Commercial Services to Measure Telomere Length

If you can have a range of single nucleotide polymorphisms and other quirks of your DNA analyzed by mail and presented via an online service, then why not the same for the length of your telomeres?

Telomeres - the terminal caps of chromosomes - become shorter as individuals age, and there is much interest in determining what causes telomere attrition since this process may play a role in biological aging. The leading hypothesis is that telomere attrition is due to inflammation, exposure to infectious agents, and other types of oxidative stress, which damage telomeres and impair their repair mechanisms. Several lines of evidence support this hypothesis, including observational findings that people exposed to infectious diseases have shorter telomeres.

At least two nascent companies presently aim to commercialize telomere measurement technologies: Telomere Health and Life Length were recently featured in Scientific American:

"Knowing whether our telomeres are a normal length or not for a given chronological age will give us an indication of our health status and of our physiological 'age' even before diseases appear," says Maria A. Blasco, who heads the Telomeres and Telomerase Group at the Spanish National Cancer Research Center and who co-founded the company Life Length in September. Telomere research pioneer Calvin B. Harley, who co-founded Telome Health last spring with Nobel laureate Elizabeth H. Blackburn, considers telomere length "probably the best single measure of our integrated genetics, previous lifestyle and environmental exposures." Beginning as early as this spring, the companies will offer telomere-measurement tests to research centers and companies studying the role of telomeres in aging and disease; the general public may have access by the fall through doctors and laboratories, perhaps even directly.

I think that these initiatives are not so interesting in and of themselves, but should be considered as part of a powerful trend now underway. The marketplace for personal biochemical information supplied on demand, via mail and internet, will only grow as the underlying technologies become cheaper, more reliable, and possible to run at scale. One very desirable next stage in the evolution of this marketplace is to do away with the mail portion - the need to send samples in envelopes to a central processing location. The tools of analysis are becoming ever cheaper, and it won't be too many more years before it is cost-effective for most people in the developed world to produce raw data from their own biochemistries with desktop devices at home. The results will be sent over the network to be processed, analyzed, and matched against sophisticated databases owned by for-pay subscription services.

This vision will of course be fought against tooth and nail by the myriad entrenched interests in the command and control style medical systems of the Western nations - those who benefit from medical regulation at the expense of progress. These interests can't stop the internet, however, and nor can they regulate devices that connect to encrypted services outside the US. Distributed medicine, in which a great deal of the process of managing diagnosis and data collection rests with ordinary people, is the inevitable end result of falling costs in biotechnology and communication technologies. This is a good thing, and the sooner all opposed give up and go home, the better.

Epigenetics and the Aging of Stem Cells

A recent review: "The function of adult tissue-specific stem cells declines with age, which may contribute to the physiological decline in tissue homeostasis and the increased risk of neoplasm during aging. Old stem cells can be 'rejuvenated' by environmental stimuli in some cases, raising the possibility that a subset of age-dependent stem cell changes is regulated by reversible mechanisms. Epigenetic regulators are good candidates for such mechanisms, as they provide a versatile checkpoint to mediate plastic changes in gene expression and have recently been found to control organismal longevity. Here, we review the importance of chromatin regulation in adult stem cell compartments. We particularly focus on the roles of chromatin-modifying complexes and transcription factors that directly impact chromatin in aging stem cells. Understanding the regulation of chromatin states in adult stem cells is likely to have important implications for identifying avenues to maintain the homeostatic balance between sustained function and neoplastic transformation of aging."


Thioflavin T Extends Life in Nematode Worms

Another hit in the search for compounds that extend life in lower animals: "Basic Yellow 1, a dye used in neuroscience laboratories around the world to detect damaged protein in Alzheimer's disease - [also] known as Thioflavin T, (ThT) - extended lifespan in healthy nematode worms by more than 50 percent and slowed the disease process in worms bred to mimic aspects of Alzheimer's. The research, conducted at the Buck Institute for Research on Aging, could open new ways to intervene in aging and age-related disease. The study highlights a process called protein homeostasis - the ability of an organism to maintain the proper structure and balance of its proteins, which are the building blocks of life. Genetic studies have long indicated that protein homeostasis is a major contributor to longevity in complex animals. Many degenerative diseases have been linked to a breakdown in the process. ... this study points to the use of compounds to support protein homeostasis, something that ThT, did as the worms aged. ThT works as a marker of neurodegenerative diseases because it binds amyloid plaques - the toxic aggregated protein fragments associated with Alzheimer's. In the nematodes ThT's ability to not only bind, but also slow the clumping of toxic protein fragments, may be key to the compound's ability to extend lifespan ... We have been looking for compounds that slow aging for more than ten years and ThT is the best we have seen so far. But more exciting is the discovery that ThT so dramatically improves nematode models of disease-related pathology as well. ThT allows us to manipulate the aging process, it has the potential to be active in multiple disease states and it enhances the animal's innate ability to deal with changes in its proteins."


Bacteria Complicate the Picture for AGEs and Aging

The many types of advanced glycation endproducts, or AGEs, build up with age. These are forms of sugary gunk that glue together important components in your cellular machinery, and enough of that going on would ultimately become a fatal problem. AGE levels are probably (for most people) more of a contributory cause than principle cause of age-related degeneration, however. The other things kill you first - but it's all a matter of accumulation, and every form of unrepaired biological damage plays its part in hastening the end.

It is likely that the way in which AGEs cause issues has just as much to do with making cells act in counterproductive ways as it does with outright destruction of essential mechanisms. An important focus of research is RAGE, the cellular receptor for AGEs, which is involved in the inflammatory response. As I'm sure you know by now, chronic inflammation is very bad for you over the long term, and goes a long way towards degrading health and remaining longevity. If your body is flooded with AGEs, then one consequence is inflammation - and that in turn will cause harm over time in many different ways.

The picture of AGEs and aging is already complicated by diet - some AGE levels are very variable, and depend on what you happen to be eating - and metabolic conditions such as diabetes wherein the overall behavior of human metabolism is quite different from that of an aged but otherwise normal person. Much of the modern populace eats far too much, and far too much sugar as well, which leads to these sorts of conditions of overnutrition.

Today I noticed an open access paper that adds another layer of complexity to the picture of AGEs and aging. Bacteria produce AGEs, and RAGE and its connection to the inflammatory response may be a component part of the immune system - a mechanism that evolved long before we humans had ready access to the damaging levels and types of food we presently consume.

Advanced Glycated End Products (AGEs) are formed by non-enzymatic protein glycation and are implicated in several physiological aspects including cell aging and diseases. Recent data indicate that bacteria - although short lived - produce, metabolize and accumulate AGEs. Here we show that Escherichia coli cells secrete AGEs by the energy-dependent efflux pump systems. Moreover, we show that in the presence of these AGEs there is an upshift of pro-inflammatory cytokines by mammalian cells.

Thus, we propose that secretion of AGEs by bacteria is a novel avenue of bacterial-induced inflammation which is potentially important in the pathophysiology of bacterial infections. Moreover, the sensing of AGEs by the host cells may constitute a warning system for the presence of bacteria.

So in short, it would seem plausible that the reaction to accumulating AGEs is yet another way in which both modern overnutrition and the established course of aging act separately but combine to sabotage the evolved workings of the immune system. We already know that the immune system is formed to be very efficient in youth but structurally fails over time, so one more mechanism that follows this pattern shouldn't be too surprising.

The only good news here is that safely getting rid of AGEs should be one of the least challenging aspects of aging for the present pharmaceutical research and development community to tackle over the next few decades - as and when they get around to deciding that they should be working on that. Producing drugs, bioremediation therapies, or immune therapies to break down specific forms of unwanted chemical will soon enough be the core competency of the pharmaceutical industry.

h+ Magazine on Telomeres and Telomerase

An introductory article at h+ Magazine looks at the role of telomeres and telomerase in aging: "Several thousand studies have been published on telomeres and telomerase, which are now known to maintain genomic stability, prevent the inappropriate activation of DNA damage pathways, partially determine disease susceptibility/resistance and regulate cellular and organism-wide viability and aging. Telomerase expression [in conjunction with other genetic alterations] also extends the lifespan and reverses senescence-associated pathologies in mice. ... In humans telomere length and integrity plays a role in some diseases, disease susceptibility, aging and even in mediating the deleterious effects of long-term psychological stress. Several human genetic diseases are caused by alterations in telomerase function. For example, individuals with dyskeratosis congenita (DC) ... Many aspects of DC resemble normal aging, although at an accelerated rate. Individuals with DC are born with unusually short telomeres and not surprisingly, the expression of unmutated telomerase in DC cells corrects many of their molecular defects and lengthens their telomeres. ... Normal cellular telomerase expression is insufficient to prevent telomere shortening with each cell division and hence, telomeres shorten with aging, eventually causing age-related changes. The process is complex, and different cell types and organs show different rates of telomere shortening, although overall telomere shorten most rapidly in growing cell populations. Interestingly, high telomere stability correlates with human longevity while caloric restriction (the only known intervention that increases the [maximum] mammalian lifespan), reduces the rate of telomere shortening, although it does not increase telomerase expression. Last, malignant tumors overexpress telomerase, allowing them to grow indefinitely. One reason why most normal cells of the human body do not express high levels of telomerase might be to prevent cancer."


