. But everyone will benefit, because it is the interest of all states: diseases associated with old age have an astronomical cost. The ability to age in good health would be to public interest because it would make considerable savings.

Link: http://translate.google.com/translate?u=http://www.parismatch.com/Actu/Environnement-et-sciences/Ce-chercheur-veut-nous-faire-vivre-1000-ans-545950

Cellular senescence is a reaction to internal damage and the surrounding circumstances a cell finds itself in. A senescent cell ceases dividing and adopts a range of behaviors that provide a mix of benefits and harm. It provides some resistance against cancer, as a senescent cell is harder to turn cancerous and the immune system tends to destroy senescent cells. On the other hand senescent cells emit signals that harm surrounding tissue integrity and raise the odds of other nearby cells also becoming senescent - which is probably desirable from the point of view of suppressing cancer, but it also harms health, and to a certain degree cancers adapt to this situation and thrive because of it. Cellular senescence is an evolutionary struggle in mid-throes: senescence is a mechanism that has its origin in embryonic development, then repurposed to resist cancer, and now cancers in turn strive to turn it to their advantage.

From our point of view as individuals, cellular senescence is a now a net loss. We will deal with cancer through new technology: medicine is on track to achieve a first pass at that goal within a few decades. But cellular senescence is a root cause of aging. Senescent cells accumulate over time, degrading health and contributing to the downward spiral of degeneration and frailty. Studies in mice have provided evidence to reinforce theory on this point: targeted removal of senescent cells provides extension of healthy life span, at least in animals engineered to have more than the usual number of senescent cells. Work is presently underway to demonstrate the same in normal mice.

I noticed a recent paper today which provides another example of a means to address an artificial increase in the numbers of senescent cells. Rats were treated with a carcinogenic substance that increases the number of senescent cells in the liver, a model for generating cancers for study, and then provided with an infusion of fresh liver cells - just plain cells, not stem cells. That prevented or reversed the induced increase in cellular senescence.

Clearance of senescent hepatocytes in a neoplastic-prone microenvironment delays the emergence of hepatocellular carcinoma

Increasing evidence indicates that carcinogenesis is dependent on the tissue context in which it occurs, implying that the latter can be a target for preventive or therapeutic strategies. We tested the possibility that re-normalizing a senescent, neoplastic-prone tissue microenvironment would exert a modulatory effect on the emergence of neoplastic disease.

Rats were exposed to a protocol for the induction of hepatocellular carcinoma (HCC). [One] group of animal was then delivered 8 million normal hepatocytes, via the portal circulation. Hepatocytes transplantation resulted in a prominent decrease in the incidence of both pre-neoplastic and neoplastic lesions. At the end of 1 year 50% of control animals presented with HCC, while no HCC were observed in the transplanted group.

Extensive hepatocyte senescence was induced by the carcinogenic protocol in the host liver; however, senescent cells were largely cleared following infusion of normal hepatocytes.

This is pretty interesting. Is the case that delivery of large numbers of ordinary adult cells into tissue could cull senescent cells, or remove their senescent state, or greatly slow their accumulation? One has to be skeptical, however, given that this is not taking place in old mice, and it is an artificial process of induced senescence rather than the results of aging. Further, the liver is somewhat unusual among organs in mammals, capable of far more regeneration than other complex tissues. Ordinary liver cells may be more versatile and restorative than other types of cell.

The authors present an interesting set of ideas on cellular senescence further down in this paper:

An intriguing interpretation of cell senescence postulates that this unique phenotype emerges when a cell integrates two types of signals: one that reads for growth and one that imposes a block in the replicative cycle. For example, DNA damaging agents do not induce senescence in quiescent cells; however, they do so if the presence of persistent DNA damage and cell cycle arrest is coupled with growth promoting stimuli. Under these conditions, cells switch on the senescence program and express markers related to both cell cycle block and growth stimulation.

The researchers believe that an examination of changes in gene expression profiles in the rats in this study support this view. The changes visible after exposure to the carcinogen were reversed by delivery of new liver cells, which went on to repopulate the liver and - presumably - change the environment such that senescent cells were either removed, restored to non-senescent states, or not created.

The current consensus on what to do about senescent cells and their effect on long-term health focuses on building means of targeted destruction, in the same way as cancer cells are nowadays being targeted based on their distinctive chemistry. Numerous research groups are working on the components of future treatments to clear out senescent cells, although it must be said that there is very little funding for this in comparison to other areas of research. Sadly this is the story for much of the science most relevant to extending healthy human life.

In comparison, reversing senescence in situ is thought to be hard, or at least harder. Certainly far less is known about how to go about it. This study, even though a reversal of an artificial situation, is a starting point. I'd very much like to see someone try the straightforward cell delivery approach in the same way in old rats. Perhaps it will work, or perhaps the new cells will be overwhelmed and their benefits largely disabled by the old cellular environment they are introduced into. Either way, it seems something that should be tried based on the results here.

There is that part of the mind that assumes we are immortal, no matter how rational or informed we might be about the real state of the world and our own personal future - absent intervention - of aging, suffering, and death. Organized religion may have its origin in this, coupled with our tendencies towards anthropomorphism and desire for immediate answers to replace unknowns, even if those answers are incorrect. The line of thinking in a prehistoric society runs as follows: if we are immortal, then so are our dead ancestors, and who is moving the sun? These things lead to their natural conclusions.

To what degree is the inner assumption of immortality - in and of itself - something that drives public disinterest in work on rejuvenation biotechnology? I'm not completely convinced that it is important versus, say, the influence of modern religious culture, or the widespread mistaken belief that extending life would mean extending the period of frailty and suffering in old age. But it is a part of the puzzle: why are people so unwilling to help their future selves avoid pain, suffering, and death?

Most studies on immortality or "eternalist" beliefs have focused on people's views of the afterlife. Studies have found that both children and adults believe that bodily needs, such as hunger and thirst, end when people die, but mental capacities, such as thinking or feeling sad, continue in some form. But these afterlife studies leave one critical question unanswered: where do these beliefs come from? Researchers have long suspected that people develop ideas about the afterlife through cultural exposure, like television or movies, or through religious instruction. But perhaps [these] ideas of immortality actually emerge from our intuition. Just as children learn to talk without formal instruction, maybe they also intuit that part of their mind could exist apart from their body.

[Researchers] interviewed children from an indigenous Shuar village in the Amazon Basin of Ecuador. For comparison, [they] also interviewed children from an urban area near Quito, Ecuador. Both groups gave remarkably similar answers, despite their radically different cultures. The children reasoned that their bodies didn't exist before birth, and that they didn't have the ability to think or remember. However, both groups also said that their emotions and desires existed before they were born. For example, while children generally reported that they didn't have eyes and couldn't see things before birth, they often reported being happy that they would soon meet their mother, or sad that they were apart from their family. "They didn't even realize they were contradicting themselves. Even kids who had biological knowledge about reproduction still seemed to think that they had existed in some sort of eternal form. And that form really seemed to be about emotions and desires."

Why would humans have evolved this seemingly universal belief in the eternal existence of our emotions? [It] might be a by-product of our highly developed social reasoning. "We're really good at figuring out what people are thinking, what their emotions are, what their desires are." We tend to see people as the sum of their mental states, and desires and emotions may be particularly helpful when predicting their behavior. Because this ability is so useful and so powerful, it flows over into other parts of our thinking. We sometimes see connections where potentially none exist, we hope there's a master plan for the universe, we see purpose when there is none, and we imagine that a soul survives without a body.

Link: http://www.bu.edu/news/2014/01/27/boston-university-study-examines-the-development-of-childrens-prelife-reasoning/

This popular science article looks at efforts in one laboratory to develop a supply of decellularized animal kidneys for transplantation into human recipients. At the present time decellularization appears to be the most practical way to make xenotransplantation viable: replacing the animal cells with human cells removes most of the issues of transplant rejection. Xenotransplantation would be a transitional source of organs, bridging the gap between today and a future in which organs are grown directly from a patient's own cells when required, or in which the need for organ transplants is eliminated by methods of manipulating cell behavior to spur regrowth and regeneration in situ:

In the ground-floor labyrinth that connects UF Health Shands Hospital to the UF health sciences campus, a handful of scientists are super excited about research that one day could mean the end of long waiting lines for kidney transplant patients. The promise lies in a soft sponge-like structure that is about the size of a bar of soap and is considered a "scaffold" for building healthy human kidneys. The soap-sized structure is a baby pig's kidney, drained of its blood and cells. Over the course of three days, chemicals strip the kidney of swine cells so it can be injected with human stem cells.

Scientists also have successfully grown human stem cells with other, "easier" organs such as the bladder and trachea. "The kidney is one of the most difficult because of the complexity of the organ." The scaffold is not, however, just an inert skeleton. It contains proteins with chemical signals that guide human stem cells once they are implanted, or "seeded," inside the scaffold. The kidney contains 30 different cell types, so the stem cells can differentiate into these types once inside the scaffold.

The scaffold also is continuously pumped with nutrients such as oxygen, sugars and proteins to help the stem cells develop into a newly formed kidney. The scaffold gradually begins to redden as it morphs into an adult kidney. "It's still very new and very exciting."

Link: http://www.ocala.com/article/20140124/ARTICLES/140129793/1402/NEWS?p=all&tc=pgall

Myostatin is a protein involved in regulating muscle growth in mammals. Occasionally natural mutants are born with a dysfunctional myostatin gene, and these individuals enjoy the wide-ranging benefits resulting from considerable additional muscle mass and less fat tissue throughout life, resulting in a lower incidence of a range of age-related conditions. There are even a few human myostatin mutants at the present time.

Studies in mice suggest that a number of ways to manipulate the activity of myostatin are comparatively safe, producing benefits with no significant side-effects. Conversely there are other methodologies that might be acceptable in a less risk-averse era, but which would never be developed into treatments or enhancement technologies when better options are available. They have shown unpleasant or unpredictable side-effects, and efforts to further their implementation have been dropped.

Why is all this relevant? Because we lose muscle mass and strength steadily with age, a condition known as sarcopenia, and the frailty that this produces speeds the downward spiral by making it ever harder to maintain a physically active lifestyle. Insofar as sarcopenia results from a chain of consequences that works out from the fundamental cellular and molecular damage that causes aging, a working package of rejuvenation treatments after the SENS model would both prevent and reverse this loss of muscle. But a patch treatment based on myostatin inhibition is a very much closer prospect, something that has already been accomplished in numerous ways in mice in recent years. Such a treatment wouldn't do anything about the underlying damage of aging, and thus would probably do little to extend life span, but it would greatly ameliorate one narrow outcome of aging in later life.

It is worth noting that sarcopenia is not yet recognized as a disease by FDA regulators despite years of engagement by the scientific community, millions of dollars in lobbying, and so on. Thus no-one can develop a commercial treatment for sarcopenia in the US, and this negatively impacts the ability to raise funds all the way back down the research and development chain. It's the same old story of costs imposed and progress held back.

Here is a very readable and informative short open access review paper on myostatin, sarcopenia, and the prospects for building a treatment:

Myostatin and Sarcopenia: Opportunities and Challenges - A Mini-Review

Since its discovery, multiple strategies to disrupt myostatin activity have been developed, including neutralizing antibodies, propeptides, soluble ActRIIB receptors, and interacting proteins (GASP-1, follistatin and FLRG). Although alterations in myostatin expression and activity in the context of aging are incompletely understood, several of its characteristics make it a unique and desirable therapeutic target for sarcopenia.

First, postnatal inhibition of myostatin unequivocally increases skeletal muscle mass in adult and older mammals. Specifically, we have observed that weekly injections of a neutralizing antibody to myostatin for 4 weeks significantly increases the relative weights of individual muscles by up to 17% in aged mice and improved indices of muscle performance and whole-body metabolism.

Second, the effects of targeted inhibition of myostatin are highly specific to skeletal muscle. Despite profound increases in skeletal muscle in the various species in which myostatin has been mutated, the masses of other organs and prevalence of cancer appear largely unaffected. In fact, several lines of evidence suggest that disruption of myostatin signaling may positively influence age-associated changes in other tissues - either directly or indirectly. Aged myostatin null mice exhibit increased bone mineral density and improved ejection fraction compared to wild-type mice. Moreover, mice in which the myostatin gene has been mutated or deleted are resistant to diet-induced obesity, dyslipidemia, atherogenesis, hepatic steatosis, and macrophage infiltration/activation in adipose tissue and skeletal muscle.

It is critically important to note that all strategies to inhibit myostatin are not created equal. Neutralizing antibodies and propeptides are designed to specifically target myostatin, but other approaches are less discerning. For example, there is significant enthusiasm regarding the myostatin interacting protein, follistatin, as an anabolic intervention. This has partly resulted from the finding that transgenic muscle-specific overexpression of follistatin caused a further doubling, or in sum, a quadrupling of muscle mass in the double-muscled myostatin null mouse. This suggests follistatin drives skeletal muscle growth in part through a mechanism other than inhibiting myostatin.

However, if not confined to skeletal muscle, pharmacological administration of follistatin would modulate the activity of numerous molecules other than myostatin [and] jeopardize pituitary and gonadal function. Similarly, pharmacological administration of soluble ActRIIB offers more horsepower with regard to muscle growth than more targeted means to inhibit myostatin but at the cost of less specificity and greater risk.

The change we'd like to see in medicine is a move away from fixing things after high-mortality-risk events, and towards preventing those events from occurring in the first place. All too much of modern medical research is focused on rebuilding and patching up survivors, rather than addressing the root causes of fatal age-related conditions. Better rebuilding and patching does provide some improvement in the state of affairs, and when it is all you can do it is a good approach - but this is no longer all that can be done. We live in an age in which the causes of degenerative aging and all age-related disease are known and can be worked on.

If even a tenth of the research effort that goes into fixing heart damage went into preventing heart damage by repairing the cellular and molecular damage that causes aging, we'd all be far better off. That said, this technology looks like it may have far broader applications than just reducing the impact of heart attack damage on survivors:

After a heart attack, much of the damage to the heart muscle is caused by inflammatory cells that rush to the scene of the oxygen-starved tissue. But that inflammatory damage is slashed in half when microparticles are injected into the blood stream within 24 hours of the attack. When biodegradable microparticles were injected after a heart attack, the size of the heart lesion was reduced by 50 percent and the heart could pump significantly more blood.

The particles are made of poly(lactic-co-glycolic) acid [and] are designed to have a negative charge on their surface. This makes them irresistible to the inflammatory monocytes, which have a positively charged receptor. When the inflammatory cell bonds to the microparticle, a signal on the cell is activated that announces it's dying and ready for disposal. The cell then travels to the spleen, the natural path for the removal of dying cells, rather than going to the site of the inflammation.

The scientists' study showed the microparticles reduced damage and repaired tissue in many other inflammatory diseases. These include models of West Nile virus, colitis, inflammatory bowel disease, multiple sclerosis, peritonitis and a model that mimics blood flow after a kidney transplant. "We're very excited. The potential for this simple approach is quite extraordinary. Inflammatory cells pick up immune-modifying microparticles and are diverted down a natural pathway used by the body to dispose of old cells. It's amazing that such a simple detour limits major tissue damage in such a wide range of diseases."

Link: http://www.eurekalert.org/pub_releases/2014-01/nu-had010914.php

This paper provides another example of the influence of exercise on life span, even in the old. In statistical human studies all you can usually show are associations, but it is clear from animal studies in shorter lived species that there is a causative link between regular exercise and healthy life expectancy.

There has been extensive research showing that among generally healthy, cancer-free populations, physical activity extends longevity. But there has been relatively little such research on physical activity among cancer survivors. Researchers examined data from the Harvard Alumni Health Study, an ongoing study of men who entered Harvard as undergraduates between 1916 and 1950. Researchers looked at 1,021 men (average age 71) who previously had been diagnosed with cancer. In questionnaires conducted in 1988, men reported their physical activities, including walking, stair-climbing and participation in sports and recreational activities. Their physical activities were updated in 1993, and the men were followed until 2008.

Compared with men who expended fewer than 2,100 calories per week in physical activity, men who expended more than 12,600 calories per week were 48 percent less likely to die of any cause during the follow-up period. This finding was adjusted for age, smoking, body mass index, early parental mortality and dietary variables. (By comparison, a 176-pound man who walks briskly for 30 minutes a day, five days a week burns 4,200 calories.) There were similar findings for mortality from cancer and cardiovascular disease: the most physically active cancer survivors were 38 percent less likely to die of cancer and 49 percent less likely to die of cardiovascular disease during the follow-up period.

Link: http://medicalxpress.com/news/2014-01-physical-significantly-cancer-survivors.html

Gathering support for any cause in medical research is a slow process of bootstrapping. This is just as much the case for research into extending human life as for any other form of medical technology. Treatments and capabilities presently taken for granted were all bootstrapped at some point in the past, and the pioneers all had to climb the cliffs of skepticism and inertia. No matter how beneficial, new ideas and technologies are resisted and ignored at first. People don't like change.

Funds raised is one way to measure support for research, and another is the amount of time and energy people put into writing on the topic. In both cases SENS rejuvenation research - and even the broader and less promising efforts to work on enhancing human longevity - has a long way to go to reach the enthusiastic levels of support enjoyed by the stem cell or cancer research communities. Rejuvenation research will ultimately have to rise to those heights to achieve clinical application and widespread availability of treatments, but it is quite possible that demonstrations of rejuvenation in mice will precede that point by decades.

So attention, discussion, and writing is important. I'm always pleased to see new faces talking about SENS and other aspects of longevity science, and look forward to the day on which I don't recognize the origin of most of what I read online about rejuvenation biotechnology and the broader field of longevity science.

The scientific pursuit of eternal youth

"I resolve to not get any older." This may seem like a somewhat outlandish New Year's resolution, a desire more grounded in the realm of science fiction than science itself. But a growing group working in the field of biogerontology would argue that it is not. I was able to get an update on the state of the science at a session organized by Dr. Aubrey de Grey, Chief Scientific Officer of the anti-aging organization SENS (Strategic Engineering Negligible Senesence) Research Foundation, last month at the World Stem Cell Summit in San Diego.

