Fight Aging! Newsletter, February 3rd 2014

February 3rd 2014

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

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  • The Prospects for Myostatin Therapies to Reverse Age-Related Loss of Muscle Mass and Strength
  • Can Delivery of New Cells to Tissue Slow or Reverse the Accumulation of Senescent Cells?
  • More Recent Coverage of SENS Research
  • A Rejuvenation Biotechnology Update from Methuselah Foundation and SENS Research Foundation
  • Weak Evidence Against a Significant Role for Nuclear DNA Damage in Aging
  • Latest Headlines from Fight Aging!
    • Physical Activity Associated With Longer Life Spans in Cancer Survivors
    • Microparticle Therapy Reduces Damage Following Heart Attack
    • Working on Decellularized Kidneys for Xenotransplantation
    • The Assumption of Immortality
    • A French Language Interview With Aubrey de Grey
    • Another Step Towards Hair Regeneration
    • Engineering Skin With Capillaries
    • Slower Reaction Time Correlates With Increased Mortality Risk
    • A Spanish Language Interview With Aubrey de Grey
    • A Simpler Path to Creating Pluripotent Stem Cells


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.


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.


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."


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.

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.


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.


Monday, January 27, 2014

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.

Monday, January 27, 2014

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."

Tuesday, January 28, 2014

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."

Tuesday, January 28, 2014

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.

Wednesday, January 29, 2014

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.

Wednesday, January 29, 2014

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."

Thursday, January 30, 2014

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.

Thursday, January 30, 2014

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.

Friday, January 31, 2014

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.

Friday, January 31, 2014

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.


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