A Bacterial Approach to Targeted Therapies

One approach to developing targeted therapies is to co-opt existing biological structures, such as cells and bacteria: "Scientists have developed bacteria that serve as mobile pharmaceutical factories, both producing disease-fighting substances and delivering the potentially life-saving cargo to diseased areas of the body. ... [Researchers] chose the term 'bacterial dirigibles' because the modified bacteria actually have the fat-cigar look of blimps and zeppelins, those famous airships of yesteryear. ... We're building a platform that could allow bacterial dirigibles to be the next-generation disease fighters. ... traditional genetic engineering reprograms bacteria so that they produce antibiotics, insulin, and other medicines and materials. The bacteria grow in nutrient solutions in enormous stainless steel vats in factories. They release antibiotics or insulin into vats, and technicians harvest the medicine for processing and eventual use in people. The bacterial dirigible approach takes bioengineering a step further. Scientists genetically modify bacteria to produce a medicine or another disease-fighting substance. Then, however, they give the bacteria a biochemical delivery address, which is the locale of the disease. Swallowed or injected into the body, the bacteria travel to the diseased tissue and start producing substances to fight the disease. ... We have created a genetic circuit that endows E. coli with targeting, sensing and switching capabilities. ... The 'targeting' molecule is attached to the outer surface of the bacteria. It gives the bacteria an ability to 'hone in' on specific cells and attach to them - in this instance, the intestinal cells where other strains of E. coli cause food poisoning symptoms. Inside the bacteria is a gene segment that acts as 'nanofactory.' It uses the bacteria's natural cellular machinery to make drugs, such as those that can fight bacterial infections, viruses, and cancer. The nanofactory also could produce signaling molecules that enable the dirigible to communicate with natural bacteria at the site of an infection. Some bacteria engage in a biochemical chit-chat, termed 'quorum sensing,' in which they coordinate the activities needed to establish an infection. Bacteria dirigibles could produce their own signaling molecules that disrupt quorum sensing."


Regeneration of the Pancreas, Demonstrated in Mice

Amongst the fast track papers at Rejuvenation Research, there is one that describes a stem cell therapy for regenerating damage to the pancreas.

We demonstrate that intravenous delivery of human, or rat, pancreas-derived pathfinder (PDP) cells can totally regenerate critically damaged adult tissue and restore normal function across a species barrier.

One of the more interesting aspects of this demonstration is that rat or human pathfinder cells introduced into mice spur rapid regeneration that produces overwhelmingly mouse tissue rather than rat or human tissue - and all without causing immune issues. These "pathfinder cells" are a form of stem cell found in adult tissues; the name is a branding effort by the for-profit research group Pathfinder, LLC, and is aimed at distinguishing in the marketplace the exact form of stem cell they work with. This process of branding cell configurations or particular forms of cellular reprogramming is something we'll be seeing much more of in the future, no matter how irritating it may be to folk who are just trying to follow the science.

You might find the press release an easier read than the research paper:

the Company's unique cell-based therapy is able to completely reverse diabetes in a mouse model. ... With only two treatments with [pathfinder cells], just days after induction of diabetes, we were able to quickly regenerate critically damaged pancreatic tissue, restoring and maintaining normal glucose levels and healthy body weight. ... Immunohistochemical analyses of animal tissues confirmed [that] treatment lead to regeneration of pancreatic beta-cells and formation of functional islets, which displayed normal architecture. Further examination determined that the regenerated islets consisted overwhelmingly of mouse cells, and to a much lesser extent, donor [rat or human] PCs (0.05-0.18%).

Reading between the lines, I'm given to wonder whether these "pathfinder cells" are in fact much the same thing as the very small embryonic-like stem cells that another group claims to exist in most tissues in the body.

One group of researchers believe that every tissue in the body is supported by a left-over population of fully pluripotent stem cells [(PSCs)] that might be easily accessible for use in therapies. ... In this review we present an evidence that adult tissues contain remnants from development; a population of PSCs that is deposited in various organs as a backup for primitive stem cells, plays a role in rejuvenation of the pool of more differentiated tissue-committed stem cells (TCSCs), and is involved in organ regeneration. These cells share several markers with epiblast/germ line cells and have been named very small embryonic-like stem cells (VSELs).

If, as here, researchers are already demonstrating promising results with stem cell populations isolated from adult tissues, then it shouldn't be too many more years before these forms of stem cell are well classified (and given more sensible names).

The Prospect of Implanted Metabolic Monitors

Optimizing health, measuring progression of age-related change in metabolism, and detecting disease are far more challenging today than they will be in the future. We can envisage sophisticated implanted devices that cheaply and continuously measure aspects of our biology that are presently expensive to test - and the first steps in the development of such implanted monitors are already underway. "Michael Cima and his team developed an implantable sensor that uses antibodies attached to nanoparticles to detect cancer related biomarkers. In 2009 Cima showed that he could implant these devices into human tumors in mice and then 'read' the cancer growth using MRI. No biopsies need. Over the past few years, Cima and his team have adapted their work to create a very similar device that measures biomarkers related to heart damage. ... This work is very exciting, but still very early in development. As we've said many times before, successes with mice experiments and successes with human experiments can be miles apart. The 5mm cylindrical cancer implant and the 8mm heart monitoring disk both need more time to be perfected. The antibodies used to detect biomarkers have a limited lifetime in the body. Currently an implant probably wouldn't last much longer than two months. ... If MIT continues to see good results with these early prototypes, there's a good chance we'll see similar devices in clinical trials in the near future. Cima thinks that such experiments could be as little as five years away. The lowest hanging fruit are implants that could monitor for pH levels - acidity is often a hallmark of cancer cells. After that, we may see versions that can accurately detect hormone levels and drug responses."


More on Germ Cells and Fatty Acid Metabolism

A very readable editorial on recent research into the connection between germ cells and longevity: " For reasons still unknown, a roundworm without its germ cells lives 60% longer than one with those cells intact. And you don't even need to actually remove them - mutations that impair their proliferation also extend life. ... The authors began their exploration by searching for nuclear receptors that were required for the life-extension effect, reasoning that one or more such receptors were likely to play a key role in controlling longevity pathways. Using RNAi in long-lived worms with a known germline proliferation mutation, they shut down hundreds of receptors, looking for those that would reverse the lifespan extension. They found only one, called nhr-80, which they showed acted specifically within the germline-mediated longevity pathway, and not any of the several other pathways known to extend lifespan. This result provided the first experimental evidence that lifespan extension through ablation of the germline can occur in the absence of insulin signaling, one of the best characterized pathways affecting lifespan. Mutation of nhr-80 to prevent expression of the gene prevented the longevity effect, while overexpression increased it, in both cases only when germline cells were absent. ... As a transcription factor, NHR-80 regulates gene expression. Its known targets include a group of enzymes involved in lipid metabolism called desaturases. Desaturases convert saturated fatty acids, such as stearic acid, into unsaturated fatty acids, such as oleic acid, a conversion that significantly alters the physical and biological properties of the fats made from them. The authors show that genes for several desaturases are highly expressed in long-lived germline mutants. ... While worms are not humans, we share many of the same cellular mechanisms, and it is possible the same life-extending effects of this germline-loss/fatty acid increase pathway will be found in us."


Respectable Manias and Well-Thought-Of Delusions

Manias and delusions: both words that found their modern footing in Victorian times, alongside the formation of a populism that links insanity with any belief declared to be wrong. In an earlier century, Shakespeare inked the accusation "Thou art mad," but readily casting the slur of insanity upon everyone who fails to agree with you is a more recent cultural creation, I think. Politics has not been improved by it, for all that there is still little real difference between contemporary reds and blues and the blues and greens of antiquity.

It is unfortunately the case that we live in a world in which a great many people choose to hold self-evidently incorrect and harmful beliefs. It really doesn't matter where you yourself stand in the grand spectrum of ideas, there is still at least one vast group of people who hold beliefs - and undertake actions based on those beliefs - that you would consider nothing short of madness. Take the comparative few of us who rationally value human life and scientific progress, for example: our view is of the other 99.9% of humanity clearly and deliberately walking a path of individual self-destruction. The masses reject or shun or remain in deliberate ignorance of every available path that might lead to longer healthy lives or a chance at avoiding oblivion at death.

The world is populated with people who fail to take care of their health, who avoid thinking about progress in medicine, who laugh at cryonics, and who declare that they want to age and die. Every year, more than fifty million of them do die, decay, and the data that makes up their minds, encoded in the fine structure of the brain, is lost to oblivion. Every year, hundreds of millions suffer in terrible pain and frailty caused by age. And yet we know, from our everyday experience with the human nature of those around us, that after the advent of working rejuvenation therapies, the vast majority of people will use those technologies.