Dr. de Grey was careful to make an important distinction about this vein of research and addressed what is known as the "Tithonus Error" - an assumption that postponing aging would extend ill-health rather than health span. In the Greek legend, Tithonus was granted immortality by Zeus at the bequest of his Titan lover and kidnapper, Eos, who in an unfortunate twist forgot to ask for Tithonus' eternal youth, cursing him to living forever in a "loathsome old age...unable to move nor lift his limbs". This public misconception thus mistakes the goal of biogerontology to extend the unhealthy phase of our life rather than the healthy. The therapeutic goal is to shift the balance between how much of our lives are lived as healthy and productive members of society and delay or prevent the onset of age-related disorders such as cancer, cardiovascular disorders and neurodegenerative disease (to name a few).

Dr. de Grey recently examined the state of messaging related to biogerontology and expounded upon the risks in promising too much in the field, lessons that have certainly been learnt in the field of stem cell research and gene therapy. It is clear from the highly accomplished scientific advisory board of SENS Research Foundation that there is considerable conceptual backing behind their goals, but a clear takeaway from the session was that they have only recently begun to enter the area of realistically achieving their goals and meeting expectations.

Do You Want To Live To Be 1,000? Better Listen Real Hard To Aubrey de Grey.

Q: What do you mean when you say ageing is no longer immutable?

A: I don't say that: I say that we are in striking distance of making it no longer immutable. What that means is that we have a good chance of developing, in the next few decades, medicines that can not only slow down the accumulation of the damage of ageing but actually repair that damage, thereby greatly postponing the disease and disability that it causes.

Q: Do you still believe the "first person to live to 1,000 is already alive"?

A: Yes I do, with high probability (note that I've only ever said "probably"). The same logic I always set out - that the first-generation rejuvenation therapies which we may well have within a couple of decades will only extend healthy life by maybe 30 years, but that that will be enough to let us figure out what to do next to re-rejuvenate the same people 30 years later, etc - is still valid.

Q: You said in a recent talk that ageing is the world's "most important problem". Is it more important than all of the problems we face (of which overpopulation, pollution, energy shortage, climate crisis, mass species extinction, desertification, ocean acidification, overfishing, general scientific illiteracy and human nature itself are but a few) which threaten the quality of our life? And why?

A: Yes, obviously it's more important than any other problem. How is any other problem even a problem at all, if you're already dead? The right way of thinking about this is that defeating ageing will give us a proper perspective on the long-term importance of other problems.

Q: What is your retort to those who say extending life is "unnatural"?

A: I simply point out that by the same token one can say that all medicine - or even all technology, all the way back to fire and the wheel - is unnatural. Or, conversely, that it is natural for humans to seek to create the unnatural as ways to improve their quality of life, and unnatural for humans to submit to living with nature as they find it.

Q: Finally, are you optimistic about the future?

A: I don't like the word "optimistic" because so many people interpret it to mean "over-optimistic". I'm realistic about the future: I have a more optimistic view than many other people, but only for very rational reasons based on actual data.

Researchers here dig in to the details of one of the mechanisms that might explain variations in the ability to heal from heart injuries - and which might be manipulated to improve the situation:

The immune system plays an important role in the heart's response to injury. But until recently, confusing data made it difficult to distinguish the immune factors that encourage the heart to heal following a heart attack, for example, from those that lead to further damage. Now, [researchers] have shown that two major pools of immune cells are at work in the heart. Both belong to a class of cells known as macrophages. One appears to promote healing, while the other likely drives inflammation, which is detrimental to long-term heart function.

"Macrophages have long been thought of as a single type of cell. Our study shows there actually are many different types of macrophages that originate in different places in the body. We found that the heart is one of the few organs with a pool of macrophages formed in the embryo and maintained into adulthood. The heart, brain and liver are the only organs that contain large numbers of macrophages that originated in the yolk sac, in very early stages of development, and we think these macrophages tend to be protective."

Healthy hearts maintain this population of embryonic macrophages, as well as a smaller pool of adult macrophages derived from the blood. But during cardiac stress such as high blood pressure, not only were more adult macrophages recruited from the blood and brought to the heart, they actually replaced the embryonic macrophages. The complex interplay between these immune cells in the heart may provide an explanation for why some people experience healing following a heart attack but others don't.

"Now that we can tell the difference between these two types of macrophages, we can try targeting one but not the other. We want to try blocking the adult macrophages from the blood, which appear to be more inflammatory. And we want to encourage the embryonic macrophages that are already in the heart to proliferate in response to stress because they do things that are beneficial, helping the heart regenerate."

Link: https://news.wustl.edu/news/Pages/26362.aspx

An example of ongoing experiments and improvements in methodology for stem cell treatments:

[Researchers] report they have developed human induced-pluripotent stem cells (iPSCs) capable of repairing damaged retinal vascular tissue in mice. The stem cells, derived from human umbilical cord-blood and coaxed into an embryonic-like state, were grown without the conventional use of viruses.

"We began with stem cells taken from cord-blood, which have fewer acquired mutations and little, if any, epigenetic memory, which cells accumulate as time goes on." The scientists converted these cells to a status last experienced when they were part of six-day-old embryos. Instead of using viruses to deliver a gene package to the cells to turn on processes that convert the cells back to stem cell states, [the] team used plasmids, rings of DNA that replicate briefly inside cells and then degrade.

Next, the scientists identified high-quality, multipotent, vascular stem cells generated from these iPSC that can make a type of blood vessel-rich tissue necessary for repairing retinal and other human material. They identified these cells by looking for cell surface proteins called CD31 and CD146. [The] team injected the newly derived iPSCs into mice with damaged retinas, the light-sensitive part of the eyeball. Injections were given in the eye, the sinus cavity near the eye or into a tail vein. When the scientists took images of the mice retinas, they found that the iPSCs, regardless of injection location, engrafted and repaired blood vessel structures in the retina.

Link: http://www.eurekalert.org/pub_releases/2014-01/jhm-lvs012314.php

We humans are capable of the most mundane of evils. Perhaps the most pervasive in this age in which no decision is permitted to be private and individual any more, in which government is used as a lever to open up access to the minutiae of everyone's lives and pour them onto the public stage to be regulated and inspected, is the evil of seeking to deprive others of a benefit that the seeker would readily make use of were it theirs. Money, and all the trappings of wealth, are the classic example. There is no evil as boring and ubiquitous as the person who works to tear down those who have more than he does, even as he strives to accumulate more for himself.

When it comes to enhancing human longevity, there is no harm done to the world by the personal choice to stand to one side, not participate, and age and die. It seems a waste and a shame, but freedom comes with the option to shun potential and refuse opportunity: it wouldn't be freedom if it didn't. All too many people who declare their intent to do this are clearly availing themselves of all the advantages of modern medicine, however. Their position is incoherent. Put them fifty years in the past and they would be arguing against the very technologies that are keeping them alive in good health. Put them fifty years into the future and they would be taking advantage of rejuvenation treatments just like the majority of the population. But again, it is a choice to act and think this way, and for so long as it is a personal choice it doesn't harm progress.

The real problem is those who seek to forge the world to their view: who would use the state as a lever to block and hold back work on rejuvenation treatments for everyone. This is a great evil, the consequences of its success measured in millions of lives for each month of delay, and the ongoing suffering and pain of hundreds of millions more.

The Moral Bankruptcy of Deathism

As research related to life extension has progressed and the concept has begun to register with the mass public mind, we increasingly face objections arguing not that we can't achieve it, but that we shouldn't. In-vitro fertilization, therapeutic cloning, stem-cell research, and other medical innovations of recent times have met with the same agitated yammering about going against nature. The objections to anti-aging research are just the latest incarnation of the same old mentality.

Another tack some people take is to insist that they personally would not want to extend their lives indefinitely. I doubt this - very few people, in practice, refuse an opportunity to save their own lives when death is staring them in the face - but even if they're telling the truth, it's perfectly irrelevant to the larger issue of whether research in the field should keep going. Even when radical life extension becomes a reality, anyone who seriously objects to the idea will be free to refuse whatever therapies are involved, just as adults today are free to refuse blood transfusions or other medical treatments to which they object on whatever grounds. The fact that some people and religious sects have such objections is not a basis for arguing that blood transfusion should not have been invented.

And this is the key point: the deathist moral position is an abominable one. It boils down to saying that I need to die because of your visceral discomfiture with something.

We're already quite some ways down this road. During the [19th and 20th centuries], life expectancy at birth in developed countries roughly doubled, from about 40 years to about 80, due to vaccines, antibiotics, and various other innovations. All the clichéd objections that are now made to radical life extension - overpopulation, cultural stagnation due to having too many old people around, widening the gap between rich and poor countries, etc. - could just as easily have been made in 1900 against these achievements. But it would be an audacious deathist indeed who would argue today that we should not have invented vaccines, or should stop using them now.

Mitochondria are important in aging. Each cell has its self-replicating herd of mitochondria, which play a vital role in many processes. Unfortunately they become damaged over time. Most damage to individual mitochondria can be rescued since they have limited repair processes, are recycled by other cellular processes when damage is detected, and can divide and merge like bacteria. Further they are more like enclosed bags of liquid than fixed machines, and promiscuously swap component parts with with another inside a cell. Cells can even deliver whole mitochondria to one another when in close contact.

Thus mitochondrial dynamics are pretty complex, all told, and researchers continue to discover new aspects even now. Some forms of mitochondrial damage are persistent, however: they interfere with the process of culling damaged mitochondria, and so replicate throughout a cell making it dysfunctional and harmful to the surrounding tissue. This is one of the causes of aging.

There are a number of proposed ways to treat and reverse this problem, most quite close to realization, and some of which are more robust than others. Delivery of new unbroken mitochondria or mitochondrial parts will bring short-term benefits but it won't last - the damaged forms of mitochondria will win out again, just as they did in the first place. Nonetheless, more researchers are looking into this sort of approach than are working on the SENS strategy of creating backup sources of mitochondrial parts in the cell nucleus. This research is of interest to this line of work:

A research team has identified a protein that increases the transfer of mitochondria from mesenchymal stem cells to lung cells. [The] delivery of mitochondria to human lung cells can rejuvenate damaged cells. The migration of mitochondria from stem cells to epithelial cells also helps to repair tissue damage and inflammation linked to asthma-like symptoms in mice.

"Our results show that the movement of mitochondria from stem cells to recipient cells is regulated by the protein Miro1 and is part of a well-directed process. The introduction of mitochondria into damaged cells has beneficial effects on the health of cells and, in the long term, we believe that mesenchymal stem cells could even be engineered to create more effective therapies for lung disease in humans."

Earlier work revealed that mitochondria can be transferred between cells through tunneling nanotubes, thread-like structures formed from the plasma membranes of cells that bridge between different types of cells. Stem cells can also use tunneling nanotubes to transfer mitochondria to neighboring cells and the number of these nanotubes increases under conditions of stress.

Link: http://www.embo.org/news/research-news/research-news-2014/stem-cells-improve-damage-in-other-cells-by-exporting-mitochondria

The free radical theory of aging had a long time in the sun, but - like so many other narrow theories of aging that led to the present diversity of understanding - it is clearly neither the whole picture nor even particularly correct in its original formulation. This researcher is thinking along these lines, with a viewpoint similar to that of the SENS program for rejuvenation research:

The free radical theory of aging posits that aging is caused by accumulation of damage inflicted by reactive oxygen species (ROS). Although this concept has been very useful in defining the contribution of oxidative damage to the aging process, an increasing number of studies contradict it. The idea that oxidative damage represents only one of many causes of aging also has limitations, as it does not explain causal relationships and inevitability of damage accumulation.

Here, it is discussed that infidelity, heterogeneity, and imperfectness of each and every biological process may be responsible for the inevitable accumulation of by-products and other damage forms. Although ROS are prototypical by-products, their contribution to aging is governed by the metabolic organization of the cell, its protective systems, and genotype. These factors are controlled by natural selection and, like dietary and genetic interventions that extend lifespan, change the composition of cumulative damage and the rates of accumulation of its various forms.

Oxidative damage, like other specific damage types viewed in isolation or in combination, does not represent the cause of aging. Instead, biological imperfectness, which leads to inevitable accumulation of damage in the form of mildly deleterious molecular species, may help define the true root of aging. Free radical and other specialized damage theories served their purpose in the understanding of the aging process, but in the current form they limit further progress in this area.

Link: http://dx.doi.org/10.1089/ars.2013.5228

Via Maria Konovalenko, I see that the Third International Conference on the Genetics of Aging and Longevity will be held in Sochi, Russia, in April. This is one of the more visible results of the work undertaken by the community of Russian advocates and researchers focused on the extension of health human lifespan. They have a vision for needed research and development that is different from both that of the US mainstream and the disruptive repair-based focus of SENS rejuvenation research, as it is largely informed by programmed aging theories. You can peruse some of the translated downloadable materials at the English language site of the Science for Life Extension Foundation to get an idea of this focus. Alexei Moskaliev's blog is another good resource, though not everything available for viewing there is in English.

While I might not agree with the viability of work based on an assumption of programmed aging, the energetic Russian contingent of the broader community does great work, and helps to bring greater attention to the field as a whole. Their unabashed and straightforward focus on radical life extension and the end of degenerative aging as logical and desirable goals of aging research is very welcome, and I'd like to see more of that from the English language scientific community. The Genetics of Aging and Longevity conference series in particular is turning into an influential event, and the list of those involved looks like a Who's Who of noteworthy figures in mainstream aging and longevity research.

Third International Conference on the Genetics of Aging and Longevity

The third international conference "Genetics of aging and longevity" will take place in Sochi, Russia from 6th till 10th of April, 2014. The event is held by "Science for Life Extension" foundation and Institute of Biology of Ural department of Russian Academy of Science.

With this conference being held once in two years, it is the fourth time for it to happen and the third time to be international. As a result of the previous conference in 2012, this event has become the central discussing board of longevity and aging issues in Russia, uniting the field's leading scientists from all over the world. Having received wide international recognition, it has become a must-see point in longevity science agenda.

Back in 2012, more than 700 people visited the conference in four days of its work, including genetics scientists, bio-informatics specialists, biologists, doctors, journalists, entrepreneurs and investors. Conference of 2014 will bring together some of the most well-known scientists and representatives of the world's leading longevity laboratories and institutions from the US, Europe, Russia and Asia. The program committee consists of thirty experts responsible for delivering the highest level of scientific content possible and providing the latest data.

Experts, business representatives, public figures and authorities will join together to discuss fundamental science as well as more practical applied science issues. Along with the unique scientific content, round tables and informal meetings with world's leading experts will be held, giving everyone a chance to discuss a large variety of questions, including investment opportunities in the field of slowing aging and treating age-related diseases.

The event will reveal the on-growing demand on longevity research both in science and in business. Some of the materials for the "Genetics of aging and longevity" conference have never been published before and will be first presented on the conference, forecasting the future of longevity science. We welcome you to one of the most exciting science events of 2014!

Researchers are trying a new approach to speeding regrowth of tissue guided by a scaffold structure:

Studies suggest that increasing angiogenesis - the formation of new blood vessels - may help to heal wounds. One way to enhance the development of blood vessels is through the delivery of growth factors directly to wounds; yet multiple growth factors are needed to produce mature blood vessels, and their concentration as well as the timing of their application must be carefully orchestrated to facilitate proper growth. An alternative approach involves delivering siRNA - short, double-stranded RNA molecules designed to silence a gene of interest - to cells in order to influence genes that induce the formation of new blood vessels.

[Researchers used] a novel tissue scaffold that can deliver siRNA to nearby cells over a period of several weeks. Using an siRNA dose 10-100-fold lower than previous studies, the research team efficiently silenced the expression of PHD2 - a protein that normally inhibits blood vessel formation - locally within a biodegradable tissue scaffold. At 33 days post-implant, the scaffolds that delivered PHD2 siRNA had a three-fold increase in the volume of local blood vessels.

To achieve sustained delivery, the researchers first packaged siRNA into nanoparticles, which protect siRNA from being degraded by enzymes found in the extracellular environment. They then combined these nanoparticles with varying amounts of a substance called trehalose. This nanoparticle-trehalose combination was then embedded into a biodegradable tissue scaffold, which they implanted under the skin of a mouse. Trehalose acts as a porogen, meaning it creates pores in the tissue scaffold. As a result, the rate at which nanoparticles are released from the scaffold is directly influenced by the amount of trehalose added. Based on the quantity of trehalose, the system can be tuned to release the nanoparticles to the surrounding cells immediately or over a period of several weeks.

Link: http://www.nibib.nih.gov/news-events/newsroom/breakthrough-technology-enables-gene-silencing-heal-wounds

A range of different manipulations of myostatin have been shown to safely and significantly increase muscle mass and strength in mice. Some rare natural myostatin mutants exist in our species and other larger mammals. All in all it seems like a promising line of research to ameliorate age-related muscle loss, whether or not it rises to the level of diagnosis as sarcopenia. This doesn't address the underlying causes, but it could greatly increase the buffer of muscle tissue to resist those causes: a patch, but not a bad patch, given the large degree to which muscle mass is gained in these experiments.

Mammalian aging is accompanied by a progressive loss of skeletal muscle, a process called sarcopenia. Myostatin, a secreted member of the transforming growth factor-β family of signaling molecules, has been shown to be a potent inhibitor of muscle growth. Here, we examined whether muscle growth could be promoted in aged animals by antagonizing the activity of myostatin through the neutralizing activity of the myostatin propeptide.

We show that a single injection of an AAV8 virus expressing the myostatin propeptide induced an increase in whole body weights and all muscles examined within 7 weeks of treatment. Our cellular studies demonstrate that muscle enlargement was due to selective fiber type hypertrophy, which was accompanied by a shift toward a glycolytic phenotype. Our molecular investigations elucidate the mechanism underpinning muscle hypertrophy by showing a decrease in the expression of key genes that control ubiquitin-mediated protein breakdown. Most importantly, we show that the hypertrophic muscle that develops as a consequence of myostatin propeptide in aged mice has normal contractile properties. We suggest that attenuating myostatin signaling could be a very attractive strategy to halt and possibly reverse age-related muscle loss.