So it is challenging at times to avoid throwing up our hands and declaring the inhabitants of the world delusional. Mad, the insane populace of a wasteland in which every structure is ruined as soon as it is built. But stepping back, you might look on the way things are as one more aspect of the attention economy: a person only has so much attention to give, and the specialties of work, networking, and hobbies eat up most of that available attention. Everyone seems like an idiot - or ill-informed, or delusional - if they venture into areas where they haven't been paying attention. Unfortunately, it is the human urge to avoid both looking like a fool and appearing ignorant, no matter the circumstances. Better to say your piece and glare at everyone who might gainsay you than to retreat in silence - or so says the inner ape. It is not always a good idea to listen to that voice, of course.

I think that this sort of interplay of activity, economics of action, and the less useful base human urges contributes somewhat to the prevalence of people finding smart ways to say profoundly stupid things, as I mentioned in an older post. Such as, for example, the legion of pundits and common folk who line up to proclaim their willingness to age and die, offering little more than puffery and empty platitudes in support of that notion. I have nothing against people who genuinely feel that way: turning away from the opportunities offered by biotechnology should be, like all things pertaining to your own life, a free and respected choice. But it is painful, just painful, to read and listen to the meandering, content-free, non-arguments that the pundits amongst these folk tend to make. I can respect a simple "it's just not for me." You don't need a justification for a personal choice - and staying silent is certainly better than something of this ilk:

Would I want to live forever? No way. Do I want to die? Certainly not now. But I do need to die, hopefully for my ultimate individual good as Meilaender states, but beyond that - corporeal cessation is the right, natural, and ultimately necessary way of things.

That referenced piece of work frustratingly combines clear thinking on the mechanics of longevity science with what is still largely a rejection of the possibilities it offers. As is often the case, that rejection is framed as the desire to avoid change, any change:

Once we begin to attend to the parent-child bond, to the relation between generations, we have begun to think not just of life but of a 'complete life' - a life marked in some way by stages and movement, a life that has shape and not just duration, a life whose moments are not identical but take their specific character from their place in the whole. Moreover, it is difficult to imagine a 'relation between the generations' that does not include aging - coming into being and going out of being. This may stand in some tension with the thirst for indefinitely more life that most of us sometimes experience, but it is hard to imagine a characteristically human life without it. And from this perspective, a simple thirst for more (and more) life might seem to carry an unmistakable whiff of narcissism, for it is hard to imagine how we can act responsibly toward the generations that succeed us if we cling firmly (and desperately?) to our own continued youth.

These authors seem so very willing to sacrifice countless lives for their vague need for the present state of the world to continue. It is hard to see past that willingness to embrace the suffering and death of millions to the thought processes underneath - harder for me to understand than the thinking of people who, like I once was, are simply ignorant in youth, numb with indoctrination and yet to develop their own ideas.

Still, there are people in this world who, as of the moment, genuinely feel no need to extend their lives or do anything about the painful, debilitating degenerations of aging they will suffer in the years ahead. They have thought this through and that is where they stand. I think that this shows a distinct lack of foresight and empathy, but you have to respect the positions developed by other people. The right thing to do is make the attempt to persuade them to see things otherwise, but ultimately peace of mind in this life comes with accepting that most people do not hold your views - or even views that you can easily understand. Progress in advocacy and raising up mass movements lies in working steadily and well to change that fact, not in running around in fits of existential angst appropriate to the scale of the problem. As in so many aspects of life, the instinctive response provided by the ape within is not the helpful one.

When the world is delusional, work to change it. You can do no better, and certainly a great deal worse.

The Naked Mole Rat Challenge

From a recent review paper: "Naked mole rats (NMRs; Heterocephalus glaber) are the longest-living rodents known, with a maximum lifespan of 30 years— - 5 times longer than expected on the basis of body size. These highly social mouse-sized rodents, naturally found in subterranean burrows in the arid and semiarid regions of the horn of Africa, are commonly used in behavioral, neurological, and ecophysiological research. Very old NMRs (>28 years), like humans, show signs of age-associated pathologies (e.g., muscle loss) as well as the accumulation of lipofuscin pigments, but no signs of tumorigenesis. Indeed, for at least 80% of their lives NMRs maintain normal activity, body composition, and reproductive and physiological functions with no obvious age-related increases in morbidity or mortality rate. Their long lifespan is attributed to sustained good health and pronounced cancer resistance. Clearly physiological and biochemical processes in this species have evolved to dramatically extend both their good health and lifespan. We and others have tested various current theories using this species as an exceptionally long-lived animal model of successful abrogated aging. Surprisingly, NMRs have high levels of oxidative stress and relatively short telomeres, yet they are extremely resilient when subjected to cellular stressors and appear capable of sustaining both their genomic and protein integrity under hostile conditions. The challenge is to understand how these animals are able to do this. Elucidating these mechanisms will provide useful information for enhancing human life- and healthspan, making the naked mole rat a true “supermodel” for aging research and resistance to chronic age-associated diseases."


Calorie Restriction in Primates

Long running studies of calorie restriction in primates remain promising: "In the 75 years since the seminal observation of Clive McCay that restriction of calorie intake extends the lifespan of rats, a great deal has been learned about the effects of calorie restriction (CR; reduced intake of a nutritious diet) on aging in various short-lived animal models. Studies have demonstrated many beneficial effects of CR on health, the rate of aging, and longevity. Two prospective investigations of the effects of CR on long-lived nonhuman primate (NHP) species began nearly 25 years ago and are still under way. This review presents the design, methods, and main findings of these and other important contributing studies, which have generally revealed beneficial effects of CR on physiological function and the retardation of disease consistent with studies in other species. Specifically, prolonged CR appears to extend the lifespan of rhesus monkeys, which exhibited lower body fat; slower rate of muscle loss with age; lower incidence of neoplasia, cardiovascular disease, type 2 diabetes mellitus, and endometriosis; improved insulin sensitivity and glucose tolerance; and no apparent adverse effect on bone health, as well as a reduction in total energy expenditure. In addition, there are no reports of deleterious effects of CR on reproductive endpoints, and brain morphology is preserved by CR. ... More research is needed to delineate the mechanisms of the desirable outcomes of CR and to develop interventions that can produce similar beneficial outcomes for humans. This research offers tremendous potential for producing novel insights into aging and risk of disease."


We Age Because the World Changes

Aging is an inevitability, or so we have to assume: the processes of evolution blindly but efficiently explore the space of possible living creatures, and have been doing so for a very, very long time. We might think that surely a very long-lived or ageless species would have a great advantage in evolutionary competition, its individual members able to produce descendants for far longer than competitors in more short-lived species. Yet virtually all species - with only a very few exceptions - age in easily measured ways. The species that age are also the species that have won in evolutionary terms, and therefore prospered and spread. Why is this?

A recent open access paper (in PDF format) explores one of the approaches used to answer this question, and does so in a very readable fashion:

Living organisms shouldn't age, at least if that could be helped (many of use would certainly like that, but our wishes are not a valid argument). Evolution works in a way that any species whose representatives have any distinct disadvantage will be driven to extinction. It makes sense then to assume that, if aging could be avoided, species that showed senescence as the individuals grow older should be replaced by others where aging does not happen (or happens at a much slower rate). Senescence increases mortality and an individual who dies of old age will leave, in average, a smaller number of descendants than another individual that does not age and manages to live and reproduce for a longer time. And yet many known living organisms show senescence. The time it takes for an individual to show signs of old age varies greatly among species, but aging seems so natural that many people fail to realize there is an apparent contradiction between senescence and evolution.


Understanding why we age is a long-lived open problem in evolutionary biology. Aging is prejudicial to the individual and evolutionary forces should prevent it, but many species show signs of senescence as individuals age. Here, I will propose a model for aging based on assumptions that are compatible with evolutionary theory: i) competition is between individuals; ii) there is some degree of locality, so quite often competition will between parents and their progeny; iii) optimal conditions are not stationary, mutation helps each species to keep competitive.

When conditions change, a senescent species can drive immortal competitors to extinction. This counter-intuitive result arises from the pruning caused by the death of elder individuals. When there is change and mutation, each generation is slightly better adapted to the new conditions, but some older individuals survive by random chance. Senescence can eliminate those from the genetic pool. Even though individual selection forces always win over group selection ones, it is not exactly the individual that is selected, but its lineage. While senescence damages the individuals and has an evolutionary cost, it has a benefit of its own. It allows each lineage to adapt faster to changing conditions.

We age because the world changes.

And there is illustrated one of the present competing viewpoints on the origins of aging.

An Update on Germ Cells and Longevity

Researchers continue to investigate the link between germ cells and longevity in lower animals. In this open access paper, changes to fat metabolism are implicated as an important mechanism: "Removing the germ line of Caenorhabditis elegans extends its lifespan by approximately 60%. Eliminating germ cells also increases the lifespan of Drosophila, suggesting that a conserved mechanism links the germ line to longevity ... Reproduction and aging are two processes that seem to be closely intertwined. Experiments in Caenorhabditis elegans and Drosophila have shown that depletion of the germ line increases lifespan and that this process depends on insulin and lipophilic-hormone signaling. Recently, it was demonstrated that when germline stem cells (GSCs) cease to proliferate, fat metabolism is altered and this affects longevity. In this study, we have identified a nuclear hormone receptor, NHR-80, that mediates longevity through depletion of the germ line by promoting fatty acid desaturation. ... Our results reinforce the notion that fat metabolism is profoundly altered in response to GSC proliferation, and the data contribute to a better understanding of the molecular relationship between reproduction, fat metabolism, and aging."


Immune Therapy Versus Pancreatic Cancer

An example of the sort of immune system engineering that is presently taking place in the laboratory: "Until this research, we thought the immune system needed to attack the cancer directly in order to be effective. Now we know that isn't necessarily so. Attacking the dense tissues surrounding the cancer is another approach, similar to attacking a brick wall by dissolving the mortar in the wall. Ultimately, the immune system was able to eat away at this tissue surrounding the cancer, and the tumors fell apart as a result of that assault. These results provide fresh insight to build new immune therapies for cancer. ... pancreatic cancer patients received standard gemcitabine chemotherapy with an experimental antibody [that] binds and stimulates a cell surface receptor called CD40, which is a key regulator of T-cell activation. The team initially hypothesized that the CD40 antibodies would turn on the T cells and allow them to attack the tumor. The treatment appeared to work, with some patients' tumors shrinking substantially and the vast majority of tumors losing metabolic activity after therapy, although all of the responding patients eventually relapsed. When the researchers looked at post-treatment tumor samples, obtained via biopsy or surgical removal, there were no T cells to be seen. Instead, they saw an abundance of another white blood cell known as macrophages. ... When the investigators treated mice that developed pancreatic cancer with gemcitabine in combination with CD40 antibodies, the results looked like those of the human trial. Some mouse tumors shrank and were found to be loaded with macrophages but contained few or no T cells. Closer inspection showed that the macrophages were attacking what is known as the tumor stroma, the supporting tissue around the tumor. Pancreatic tumors secrete chemical signals that draw macrophages to the tumor site, but if left to their own devices, these macrophages would protect the tumor. However, treating the mice (or patients) with CD40 antibodies seemed to flip that system on its head. ... It is something of a Trojan horse approach. The tumor is still calling in macrophages, but now we've used the CD40 receptor to re-educate those macrophages to attack - not promote - the tumor."


An Approach to Step One of the Vegas Group: Bootstrapping the Codex

UPDATE 05/21/2011: The Vegas Group initiative launched soon after this post, and was later renamed to Open Cures, with a new website and a new mailing list. Please do drop by and take a look at what we're working on.

The Vegas Group: a so far fictional community of the next ten years that will merge the longevity advocacy and open biotech communities in order to (a) reverse engineer the most promising life-span-enhancing techniques demonstrated in the laboratory, (b) translate that work into human rejuvenation biotechnologies, and (b) make these therapies available for use via medical tourism to Asia-Pacific region clinics.

So I have been pondering how best to make the vision of the Vegas Group a reality: what steps do we take so that we wake up six or seven years from now to an open source biotech community whose members are working on enabling the best longevity therapies produced by the formal research community - and who have the overseas connections to enable responsible use of resulting therapies in a clinical setting.

The path to this future involves networking and community building in a whole new and different direction from that taken by much of the longevity advocacy community - and the construction of a codex of information, a how-to manual of recipes for replicating specific products of the formal research community in longevity science. Networking makes the world go round, and that is the most important part of any attempt to create the Vegas Group, or indeed any human endeavor: making relationships and persuading people to join in. But this is not where I can be the most effective.

So any step one for me will involve considering the codex: what it is, and how it will be constructed, maintained, and made useful to the seeds of what will be the Vegas Group - however that organization ultimately comes about, and whatever form it ultimately takes. It is very clear to me that open biotechnology will grow into a massive semi-professional sphere of activity, exactly like the open source software community today. I want to take advantage of the wave that is coming, and produce a work that will both aid that wave and in turn be aided by it.

When thinking about the way in which contributions of content are made voluntarily to any given community or site - such as Wikipedia, or blogs such as this one, or the documentation repository at your workplace - it is self-evident that very, very few people step up to produce good content. Wikipedia works because a great many people each contribute just a little, a continual process of polishing, one grain of sand at a time, applied to the bulk outlines contributed by the motivated few. But for smaller groups, you don't get polishing, you just get next to nothing in the way of contributions.

So I'm fairly certain that for the Vegas Group codex, while a wiki model may be helpful as an adjunct to a motivated community further down the line, it isn't a way to get things written at the outset - it's not a way to provide the corpus of work that a community can later polish. There are few biotechnologists in the world in comparison to, say, football fans. Look at the number of science bloggers as compared with other topics, for example. Despite this, there are still initiatives out there, however, working on pulling together repositories of techniques and knowledge: OpenWetWare for example. So the concept of producing an open collection of techniques and recipies is not a foreign one to the biotechnology community - it's just not very advanced at this stage, at least not in comparison to the bodies of knowledge associated with larger communities.

Thus I think that a larger seed, a bigger online repository of freely available and reliable recipes for longevity-related biotechnology, would act as an attractor for people willing to tinker and help out. The same class of supporters and advocates who produced initiatives like OpenWetWare will contribute to help polish its contents. Overall, the concept of a codex seems to me to be where a comparatively small amount of money could be leveraged to good effect. Consider this:

  • Creating an initial repository website and content management system isn't a significant cost given the present state of open source content management software - it's almost something I could undertake myself.
  • People with significant knowledge of biotechnology are remarkable cheap to engage at the post-graduate level. Consider that a few thousand dollars of post-graduate time can net you a long and well-informed analysis, or detailed explanation of a specific methodology.
  • It wouldn't be a good piece of writing of course - no offense is intended when I say that few post-graduate scientists can write well. Writing well is hard, and just as much a specialty as is becoming a scientist; few people have the time and inclination to specialize in more than a few things, and why should one of them be writing?
  • Fortunately, people who can write well are always in supply, desperate for work, and inexpensive. It is a buyer's market.

So I can envisage a guiding council of advisors putting together a plan for the hierarchy of topics they would like to see in the Vegas Group codex, from basic methods in biotechnology through to best attempt reverse engineering of things we know to be possible and that have been published: such as Cuervo's work on restoring youthful levels of autophagy, or protofection to replace mitochondrial DNA. The end result of that process might look something like a distillation of Fight Aging! mixed with the very elegant materials produced by the Science for Life Extension Foundation.

Codex project volunteers would then run an ongoing process of hiring post-graduates and interested researchers to write, and passing the results to starving authors who improve the output to a quality suitable for the open biotechnology community. There would of course be some back and forth between the post-graduates and the starving authors in order to reduce the inevitable translation errors, but I see this as a viable way to produce a body of knowledge that is sufficiently good to begin with - not perfect, not even necessarily very good, but sufficient.

Since only a comparatively limited reach of biotechnology is under consideration, the cost of bootstrapping such a project might be less than a few hundred thousand dollars. The things I would need to understand before getting seriously underway on a Vegas Group codex are largely related to validating that price tag. A few hundred thousand dollars would mean that it is worth starting with ten thousand dollars, some volunteers, spare time, and raising funds as we go based on the quality of work exhibited. That would be true bootstrapping, but I'd have to give thought in advance to:

  • The actual cost of generating the materials - something that I suspect won't be clear until the project is at least twenty articles in. I have a fair grasp on the range of costs for writing for hire, in fields that range from very specialist (pricey) and completely generalist (a few cents a word), but I've no idea where this market falls in that spread of values, nor how much management and general cat-herding of writers would be required.
  • The predicted size of a sufficiently large body of information, as set out by guiding experts. Is it a hundred articles, a hundred videos, a thousand images, or half that, or ten times that?
  • How to make this project attractive to the existing open biotechnology community even in its earliest stages. There is no such thing as "build it and they will come" - if anything building in isolation guarantees that you'll have few visitors.

Which comes right back around to networking and relationships: as I said, they make the world go round. On that topic, I am sadly lacking in a knowledge of the current state of the open biotechnology community - something that will have to change as I give more thought to the Vegas Group idea. No sense in reinventing the wheel if there is a wheel out there already ... or even a half-built wheel, a project where lessons were learned.

Nuclear DNA Damage, Aging, and Stem Cells

Nuclear DNA damage accumulates with age, but is it a cause of aging? This open access paper illustrates why there is a question - as for many studies, the results do not point unambiguously in one direction or another. "Accumulation of DNA damage leading to adult stem cell exhaustion has been proposed to be a principal mechanism of aging. Here we tested this hypothesis in healthy individuals of different ages by examining unrepaired DNA double-strand breaks (DSBs) in hematopoietic stem/progenitor cells matured in their physiological microenvironment. ... The highest inter-individual variations for non-telomeric DNA damage were observed in middle-aged donors, [where] the individual DSB repair capacity appears to determine the extent of DNA damage accrual. However, analyzing different stem/progenitor subpopulations obtained from healthy elderly (>70 years), we observed an only modest increase in DNA damage accrual, [but] sustained DNA repair efficiencies, suggesting that healthy lifestyle may slow down the natural aging process. ... Based on these findings we conclude that age-related non-telomeric DNA damage accrual accompanies physiological stem cell aging in humans. Moreover, aging may alter the functional capacity of human stem cells to repair DSBs, thereby deteriorating an important genome protection mechanism leading to exceeding DNA damage accumulation. However, the great inter-individual variations in middle-aged individuals suggest that additional cell-intrinsic mechanisms and/or extrinsic factors contribute to the age-associated DNA damage accumulation." Meaning that nuclear DNA damage may or may not be a primary cause of aging, and may or may not be important in comparison to other factors.