Link: http://dx.doi.org/10.1093/gerona/glt170

The adaptive immune system that we are all born with is structurally unsound for long term use. Even if we did not accumulate any of the known forms of cellular and molecular damage thought to cause degenerative aging, the adaptive immune system would still grind itself down into a state of continual malfunction. In this it is unusual: absent damage, a liver or a heart would continue to function as well as it did in youth far beyond the present human life span.

Why would the immune system fail even absent damage? From a mechanistic standpoint - and simplifying a complex situation considerably - it fails because it has a limited supply of new T cells in adulthood, but is programmed to assign some of its T cells to remembering every new threat that it encounters. Some threats, such as otherwise largely harmless herpesviruses like CMV, are exceedingly persistent and come back again and again. Eventually there are too many memory T cells and not enough naive T cells capable of attacking new pathogens or destroying senescent and precancerous cells. The outcome is frailty: inability to resist diseases, a greater toll on the body due to cellular senescence, and a rising risk of cancer.

(There are other structural issues, such as the fact that the immune system falls into a state of chronic low-level activation, producing inflammation: it is on alert, imposing the costs of inflammation on the body, but at the same time ever more ineffective at actually doing anything useful while being on alert. But for the same of this discussion, I'll skip over that, as it may be more of a consequence of forms of low-level tissue damage that accompanies aging rather than an inherent property resulting from the composition and activities of the immune system).

I thought I'd point out a couple of papers from the research community presently focused on T cell dynamics and the aging of the immune system, all from a recent issue of Experimental Gerontology. As you take a look, bear in mind that there are many plausible near-future ways in which these problems of the aging immune system might be addressed, some of which are already well within the capabilities of the research community. For example, we might regularly treat old people with infusions of immune cells grown from their own stem cells. Or we might aim to rejuvenate the thymus through tissue engineering: it atrophies in early adulthood, and restoring it would provide a flow of new immune cells created in the body. Another option is to target and destroy the excess population of memory cells. Many are useless, duplicates fixated on CMV or other non-threatening targets. Targeted cell killing technologies under development by the cancer research community are well suited to this task.

All in all there are many options, and most are either presently possible or a bare few years away - if there is just sufficient funding and interest in moving forward to rejuvenation the aged immune system. There is far from any sort of unified consensus on what approach to take, however, or even that the sketch I provided above is in fact an important part of the overall picture. You might see the first of the papers below, for example, in which the authors propose that promising results for thymic restoration in mice will probably not translate to humans. Other researchers are much more interested in developing drugs to manipulate the organization and activities of the immune system than in targeted destruction of excess memory cells or cell therapies to deliver new immune cells. So it goes - this is par for the course in any field.

Mechanisms shaping the naïve T cell repertoire in the elderly - Thymic involution or peripheral homeostatic proliferation?

The ability of the human immune system to repel infections is drastically diminished with age. Elderly individuals are more susceptible to new threats and are less able to control endogenous infections. The thymus, which is the sole source of new T cells, has been proposed as a target for regenerative efforts to improve immune competence, as thymic activity is dramatically reduced after puberty.

In this review, we review the role of the thymus in the maintenance of T cell homeostasis throughout life and contrast the differences in mice and humans. We propose that in humans, lack of thymic T cell generation does not explain a decline in T cell receptor diversity nor would thymic rejuvenation restore diversity. Initial studies using next generation sequencing are beginning to establish lower boundaries of T cell receptor diversity. With increasing sequencing depth and the development of new statistical models, we are now in the position to test this model and to assess the impact of age on T cell diversity and clonality.

Naive T cells: The crux of cellular immune aging?

When encountering foreign antigens, naïve T cells become activated and differentiate into effector and memory T cells. They represent therefore the primary source to mount an immune response against pathogens or tumors. Recent evidence of both quantitative and qualitative alterations of naïve T cells has accumulated in aged mice, indicating that the successful generation of primary T cell responses from the naïve T cell pool may be compromised with old age.

However, the vast majority of the data supporting compromised naïve T cell priming efficacy with old age have been produced in animal models, and the situation is much less clear in humans. In the elderly, the involution of the thymus and the associated decline in thymic output result in a decreased number of naïve T cells, which is partially compensated by homeostatic proliferation. Emerging evidence suggest that alterations of the TCR repertoire diversity and intrinsic defects of old CD4+ naïve T cells may impact on their responsiveness to antigenic stimulation. Increasing focus on the study of naïve T cells (in particular CD8+) in old humans are needed to fill the gaps in our understanding of reduced cellular immunity with aging.

CD4 T cell defects in the aged: Causes, consequences and strategies to circumvent

Aging leads to reduced immunity, especially adaptive responses. A key deficiency is the poor ability to mount robust antibody response. Although intrinsic alterations in B cells with age are in part responsible, impaired CD4 T cell help makes a major contribution to the poor antibody response. Other CD4 effector responses and memory generation are also impaired.

We find delayed and reduced development of CD4 T follicular help (Tfh) cells in aged mice in response to influenza infection with reduction of long-lived plasma cells. We summarize strategies to circumvent the CD4 T cell defect in aged, including adjuvants and proinflammatory cytokines. We find that we can strongly enhance responses of aged naïve CD4 T cells by using Toll-like receptor (TLR) activated dendritic cells (DC) [and] that this leads to improved [antibody responses].

Researchers here propose that, regardless of other forms of physiological damage that degrade the brain with age, we might consider that simply having a longer period of learning behind you could cause a decline in cognitive ability. This is plausible in the theoretical sense; there are plenty of other systems in the body, such as the immune system, that experience declining effectiveness over time not only because of damage or wear and tear but also due to the way in which they are structured. Evolution doesn't produce perpetual operation, but rather systems that have peak performance for just long enough to get by - and that can result in a system that eventually grinds itself into self-destruction simply through continued normal operation.

Theoretically plausible and a meaningful effect are two very different things, however. The weight of evidence linking forms of physiological damage in the brain with levels of cognitive decline strongly suggest that damage is the overwhelming cause. These researchers are arguing from the point of view of models of how the brain works, rather than any more robust data. So I'm not giving this line of thinking too much serious consideration at this point in time. But we shall see:

In what follows, we consider the question of whether one might reasonably expect that performance on any measure of cognitive performance could or should be expected to be age- or, more specifically, experience-invariant. We shall suggest that, since the answer to this question is no, many of the assumptions scientists currently make about "cognitive decline" are seriously flawed and, for the most part, formally invalid.

We will show that the patterns of response change that are typically taken as evidence for (and measures of) cognitive decline arise out of basic principles of learning and emerge naturally in learning models as they acquire more knowledge. These models, which are supported by a wealth of psychological and neuroscientific evidence, also correctly identify greater variation in the cognitive performance of older adults, and successfully predict that older adults will exhibit greater sensitivity to the fine-grained properties of test items than younger adults.

[These] patterns of performance reflect the information-processing costs that must inevitably be incurred as knowledge is acquired. Once the cost of processing this extra information is controlled for in studies of human performance, findings that are usually taken to suggest declining cognitive capacities can be seen instead to support little more than the unsurprising idea that choosing between or recalling items becomes more difficult as their numbers increase.

Link: http://onlinelibrary.wiley.com/doi/10.1111/tops.12078/full

At some point researchers will begin earnestly trying to develop the means to replicate some of the beneficial effects of exercise via drugs, in the same way as they are presently trying to replicate the beneficial effects of calorie restriction. At the moment research is still largely exploratory, based on the handful of targets known to be related to the metabolic response to exercise:

Normal aging can result in a decline of memory and muscle function. Exercise may prevent or delay these changes. However, aging-associated frailty can preclude physical activity.

In young sedentary animals, pharmacological activation of AMP-activated protein kinase (AMPK), a transcriptional regulator important for muscle physiology, enhanced spatial memory function, and endurance. In the present study we investigated effects of AMPK agonist 5-aminoimidazole-4-carboxamide riboside (AICAR) on memory and motor function in young (5- to 7-wk-old) and aged (23-mo-old) female C57Bl/6 mice, and in young (4- to 6-wk-old) transgenic mice with muscle-specific mutated AMPK α2-subunit (AMPK-DN).

Mice were injected with AICAR (500 mg/kg) for 3-14 d. Two weeks thereafter animals were tested in the Morris water maze, rotarod, and open field. Improved water maze performance and motor function were observed, albeit at longer duration of administration, in aged (14-d AICAR) than in young (3-d AICAR) mice. In the AMPK-DN mice, the compound did not enhance behavior, providing support for a muscle-mediated mechanism.

In addition, microarray analysis of muscle and hippocampal tissue derived from aged mice treated with AICAR revealed changes in gene expression in both tissues, which correlated with behavioral effects in a dose-dependent manner. Pronounced up-regulation of mitochondrial genes in muscle was observed. In the hippocampus, genes relevant to neuronal development and plasticity were enriched. Altogether, endurance-related factors may mediate both muscle and brain health in aging, and could play a role in new therapeutic interventions.

Link: http://dx.doi.org/10.1101/lm.033332.113

Drawing on historical analogies is a common practice when trying to figure out where we are and where we're going. We're all still human, and development today proceeds according to human nature first and foremost, just the same as in the past: great progress has taken place, but when comes down to the basic organization of research, development, and commercialization of products, there are still far more similarities than differences in comparisons with any given yesteryear. We can recognize the elements of our present work in the way the Victorians and the Romans did business - so a mere few decades past into the last century seems quite safe to mine for examples.

Biotechnology is the application of the life sciences, and the foundation of medicine. At present progress in biotechnology is rapid and revolutionary. The groundwork for a series of disruptive, factor-of-ten improvements in a variety of medical technologies has already been accomplished: think of the attention given to gene sequencing over past years, for example, the world watching as costs plummeted even while capabilities increased year over year. That is just one of many, many applications in biotechnology that are improving in similar ways.

I've pointed out in the past that this present stage bears considerable resemblance to the dawn of the age of powered flight: decades in which the necessary technologies for aircraft as we recognize them were developed in isolation, for other uses, or assembled into noble failures. Then, suddenly the leap was made and in just a few further decades following that the whole nature of travel underwent a revolution - a disruptive advance in the speed and opportunity to move from place to place was achieved.

A different sort of leap occurred over the 1960s and 1970s in the development of modern computing: the move from expensive, large computing devices to cheap, small computing devices. A mere change in price is far from prosaic and boring: it drives sweeping changes in adoption and expansion in the forms of application for any given technology. The lower the barrier to entry - price in this case - the more experimentation and thinking takes place, leading to greater application of a given technology for the benefit of all. In the past I've pointed out the parallels between the early personal computing societies of the 1970s and the present diybio community: enthusiasts, hobbyists, and professionals merging their efforts as costs fall to the point at which anyone can join in and build.

If you look at the Computer History Museum's entries for 1960, 1965, and 1970, it's not unreasonable to suggest that we're somewhere in the middle there when it comes to biotechnology today. The present trend I have in mind is the move towards small, portable, low-cost laboratory equipment that can accomplish most of what was possible in a large lab ten years ago. A lab in a box by that metric is years away still, but numerous groups are making significant inroads towards that goal.

But why care about this? In truth it isn't all that important to me whether or not 2010 in biotechnology is 1960 in computing, but is important to me to have some model for the next few decades of work in medical science, and in particular the ability to make progress towards treatment and reversal of aging. How much progress is likely in the foundations, the capabilities in biotechnology (other people have looked at that exhaustively from a different angle)? Should we expect and plan for disruption of the research process to the point at which the barrier between trained professional and effective self-educated contributor blurs to nothing, as has happened for software development?

We can ask these and other questions so as to have some idea as whether matters are proceeding as fast as they might, and what new directions in effective advocacy and funding will arise in the near future. Clearly at some point if the institutions are not funding the research and development work we feel is important, it will be possible to do it ourselves. Given smart, motivated collaborators and crowdfunding complex problems can be solved in software development today. Creating applications of new knowledge in molecular biology and medical science is no more complex than constructing big software projects - the differences between these two types of undertaking are the degree to which regulation obstructs change, raises costs, and prohibits participation, and the anemic, expensive nature of the presently publicly available tools for life science work. The latter will change, rapidly, and the former will simply mean that development will occur most readily in regions outside the US.

But these are things to think on as we watch and support our favored research into aging and longevity. In past decades we could only have watched - the amounts of money involved were too large for any ordinary individual to help with. But the cost of life science research is plummeting, and here and now crowdfunding of research projects that advance the state of the art is a very real thing. Medical research for your favored causes isn't just a spectator sport anymore: the times are changing.

The evidence for intermittent fasting to improve health and extend life is pretty good, but nowhere near as solid as that for calorie restriction. There appear to be separate mechanisms at work: researchers have demonstrated at least some benefits to result in laboratory animals for intermittent fasting without reduction in dietary calorie levels, for example. Additionally, the gene expression profiles of intermittent fasting and calorie restricted mice are noticeably different. Still, it seems likely that in most cases some of the benefits of intermittent fasting are derived from a reduction in overall calorie intake.

Thousands of people deliberately practice calorie restriction on the basis of the scientific evidence to date, and over the past decade or two the Calorie Restriction Society has spurred research programs that have produced pretty compelling human data. Given that intermittent fasting is in many ways an easier sell to the public in this age of obesity and low-cost food, I imagine that we'll see a similar growth in research and awareness in the years ahead. That says nothing about the relative merits or level of scientific support for outcomes at this point, of course - and on that count calorie restriction is far ahead.

Periods of deliberate fasting with restriction of solid food intake are practiced worldwide, mostly based on traditional, cultural or religious reasons. There is large empirical and observational evidence that medically supervised modified fasting (fasting cure, 200-500 kcal nutritional intake per day) with periods of 7-21 days is efficacious in the treatment of rheumatic diseases, chronic pain syndromes, hypertension, and metabolic syndrome. The beneficial effects of fasting followed by vegetarian diet in rheumatoid arthritis are confirmed by randomized controlled trials.

Further beneficial effects of fasting are supported by observational data and abundant evidence from experimental research which found caloric restriction and intermittent fasting being associated with deceleration or prevention of most chronic degenerative and chronic inflammatory diseases. Intermittent fasting may also be useful as an accompanying treatment during chemotherapy of cancer.

A further beneficial effect of fasting relates to improvements in sustainable lifestyle modification and adoption of a healthy diet, possibly mediated by fasting-induced mood enhancement. Various identified mechanisms of fasting point to its potential health-promoting effects, e.g., fasting-induced neuroendocrine activation and hormetic stress response, increased production of neurotrophic factors, reduced mitochondrial oxidative stress, general decrease of signals associated with aging, and promotion of autophagy. Fasting therapy might contribute to the prevention and treatment of chronic diseases and should be further evaluated in controlled clinical trials and observational studies.

Link: http://dx.doi.org/10.1159/000357765

The state of clinical development for tissue engineering of less complex parts of the body is far advanced beyond organ engineering. Organs like hearts, livers, and lungs are far more structurally diverse than, say, a trachea, and thus an acceptable biological substitute trachea is easier to build - well within the capabilities of today's laboratories. That translates into faster progress towards broader availability in the clinic:

Since 2008, eight patients have been given a new chance at life when surgeons replaced their badly damaged tracheas with man-made versions. This highly experimental technology is now moving from research labs to a manufacturing facility as a Boston-area company prepares to produce the scaffolds for growing the synthetic organs on a large scale.

Harvard Apparatus Regenerative Technology, or HART, is testing its synthetic trachea system in Russia and has plans for similar tests in the European Union this year. The company is working with the U.S. Food and Drug Administration to set up a trial in the United States as well. The synthetic windpipes are made by growing a patient's own stem cells on a lab-made scaffold. In the future, this technique could be adapted to create other organs, such as a replacement esophagus, heart valve, or kidney.

HART creates the scaffolds by spinning fibers about a hundredth of the width of a human hair into a tube that is made to fit each patient. Stem cells taken from a patient's bone marrow are then "rained down over the top of the scaffold, much like a chicken in a rotisserie." The cells grow on the scaffolds in a specialized rotating incubator for about two days before they are transplanted. About five days after the transplant, new cell types appear on the organ, including important cells that line the inner surface and help move mucous from the lungs by coughing. Eventually, blood vessels grow into the synthetic organ.

Link: http://www.technologyreview.com/news/522576/manufacturing-organs/

Advocacy, philanthropy, and practical efforts aimed at breaking new ground in medical science tend to ebb and flow like the tide: initiatives come in waves, as it takes some time for communities to form, evolve, digest the results of the last wave, assess new knowledge, and for newly motivated leaders to realize their roles and step forward.

The current wave, of which the most visible organizations involved in advocacy are the Methuselah Foundation, SENS Research Foundation, and the Longevity Dividend (and its supporting organizations), started out in earnest a decade ago, give or take. Tens of millions of dollars have been raised and devoted to research aimed at human rejuvenation, and a billion dollars or more for unsuccessful attempts to develop and commercialize means to modestly slow aging. Concurrently, a great deal of networking behind the scenes has led to a research community that is much more receptive to the goal of enhancing human longevity.

The start of the present wave took place ten years after a much smaller set of initiatives were launched or set underway, came and went, such as the work of the late Robert Bradbury. The 1990s were a thin time to be interested in serious work on human longevity, and the broader research community was largely disinterested in showing any sort of public support for these ideas.

The tide is coming in these past few decades, however. The waves are growing greatly in size and strength from cycle to cycle: it doesn't happen anywhere near as rapidly as we would like, but it is happening. The wave of the 1990s raised and directed only a few million dollars in funding to forward-looking causes related to longevity science, and went largely unnoticed by the broader public - but the community of supporters and advocates was significantly larger by the end than at the beginning. Concurrently tens of millions went to research into the newly discovered plasticity of longevity and aging in laboratory species: genetic engineering to discover ways to extend life through metabolic manipulation. The wave of the past decade has raised at least ten times as much as these figures on either side of the divide (the radical goals of rejuvenation versus the mainstream focus on slowing aging), and made comparatively large inroads into public and scientific perception. The times are changing, and biotechnology is progressing rapidly. What looked like pipe dreams twenty years ago are practical postgraduate research projects today.