Towards Stem Cell Therapy for Macular Degeneration

Small steps: "The notion of transplanting adult stem cells to treat or even cure age-related macular degeneration has taken a significant step toward becoming a reality. ... researchers have demonstrated, for the first time, the ability to create retinal cells derived from human-induced pluripotent stem cells that mimic the eye cells that die and cause loss of sight. Age-related macular degeneration (AMD) [gradually] destroys sharp, central vision needed for seeing objects clearly and for common daily tasks such as reading and driving. AMD progresses with death of retinal pigment epithelium (RPE), a dark color layer of cells which nourishes the visual cells in the retina. While some treatments can help slow its progression, there is no cure. The discovery of human induced pluripotent stem (hiPS) cells has opened a new avenue for the treatment of degenerative diseases, like AMD, by using a patient's own stem cells to generate tissues and cells for transplantation. For transplantation to be viable in age-related macular degeneration, researchers have to first figure out how to program the naïve hiPS cells to function and possess the characteristics of the native retinal pigment epithelium, RPE, the cells that die off and lead to AMD. ... This is the first time that hiPS-RPE cells have been produced with the characteristics and functioning of the RPE cells in the eye. That makes these cells promising candidates for retinal regeneration therapies in age-related macular degeneration."


An Overview of the Molecular Mechanisms by Which Exercise Impacts Aging

Exercise slows many of the degenerations of aging and - much like calorie restriction - this appears to be the result of changes in a multitude of biological processes and systems. In effect exercise adjusts the operation of your metabolism, moving it into a better configuration.

If you'd like a look under the hood, an overview of what is presently known of the biology that links exercise to improved long term health, you might read this recent open access review paper. It focuses on the heart, but the underlying mechanisms are of general interest:

It is generally accepted that regular exercise is an effective way for reducing cardiovascular morbidity and mortality. Physical inactivity and obesity are also increasingly recognized as modifiable behavioral risk factors for a wide range of chronic diseases, including cardiovascular diseases. Furthermore, epidemiologic investigations indicate that the survival rate of heart attack victims is greater in physically active persons compared to sedentary counterparts. Several large cohort studies have attempted to quantify the protective effect of physical activity on cardiovascular and all cause mortality. Nocon et al. in a meta-analysis of 33 studies with 883,372 participants reported significant risk reductions for physically active participants. All-cause mortality was reduced by 33%, and cardiovascular mortality was associated with a 35% risk reduction. Exercise capacity or cardiorespiratory fitness is inversely related to cardiovascular and all-cause mortality, even after adjustments for other confounding factors.


Physical inactivity is increasingly recognized as modifiable behavioral risk factor for cardiovascular diseases. A partial list of proposed mechanisms for exercise-induced cardioprotection include induction of heat shock proteins, increase in cardiac antioxidant capacity, expression of endoplasmic reticulum stress proteins, anatomical and physiological changes in the coronary arteries, changes in nitric oxide production, adaptational changes in cardiac mitochondria, increased autophagy, and improved function of sarcolemmal and/or mitochondrial ATP-sensitive potassium channels. It is currently unclear which of these protective mechanisms are essential for exercise-induced cardioprotection. ... A better understanding of the molecular basis of exercise-induced cardioprotection will help to develop better therapeutic strategies.

Being sedentary appears to be just as self-sabotaging as letting yourself become obese. It will lower your odds of living in good health for as long as you might like - and that is enormously important in this age of biotechnology. Every additional year is another year of progress in the laboratories, of progress in advocacy for longevity science, of progress towards rejuvenation therapies that could arrive in time for those of us reading this today. Failing to take care of your health will shift the odds against you, and it's already the case that far too many people will die before the advent of repair technologies for the biological damage of aging. Why add to your risk becoming one of them?

The Unreliability of Many Studies of Rodent Longevity

As noted in this paper, many researchers still fail to control for calorie intake in their studies - and thus their experimental results are largely worthless, given the impact of even mild calorie restriction on the life spans of laboratory animals: "Much of the literature describing the search for agents that increase the life span of rodents was found to suffer from confounds. One-hundred-six studies, absent 20 contradictory melatonin studies, of compounds or combinations of compounds were reviewed. Only six studies reported both life span extension and food consumption data, thereby excluding the potential effects of caloric restriction. Six other studies reported life span extension without a change in body weight. However, weight can be an unreliable surrogate measure of caloric consumption. Twenty studies reported that food consumption or weight was unchanged, but it was unclear whether these data were anecdotal or systematic. Twenty-nine reported extended life span likely due to induced caloric restriction. Thirty-six studies reported no effect on life span, and three a decrease. The remaining studies suffer from more serious confounds. Though still widely cited, studies showing life span extension using short-lived or 'enfeebled' rodents have not been shown to predict longevity effects in long-lived animals. We suggest improvements in experimental design that will enhance the reliability of the rodent life span literature. First, animals should receive measured quantities of food and its consumption monitored, preferably daily, and reported. Weights should be measured regularly and reported. Second, a genetically heterogeneous, long-lived rodent should be utilized. Third, chemically defined diets should be used. Fourth, a positive control (e.g., a calorically restricted group) is highly desirable. ... These procedures should improve the reliability of the scientific literature and accelerate the identification of longevity and health span-enhancing agents."


A Popular Science Article on Autophagy and Longevity

From Science News: "the cells of organisms from yeast to humans regularly engage in self-cannibalism. Cells chew on bits of their cytoplasm - the jellylike substance that fills their bellies - and dine on their own internal organs ... It may sound macabre, but gorging on one's own innards, a process called autophagy, is a means of self-preservation, cleansing and stress management. ... A munch here gets rid of garbage that might otherwise clog the system. A nibble there rids cells of malfunctioning parts. One chomp disposes of invading microbes. In lean times, all that stands between a cell and starvation may be the ability to bite off and recycle bits of itself. And in the last decade or so it has become clear that self-eating can also make the difference between health and disease. ... Starvation inhibits an important biological signaling system, known as the mTOR pathway - named for a key protein involved in regulating cell growth and survival, cell movement and protein production. The inhibition of mTOR sets off a cascade of reactions inside the cell that end in autophagy and may be crucial to prolonging cell life and ultimately fending off cancer. A drug that inhibits mTOR, called rapamycin, has been shown to extend life span in mice. It and calorie restriction are [amongst a handful of] methods proven to prolong longevity, suggesting both may work through autophagy to make cells live longer."


From the SENS Foundation: 2010 Research Report and SENS5 News

The SENS Foundation will be hosting the SENS5 conference in Cambridge, England at the end of August. Registration is open, and this note arrived in my in-box today:

I am writing to inform you that June 15th is the deadline for discounted registration and abstract submission for the fifth Strategies for Engineered Negligible Senescence (SENS) conference ... The conference program features 33 confirmed speakers so far, all of them world leaders in their field. As with previous SENS conferences, the emphasis of this meeting is on "applied gerontology" - the design and implementation of biomedical interventions that may, jointly, constitute a comprehensive panel of rejuvenation therapies, sufficient to restore middle-aged or older laboratory animals (and, in due course, humans) to the physical and mental robustness of young adults.

I notice that Caleb Finch will be giving the SENS Lecture, entitled "Regenerative medicine for aging: a new paradigm worth trying" - now there's an example of progress in winning over the mainstream of aging research to the SENS approach of repair rather than slowing down aging. In this context, "regenerative medicine" means SENS; SENS Foundation founder Aubrey de Grey uses the term more expansively than the general public and media, who use it only in reference to stem cell therapies.

The SENS Foundation also recently issued a research report (in PDF format) for the first ten months of last year, with a year end report to follow. You should find it interesting to see funding amounts listed for the varying strands of SENS research, as well as insight into exactly what the researchers are up to at present:

I'm delighted to be able to share with you our research report, prepared for the first 10 months of 2010, by Tanya Jones (our Director of Research Operations), working with our researchers and my CSO Team. I thought it would be of interest to our supporters, and serve as a precursor to our 2010 Year End Report, which is currently under production as part of our finalizing our 2010 accounts.


SENS Foundation conducts intramural research in its Research Center in Mountain View, California. The primary focus of our intramural work is LysoSENS - investigating novel lysosomal hydrolases against intracellular aggregates that impair cell function - and we recently produced a detailed and comprehensive LysoSENS planning document in collaboration with our extramural project at Rice University.

We have also arranged for research in the MitoSENS strand - obviating mitochondrial DNA deletions - to be conducted at the Research Center, following the negotiation of a transfer agreement with Dr Corral-Debrinski covering materials produced, and used in, previous successful work by her group. Dr Matthew "Oki" O'Connor joined us in September to initiate this project.

The relative amounts devoted to each project clearly illustrate that the Foundation's primary focus at this time is the LysoSENS project, and I can guess at some of the strategic reasoning there. Much money and many connections with industry might be gained through success in the LysoSENS platform. Not just aging, but many diseases could be effectively treated in their late stages through progress in bioremediation of this sort, and that means that big pharma and big biotech would be very interested in licensing agreements - which in turn would assist the Foundation in greatly expanding its purview and influence.

It is, however, frustrating to see far less funding devoted to MitoSENS, the project aimed at removing the contribution of mitochondrial DNA damage to aging. Everyone has an opinion, and mine (for what it's worth, which isn't all that much in this case, and nor should it be) is that mitochondrial repair would make a better primary focus. Irrespective of the methodology chosen, it seems clear that the research community as a whole is frustratingly close to something that will work to completely reverse mitochondrial damage, whether it is through allotopic expression as advocated by the SENS Foundation or periodic whole-body replacement of mitochondrial DNA as demonstrated in mice some years ago.

Yet the funds going towards mitochondrial repair - both here and generally - are in no way proportionate to the degree to which the research community believes mitochondrial DNA damage to be a cause of aging and longevity.

The advice I give myself on this issue is the same as I'll give to anyone else in the same position: if you believe that too little funding is devoted to any given research goal, then get out there and do something about it. Earn money and donate it, and persuade others to do the same. After all, that's exactly what Aubrey de Grey did in order to arrive at his present position: helping to direct a Foundation of his own creation where enthusiastic people are now writing annual reports on their progress towards engineering the end of aging.

A Necessary Level of Skepticism

Much as we'd like it to be otherwise, humans don't live as long as many people like to claim that they do. The tendency to make and believe outlandish claims of human longevity is examined in this open access paper: "People have long been fascinated with claims to extreme longevity. Ancient Roman historians attempted to tally reports of extreme age in local villages. Medieval European alchemists kept tabs on reports of centenarians, possibly to find a 'cure' for old age (the Fountain of Youth). Inexplicably, various historians and even 'scientists' such as Roger Bacon accepted outlandish and wild reports of extreme age prima facie, without a critical examination or inquiry into whether the ages reported were true. It was not until the 18th century, with the advent of demographers such as Georges Buffon (1707-1788) that a limit to the human life span was proposed, with Buffon stating that 'the man who does not die of incidental diseases reaches everywhere the age of ninety or one hundred years' .. [Even today] political, national, religious, and other motivations have led the media and even scientists to errantly accept extreme longevity claims prima facie. ... Understanding various causes of false extreme age claims is important for placing current, past, and future extreme longevity claims in context and for providing a necessary level of skepticism. ... To provide a current context to unsubstantiated age claims, we provide here some statistics concerning supercentenarian (a person age 110 years or older) prevalence. Kestenbaum and Ferguson at the U.S. Social Security Administration reported Medicare data indicating that, in 2000, there were 32,920 centenarians and out of these, 105 or 0.3% were 110 years old and older. Of 2,700 people who reportedly reached the age of 110+ years between 1980 and 1999, according to the SSA, only 355 (13%) could be confirmed."


Don't Get Fat, and Don't Stay Fat

More data to quantify just how bad excess body fat is for you: "researchers have found the number of years individuals live with obesity is directly associated with the risk of mortality. The research shows that the duration of obesity is a strong predictor of mortality, independent of the actual level of Body Mass Index (BMI). As the onset of obesity occurs earlier and the number of years lived with obesity increases, the risk of mortality associated with adult obesity in contemporary populations is expected to increase compared with previous decades. Using data from the Framingham Heart Study, 5209 participants were followed up for 48 years from 1948. The current study however only included participants who were free from pre-existing diseases of diabetes, cardiovascular diseases and cancer. The research showed that for those who had a medium number of years lived with obesity (between five years and 14.9 years), the risk of mortality more than doubled than for those who had never been obese. The risk of mortality almost tripled for those with the longest duration of obesity (more than 15 years). Furthermore, the research showed for every additional two years lived with obesity, the risk of mortality increased by between six and seven per cent. ... Before now, we did not know whether being obese for longer was any worse for you health than simply being obese. However, this research shows for the first time that being obese for longer increases your risk of mortality, no matter how heavy you actually are."


Towards Validation of the Role of Nuclear DNA Damage in Aging

Our DNA accumulates damage as we age. It is very clear that mitochondrial DNA damage is important in aging, putting efforts to develop mitochondrial repair biotechnologies high on the priority list, but is the accumulation of nuclear DNA damage also important in aging?

It is well settled that the level of nuclear DNA damage and mutation exhibited by an organism rises over time. It is also well settled that higher levels of nuclear DNA damage and mutation mean a greater cancer risk - this is one of the reasons why cancer is predominantly a disease of the old. The more cells that suffer DNA damage, the more likely it is that one or more cells experience exactly the type of damage needed to run amok as the self-replicating seeds to a cancer. But is nuclear DNA damage and mutation a cause of aging?

That increasing instability of the genome contributes to age-related degeneration is the present working assumption for much of the aging research community, but this hypothesis is not unchallenged. The lack of a definitive proof is one problem: there is no good experiment to show that reduction in nuclear DNA damage levels - and only nuclear DNA damage levels - extends life.

It is quite possible that over a normal human life span, nuclear DNA damage gives rise to cancer and not much else of significance. Equally, maybe it does have a larger role. But to answer the question one way or another, we need to see an experiment that shows extended life in mammals directly resulting from reduced levels of nuclear DNA damage.

Here is an example of new research that might lead to that experiment:

a process called acetylation regulates the maintenance of our DNA [and] determines the degree of fidelity of both DNA replication and repair. The finding builds on past research, which established that as humans evolved, we created two routes for DNA replication and repair - a standard route that eliminates some damage and a moderate amount of errors, and an elite route that eliminates the large majority of damage and errors from our DNA.

Only the small portion of our DNA that directs the creation of all the proteins we are made of - proteins in blood cells, heart cells, liver cells and so on - takes the elite route, which uses much more energy and so "costs" the body more. The remaining majority of our DNA, which is not responsible for creating proteins, takes the standard route, which requires fewer resources. ... acetylation directs which proteins take which route, favoring the protection of DNA that creates proteins by shuttling them down the elite, more accurate course.

"If we found a way to improve the protection of DNA that guides protein production, basically boosting what our body already does to eliminate errors, it could help us live longer. A medication that would cause a small alteration in this acetylation-based regulatory mechanism might change the average onset of cancers or neurological diseases to well beyond the current human lifespan."

A long drug discovery process lies between knowing these biochemical mechanisms and being able to manipulate them - but being able to manipulate the fidelity of DNA repair offers the possibility of directly establishing in mammals the degree to which nuclear DNA damage contributes to degenerative aging.

The State of Research into Human Longevity is Presently Far From Ideal

It is always good to see some of the important ideas making their way out into the world, even in forms that are not ideal. Here, for example, the idea that all is not as it should be in medical and aging research, and that far more could be done to tackle aging: "Scientists who study the biology of aging - the basic mechanisms of how our cells and tissues change with age - believe the aging process is modifiable. ... Even better, scores of peer-reviewed studies have proven that decelerating the aging process in lab animals also offers huge health benefits, dramatically delaying and lowering their incidence of chronic disease. ... If we could achieve the same exciting results in humans, we could transform the lives of older people and achieve what aging researchers call a longer healthspan. ... So what's stopping us? ... Putting a man on the moon was a defining national goal in the 20th century; in the 21st century, it should be decoding the biology of aging to find the fountain of health. ... Unfortunately, this potentially transformative work is a poor stepchild in the biomedical research enterprise. Older Americans tend to develop multiple chronic diseases [but] most research funding gets siloed into grants that study individual diseases, produce therapies that treat only one aspect of a patient's complex condition, and may add few, if any, very expensive months to life. Aging research has far greater potential to repay the public's investment than disease-centric research, because the best defense is a good offense. Getting at the root cause of a range of diseases can ultimately help us keep millions of people from developing those conditions in the first place. Although the National Institutes of Health budget exceeds $31 billion annually, the vast majority of those funds are allocated to research on specific diseases rather than the basic biology of aging, despite its potential to provide many preventive and curative strategies."


An Optimistic Response to Data on Human Longevity

Singularity Hub has an optimistic response to recent announced updates to life expectancy data: "A new record high in US life expectancy begs the question, what will your children do with 0.2 more years of living? Well, that's not exactly how life expectancy works, but it's still a time to celebrate! ... While these statistics tell us that a child born in 2009 has a good chance of living into their seventies, here at the Hub we think the real expectancy should be a hundred years more than that as upcoming technologies will continue to boost lifespans, as we fight illness, poverty, and hunger. For now, the National Vital Statistics System report shows us what progress we've already made. 10 of the 15 top causes of death are dropping, infant mortality is falling, and most age groups are doing better as well. Statistically speaking, it's a great time to be alive. And it's only going to get better. ... While the causes of death are many, and the factors behind its variation complex, it is reassuring to see that there are many emergent technologies that may help us not only live longer, but healthier as well. We're getting closer to being able to grow new organs to replace faulty ones, whether their damage comes from genetics or our own malfeasance. Or perhaps we'll augment our organs with machines, letting cybernetics extend our lives and expand our capabilities. ... There are institutions dedicated to taking all these emerging forms of technology and using them to help the billions in the developing world. Other groups are struggling to find the root causes of aging, and extend not just life expectancy, but our maximum lifespan as well."