It is about time for the next wave to begin. One might even argue that the decision by Google's board to devote hundreds of millions of dollars to mainstream longevity research marks the opening of the next decade of advocacy and research aimed at extending the healthy human life span. Again, something that looks like a tenfold multiple of funding compared to the wave now ending might occur if Google follows through with the plan as sketched to date - though it isn't at all clear that Google's Calico initiative will do anything more than augment the National Institute on Aging (NIA), and to a first approximation the NIA isn't funding anything that will lead to radical life extension or human rejuvenation.

But a rising tide raises all boats: the more that targeted treatment of aging becomes a deliberately funded and discussed goal, the easier it becomes to raise funds for rejuvenation research along the lines of the SENS model of damage repair - work that can lead to radical life extension on a comparatively short timeframe, given sufficient resources and interest.

Beyond Google, we might expect to see all sorts of new initiatives launching in the next few years: people new to the community, emboldened by what they have seen in the research community and in the efforts of groups now a decade old. Welcome aboard to all of them, I say: the more the merrier. There is still a great deal to accomplish, and the more who help out the better our chances of attaining and benefiting from the goal of working rejuvenation treatments.

The composition of gut bacteria is thought to influence aging: there is a modest range of work on this topic in laboratory animals, but nowhere near as much as on, say, the effects of calorie restriction on aging. Here is an example of ongoing investigations:

[Scientists] have promoted health and increased lifespan in Drosophila by altering the symbiotic, or commensal, relationship between bacteria and the absorptive cells lining the intestine. The research [provides] a model for studying many of the dysfunctions that are characteristic of the aging gut and gives credence to the growing supposition that having the right balance of gut bacteria may be key to enjoying a long healthy life.

The bacterial load in fly intestines increases dramatically with age, resulting in an inflammatory condition. The imbalance is driven by chronic activation of the stress response gene FOXO (something that happens with age), which suppresses the activity of a class of molecules (PGRP-SCs, homologues of PGLYRPs in humans) that regulate the immune response to bacteria. PGRP-SC suppression deregulates signaling molecules that are important to mount an effective immune response to gut bacteria. The resulting immune imbalance allows bacterial numbers to expand, triggering an inflammatory response that includes the production of free radicals. Free radicals, in turn, cause over-proliferation of stem cells in the gut, resulting in epithelial dysplasia, a pre-cancerous state.

[Researchers] increased the expression of PGRP-SC in epithelial cells of the gut, which restored the microbial balance and limited stem cell proliferation. This enhancement of PGRP-SC function, which could be mimicked by drugs, was sufficient to increase lifespan of flies. "If we can understand how aging affects our commensal population - first in the fly and then in humans - our data suggest that we should be able to impact health span and life span quite strongly, because it is the management of the commensal population that is critical to the health of the organism."

"Quite strongly" in this context means a couple of years in humans, or a few days in flies - a very minor, modest extension of life in the grand scheme of things, in other words. This is the trouble with most of present day research in the field: it aims only to slow aging, and only to slow aging a little. Ambitions are low, and this - and much of the rest of the field - certainly isn't SENS or otherwise at all relevant to a goal of radical life extension of decades or more.

Newslink: http://www.thebuck.org/buck-news/altering-community-gut-bacteria-promotes-health-and-increases-lifespan

Autophagy is a collection of cellular housekeeping processes known to be important in aging: many of the methods of altering metabolism to extend life include raised levels of autophagy in their effects. Artificially boosting autophagy beyond normal levels - or even just restoring it to youthful levels, as it declines with age - has for some years shown promise as a method of treating a range of age-related conditions, especially those that involve aggregations of misfolded proteins. Here is an example of this sort of work:

Abnormal aggregation of SNCA/α-synuclein plays a crucial role in Parkinson disease (PD) pathogenesis. SNCA levels determine its toxicity, and its accumulation, even to a small extent, may be a risk factor for neurodegeneration. One of the main pathways for SNCA degradation is chaperone-mediated autophagy (CMA), a selective form of autophagy, while aberrant SNCA may act as a CMA inhibitor.

We summarize our recent data showing that induction of CMA, via overexpression of the protein controlling its rate-limiting step, the lysosomal receptor LAMP2A, effectively decreases SNCA levels and ameliorates SNCA-induced neurodegeneration, both in neuronal cell culture systems and in the rat brain. Such findings suggest that modulation of LAMP2A and, consequently, CMA, represents a viable therapeutic target for PD and other synucleinopathies where SNCA accumulation and aggregation plays a fundamental role.

Link: http://dx.doi.org/10.4161/auto.26451

Back in the day, prior to the foundation of the SENS Research Foundation, the SENS rejuvenation research programs were first organized and funded under the auspices of the Methuselah Foundation. At the same time the Foundation also launched and promoted the Mprize for longevity science: a research prize that continues to this day in order to encourage and reward scientists who demonstrate improved degrees of healthy life extension in mice. A lot has changed since then - a great deal of progress in advocacy, and large shifts in the culture of the scientific community when it comes to research into aging and longevity, a lot of that spurred by the activities of the Methuselah Foundation.

At the present time the Methuselah Foundation focuses on speeding up tissue engineering of whole organs via the New Organ initiative, but also funds and coordinates a range of other projects - as well as remaining an influence behind the scenes in the course of the research and advocacy community. This arrived in my in-box today from the Foundation staff:

Methuselah in 2013

Thanks to you, we had a fantastic year at the Methuselah Foundation. On December 5th, we officially launched the New Organ Liver Prize at the World Stem Cell Summit (WSCS) in San Diego, and we're actively seeking title sponsorship to help us increase the $1 million prize purse. Last year, we kicked off a new partnership with Organovo to get 3D bioprinters into key labs at universities involved in regenerative medicine research. We also awarded several new grants, one to study the longevity of bowhead whales and another for research on personalized gene sequencing to improve chemotherapy treatment.

The First New Organ Prize

Many thanks to Bernie Siegel and the WSCS for hosting our launch of the $1 million New Organ Liver Prize, a five-year international competition to advance the field of tissue engineering and regenerative medicine. With gratitude to our generous donors, our invaluable board of advisors, and our prize development partners at the Institute of Competition Sciences, we're thrilled to be underway and currently sourcing teams to compete for the prize.

All the details on prize rules, team registration, partnerships, and more are now available at our brand new website. We'd love to hear what you think! You can also check out some recent media coverage on Popular Science and NBC News.

"New Parts for People"

At the WSCS in December, Methuselah CEO David Gobel gave a rousing plenary talk on the origins of New Organ. "Here's why we have the New Organ Liver Prize," Gobel said. "It seems to me species insanity that we would spend $200,000+ to restore a car like a Shelby Cobra, and yet all that car's creator Carroll Shelby could get were junkyard parts. His heart came from a dead person - it wasn't new. His kidney came from his wonderful son, but it wasn't new. And it didn't fit. None of these parts fit."

Jason Hope and another $15,000 from Fight Aging! - in a 3:1 matching donation to our good friends at the SENS Research Foundation in support of their work advancing rejuvenation science.

Silverstone Merges with BiologixTx

Thanks to the support of Methuselah Foundation donors, Silverstone Matchmaker was able to take the kidney matching software it had developed for use in isolated Local Area Networks and transition it into the cloud, enabling an integrated network of hospitals to begin coordinating transplants through the platform. Now, as of November 2013, Silverstone has entered into an agreement with BiologicTx to further advance its distribution and development.

"The acquisition of Silverstone Solutions, combined with the addition of David Jacobs to the BiologicTx team, advances our commitment to Kidney Paired Donation and greatly expands our innovative technology platform immediately and in the future," said Darrin Carrico, President and Co-Founder of BiologicTx.

Last year alone, 61 lives were saved through Matchmaker-enabled paired kidney donations. We look forward to Silverstone's continued success and are grateful to our supporters for helping to make it possible.

Looking Ahead to 2014

We've got a lot planned for 2014, including the announcement of the first round of research teams planning to compete for the New Organ Liver Prize. Stay tuned also for news of our next New Organ Prize, an organ preservation competition currently in development with the Organ Preservation Alliance incubated by Singularity University Labs in Silicon Valley.

This year, we're also looking to finalize placements of 3D tissue printers in university research labs, so if you're involved in a project that would benefit from an Organovo printer, please let us know ASAP! Send a brief executive summary describing how you would use the printer to generate advances in organ engineering to 3dprinters@neworgan.org. Special consideration is being given to microvascular engineering to enable macro tissues in 3D.

Our New Website

In conjunction with our launch of the New Organ Liver Prize, we recently overhauled our main website, and we're proud of the results. If you haven't checked it out yet, please do! We'd love to know what you think.

Crowdfunding will be an important component of future medical research: it is the logical evolution of the efforts of past decades in which philanthropic foundations raised awareness and funding to accelerate research into treatments for specific diseases. Philanthropy has long been necessary to enable the most important early stage, high-risk research to move forward. Large, established institutional funding sources have little appetite for risk and consequently do very little to move the needle on efforts to create the next generation of medical technology.

This is all very important for the future of serious rejuvenation research, such as SENS-style efforts to repair the cellular and molecular damage that causes aging. This is presently a minority component of the minority field of aging research, neither well supported nor well known. It is, however, the future of medical research if nurtured - a disruptive titan in its earliest stages of growth. For that growth to occur there must be financial support and a community of supporters willing to take on the risks of early stage research. We should keep an eye on trends that may help this to come about.

The falling cost of communication means that intermediaries such as traditionally structured per-disease research foundations are becoming less necessary. They still play an important role in digesting information from the field and educating supporters, but it is now cost-effective for scientists to reach out directly, and for supporters to educate themselves to the point of being able to pick and choose exactly which projects they wish to fund. A new infrastructure is arising to build marketplaces and tools for this process, and Microryza is one of the initiatives in this space:

Luan and Wu are both young scientists - they're in their 20s - but their thinking was based on the old entrepreneurial approach: to be successful, find a hole and fill it. The particular hole they were dealing with is that scientists are often forced to siphon off months of precious time and incalculable amounts of creative energy as they focus on writing grant proposals. Worse, for all that investment in time and energy, they may have no success to show for it.

Fully 80% of Federal grant applications are never funded, and in biomedicine, the average age of a first-time grant recipient is 42. Too many projects never get funded because they seem risky, the proposer is young, the amount is too small to be worth the paperwork, or it's simply an approach that's never been tried before. As Luan says, "It's increasingly difficult for new ideas to get off the ground, especially the innovative, high-risk ideas with the biggest impact."

The answer to small-scale innovative scientific research funding could be to leverage the worldwide power of the internet to create a microfinance funding source involving individual subscribers. According to Luan, there's a lot researchers need to learn about public outreach if they're to make their scientific crowd-funding a success. "People wanting to do crowd funding may not be using Twitter or Facebook, and they may not know where to go to reach out to the communities that are passionate about their issue."

Link: http://www.genengnews.com/insight-and-intelligence/microryza-s-new-scientific-funding-model/77900008/

Here is yet another study to add to those demonstrating that physical activity is associated with a lower risk of chronic disease. Causality for this link is well demonstrated in laboratory animals, but human studies must use statistical methods on a population, or track large numbers of people for decades, which makes it more challenging to prove that exercise causes better health. Given the weight of evidence at this point, however, that exercise improves health is a good working assumption.

The paper for this study is open access and linked in the release materials quoted below:

People who decrease sitting time and increase physical activity have a lower risk of chronic disease. Even standing throughout the day - instead of sitting for hours at a time - can improve health and quality of life while reducing the risk for chronic diseases such as cardiovascular disease, diabetes, heart disease, stroke, breast cancer and colon cancer, among others.

The researchers studied a sample of 194,545 men and women ages 45 to 106. The data was from the 45 and Up Study, which is a large Australian study of health and aging. "Not only do people need to be more physically active by walking or doing moderate-to-vigorous physical activity, but they should also be looking at ways to reduce their sitting time." Sitting for prolonged periods of time - with little muscular contraction occurring - shuts off a molecule called lipoprotein lipase, or LPL. Lipoprotein lipase helps to take in fat or triglycerides and use it for energy.

"We're basically telling our bodies to shut down the processes that help to stimulate metabolism throughout the day and that is not good. Just by breaking up your sedentary time, we can actually upregulate that process in the body."

Link: http://www.k-state.edu/media/newsreleases/jan14/rosenkranz11514.html

Stem cell research will produce knowledge and technologies essential to future rejuvenation treatments: understanding exactly why stem cell populations decline in activity with age; producing unlimited immune cells to order; growing replacement tissues and undamaged stem cells of all types, perfectly matched to the patient; and more. Unlike most of the other foundation technologies needed to create rejuvenation of the old, applications of stem cell research need little in the way of a helping hand from philanthropic organizations like the SENS Research Foundation. Work on stem cells is broad, very well funded, and energetic field - all that is really needed at this point is the occasional reminder that researchers should be focused on the effects of aging on stem cells if they want to produce effective treatments for age-related disease.

There is too much of interest going on in stem cell research, regenerative medicine, and tissue engineering to do more than point out highlights and representative snapshots here and there. What were amazing advances ten years ago occur every week nowadays in laboratories around the world: growing tissues for specific organs; isolating and learning how to work with specific populations of stem cells that support one organ or another; spurring great feats of regeneration; transplanting stem cells cultured from the patient for therapeutic benefit.

Here are a few recent examples of new work in the field, collectively illustrative of where things stand: for each quoted below, dozens more passed by largely unremarked in the past months. It is a busy time in the life sciences, and these are the opening years of a transformative era.

Belgian clinic repairs bones with novel technique

The ground-breaking technique of Saint Luc's centre for tissue and cellular therapy is to remove a sugar cube sized piece of fatty tissue from the patient, a less invasive process than pushing a needle into the pelvis and with a stem cell concentration they say is some 500 times higher. The stem cells are then isolated and used to grow bone in the laboratory. Unlike some technologies, they are also not attached to a solid and separate 'scaffold'. "It is complete bone tissue that we recreate in the bottle and therefore when we do transplants in a bone defect or a bone hole...you have a higher chance of bone formation." The new material in a lab dish resembles more plasticine than bone, but can be molded to fill a fracture, rather like a dentist's filling in a tooth, hardening in the body.

Stem Cell Replacement for Frequent Age-Related Blindness

About four and a half million people in Germany suffer from age-related macular degeneration (AMD). It is associated with a gradual loss of visual acuity and the ability to read or drive a car can be lost. The center of the field of vision is blurry, as if covered by a veil. This is caused by damage to a cell layer under the retina, known as the retinal pigment epithelium (RPE). It coordinates the metabolism and function of the sensory cells in the eye. Inflammatory processes in this layer are associated with AMD and "metabolic waste" is less efficiently recycled. To date, there is no cure for AMD; treatments can only relieve the symptoms.

[Scientists] have now tested a new method in rabbits by which the damaged RPE cells in AMD may be replaced. The researchers implanted different RPEs which were obtained, among others, from stem cells from adult human donors. After four days, the researchers used tomographic methods to check whether the replacement cells had integrated into the surrounding cell layers. "The implanted cells were alive. That is a clear indication that they have joined with the surrounding cells." After one week, the implanted cell layer was still stable. Even after four weeks, tissue examinations showed that the transplant was intact.

Harvard scientists control cells following transplantation, from the inside out

[Scientists] can now engineer cells that are more easily controlled following transplantation, potentially making cell therapies, hundreds of which are currently in clinical trials across the United States, more functional and efficient.

"Regardless of where the cell is in the body, it's going to be receiving its cues from the inside. This is a completely different strategy than the current method of placing cells onto drug-doped microcarriers or scaffolds, which is limiting because the cells need to remain in close proximity to those materials in order to function. Also these types of materials are too large to be infused into the bloodstream."

Cells are relatively simple to control in a Petri dish. The right molecules or drugs, if internalized by a cell, can change its behavior; such as inducing a stem cell to differentiate or correcting a defect in a cancer cell. This level of control is lost after transplantation as cells typically behave according to environmental cues in the recipient's body. [The new] strategy, dubbed particle engineering, corrects this problem by turning cells into pre-programmable units. The internalized particles stably remain inside the transplanted cell and tell it exactly how to act, whether the cell is needed to release anti-inflammatory factors or regenerate lost tissue.

As interest grows in treating human aging and extending life, there is also a corresponding interest in investigating long-lived species so as to establish the factors that determine differing length of life. As a companion piece to last month's post on investigations into the biology of long-lived ocean quahog clams, the species Arctica islandica, here is another paper on the subject. This one focuses on teleomere biology, with results that are largely to be expected given other studies demonstrating a very consistent stability of metabolism across the potentially centuries-long life span of this species:

The shortening of telomeres as a causative factor in ageing is a widely discussed hypothesis in ageing research. The study of telomere length and its regenerating enzyme telomerase in the longest-lived non-colonial animal on earth, Arctica islandica, should inform whether the maintenance of telomere length plays a role in reaching the extreme maximum lifespan (MLSP) of more than 500 years in this species.

Since longitudinal measurements on living animals cannot be achieved, a cross-sectional analysis of a short-lived (MLSP 40 years from the Baltic Sea) and a long-lived population (MLSP 226 years Northeast of Iceland) and in different tissues of young and old animals from the Irish Sea was performed. A high heterogeneity of telomere length was observed in investigated A. islandica over a wide age range (10-36 years for the Baltic Sea, 11-194 years for Irish Sea, 6-226 years for Iceland). Constant telomerase activity and telomere lengths were detected at any age and in different tissues; neither correlated with age or population habitat.

Stable telomere maintenance might contribute to the long lifespan of A. islandica. Telomere dynamics are no explanation for the distinct MLSPs of the examined populations and thus the cause of it remains to be investigated.

Link: http://dx.doi.org/10.1016/j.exger.2013.12.014

There is some debate over whether rapamycin extends life in mice by actually slowing aging or by merely reducing cancer risk. There will be more studies like this one in which researchers gather a great deal of data about the effects of rapamycin on epigenetic profiles and other detailed aspects of mouse biology:

Rapamycin was found to increase (11% to 16%) the lifespan of male and female C57BL/6J mice most likely by reducing the increase in the hazard for mortality (i.e., the rate of aging) term in the Gompertz mortality analysis. To identify the pathways that could be responsible for rapamycin's longevity effect, we analyzed the transcriptome of liver from 25-month-old male and female mice fed rapamycin starting at 4 months of age. Few changes ( less than 300 transcripts) were observed in transcriptome of rapamycin-fed males; however, a large number of transcripts (more than 4,500) changed significantly in females.

The male mice fed rapamycin were found to segregate into two groups: one group that is almost identical to control males (Rapa-1) and a second group (Rapa-2) that shows a change in gene expression (more than 4,000 transcripts) with more than 60% of the genes shared with female mice fed Rapa. 13 pathways were significantly altered in both Rapa-2 males and rapamycin-fed females with mitochondrial function as the most significantly changed pathway. Our findings show that rapamycin has a major effect on the transcriptome and point to several pathways that would likely impact longevity.

Link: http://dx.doi.org/10.1371/journal.pone.0083988

Over the past few years Jason Hope has donated a sizable amount of money to fund aspects of the SENS research program aimed at developing the foundations of human rejuvenation therapies. As is the case for Peter Thiel, just as important as the funding at this comparatively early stage in the revolution in aging research is the fact that influential high net worth individuals are willing to give public support to this cause. The more people who speak out to say that it is only sensible to pursue human rejuvenation, and the state of science is plausible enough to fund aggressively right here and right now, the easier it is to persuade those who still waver on the fence. Hope is presently more outspoken in his public support of SENS research than Thiel, as you might be able to tell from his website, and the more of this the better I say.

The tipping point in public persuasion for longevity science in general will come in only a few years, I think, given that large players are becoming involved - but it might take longer for SENS research, as disruptive to the status quo of the broader field of aging research as it is. All sweeping, new and better ways of making progress are initially resisted, and SENS is no exception.

Jason Hope has been engaged in reaching out to the community these past months, as you can tell by the occasional article here, his support for the year end matching funds just past, a plethora of press releases, and the three-part item at Next Big Future quoted below. I am always very pleased to see people with far more leverage and influence than I wholeheartedly endorsing the work of the SENS Research Foundation and its allied labs and scientists - this remains all too rare an event:

SRF Ends the Long History of Aging

Alzheimer's, cardiovascular disease, diabetes, and other age-related diseases are expensive and dramatically reduce quality of life. The average couple can expect to pay $220,000 in medical expenses throughout their retirement. Age-related illnesses pepper the top ten causes of death in the United States. Despite all the time, money, and effort invested in the treatment of these diseases, scientists have not yet cured any of them.

Those who participated in the early days of the SENS Research Foundation hoped to develop a strategy to mitigate the signs of aging that cause misery and early death. SRF founders predicted that aging would come under medical control someday with advanced technologies, such as gene therapy, stem cell therapy, and immune stimulants.

The founders of the SENS Research Foundation also said they expected this to happen within your lifetime. SENS believes senescence is an engineering problem that they can fix through organized collaboration between the scientific community, policymakers, and the public. SRF aims to create and maintain collaborations that work toward ending the disability, misery and early death associated with the aging process.

The End of Aging is Near

Despite all the advances in medical science, man has yet to cure any age-related diseases. Heart disease, cancer, diabetes, and other illnesses continue to ravage our bodies while we grow old, despite the best efforts of our doctors and mountains of medicine.

The SENS Research Foundation, or SRF, hopes to change all that. Through continued collaborative research, education and outreach, SENS will continue to build the industry that permanently eradicates old-age diseases. SRF establishes a path that leads us from where we are today, a time where the scientific community has the wherewithal to lay out a detailed plan like this one, to a tomorrow when prototype therapies reduce the signs of aging in laboratory mice. Because mice experience many of the same aging processes as humans do, negligible senescence in humans is possible.

Reaching for negligible senescence through anti-aging strategies has real-world applications that go far beyond reducing wrinkles and sagging skin in old people. Age-related illnesses, like heart disease, cancer and diabetes are debilitating and expensive. The increases in cost and decrease of quality of life will become more profound as a growing number of people live longer. Without a clear-headed approach to negligible senescence, the aging process will cripple an increasing population worldwide.

SRF Continues Its Fight Against Aging

At its core, SRF is a research foundation. Scientists and administrators associated with the foundation conduct and coordinate research into developing the fundamental technologies capable of halting the aging process. SRF also funds research at universities around the world and in SENS own SRF Research Center in Mountain View, California.

The SRF Research Center houses their internal research laboratory, where their scientists perform advanced rejuvenation biotechnology research. The focus of this work is to address the root causes of aging on a molecular level in a systematic and comprehensive way. Currently, the work of the SRF Research Center focuses on the Mitochondrial Mutations Research Project, LysoSENS, and OncoSENS.

The Mitochondrial Mutations Research Project strives to correct time-related damage to the "powerhouse" of human body cells, mitochondria. Researchers with LysoSENS work towards clearing out the waste that accumulates in cells over time. The OncoSENS research objective is to make cancer mutations harmless.

An interesting approach to the challenges of cartilage regrowth is outlined here:

Articular cartilage is the tissue that lines joints such as hips, knees and shoulders, providing cushioning and smooth movement. Similar to bones and muscles, cartilage only stays healthy and strong through loading, or applying force, through physical activity. Until recently, researchers did not know how cartilage converts mechanical loading into the ion channel signals that promote growth. Understanding how cartilage senses mechanical loading could equip researchers with the knowledge needed to prevent or better treat joint diseases.

"Mechanical loading plays a critical role in the overall health of the cartilage. If we can figure out how cartilage cells sense mechanical loads, we can trick them into thinking they are being exercised or stop them from responding to abnormal loading. Think of it as artificial exercise for your cartilage."

Researchers looked at articular cartilage cells from pigs and focused on TRPV4, an ion channel abundant in cartilage cells that can be turned on during mechanical loading. When the researchers "exercised" the cartilage cells using mechanical loading, the cells sensed the loading and grew cartilage tissue. When they added a compound that blocked TRPV4, essentially turning off signals from the ion channel, the cartilage did not grow and the effects of the mechanical loading were lost.

Next, the researchers substituted mechanical loading for a chemical that activated TRPV4. Without having to exercise the cartilage, they observed the growth of cartilage even more so than with the mechanical loading. The findings suggest that TRPV4 is responsible for sensing mechanical loading in the cartilage. Now that they know that turning on TRPV4 can simulate the effects of mechanical loading in cartilage cells, the researchers are looking at ways to harness this potential.

Link: http://www.eurekalert.org/pub_releases/2014-01/dumc-css010914.php

Researchers here suggest that primates - and humans especially - are comparatively long-lived among mammalian species because of differences in metabolism that lead them to burn fewer calories. There is a strong association between resting metabolic rate and longevity in mammals, although one should view this as an emergent property of other aspects of biology, such as the structure and operation of mitochondria, known to be important in aging. High metabolic rates also correlate with increased mortality within a species. This is interesting, but not really actionable when it comes to doing something about aging:

Most mammals, like the family dog or pet hamster, live a fast-paced life, reaching adulthood in a matter of months, reproducing prodigiously (if we let them), and dying in their teens if not well before. By comparison, humans and our primate relatives (apes, monkeys, tarsiers, lorises, and lemurs) have long childhoods, reproduce infrequently, and live exceptionally long lives. Primates' slow pace of life has long puzzled biologists because the mechanisms underlying it were unknown.

An international team of scientists working with primates in zoos, sanctuaries, and in the wild examined daily energy expenditure in 17 primate species, from gorillas to mouse lemurs, to test whether primates' slow pace of life results from a slow metabolism. Using a safe and non-invasive technique known as "doubly labeled water," which tracks the body's production of carbon dioxide, the researchers measured the number of calories that primates burned over a 10 day period. Combining these measurements with similar data from other studies, the team compared daily energy expenditure among primates to that of other mammals.

"The results were a real surprise. Humans, chimpanzees, baboons, and other primates expend only half the calories we'd expect for a mammal. To put that in perspective, a human - even someone with a very physically active lifestyle - would need to run a marathon each day just to approach the average daily energy expenditure of a mammal their size."

Link: http://www.eurekalert.org/pub_releases/2014-01/lpz-pnw011314.php

The latest mail from the SENS Research Foundation notes that the doors are open for students to apply to the 2014 Summer Scholar Program. Talented students studying molecular biology and regenerative medicine have a chance to advance their career prospects while working on cutting edge projects: you can see some of the work accomplished by past interns at the Foundation as an example of this type of program.

Keeping an eye on the long term, this is one of the important organizational Foundation projects. Building rejuvenation biotechnologies is a project of a few decades even if fundraising and persuasion goes well. Those researchers at the peak of their careers who will lead the final stages of work on first generation rejuvenation therapies are still in school today - and public perceptions of biogerontology remain far from what they should be. It is still very necessary here and now to demonstrate to younger researchers in the life sciences that biogerontology is not a boring niche, but rather the exciting, barnstorming, revolutionary early years of the next generation of medicine. This presently small field will grow to dominate and define the mainstream of medical research and development by the 2030s and beyond - a showcase for all the best and brightest applications of molecular biology, genetic engineering, cell therapies, and other presently young fields. Opportunities for achievement, scientific fame, wealth, and the saving of lives on a grand scale will abound in the years ahead.

2014 SRF Summer Scholar Applications Are Here

SENS Research Foundation is proud to offer undergraduate students the opportunity to work with world-renowned leaders of the regenerative medicine field as part of the 2014 SRF Summer Scholars Program.

SRF is again partnering with the Buck Institute for Research on Aging and the Wake Forest Institute for Regenerative Medicine (WFIRM). In addition, three new universities will be participating in the Summer Scholars Program this year.

The Centre for the Advancement for Sustainable Medical Innovation (CASMI) will be hosting SRF Summer Scholars at the University of Oxford and the University College London. And, student research will also be conducted at the Harvard Stem Cell Institute and Harvard School of Medicine.

Students interested in conducting research to combat the diseases of aging should visit http://sens.org/2014-summer-scholars. We also invite you to forward the program flyer to any university, organization, or student you think might be interested in a paid regenerative medicine internship this summer.

The Foundation hit their November 2013 goal for $100,000 by the end of the year. Many thanks are due to to all of you whose donations helped to meet the impromptu matching funds that were assembled at the end of last year in response:

SENS Research Foundation Year-End Fundraising Campaign a Success

In November 2013, SRF announced our year-end fundraising campaign. We set a goal to raise $100,000 in a little over six weeks. You, our supporters, came through for us in an incredible way. Everyone at SRF was thrilled by the overwhelming response. We initially received 3 grants from the Methuselah Foundation, Jason Hope, and Fight Aging! Each offered to match the first $15,000 we raised. We then received an additional grant of $15,000 in December from Michael Cooper.

All in all, we raised over $105,000 in donations and matching grants. We are so grateful to everyone who helped make it possible for us to meet and even exceed our campaign goal. We would also like to thank our sustaining supporters, individuals who have arranged to donate to us monthly all year long to help fund our efforts to fight age-related disease. And of course thank you to all of our matching grant providers.

Watch your inbox throughout the coming months for exciting news about our plans to further expand the work of SENS Research Foundation. Our mission - to transform the way the world researches and treats age-related disease - can only be achieved with your continued support.

"We all want to live longer, healthier lives. In order to achieve this we need to change our approach to medicine. It's not just about treating, it's about preventing." - Jason Hope

Thank you again for all your support in 2013 and into the future.

Despite a long, slow trend upwards in life expectancy (at birth, as an adult, and for old people) there are still those researchers who believe that there are limits on human life span. This is on the one hand silly: the scientific community will in time overcome the causes of aging. On the other hand it is most likely true that there exist one or more slow degenerative processes still largely unaffected by modern medicine that kill everyone who survives all of the common causes of age-related death.

Based on autopsy data from supercentenarians, a good candidate for a present lifespan-limiting process in humans is the development of senile amyloidosis: misfolded proteins aggregate to clog the heart and blood vessels. But we can easily envisage ways to treat this condition, such as by training the immune system to destroy the errant proteins, as is presently under development in the Alzheimer's research community.

Aging and age-related death are composed of a laundry list of items that can all be tackled successfully by the near future of medical research: it's just a matter of prioritizing and funding the necessary work, something that at present the public and broader research community has little enthusiasm for, sadly.

The past 200 years have enabled remarkable increases in human lifespans through improvements in the living environment that have nearly eliminated infections as a cause of death through improved hygiene, public health, medicine, and nutrition. We argue that the limit to lifespan may be approaching. Since 1997, no one has exceeded Jeanne Calment's record of 122.5 years, despite an exponential increase of centenarians. Moreover, the background mortality may be approaching a lower limit.

We calculate from Gompertz coefficients that further increases in longevity to approach a life expectancy of 100 years in 21st century cohorts would require 50% slower mortality rate accelerations, which would be a fundamental change in the rate of human aging. Looking into the 21st century, we see further challenges to health and longevity from the continued burning of fossil fuels that contribute to air pollution as well as global warming. Besides increased heat waves to which elderly are vulnerable, global warming is anticipated to increase ozone levels and facilitate the spread of pathogens. We anticipate continuing socioeconomic disparities in life expectancy

Pessimism abounds in this age of ours that is characterized by wealth, plenty, and rapid, accelerating progress in technology and medicine. There is nothing new about that, of course. People have long been entranced by the false vision of doom ahead.

Link: http://dx.doi.org/10.1159/000357672

Mitochondria are important in aging, and the process by which they become damaged and contribute to degenerative aging starts with the fact that they emit reactive oxidants as a byproduct of their normal operation. The best approaches to removing this cause of aging involve repair of mitochondrial damage or altering cells to make the damage irrelevant, but researchers are also investigating ways to target antioxidants to the mitochondria. Additional antioxidants to augment natural ones soak up more of the oxidants and thus in theory slow down the pace of damage and the pace of aging. Studies carried out with plastinquinone mitochondrially targeted antioxidants seem to bear this out.

Mitochondrially targeted antioxidants are nowhere near as effective a strategy as repair, however. They cannot reverse or halt this contribution to aging, they can only somewhat slow it. But here is news of another type of mitochondrial antioxidant in early studies:

describe how in laboratory tests, they compared the protection offered against either UVA radiation or free radical stress by several antioxidants, some of which are found in foods or cosmetics. While UVB radiation easily causes sunburn, UVA radiation penetrates deeper, damaging our DNA by generating free radicals which degrades the collagen that gives skin its elastic quality.

The [team] found that the most potent anti-oxidants were those that targeted the batteries of the skin cells, known as the mitochondria. They compared these mitochondrial-targeted anti-oxidants to other non-specific antioxidants such as resveratrol, found in red wine, and curcumin found in curries, that target the entire cell. They found that the most potent mitochondrial targeted anti-oxidant was Tiron - 4,5-Dihydroxy-1,3-benzenedisulfonic acid disodium salt monohydrate - which provided 100%, protection of the skin cell against UVA sun damage and the release of damaging enzymes causing stress-induced damage.

Resveratrol, the antioxidant found in red wine, was found to protect against 22% of both the ultraviolet A radiation and stress-induced damage. NAC, a frequently used laboratory-based anti-oxidant, offered 20% protection against oxidative stress and 8% against UVA and curcumin offered 16% protection against oxidative stress and 8% against UVA. In comparison Tiron offered 100% protection against UVA radiation and 100% protection against oxidative stress

The team intends to take the work forward by further understanding the mechanism of how Tiron works, developing a compound similar to Tiron and testing for toxicity in humans. They say it will be several years before it is ready for use as a skin product or supplement.

If this interests you, bear in mind that other injected or ingested mitochondrially targeted antioxidants have far more work done on them, have more impressive effects at the cellular level, are shown to prevent or slow a range of age-related conditions, and yet still cannot extend life greatly in laboratory animals: 10% in flies, for example, far less than the extension of life obtained through calorie restriction.

Link: http://www.ncl.ac.uk/press.office/press.release/item/looking-younger-for-longer

The financial costs of degenerative aging are vast. Each year hundreds and possibly thousands of times what it would cost to fully develop a demonstration of first generation SENS rejuvenation biotechnologies is spent or lost due to aging and age-related disease. This is depressing but fairly standard for any field of research and development: the funds allocated towards finding ways to improve the situation are usually minuscule in comparison to the funds that go towards running, coping with, or propping up the status quo. It's amazing that anything ever improves when you look at that split of investment.

You can look back into the Fight Aging! archives to find various estimates from the research community on the ongoing cost of specific diseases. The costs incurred by stroke patients in the US alone are thought to be in the vicinity of $50 billion each year, for example. Various forms of skeletal and muscular degeneration may add another $20 billion, and some researchers suggests that dementia costs more than $150 billion each year. Grand totals in the US from mainstream data providers approach $300 billion in direct costs, with much more in lost productivity every year.

Here researchers run worldwide numbers on heart failure, another of the major causes of age-related death. The total given in the abstract is surprisingly low, considering per-condition cost estimates I've seen elsewhere, such as those mentioned above:

The annual global economic burden of heart failure

We estimated the overall cost of heart failure in 2012, in both direct and indirect terms, across the globe. Existing country-specific heart failure costs analyses were expressed as a proportion of gross domestic product and total healthcare spend. Using World Bank data, these proportional values were used to interpolate the economic cost of HF for countries of the world where no published data exists. Countries were categorized according to their level of economic development to investigate global patterns of spending.

197 countries were included in the analysis, covering 98.7% of the world's population. The overall economic cost of HF in 2012 was estimated at $108 billion per annum. Direct costs accounted for ~60% ($65 billion) and indirect costs accounted for ~40% ($43 billion) of the overall spend. Heart failure spending varied widely between high-income and middle and low-income countries. High-income countries spend a greater proportion on direct costs: a pattern reversed for middle and low-income countries.

The indirect costs that include lost productivity are more usually several times the size of the direct costs, but that all depends on methodology and definitions. The total for direct costs globally is a small multiple of US-only direct costs in other conditions, so perhaps these scientists are defining heart failure very narrowly, excluding the costs of the chronic conditions and events such as heart attacks that lead to heart failure.

Either way, these are the costs that might be avoided through the development of rejuvenation therapies. Some people are persuaded by finances rather than human costs of suffering and death: the numbers have long been very persuasive. The cost of even fully funded development is small compared to the costs of aging as they stand today.