RasGrf1 Deficiency in Mice Causes a 20% Increase in Maximum Life Span

A recent open access paper from a Spanish research group outlines yet another methodology to add to the growing list of ways to increase healthy life span in mice. Progress is signified by diversity these days; there are, I think, more than twenty different demonstrated methods of bringing about meaningful extension of life in mice as of today.

RasGrf1 deficiency delays aging in mice:

We observed that mice deficient for RasGrf1-/- display an increase in average and most importantly, in maximal lifespan (20% higher than controls). This was not due to the role of Ras in cancer because tumor-free survival was also enhanced in these animals.

Aged RasGrf1-/- displayed better motor coordination than control mice. Protection against oxidative stress was similarly preserved in old RasGrf1-/-. IGF-I levels were lower in RasGrf1-/- than in controls. Furthermore, SIRT1 expression was increased in RasGrf1-/- animals. Consistent with this, the blood metabolomic profiles of RasGrf1-deficient mice resembled those observed in calorie-restricted animals.


Our observations link Ras signaling to lifespan and suggest that RasGrf1 is an evolutionary conserved gene which could be targeted for the development of therapies to delay age-related processes.

The results are similar to those noted for PAPP-A knockout mice - both longer lives and less cancer. At this stage it's anyone's guess as to whether many of these methodologies in fact operate through the same thicket of connections and mechanisms in mammalian biochemistry. Time, and further research, will tell.

RasGrf1 was mentioned here last year in connection with the intriguing bi-maternal mice:

mice artificially produced with two sets of female genomes have an increased average lifespan of 28%. Moreover, these animals exhibit a smaller body size, a trait also observed in several other long-lived mouse models. One hypothesis is that alterations in the expression of paternally methylated imprinted genes are responsible for the life-extension of bi-maternal mice. Considering the similarities in postnatal growth retardation between mice with mutations in the Rasgrf1 imprinted gene and bi-maternal mice, Rasgrf1 is the most likely culprit for the low body weight and extended lifespan of bi-maternal mice.

This latest work adds weight to the supposition quoted above.

Living Like a Centenarian

The modest goals of the mainstream longevity science community are outlined by one of its members in this article - to enable everyone to age as slowly as only some people presently do. No radical life extension or rejuvenation, as would be enabled by the damage repair approach to longevity science, but rather just a gentle slowing of aging, enabled by technologies that would probably not emerge in time to benefit those of us in middle age today. "It is the aging of our cells that causes us to develop most diseases, says Dr. Nir Barzilai, professor of medicine and genetics at the Albert Einstein College of Medicine in New York. 'We know this, paradoxically, because of the amazing success we have had in treating heart disease. We have been able to save people from heart attacks with stents and bypass surgery - only to find that within a year or two they develop Alzheimer's, diabetes or cancer at an alarming rate. Why? Because we have never treated the underlying aging of their cells. We have simply treated the disease manifestation.' So, explains Barzilai, if we can find the processes in the body that control aging and find a way to treat them, we will be able to protect people from the diseases of aging. Barzilai heads a unique longevity study of more than 500 people who have reached the age of 100. The LonGenity study is looking at the genetic makeup of centenarians to identify the biological markers that explain why they live so long and so well. Because the remarkable thing about these people is not simply that they live to the age of 100, it is that they live to 100 in pretty good health. Just why they live that long without getting sick and dying is what Barzilai wanted to find out."


Gene Therapy Trials to Treat Parkinson's Disease

Via EurekAlert!: "A gene therapy called NLX-P101 dramatically reduces movement impairment in Parkinson's patients, according to results of a Phase 2 study ... The approach introduces a gene into the brain to normalize chemical signaling. ... The study is the first successful randomized, double-blind clinical trial of a gene therapy for Parkinson's or any neurologic disorder ... Half of patients receiving gene therapy achieved dramatic symptom improvements, compared with just 14 percent in the control group. Overall, patients receiving gene therapy had a 23.1 percent improvement in motor score, compared to a 12.7 percent improvement in the control group. ... Improved motor control was seen at one month and continued virtually unchanged throughout the six-month study period. ... Gene therapy is the use of a gene to change the function of cells or organs to improve or prevent disease. To transfer genes into cells, an inert virus is used to deliver the gene into a target cell. In this case, the glutamic acid decarboxylase (GAD) gene was used because GAD makes a chemical called GABA, a major inhibitory neurotransmitter in the brain that helps 'quiet' excessive neuronal firing related to Parkinson's disease. ... In Parkinson's disease, not only do patients lose many dopamine-producing brain cells, but they also develop substantial reductions in the activity and amount of GABA in their brains. This causes a dysfunction in brain circuitry responsible for coordinating movement."


Stem Cells Improve Condition of Long-Damaged Hearts

A recent early stage trial demonstrated that first generation autologous stem cell transplants should be beneficial even if provided long after a serious damage has occurred. Large numbers of transplanted stem cells, grown over a period of weeks from a patient's own cells, can spur the body to heal injuries that would normally linger:

Heart Damage Improves, Reverses After Stem Cell Injections in a Preliminary Human Trial:

Researchers have shown for the first time that stem cells injected into enlarged hearts reduced heart size, reduced scar tissue and improved function to injured heart areas ... while this research is in the early stages, the findings are promising for the more than five million Americans who have enlarged hearts due to damage sustained from heart attacks. These patients can suffer premature death, have major disability and experience frequent hospitalizations. Options for treatment are limited to lifelong medications and major medical interventions, such as heart transplantation


Using catheters, researchers injected stem cells derived from the patient's own bone marrow into the hearts of eight men (average age 57) with chronically enlarged, low-functioning hearts.

"The injections first improved function in the damaged area of the heart and then led to a reduction in the size of the heart. This was associated with a reduction in scar size. The effects lasted for a year after the injections, which was the full duration of the study,"


"This therapy improved even old cardiac injuries. [Some] of the patients had damage to their hearts from heart attacks as long as 11 years before treatment."

This is generally good news for people who presently bear injuries and damage - or expect to suffer damage in the years between now and when stem cell medicine is in its prime. The most plausible future outcome looks to be that even the early stage and comparatively crude transplant therapies will provide significant benefits above and beyond any present form of medicine.

Of course, they would arrive far more rapidly and be far less costly in a world absent the FDA - but there is always medical tourism. A range of stem cell therapies that are presently forbidden from commercial development in the US have been available for several years elsewhere in the world:

The FDA forbids the development of new medical technologies long past the point at which any sane person would consider them a good risk, and in the process makes these technologies vastly more expensive. Medical tourism is a sane response to heavy-handed and unaccountable government employees: "Gregg Victor is one of the 1.5 million Americans who traveled abroad to get medical treatments last year. ... More than a few were pursuing new stem-cell-based treatments unavailable in the States ... 'I am not waiting for the FDA to rule to get treatments,' says Gregg Victor, who chose her clinic in Germany after spending a year and a half looking into stem cell treatments available all over the world. ... Jordan happened upon TheraVitae, a Bangkok-headquartered biotechnology company that markets 'VesCell stem cell treatments' via licensing agreements with four clinics in Thailand ... Thai doctors injected 25 million of his own stem cells into Jordan's heart. Twenty thousand miles, 22 days, a cardiac arrest and $43,000 later, he came home to his wife with an ejection fraction between 30% and 35%. Even Jordan's doctor had to admit he was happy with the results." Results are mixed, much as you'd expect. Caveat emptor, and do your research - but a great many people are materially benefiting from technologies still forbidden by their own governments.

More on Cellular Housekeeping Versus Neurodegenerative Diseases

Researchers recently demonstrated that increased cellular housekeeping could slow neurodegeneration, and here a different group show the same outcome: "Cells, which employ a process called autophagy to clean up and reuse protein debris leftover from biological processes, were the original recyclers. A team of scientists [have] linked a molecule that stimulates autophagy with the reduction of one of Alzheimer's disease's major hallmarks, amyloid peptide. Their finding suggests a mechanism that could be used to eliminate built-up proteins in diseases such as Alzheimer's, Down syndrome, Huntingdon's and amyloid-beta, the protein aggregates that cause Alzheimer's plaques. Increasing autophagy, either through a drug or a natural process such as diet, could improve the outcome for people with neurodegenerative diseases ... The researchers [tested] various compounds for their ability to reduce the buildup of amyloid-beta by exposing cultured cells to compounds known to activate autophagy. They then compared the effect of these compounds by removing growth factors from the culture medium, a well-established stimulant of autophagy known as 'starvation.' The researchers found that SMER28 was the most effective compound, and focused their studies on it to characterize the cellular components involved in this phenomenon. They compared the effect of SMER28 on amyloid-beta formation using normal cells or cells where the expression of genes known to be involved in autophagy was reduced or abolished. They found that three important autophagic players were involved, and one of them was essential for SMER28's effect."