Regenerative medicine is progressing towards the ability to reliably repair nerve damage. As for the growth of blood vessels, this is challenging and a work in progress, with some demonstrated successes but still a way to go yet towards the realization of a comprehensive technology platform for nerve regeneration:

We previously developed a collagen tube filled with autologous skin‐derived stem cells (SDSCs) for bridging long rat sciatic nerve gaps. Here we present a case report describing a compassionate use of this graft for repairing poly‐injured motor and sensory nerves of upper arms of a patient. Preclinical assessment was performed with collagen‐SDSCs implantation in rats after sectioning sciatic nerve. For the patient, during the 3‐year follow‐up period, functional recovery of injured median and ulnar nerves was assessed by pinch gauge test and static two‐point discrimination and touch test with monofilaments, along with electrophysiological and MRI examinations.

Preclinical experiments in rats revealed rescue of sciatic nerve and no side effects of patient‐derived SDSCs transplantation (30 and 180 days of treatment). In the patient treatment, motor and sensory functions of the median nerve demonstrated ongoing recovery post‐implantation during the follow‐up period. The results indicate that the collagen/SDSCs artificial nerve graft could be used for surgical repair of larger defects in major lesions of peripheral nerves, increasing patient quality of life by saving the upper arms from amputation.

Link: http://dx.doi.org/10.3727/096368913X675700

This study shows that avoiding an accumulation of excess fat tissue is more beneficial than physical fitness when it comes to long term health, as measured by reduced risk of suffering heart disease. This seems plausible based on a survey of data gathered in various mouse studies on fat, exercise, and life span. Calorie restriction and even surgical removal of visceral fat extend maximum life span while exercise only improves healthspan. The best bet is to be both fit and lean, of course:

[Researchers] analysed data from 743,498 Swedish men who received a medical examination at the age of 18 when they were conscripted into national service from 1969 to 1984. The men's fitness level was measured with a bicycle test in which the resistance was gradually increased until they were too exhausted to continue. The men were monitored for an average of 34 years until they suffered a heart attack or died or until 1 January 2011, whichever came first.

The study shows that being physically fit in your teenage years reduces the risk of a heart attack later in life. Fit but overweight or obese men also ran a significantly higher risk of suffering a heart attack than unfit, lean men. "While being physically fit at the end of your teens can reduce the risk of heart attack, fitness alone does not appear to fully compensate for the risks with being overweight or obese. In other words, having a normal weight is more important than being in good physical shape, but it is even better to be both fit and have a normal weight."

The study shows that with every 15% increase in physical fitness, the risk of suffering a heart attack 30 years later is reduced by around 18 percent after factoring in different variables such as socioeconomic background and Body Mass Index, BMI. The results also indicate that regular fitness training late in your teenage years is consistent with a 35% lower risk of a premature heart attack.

Link: http://www.medfak.umu.se/english/about-the-faculty/news/newsdetailpage/unfit-lean-people-are-better-protected-against-heart-attacks-than-fit-obese-people.cid228065

Alagebrium (or ALT-711) was an early and ultimately unsuccessful foray into the development of an AGE-breaker drug: a treatment intended to safely break down the build up of advanced glycation end-products (AGEs) that characterize aged tissue. These are chemical cross-links that form as a byproduct of the normal operation of metabolism, and which glue together proteins to cause various forms of harm, such as destroying the elasticity of skin and blood vessels. Eventually this process contributes significantly to age-related disease and death, meaning that any attempt to treat and reverse aging by attacking the causes must include proficient AGE-breakers.

The attempted clinical development of alagebrium followed initially promising studies in rats, but as it turns out the types of AGE important in human tissue are not the same at all, and as a consequence alagebrium had no meaningful effect in human trials. This was sufficiently well determined that you can color me surprised to see that anyone is continuing with the thankless but important work of confirming past negative results for this line of research. But here we have it:

The effect of an advanced glycation end-product crosslink breaker and exercise training on vascular function in older individuals: a randomized factorial design trial.

Aging leads to accumulation of irreversible advanced glycation end-products (AGEs), contributing to vascular stiffening and endothelial dysfunction. When combined with the AGE-crosslink breaker Alagebrium, exercise training reverses cardiovascular aging in experimental animals. This study is the first to examine the effect of Alagebrium, with and without exercise training, on endothelial function, arterial stiffness and cardiovascular risk in older individuals.

Forty-eight non-exercising individuals (mean age 70 ± 4 years) without manifest diseases or use of medication were allocated into 4 groups for a 1-year intervention: Exercise training and Alagebrium (200 mg/day); exercise training and placebo; no exercise training and Alagebrium (200 mg/day); and no exercise training and placebo. We performed a maximal exercise test (VO2max) and measured endothelial function. Arterial stiffness was measured using pulse wave velocity. Cardiovascular risk was calculated using the Lifetime Risk Score (LRS).

In the exercise training groups, LRS and VO2max improved significantly (23.9 ± 4.5 to 27.2 ± 4.6 mLO2/min/kg). Endothelial response to the vasoactive substances did not change, nor did arterial stiffness in any of the four groups. In conclusion, one year of exercise training significantly improved physical fitness and lifetime risk for cardiovascular disease without affecting endothelial function or arterial stiffness. The use of the AGE-crosslink breaker Alagebrium had no independent effect on vascular function, nor did it potentiate the effect of exercise training. Despite the clinical benefits of exercise training for older individuals, neither exercise training nor Alagebrium (alone or in combination) was able to reverse the vascular effects of decades of sedentary aging.

Present work on AGE-breaker development is very limited indeed. At the present time it is known that one type of AGE - glucosepane - makes up the overwhelming majority of AGEs present in human tissue, so in theory finding ways to treat and reverse AGE build up in our species is in fact a comparatively simple research and development undertaking. Unfortunately the drug development community has little infrastructure in place for working with this sort of compound, and little interest in building that infrastructure: groups with funding tend to find other things to work on, where there is a shorter and more certain path to producing a useful end result.

This is where the SENS Research Foundation comes into the picture. The Foundation is presently funding research to produce the tools needed to work with glucosepane and thereafter produce technology demonstrations to show that it can be cleared from tissues. Hopefully work on AGE-breakers will pick up again over the next few years as a result of this intervention. This whole situation might not be the best candidate for an example of clearly useful near-term medical research and development that should yield enormous benefits, but yet just isn't happening - but it is certainly up there in the charts. From a distance we might see constant progress, but down in the weeds every field is beset with this sort of problem.

This study shows that in Ontario the number of centenarians in the population has been rising at about twice the rate of the population as a whole over the past twenty years. This is most likely representative of most wealthier regions of the world, where life expectancy for adults is climbing at around a year every decade as an incidental result of general improvements in medical technologies. This pace should pick up considerably as the research community becomes more interested in targeting aging deliberately, but note that your personal odds of reaching the age of 100 under present levels of medical technology are still very poor. The only way to improve these odds significantly is to support research into human rejuvenation such as that carried out by the SENS Research Foundation.

All individuals living in Ontario aged 65 and older on April 1 of each year between 1995 and 2010 were identified and divided into three age groups (65-84, 85-99, ≥100). A detailed description was obtained on 1,842 centenarians who were alive on April 1, 2010.

The number of centenarians increased from 1,069 in 1995 to 1,842 in 2010 (72.3%); 6.7% were aged 105 and older. Over the same period, the number of individuals aged 85 to 99 grew from 119,955 to 227,703 (89.8%). Women represented 85.3% of all centenarians and 89.4% of those aged 105 and older. Almost half of centenarians lived in the community (20.0% independently, 25.3% with publicly funded home care). Preventive drug therapies (bisphosphonates and statins) were frequently dispensed. In the preceding year, 18.2% were hospitalized and 26.6% were seen in an emergency department. More than 95% saw a primary care provider, and 5.3% saw a geriatrician.

The number of centenarians in Ontario increased by more than 70% over the last 15 years, with even greater growth among older people who could soon become centenarians. Almost half of centenarians live in the community, most are women, and almost all receive care from a primary care physician.

Link: http://dx.doi.org/10.1111/jgs.12613

Effective development of treatments for cancer will involve finding actionable commonalities that exist in as many cancers as possible. Focusing on targets that only exist in a few cancers will necessarily be a much longer and more expensive process. Here researchers demonstrate the ability to direct the immune system to attack cancer cells expressing the protein p62 / sequestosome 1:

Autophagy plays an important role in neoplastic transformation of cells and in resistance of cancer cells to radio- and chemotherapy. p62 (SQSTM1) is a key component of autophagic machinery which is also involved in signal transduction. Although recent empirical observations demonstrated that p62 is overexpressed in variety of human tumors, a mechanism of p62 overexpression is not known. Here we report that the transformation of normal human mammary epithelial cells with diverse oncogenes (RAS, PIK3CA and Her2) causes marked accumulation of p62.

Based on this result, we hypothesized that p62 may be a feasible candidate to be an anti-cancer DNA vaccine. Here we performed a preclinical study of a novel DNA vaccine encoding p62. Intramuscularly administered p62-encoding plasmid induced anti-p62 antibodies and exhibited strong antitumor activity in four models of allogeneic mouse tumors - B16 melanoma, Lewis lung carcinoma (LLC), S37 sarcoma, and Ca755 breast carcinoma.

In mice challenged with Ca755 cells, p62 treatment had dual effect: inhibited tumor growth in some mice and prolonged life in those mice which developed tumor size similar to control. P62-encoding plasmid has demonstrated its potency both as a preventive and therapeutic vaccine. Importantly, p62 vaccination drastically suppressed metastasis formation: in B16 melanoma where tumor cells were injected intravenously, and in LLC and S37 sarcoma with spontaneous metastasis. Overall, we conclude that a p62-encoding vector(s) constitute(s) a novel, effective broad-spectrum antitumor and anti-metastatic vaccine feasible for further development and clinical trials.

Link: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=1397&path%5B%5D=1592

The cryonics industry offers the means to store your body and brain immediately following death. This involves vitrification rather than freezing (to avoid ice crystal formation) and then indefinite low temperature preservation: for so long as the fine structure of the brain is preserved the possibility remains for future restoration to life in an age with more advanced capabilities in medicine and nanotechnology. Cryonics is the only plausible presently available stopgap measure to prevent the vast ongoing loss of life due to aging, and it is a great horror that so far it has remained a niche industry, even as tens of millions of lives are lost to oblivion with each passing year. In a better world they could all have been saved, preserved for a wealthier technological future capable of rebuilding bodies and reversing vitrification.

A number of countries outside the US have cryonics organizations of one form or another, although the only providers offering low-temperature storage are in the US and Russia at this time. Australia might also see a provider launch in the near future, but in general people in other parts of the world should plan on moving as a part of any end of life organization. The alternative is probably going to be expensive and much less certain; moving trained staff to where they are needed and then transporting the cryopreserved patient afterwards is a good deal more complicated. Moving closer to the provider is generally advised as the most optimal course in any case, regardless of where you live: it will increase the chances of a good outcome.

The UK, like Australia, is home to organized cryonics supporters whose numbers have not yet expanded to the degree needed to launch a local provider and storage center. Given the level of regulation in the UK that would probably be more of a challenge than it is in Russia, home to KrioRus. What they can do is to form their own volunteer associations and companies to provide standby services: the early stages in the process of preparation for vitritication, or actual vitrification itself. Here is a good press piece that manages to avoid slipping into most of the lazy modes of coverage that attend any non-mainstream activity:

Why this big freeze could take us back to the future

"My wife thinks it's weird," says Tim Gibson, whose house we're in. "But I tell her it's weird not to at least try."

The group are cryonicists. They are among the 100 or so Brits who have paid to have their bodies frozen when they die so, one day, they might be brought back to life. They have arranged for their brains to be pumped with anti-freeze and their bodies to be stored in liquid nitrogen until science has advanced to a point where they can be resurrected. And today - in this pleasant Meadowhead family home - they are learning how to do the preserving.

Around 1982 Sussex care home owner Alan Sinclair set up Cryonics UK - a volunteer group where members take a pledge that when one dies the others will be on hand to immediately preserve the body and then have it shipped to America for permanent storage. Only a handful have so far made that ultimate journey. Tim, a 42-year-old father-of-two, joined the group around 1992 and took over in 2009. His Meadowhead home is now the HQ. Members meet there every three months.

Aren't members - who are charged £10-15 a month - simply throwing their money away on a one-in-a-million chance? "Could be," nods Tim. "We certainly don't promise anything. You could die in such a way that we can't preserve your body in the first place and then it's over before it starts. All we say is we will do whatever we can to preserve your body and then what happens in the future happens."

"I look at it like buying a lottery ticket," he says. "I'm pretty certain I won't win and nothing will come of it. But I'm still going to keep buying it on the off chance. What have I got to lose?"

It is, indeed, weird not to try. It is a strange thing to live in a world in which near everyone is determinedly trudging towards oblivion with no intent to do anything about it.

I'd missed this journal editorial from last month on the topic of the current scientific consensus on the utility (or rather lack of utility) of dietary supplements. The evidence presently strongly favors the view that for people who have no vitamin deficiencies adding more dietary supplements does nothing or may even harm long term health - such as when dietary antioxidants block the hormetic processes necessary to benefit from exercise. The supplement industry is somewhat louder than the scientific community, however.

Reviews and guidelines that have appraised the role of vitamin and mineral supplements in primary or secondary prevention of chronic disease have consistently found null results or possible harms. Evidence involving tens of thousands of people randomly assigned in many clinical trials shows that β-carotene, vitamin E, and possibly high doses of vitamin A supplements increase mortality and that other antioxidants, folic acid and B vitamins, and multivitamin supplements have no clear benefit.

The large body of accumulated evidence has important public health and clinical implications. Evidence is sufficient to advise against routine supplementation, and we should translate null and negative findings into action. The message is simple: Most supplements do not prevent chronic disease or death, their use is not justified, and they should be avoided. This message is especially true for the general population with no clear evidence of micronutrient deficiencies, who represent most supplement users in the United States and in other countries.

The evidence also has implications for research. Antioxidants, folic acid, and B vitamins are harmful or ineffective for chronic disease prevention, and further large prevention trials are no longer justified. Vitamin D supplementation, however, is an open area of investigation, particularly in deficient persons. Clinical trials have been equivocal and sometimes contradictory.

With respect to multivitamins, [studies] and previous trials indicate no substantial health benefit. This evidence, combined with biological considerations, suggests that any effect, either beneficial or harmful, is probably small. As we learned from voluminous trial data on vitamin E, however, clinical trials are not well-suited to identify very small effects, and future trials of multivitamins for chronic disease prevention in well-nourished populations are likely to be futile. Although available evidence does not rule out small benefits or harms or large benefits or harms in a small subgroup of the population, we believe that the case is closed - supplementing the diet of well-nourished adults with (most) mineral or vitamin supplements has no clear benefit and might even be harmful. These vitamins should not be used for chronic disease prevention. Enough is enough.

Link: http://dx.doi.org/10.7326/0003-4819-159-12-201312170-00011

One of the arguments for focusing on repair strategies for reversing aging rather than manipulation of metabolism to slow aging is that metabolism is fantastically complex. Researchers don't have anywhere near enough understanding to safely alter metabolic operation in desired ways, and even simply trying to replicate aspects of the known and easily studied altered state of calorie restriction has proven to be very challenging. So there is no comprehensive plan on how to slow aging in this way. We can compare that absence to the existence of the comprehensive SENS plan on how to repair damage to reverse aging - and in that case we don't need to know anywhere near as much about how metabolism works. We just need to identify the damage and determine how to produce means of repair, and this goal has already been achieved.

An example of the complexity of metabolism and its interaction with the processes of aging is provided by this research, which illustrates that there is still much to be cataloged and understood in one of the longest known longevity mutations:

Twenty years ago it was discovered that loss of insulin/IGF-1-like signaling (IIS) - such as occurs in daf-2(-) mutants - dramatically extends longevity in the nematode C. elegans via the FOXO transcription factor DAF-16. Under favorable conditions, DAF-16 remains cytosolic and transcriptionally inactive; under stress, it is driven into the nucleus, leading to both up-regulation and down-regulation of large sets of genes, referred to as Class I and II, respectively. Identifying these genes and their functions is key to understanding the molecular and biochemical determinants of aging and longevity. While several studies have been performed to determine the genes regulated by DAF-16, agreement on the identity of targets has been limited to a relatively small number of top responders. Moreover, recent results have made it clear that while DAF-16 is responsible for the activation of Class I genes through the DAF-16 binding element (DBE), it does not interact directly with the upstream promoter regions of Class II genes, leaving the down-regulation of the latter in IIS mutants unexplained.

To address these issues, we first performed a careful meta-analysis of all available genomewide expression profiles with DAF-16 active (nuclear) vs. inactive (cytosolic or null). We reprocessed relevant raw data from various laboratories, and used a voting algorithm developed specifically for this purpose to construct a consensus ranking of all C. elegans genes in terms of their responsiveness to DAF-16. This allowed us to redefine Class I and Class II targets with unprecedented sensitivity and specificity. Next, using a combination of computational and experimental methods, we discovered that the little-studied transcription factor PQM-1 regulates Class II genes (and Class I to a lesser extent), via the DAF-16 associated element (DAE). [PQM-1] binding is strongly associated with both proximal upstream DAE occurrence and responsiveness to DAF-16. Indeed, a reporter gene assay confirmed that PQM-1 activates transcription in a DAE-dependent manner.

Next, we investigated whether and how PQM-1 subcellular localization depends on IIS status. [We] found that the nuclear presence of PQM-1 and DAF-16 is controlled by IIS in opposite ways. A model emerged in which both the DBE and the DAE contribute to the expression of Class I genes, while Class II genes are exclusively controlled through the DAE. Under normal conditions, the DAE-dependent transcriptional activation of Class II genes by nuclear PQM-1 enables growth and development. Upon acute stress, PQM-1 leaves the nucleus while DAF-16 enters. The nuclear exit of PQM-1 causes expression of Class II genes to fall in response to loss of activation through the DAE; at the same time, DAF-16 moves into the nucleus, where its binding to the DBE in the upstream promoter region of Class I genes activates a stress response in the cell.

Link: http://www.impactaging.com/papers/v6/n1/full/100628.html

It is interesting to theorize that a range of treatments as effective as some drugs might emerge from the use of electromagnetic fields in medicine. Researchers are still in the very early stages of establishing the boundaries of the possible, however - you might look at work involving transcranial magnetic stimulation as an example of present explorations. Clearly it is possible to influence biology with electromagnetism, but what types of influence are plausible and controllable? It doesn't seem completely out of the question that some forms of electromagnetic field could change the behavior of cells in ways that are similar to that achieved with specific types of globally applied drug compounds, but it remains an open question as to how useful or limited this might prove to be.

Here researchers provide evidence for one desirable outcome that can be attained via suitable magnetic fields. They demonstrate an effective boost to rates of neurogenesis, the creation of new neurons in the brain. Higher rates of neurogenesis imply greater neuroplasticity, the ability of the brain to adapt, repair, and resist minor damage - which overall seems to be a good thing to aim for. In this work the scientists are not increasing the pace at which new neurons are created, as is the case in some other approaches, but are instead enhancing the survival of those cells.

Extremely low-frequency electromagnetic fields enhance the survival of newborn neurons in the mouse hippocampus

In recent years, much effort has been devoted to identifying stimuli capable of enhancing adult neurogenesis, a process that generates new neurons throughout life, and that appears to be dysfunctional in the senescent brain and in several neuropsychiatric and neurodegenerative diseases. We previously reported that in vivo exposure to extremely low-frequency electromagnetic fields (ELFEFs) promotes the proliferation and neuronal differentiation of hippocampal neural stem cells (NSCs) that functionally integrate in the dentate gyrus.

Here, we extended our studies to specifically assess the influence of ELFEFs on hippocampal newborn cell survival, which is a very critical issue in adult neurogenesis regulation. Mice were injected with 5-bromo-2′-deoxyuridine (BrdU) to label newborn cells, and were exposed to ELFEFs 9 days later, when the most dramatic decrease in the number of newly generated neurons occurs. The results showed that ELFEF exposure (3.5 h/day for 6 days) enhanced newborn neuron survival.

The effects of ELFEFs were associated with enhanced spatial learning and memory. In an in vitro model of hippocampal NSCs, ELFEFs exerted their pro-survival action by rescuing differentiating neurons from apoptotic cell death. Western immunoblot assay revealed reduced expression of the pro-apoptotic protein Bax, and increased levels of the anti-apoptotic protein Bcl-2, in the hippocampi of ELFEF-exposed mice as well as in ELFEF-exposed NSC cultures, as compared with their sham-exposed counterparts. Our results may have clinical implications for the treatment of impaired neurogenesis associated with brain aging and neurodegenerative diseases.

Will the same thing happen to the promise of extended longevity as happened to the space program in the past half century - an early push, and then lack of interest and stagnation? I don't think that this is a likely model, due to the very different institutions and costs. It is comparatively cheap to contribute to progress in medicine, and many groups have the ability to do so usefully at this time.

Nonetheless, this is one of the nagging fears that motivates us to action - that present public disinterest in enhanced longevity will spread to the medical community, rather than giving way in the face of clear signs of progress and benefits emerging from the lab. That no new groups will arise to carry forward the torch of progress.

Again, I don't think that this is as plausible as a future of continued progress. But will that progress be fast enough to help us? That depends on what we do - progress only happens when it is made to happen. We build the future. If you want something done, you have to work on it:

My greatest fear about the future is not of technology running out of control or posing existential risks to humankind. Rather, my greatest fear is that, in the year 2045, I will be 58 years old and already marked by notable signs of senescence, sitting at the kitchen table, drinking my morning coffee, and wondering, "What happened to that Singularity we were promised by now? Why did it not come to pass? Why does the world of 2045 look pretty much like the world of 2013, with only a few cosmetic differences?" My greatest fear is that, as I stare into that mug of coffee, I would recognize that it will all be downhill from there, especially as "kids these days" would pay no more attention to technological progress and life-extension possibilities than their predecessors did.

My greatest fear is that they would consider me a quixotic old man, fantasizing about a future that never was, while they struggle to make ends meet in an ever-more hostile economy (which would look much like our own, except farther along in the sequence of gradual decay, because nobody cares), strangled by labyrinthine restrictions arising out of Luddism and change-aversion within the widespread society. In short, my greatest fear is that our present will be our future, except that I and the present generation of longevity activists will lose our youthful vitality and will ourselves be rapidly approaching the abyss of oblivion.

Link: http://ieet.org/index.php/IEET/more/stolyarovii20140105

Humans are long-lived in comparison to other primates, as well as in comparison to other mammal species of a similar size. Given that we don't experience the same degree of enhanced longevity in response to calorie restriction as occurs in shorter-lived species, some researchers have hypothesized that in the course of evolving greater longevity - perhaps due to the grandmother effect - some of the changes that occur in metabolism under calorie restriction in those shorter-lived species become permanently turned on in humans.

If this is in fact true, then we would expect only limited benefits to result from the development of calorie restriction mimetic drugs: anything that looked promising in mice and even primates would not work as well in people. We might think, however, based on the degree to which calorie restriction is demonstrated to improve health in humans, that this hypothesis of always-on calorie restriction responses is not the case. The research here adds some supporting evidence to this view, but leaves standing the question of how calorie restriction can produce similar sweeping changes in health and metabolism in both humans and mice, and yet only the mice have a large extension of life span:

Caloric restriction (CR) and chemical agents, such as resveratrol and rapamycin that partially mimic the CR effect, can delay morbidity and mortality across a broad range of species. In humans, however, the effects of CR or other life-extending agents have not yet been investigated systematically. Human maximal lifespan is already substantially greater compared to that of closely related primate species. It is therefore possible that humans have acquired genetic mutations that mimic the CR effect.

Here, we tested this notion by comparing transcriptome differences between humans and other primates, with the transcriptome changes observed in mice subjected to CR. We show that the human transcriptome state, relative to other primate transcriptomes, does not match that of the CR mice or mice treated with resveratrol, but resembles the transcriptome state of ad libitum fed mice. At the same time, the transcriptome changes induced by CR in mice are enriched among genes showing age-related changes in primates, concentrated in specific expression patterns, and can be linked with specific functional pathways, including insulin signalling, cancer, and the immune response.

These findings indicate that the evolution of human longevity was likely independent of CR-induced lifespan extension mechanisms. Consequently, application of CR or CR-mimicking agents may yet offer a promising direction for the extension of healthy human lifespan.

Link: http://dx.doi.org/10.1371/journal.pone.0084117

A reader pointed me to the 700 for Science site a few days back. This is a vetted social network of research advocates and scientists with a medical and biotechnology focus, defining its own place on the spectrum that includes research crowdfunding, non-profit advocacy, and scientific fundraising for specific projects. The current project focus is similar to that of the Methuselah Foundation and New Organ initiative: driving the research and development community towards faster realization of tissue engineered, patient-matched organs. These organs will be created as needed and transplanted with minimal risk of rejection, as they are grown from the patient's own cells.

700 for Science FAQ

We are an international nonprofit organization comprised of research scientists, business and industry leaders, entrepreneurs and investors in early-stage technologies. Collectively, we are creating a community of experts willing to support novel biotech and clean technologies with real social value.

Early-stage technologies no longer qualify for research funds and because they generally still need to demonstrate proof-of-concept, they are often too risky to attract downstream money. As a result many technologies with significant social value are languishing. Our network of experienced commercialization experts can often help startups with small contributions of time and talent and, occasionally, funding from angel investors.

Our members select a core group of technologies from those submitted throughout the year. The annual Portfolio700 is announced in January. Throughout the rest of that calendar year, we identify and execute key activities that will help advance these technologies. Once selected, a technology remains a part of Portfolio700 - receiving support from the organization and our members - for three years.

The organization has set up separate web sites for the two collaborative projects currently published, both of which are worth a look. The current state of progress is that a summit will occur later this year and a research consortium is forming: the hard work of raising funds and coordinating research is to follow.

It is interesting that both 700 for Science and New Organ choose to focus on the liver as the first target for organ engineering: this most likely reflects the state of thought in the field as to which goals will be easiest or are presently closest to realization. The liver is the human organ with the greatest natural ability to regenerate itself, which might prove to be a head start, or it might not - we shall see.

Whole Organ

Great technical challenges must be resolved if we are to engineer whole organs. On April 30, 2014, the world's recognized experts are gathering to form a transdisciplinary international scientific consortium. Our goal? To create a transdisciplinary, science-driven effort to engineer a human liver.

We're at a watershed moment in medical history. The world's top research teams are ready to focus on the goal of engineering a replacement liver for human transplantation. Now it's time to come together and forge partnerships to overcome daunting technical challenges. And since hard math is a part of any bold endeavor, we'll also determine the best strategy for leveraging grant-supported research.

Solving Organ Shortage

We've conceived an ambitious agenda of research and policy-making initiatives aimed at solving the organ shortage. Now we're ready to begin. Research over the past decade yielded a flurry of information about the nature of adult stem cells, progenitor cells and their differentiated cell types. Then came the breakthrough discovery of induced pluripotent stem cells and progress has been breathtaking ever since. Now the research community is ready to use these cells to address the growing organ shortage and improve the quality of life for transplant recipients.

Advocating for replacement organs is the exciting part. Aligning with a broad-based constituency of organizations to create a comprehensive strategy to address the organ shortage will require a new level of resourcefulness. The mission of SOS is to anticipate needs, overcome roadblocks, augment the work of likeminded organizations and enlist allies who share our vision. Our work has just begun.

Telomerase is of primary interest to the research community for its role in lengthening telomeres, the protective caps on the ends of chromosomes. This is an important function in cell dynamics: telomeres shorten with each cell division, forming a crude clock that limits the number of times cells divide in populations without significant telomerase activity. Age tends to reduce average telomere length in tissues, but this seems most likely a measure of damage and changes rather than a form of damage in and of itself - a consequence, not a cause of aging. Nonethless, using genetic engineering to boost levels of telomerase in mice leads to extension of life. In past years there has been some suggestion that telomerase might help maintain mitochondrial integrity against oxidative damage, and this could be why it can be used to extend life. But this is still an open question.

Most cancers abuse telomerase to keep their cells dividing to form tumors, and the SENS anti-cancer strategy of WILT would involve suppressing telomerase as a part of the way to strike at the root commonality shared by all cancer. But what else might telomerase do? There is no shortage of proteins in the body that have multiple important roles: evolution clearly often leads to reuse of existing components. If telomerase has other roles, this would complicate WILT. Here is a recent paper that looks into the evidence for other activities on the part of telomerase:

For more than a decade, diverse telomerase mouse models have provided us with precious opportunities for evaluating the patho-physiological significance of telomerase in genetically defined environments and at an organismal level. With an emphasis on defective telomeres, these mouse models have considerably contributed to understanding a broad spectrum of phenomena associated with cancer and ageing. Furthermore, growing evidence has indicated that defective telomerase functions are involved in distinct diseases other than human cancers including dyskeratosis congenita, atherosclerosis, and renal diseases.

Despite the evident roles in telomeres, currently emerging extra-telomeric functions of telomerase are completely changing the scope of this enzyme. Notably, the direct roles of TERT in transcriptional regulation provide good rationale for several phenotypes that cannot be explained by telomere dysfunction, and their physiological significance has been also confirmed using telomerase mouse models. As might be expected, these lines of evidence make us consider that diverse observations supporting extra-telomeric roles of telomerase should be scrutinized and validated in vivo by generating novel mouse models.

For example, in addition to the effect of short telomeres on mitochondria, mitochondrial targeting of telomerase upon certain stressful conditions, and the recently identified RNA-dependent RNA polymerase activity of TERT indicates that telomerase has direct roles in mitochondria. Furthermore, considering the important roles of telomerase in cellular homeostasis, telomerase may be a critical factor for regulating the subcellular organelle homeostasis. Undoubtedly, we believe that these extra-telomeric functions of telomerase should be intimately associated with life span regulation, and that some regions of TERT, other than the RT domain, will be required for mediating protein-protein interactions with known functions in controlling the life span of an organism.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3874908/

Following on from last week's post on intermittent fasting research, here is a profile of the scientist coordinating that study and other, related work:

[Valter Longo worked] in the UCLA lab of Roy Walford, a renowned practitioner of calorie restriction for longevity. For part of that time, Longo used a video conferencing system to communicate with Walford, who was sealed inside a self-contained glass structure called Biosphere 2 in the Arizona desert from 1991 to 1993. After a couple of years, Longo decided that he wanted to bring a more molecular approach to questions of aging. Looking at yeast, a very simple unicellular organism, he discovered a group of genes that promote the aging process in response to glucose. By knocking out these genes, he could mimic a calorie- and glucose-restricted diet and extend the life span of yeast.

First as a postdoctoral fellow and then as a faculty member and director of the Longevity Institute at USC, Longo has continued this research into the genes that control aging. In 2001, he discovered another important group of yeast genes that control both aging and overall growth in response to amino acids. He later found a population of humans in Ecuador that had a mutation in the equivalent genes. As a result, they lacked a growth-hormone receptor, and this made them both small in stature and long-lived, with very little susceptibility to diabetes or cancer.

By inhibiting these same groups of genes either by mutations or starvation, Longo has found evidence that healthy cells might receive protection not only from the stresses of aging, but also from the effects of chemotherapy, and that cancer cells might become more sensitive to chemotherapy. Clinical trials are currently underway [to] explore whether fasting can improve outcomes in patients receiving chemotherapy for lymphoma as well as breast, prostate and colorectal cancers.

Link: http://news.usc.edu/#!/article/58074/wanted-a-recipe-for-longevity/

Serious discussion about calorie restriction and intermittent fasting in the popular press is comparatively rare - anything that involves changes of diet will quickly be buried by idiocy as a general rule, if not by the author of the piece, then shortly thereafter. Dieting is just one of those topics in which rationality seems to flee the building whenever it comes up.

Both calorie restriction and intermittent fasting are shown to extend life and greatly improve health in mice and many other species, but they might not operate through exactly the same mechanisms. Intermittent fasting in which calorie intake is maintained at the same level as non-fasting rodents has been shown to produce some extension of life and health benefits in studies for example - equally other studies suggest that this might not be the case. For my money I'd wager the bulk of the effect is calorie based: intermittent fasting tends to result in a lower overall calorie intake, and we know that calorie intake has a large effect on health and longevity in comparison to everything else that you can try in mice.

There is a lot more research into calorie restriction than exists for intermittent fasting strategies such as alternate day fasting. You should bear that in mind when reading around the topic. Calorie restriction really is the gold standard for evidence when it comes to things you can do that will positively affect your health. Intermittent fasting is merely at the interesting and convincing level, worth the balance of risk and reward in my eyes, but nowhere near as well supported as, say, regular moderate exercise.

The present scientific consensus on calorie restriction is that it won't significantly extend life in humans. Perhaps 5-10% at most. This comes from a combination of evolutionary considerations and common sense. If calorie restriction could extend human life by 40%, as it does in mice, then we would have known all about this for centuries at least. Researchers believe that calorie restriction is an adaptation that allows better survival of periodic famine, something that tends to happen on a seasonal timescale - which is long for mice, but short for humans. So there is evolutionary pressure for mice to be able to extend lives considerably in response to a lack of food, but not so for humans. Apparently there is still evolutionary pressure for the creation of health benefits, however, as the short term effects of calorie restriction on the operation of metabolism and resistance to age-related disease are quite similar in both mice and humans.

When it comes to intermittent fasting there really isn't a consensus on life span effects. There isn't enough data and a big enough body of work for that to exist yet. It is generally believed to be a good thing for health, however. With that all said, take a look at this popular science series from the BBC, which examines a mild form of intermittent fasting - really just "intermittent eating somewhat less," a far cry from alternate day fasting in which practitioners only eat at all every other day.

Intermittent fasting: Trying it out for science

Curious about the scientific research that goes into devising a new diet, I decided to volunteer as a subject in a five-month clinical trial at the University of Southern California (USC). As a human guinea pig, I signed up to test a strict diet regime and subject myself to a battery of clinical tests to evaluate its effect on my body.

It involved surviving, for five consecutive days, on a narrow range of foods that contained as little as 500 calories per day - about a quarter of the average person's consumption. There was to be no cheating, no falling off the wagon and no treats. It was an opportunity to be part of study that may help scientists unravel the complex relationship between food and the human body.

The clinical trial, which is still ongoing, is designed to investigate the feasibility, safety, potential benefits and psychological changes associated with a calorie-restricted diet. It is based on previous experiments, at a number of institutions, which have shown that mice live longer and healthier lives if their food intake is cut by up to 30%.

Intermittent fasting: Enduring the hunger pangs

The limited selection of food (with no choice of flavours) means that everything has to be eaten. It's monotonous... but at least it makes meal planning easy for five days. "The reason why diets don't work is because they are very complicated and people have an interpretation problem," says Dr Valter Longo, director of the University of Southern California (USC) Longevity Institute. "The reason I think these [intermittent fasting] diets work is because you have no interpretation. You either do it or you don't do it. And if you do it you're going to get the effect."

Intermittent fasting: The good things it did to my body

During each five-day fasting cycle, when I ate about a quarter the average person's diet, I lost between 2kg and 4kg (4.4-8.8lbs) but before the next cycle came round, 25 days of eating normally had returned me almost to my original weight. But not all consequences of the diet faded so quickly. "What we are seeing is the maintenance of some of the effects even when normal feeding resumes," explains Dr Valter Longo, director of USC's Longevity institute, who has observed similar results in rodents.

Arguably, the most interesting changes were in the levels of a growth hormone known as IGF-1 (insulin-like growth factor). High levels of IGF-1, which is a protein produced by the liver, are believed significantly to increase the risks of colorectal, breast and prostate cancer. Low levels of IGF-1 reduce those risks.

"In animals studies we and others have shown this to be a growth factor that is very much associated with ageing and a variety of diseases, including cancer," says Longo. Studies in mice have shown that an extreme diet, similar to the one I experienced, causes IGF-1 levels to drop and to stay down for a period after a return to normal eating. My data showed exactly the same pattern. "You had a dramatic drop in IGF-1, close to 60% and then once you re-fed it went up, but was still down 20%," Longo told me.

Mitochondrial DNA damage is theorized, with a great deal of evidence in support, to be one of the causes of degenerative aging. This research is somewhat relevant, but the focus on point mutations is problematic: there is other research in mice to demonstrate that point mutations in mitochondrial DNA are not all that important. The important types of damage are more severe, such as deletions in which stretches of DNA are simply dropped. The mice used here do in fact have an increased number of deletions, even though that isn't mentioned in the abstract below, so be careful of claims of associations of dysfunction with point mutations.

A decline in the replicative and regenerative capacity of adult stem cell populations is a major contributor to the ageing process. Mitochondrial DNA (mtDNA) mutations clonally expand with age in human stem cell compartments including the colon, small intestine and stomach and result in respiratory chain deficiency. Studies in a mouse model with high levels of mtDNA mutations due to a defect in the proof-reading domain of the mtDNA polymerase γ (mtDNA mutator mice) have established causal relationships between the accumulation of mtDNA point mutations, stem cell dysfunction and premature ageing.

These mtDNA mutator mice have also highlighted that the consequences of mtDNA mutations upon stem cells vary depending on the tissue. In this review we present evidence that these studies in mice are relevant to normal human stem cell ageing and we explore different hypotheses to explain the tissue specific consequences of mtDNA mutations. In addition, we emphasize the need for a comprehensive analysis of mtDNA mutations and their effects on cellular function in different ageing human stem cell populations.

Link: http://dx.doi.org/10.1111/acel.12199

A calorie restriction mimetic - usually a drug - is a treatment that can recapture some of the same alterations to metabolism caused by the practice of calorie restriction. Since calorie restriction extends life and improves health, so should a calorie restriction mimetic. Most such work at the moment focuses on finding existing drugs that have some calorie restriction mimetic effects and side-effects that are manageable. Regulation makes it so expensive to produce new medical technologies that research and development is guided into marginal repurposing of existing drugs rather than working on better new directions.

Here is an example of the other end of the drug design spectrum, in which researchers work on identifying which epigenetic alterations should be made, and then think about how to design drugs to make those alterations. Despite the headlines none of this can turn off or reverse aging - it can only slow it down modestly, the same way that calorie restriction does. If you want rejuvenation, you have to look at the SENS approach of damage repair biotechnologies, not epigenetic manipulation.

Restricting calorie consumption is one of the few proven ways to combat aging. Though the underlying mechanism is unknown, calorie restriction has been shown to prolong lifespan in yeast, worms, flies, monkeys, and, in some studies, humans. Now [researchers] have developed a computer algorithm that predicts which genes can be "turned off" to create the same anti-aging effect as calorie restriction. "Most algorithms try to find drug targets that kill cells to treat cancer or bacterial infections. Our algorithm is the first in our field to look for drug targets not to kill cells, but to transform them from a diseased state into a healthy one."

[This] lab is a leader in the growing field of genome-scale metabolic modeling or GSMMs. Using mathematical equations and computers, GSMMs describe the metabolism, or life-sustaining, processes of living cells. Once built, the individual models serve as digital laboratories, allowing formerly labor-intensive tests to be conducted with the click of a mouse. [The algorithm, a] "metabolic transformation algorithm," or MTA, can take information about any two metabolic states and predict the environmental or genetic changes required to go from one state to the other.

Some of the genes that the MTA identified were already known to extend the lifespan of yeast when turned off. Of the other genes found, [researchers] sent seven to be tested [and] found that turning off two of the genes, GRE3 and ADH2, in actual, non-digital yeast significantly extends the yeast's lifespan. "You would expect about three percent of yeast's genes to be lifespan-extending. So achieving a 10-fold increase over this expected frequency, as we did, is very encouraging."

Since MTA provides a systemic view of cell metabolism, it can also shed light on how the genes it identifies contribute to changes in genetic expression. In the case of GRE3 and ADH2, MTA showed that turning off the genes increased oxidative stress levels in yeast, thus possibly inducing a mild stress similar to that produced by calorie restriction.

Link: http://www.aftau.org/site/News2?page=NewsArticle&id=19593

There has been growing interest in grassroots political organization among members of the longevity advocacy community in the past couple of years. Unlike efforts such as the Longevity Dividend, which aims at the lobbying process to direct established flows of public funding towards longevity science, the grassroots is starting with the formation of single issue political parties in different countries. As an approach to activism this has a long history in Europe, though less so in the US by virtue of the differences in electoral systems. You might look at the Green and Pirate parties as successful examples of the type.

One outcome of all this was the creation of the International Longevity Alliance a little over a year ago. This organization acts as a point of organization and coordination for various local groups in different countries, and is an umbrella for a number of lines of volunteer work, some which focus as much on science as on advocacy and politics. But take a look for yourself, as here is an annual report for the past year and roadmap looking ahead:

International Longevity Alliance (ILA) - Annual Report for 2013 - Roadmap for 2014

The ILA's mission is to to promote the advancement of healthy longevity for all people through scientific research, technological development, medical treatment, public health, education, advocacy and social activism. In the past year, ILA has grown. ILA groups now exist in over 50 countries, with unofficial membership ranging in the thousands. It is on its way to official registration in France as a "Fonds de Dotation" (Endowment Fund) and will act as an alliance of pro-longevity non-profit organizations ("NPOs") from around the world.

Officially affiliated groups already exist in Russia, France, India and Finland. Other national ILA NPOs are on their way to registration in Israel, Germany, Ukraine, Colombia, Canada, the United States and other countries. We anticipate that existing pro-longevity organizations will also join as federated members, so that by the end of 2014 ILA will become a well established network of formally registered NPOs, as well as informal groups and individuals around the world, united for the purpose of achieving healthy longevity for all.

You might also take a look at the Denigma platform that is now under the ILA umbrella. Ideally those working on it will be able to produce something as useful and well-regarded as, say, the Human Ageing Genomic Resources site at the end of the day - and this is not an unreasonable goal, considering what they have accomplished to date.

Denigma (Deciphering the Enigma of Aging), based on the Linux open-source operating system, is the main ILA IT platform to collect, hold and distribute information. In 2013, the platform was extensively developed. Deliverables produced during this year include: the building of Denigma Legacy: denigma.de; Longevity Variant Database: longevitydb.org; Denigma Destiny: denigma.org.

We have used the platform to establish molecular profiles on ageing and powerful biomarkers to accurately measure biological age and effect of anti-aging interventions (focusing on genetic targets and functional prediction on miRNAs). We have used it to analyze aging-suppressor gene activity measurements (data analysis to link levels with phenotype); to reveal the role of mitochondrial heteroplasmy and metabolic influence (link levels with phenotype); to validate the role of aging as the main cause of diseases. We have provided exact descriptions of the individual influences of aging hallmarks and created hundreds of ontologies and linked annotated data on aging.

They are also helping to set up and fund studies, though of course I'd be happier to see more SENS-like work aimed at reversal of aging and less of the drug testing with the aim of merely slowing aging. All publicity is good, and initiative in setting up studies is to be commended, but I just don't see that any great payoff is likely to result from this sort of screening work. Of course I - and other SENS supporters - are in something of a minor in holding this viewpoint:

ILA is initiating projects to test life-extending interventions in mice, other domestic animals and simpler organisms using both academic and do-it-yourself biology platforms. In 2013, we initiated a project on life-span extension in mice in cooperation with the Institute of Gerontology in Kiev, Ukraine. Test protocols have been developed for potential anti-aging drugs, as well as a plasma test for pathologies. Logistic procedures have been established. The do-it-yourself biology platform has been further strengthened to encourage testing life-extending interventions in rats and hamsters at home.

A top priority for 2014 will be to establish a screening project to test lifespan-extending interventions in mice. Funding for this large screening project will be actively sought in 2014.

So all in all there's a lot going on in that portion of the community: good news, I think, to see so much activity in comparison to the desert of past years. The European and Russian groups are really pulling together and getting stuff done - more power to them. I hope to see the ILA volunteers continue the good work, and hopefully come around to more of a SENS viewpoint in their future fundraising and scientific initiatives.

There is always something promising taking place in the lab with respect to Alzheimer's disease and other forms of age-related neurodegeneration, but all too few such line items successfully work their way through the chain to clinical application.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by amyloid beta (Aβ) deposits, hyperphosphorylated tau deposition, and cognitive dysfunction. Abnormalities in the expression of brain-derived neurotrophic factor (BDNF), which plays an important role in learning and memory formation, have been reported in the brains of AD patients. A BDNF modulating peptide (Neuropep-1) was previously identified by positional-scanning synthetic peptide combinatorial library.

Here we examine the neuroprotective effects of Neuropep-1 on several in vitro neurotoxic insults, and triple-transgenic AD mouse model (3xTg-AD). Neuropep-1 protects cultured neurons against oligomeric Aβ1-42, 1-methyl-4-phenylpyridinium, and glutamate-induced neuronal cell death. Neuropep-1 injection also significantly rescues the spatial learning and memory deficits of 3xTg-AD mice compared with vehicle-treated control group. Neuropep-1 treatment markedly increases hippocampal and cortical BDNF levels. Furthermore, we found that Neuropep-1-injected 3xTg-AD mice exhibit dramatically reduced Aβ plaque deposition and Aβ levels without affecting tau pathology. Neuropep-1 treatment does not alter the expression or activity of full-length amyloid precursor protein, α-, β-, or γ-secretase, but levels of insulin degrading enzyme, an Aβ degrading enzyme, were increased. These findings suggest Neuropep-1 may be a therapeutic candidate for the treatment of AD.

Link: http://dx.doi.org/10.1016/j.neurobiolaging.2013.10.091

Mitochondria are important in aging, and in particular their relationship to aging appears to be somewhat mediated by how resistant their membranes are to oxidative damage - the evidence and theorizing around this is known as the membrane pacemaker hypothesis. You'll recall that mitochondria are effectively the cell's power plants, generating chemical energy stores for use in many cellular processes. In the course of their operation they generate a continued flow of reactive free radicals that can cause oxidative damage - they themselves are the most likely target for that damage, but because they occupy such an important position in the cell there are ways in which their damage can lead to worse outcomes for the cell as a whole, and also for surrounding tissue. This process is one of the causes of aging, and it is why the development of mitochondrial repair technologies is important.

Here is an open access paper that reviews what is known about the link between membrane composition and longevity in various species. In general I view this as supporting evidence for the need for mitochondrial repair: I don't expect that anything of practical use in the near term can result from trying to change the composition of our mitochondrial membranes.

The appearance of oxygen in the terrestrial atmosphere represented an important selective pressure for ancestral living organisms and contributed toward setting up the pace of evolutionary changes in structural and functional systems. The evolution of using oxygen for efficient energy production served as a driving force for the evolution of complex organisms. The redox reactions associated with its use were, however, responsible for the production of reactive species (derived from oxygen and lipids) with damaging effects due to oxidative chemical modifications of essential cellular components.

Consequently, aerobic life required the emergence and selection of antioxidant defense systems. As a result, a high diversity in molecular and structural antioxidant defenses evolved. In the following paragraphs, we analyze the adaptation of biological membranes as a dynamic structural defense against reactive species evolved by animals. In particular, our goal is to describe the physiological mechanisms underlying the structural adaptation of cellular membranes to oxidative stress and to explain the meaning of this adaptive mechanism, and to review the state of the art about the link between membrane composition and longevity of animal species.

Link: http://www.frontiersin.org/Journal/10.3389/fphys.2013.00372/full

Researchers who theorize that aging is the result of damage accumulation have to explain why evolutionary processes fail to select for longer lives by favoring, say, better mechanisms for damage repair. These explanations exist and are generally robust, though there is always some ongoing level of debate over details, such as why we humans live for so long in comparison to other primates or other mammals our own size. Researchers who theorize that aging is an evolved genetic program have the opposite challenge, which is to explain how evolution selects for shorter lives than would otherwise be the case: what is the value of death-assurance mechanisms? Here too explanations exist, are generally robust, and there is an ongoing level of debate over details.

The mainstream consensus of the research community supports the view of aging as damage rather than aging as a genetic program, both from the point of view of molecular biology and evolutionary considerations. It is worth noting that even in a world in which aging is damage accumulation, the world in which I believe we live in, there can still be species that appear to suffer programmed aging on top of that. Salmon are a good example: it's worth looking into what that looks like as a response to external environmental factors.

Here, as a matter of interest, is a paper on the core issue relating to the hypothetical evolution of programmed aging: how can internal death-promoting mechanisms be adaptive for a species? This paper is open access, but note that it has no abstract - you'll have to click on the "Full Text" tab to view it, or alternatively download the PDF version.

Are Internal, Death-Promoting Mechanisms Ever Adaptive?

The idea that self-inflicted organismal death could be adaptive sounds, at face value, absurd. An adaptation is a trait that is suitable (apt) for the current circumstances or environmental challenges, and archetypal examples include traits that promote survival. Natural selection is the mechanism that produces adaptations. In describing natural selection, Darwin (1859) emphasized the struggle for survival: "Two canine animals in a time of dearth may be truly said to struggle with each other which shall get food and live. But a plant on the edge of a desert is said to struggle for life against the drought......". How could an inherited trait that promotes death, rather than survival, possibly be adaptive?

Four categories encompass the major possible evolutionary explanations for the cause of death of an organism. First, death (or an increased probability of death) could inevitably occur despite the efforts or traits of the organism. Second, internal mechanisms that promote death could exist in spite of selective pressure against them. Third, death could occur as a side-effect of a mechanism within the organism that has another function or benefit. Fourth, death could occur because of a mechanism within the organism that evolved explicitly to cause death. This fourth category is the only one in which the mechanism promoting death is an adaptation for promoting death, and cases in this category can only be explained by selection at a hierarchical level other than the organism.

In all categories except the first, we can reasonably expect to see active mechanisms within an organism that promote death. This review was motivated by the observation that diverse organisms apparently have such active, internal death-promoting mechanisms and by the subtle and difficult conceptual issues that understanding the evolution of this kind of trait raises.

A great deal of philosophical and metaphysical thought is devoted to the topic of mind uploading. We are moving into an age in which the emulation of human brains in software will be possible, and clearly strong artificial intelligence will result from that work, even if not achieved through other means.

There is considerable overlap between supporters of longevity science and supporters of work on strong AI. A large contingent of people view mind uploading - making a copy of their mind and then running it in software - as a perfectly valid approach to achieving radical life extension. Look at the 2045 Initiative, for example, as a determined outgrowth of this community. This appears fine if you believe that a copy of you is you, but the problem is that this is not the case. A copy is a copy, its own entity. There are also other rather important existential issues inherent in existing as software rather than hardware: are you a continuous being, or are you just a sequence of disconnected, momentary separate beings, each destroyed an instant after its creation? A shadow of life and an ongoing atrocity of continual murder, not actual life.

So the details of implementation matter. Replace your neurons as they die, gradually, with long-lasting machinery that serves the same purpose in hardware and you are still you. Nothing is different as you transition continuously from flesh to machine. But to copy the brain and throw it away, to replace it instantly with that same end result is death. So far as I can see there is no near-future technology of gradual machine replacement that is likely to provide radical life extension on the same timeframe as work in rejuvenation medicine. Artificial neurons for gradual replacement are a long way away in comparison to implementation of the SENS vision for reversal of human aging.

In any case, here is a little philosophical reading on mind uploading, with links to much more in the way of thought on the subject. It might not be terribly relevant to our future, but that doesn't stop it from being interesting:

A couple of years ago I wrote a series of posts about Nicholas Agar's book Humanity's End: Why we should reject radical enhancement. The book critiques the arguments of four pro-enhancement writers. One of the more interesting aspects of this critique was Agar's treatment of mind-uploading. Many transhumanists are enamoured with the notion of mind-uploading, but Agar argued that mind-uploading would be irrational due to the non-zero risk that it would lead to your death. The argument for this was called Searle's Wager, as it relied on ideas drawn from the work of John Searle.

This argument has been discussed online in the intervening years. But it has recently been drawn to my attention that Agar and Neil Levy debated the argument in the pages of the journal AI and Society back in 2011-12. Over the next few posts, I want to cover that debate. I start by looking at Neil Levy's critique of Agar's Searlian Wager argument.

The major thrust of this critique is that Searle's Wager, like the Pascalian Wager upon which it is based, fails to present a serious case against the rationality of mind-uploading. This is not because mind-uploading would in fact be a rational thing to do - Levy remains agnostic about this issue - but because the principle of rational choice Agar uses to guide his argument fails to be properly action-guiding. In addition to this, Agar ignores considerations that affect the strength of his argument, and is inconsistent about certain other considerations.

Link: http://philosophicaldisquisitions.blogspot.com/2014/01/is-mind-uploading-existentially-risky.html

If regular exercise were a drug, people would stampede to buy it at any price. It is more effective for prevention and treatment of near all common chronic conditions - and for healthy people too - than any presently available medical technology. The only thing to match it (and even do somewhat better) is the practice of calorie restriction. To be clear, you can't exercise your way out of aging to death on a broadly similar schedule to your peers - but exercise does correlate with a longer life expectancy, and given that we're in a race between aging and the development of rejuvenation biotechnologies to reverse aging, it would be foolish not to take every proven advantage along the way.

If there were a drug that treated and prevented the chronic diseases that afflict Americans and we didn't give it to everyone, we'd be withholding a magic pill. If this drug was free, in a country that spends more than $350 billion annually on prescription drugs, where the average 80-year-old takes eight medications, we'd be foolish not to encourage this cheaper and safer alternative as first-line treatment. If every doctor in every country around the world didn't prescribe this drug for every patient, it might almost be considered medical malpractice.

We have that drug today, and it's safe, free, and readily available.

Exercise has benefits for every body system; it is effective both as a treatment and for prevention of disease. It can improve memory and concentration, lessen sleep disorders, aid heart disease by lowering cholesterol and reducing blood pressure, help sexual problems such as erectile dysfunction, and raise low libido. Exercise does it all. Even with cancer, particularly colon and recurrent breast cancer, the data show clearly that exercise is a deterrent. Newer studies on a glycoprotein called Interleukin 6 suggests that general body inflammation, a factor in almost every chronic disease, is reduced by regular exercise.

Link: http://www.slate.com/articles/health_and_science/medical_examiner/2013/12/exercise_to_prevent_cure_or_treat_disease_cancer_heart_disease_inflammation.html