Incremental Improvement in Rheumatoid Arthritis Therapies

The present generation of therapies for rheumatoid arthritis are based on TNF inhibition - a fairly crude manipulation of the immune system when considered in the grand scheme of what is possible, but one that is getting better. From Technology Review: "A new protein engineered to inhibit molecules that cause inflammation not only reduces symptoms of rheumatoid arthritis in mice but also may have potential to reverse the disease's course. Researchers hope the findings will point toward a new therapy for this crippling and difficult-to-treat disease, which occurs when the immune system attacks the body's own joints. Even medications that are most successful in halting joint inflammation are effective in only about half of the patients who try them. ... The new synthetic protein [appears] to target TNF in a far more specific fashion and could be produced at a small fraction of the cost [of present TNF inhibitors]. ... a protein called progranulin binds to TNF receptors and that administering the protein to mice with rheumatoid arthritis reduced or even eliminated their symptoms. Then they determined which fragments of progranulin were responsible for binding to TNF and combined those fragments to engineer a protein that works even better to suppress disease. Mice with mild arthritis appeared to be disease-free after several weeks of regular injections of the modified progranulin."


The Global Forum for Longevity

The Global Forum for Longevity is an industry-sponsored forum taking place later this month; fairly mainstream, no talk of radical life extension or other forms of futurism that might lead to intellectual discomfort for some. I mention it because it is a symptom of the growing interest in biogerontology on the part of the vast insurance industries of the world - which should not be a surprising phenomenon. To find people likely to pay close attention to the future of longevity science, you want to look amongst the folk who stand to gain or lose a great deal of money due to changes in human life spans. Life insurance, pensions, and other forms of making money through managing statistical risks on life expectancy data are, taken together, a very big business indeed.

So here an insurance conglomerate is, as many of them are, sponsoring an event to help spread knowledge through the system: from scientists to actuaries to risk managers and other decision makers in the food chain. Building bridges and forming communities is in and of itself a form of risk management in the long term: it is a way to lower the likelihood of unpleasant surprises by trying to better understand what the scientific community believes are likely outcomes for longevity science over the decades ahead.

Some quotes from the conference site:

We are living in an era of radical change. Longevity offers us all an opportunity to make more ambitious life choices and look to the future with renewed hope. This is why it is vitally important that we move quickly to meet the challenges which it poses for our society.

Drawing on its expertise as an insurer, AXA is playing its part by creating a space to convene an exchange between decision-makers and experts working to ensure this phenomenon is better defined and fully grasped: the Global Forum for Longevity.


Our conviction as an insurer and observer of demographic and societal changes worldwide, is that longevity is not a fate to be endured but instead an opportunity. We need to respond quickly in order to meet the challenges which it poses to our society.

"Challenges." One thing to bear in mind here is that the big insurance groups are inextricably tied in to the unsustainable pension promises made by politicians past and present in many countries around the world - unsustainable even with modest increases in longevity, never mind what is likely to result from the biotechnology revolution. So there is a certain amount of long term public relations work being undertaken by various parties so as to avoid becoming the sacrificial goat in the end when the system of entitlements collapses. You can make your own decision as to how much of the motivation behind this conference falls into that bucket versus the knowledge transfer aims discussed above.

Empires end when an entrenched elite can spend from the public purse and take on debt without immediate consequence or forethought, destroying the value of their currency in the process. Assuming (perhaps optimistically) that present economic empires survive the next couple of decades, a combination of foolish promises and increasing human longevity will be the rock that sinks them.

Micromachines Steered Through the Blood

Nanotechnology can be used to build assemblies of designed molecules that seek out specific cells - such as cancer cells - but an alternative approach to targeted therapies is to build machinery large enough to be controlled from outside the body, such as the microcarriers demonstrated here: "Soon, drug delivery that precisely targets cancerous cells without exposing the healthy surrounding tissue to the medication's toxic effects will no longer be an oncologist's dream but a medical reality ... sing a magnetic resonance imaging (MRI) system, [researchers] successfully guided microcarriers loaded with a dose of anti-cancer drug through the bloodstream of a living rabbit, right up to a targeted area in the liver, where the drug was successfully administered. This is a medical first that will help improve chemoembolization, a current treatment for liver cancer. ... The therapeutic magnetic microcarriers (TMMCs) [are made] from biodegradable polymer, [measure] 50 micrometers in diameter - just under the breadth of a hair - [and] encapsulate a dose of a therapeutic agent (in this case, doxorubicin) as well as magnetic nanoparticles. Essentially tiny magnets, the nanoparticles are what allow the upgraded MRI system to guide the microcarriers through the blood vessels to the targeted organ. During the experiments, the TMMCs injected into the bloodstream were guided through the hepatic artery to the targeted part of the liver where the drug was progressively released."


Of Stem Cells, Horses, and Humans

Because veterinary medicine is less (oppressively) regulated than human medicine, animals are benefiting from stem cell therapies that are safe enough for human use but nonetheless still illegal to commercially develop in the US: "In a very unusual breakthrough, a stem cell treatment for racehorses is ready to be tried ... on you. British scientists pioneered a technique in horses where an individuals' own stem cells are grown outside the body, then injected into the damaged tendon. There will be a clinical trial in the UK in which 24 human patients will undergo this radical new stem cell treatment for similar tendon injuries. We'll tell you about the proven benefits in racehorses so you'll understand the possible benefits in people. The test subjects who join the clinical trial will be in the unique position of enjoying a medical procedure that is years behind the veterinary equivalent. If human beings have the same barely believable 80% recovery rate, this will be a leap forward for sports medicine. ... The reason animals can get commercial drugs and treatments faster than people in the US and other Western countries is simple: there is enormous oversight in human medical research. Veterinary research is comparably simple. According to the FDA, bringing a new drug to market for humans requires pre-clinical laboratory tests, animal tests, and human clinical trials. Each one of those steps costs money, lots and lots of it. Approval for veterinary drugs is simpler, requiring a single study that proves the drug is safe and effective. Because of regulatory difference, progress on animal medical research can move very quickly compared to human research."


Finding Smart Ways to Say Profoundly Stupid Things

I notice that Science Progress has thoughtfully posted an overview of a book that, like so many, passed beneath my distracted field of vision. It's a good overview, and in reading it I'm struck by just how greatly modern fields of intellectual study have devolved into the title of this post - efforts to find smart ways to say profoundly stupid things. This isn't the aim and goal at the outset, of course, but with postmodernism leading the way, there is a well defined sort of style that accompanies the ability of a community of intellectuals to cut themselves off from rationality and evidence in order to build castles in the sky. Up becomes down and left becomes right, and all sorts of nonsense rises to rule the roost. The end result is a core of stupidity well wrapped by a tremendous expenditure of earnest intellectual effort: a sort of Emperor's new clothes situation wherein few parties involved have any incentive to point out the obvious.

Outside of theology and the worst reaches of postmodernism, this disconnect from reality is perhaps most evident in modern macroeconomics - largely an effort to convince the world against all the evidence that up is down and black is white - and the various fields of ethics, such as bioethics. The bioethics community in particular long ago lost its way.

But back to some examples from that Science Progress piece:

When I say that here, too, Agar builds his argument on an appeal to nature, I have in mind his foundational premise regarding what he calls "species relativism." The "relativism" part of that label might at first sound like a rejection of anything resembling an appeal to nature. But Agar holds that there is something good, something worth preserving, about the way members of our species typically or naturally find happiness. As he puts it, "Experiences typical of the ways in which humans live and love are the particular focus of my species-relativism" (pg.15).

So for an enhancement to count as moderate on Agar's account, it has to be "relative" to our species. As distinct from a radical or "purported" enhancement, a moderate one has to enhance a way of being that is typical of homo sapiens.


He argues that, while it is indeed reasonable to want more of "a recognizably human life," it is not reasonable to want a form of life without the sorts of experiences that are typical for members of our species. As he says, there are some Galapagos tortoises that live up to 150 years, and they no doubt enjoy experiences that are pleasurable for members of their species, but no human being would trade our "distinctively human varieties of pleasure" for distinctively tortoise varieties of pleasure. Because, however, he grants the respect in which that example is unfair - becoming a tortoise would entail diminished cognition and radical life extension would not - he needs to say more.

He begins by suggesting that de Grey's "Strategies for Engineered Negligible Senescence" (SENS) might create an obsessive fear of death, which might come to completely dominate the lives of those who adopted such strategies. Agar worries that, because negligibly senescent people would have more years of life to lose if they failed in one of their projects, they would have a strong reason not to take any risks at all (pg. 116). Indeed, at this point he invokes the concern that later in the book he will call its central theme: the concern about alienation, about becoming separated from the kinds of, here, risky experiences that constitute human lives as we know them. According to Agar, de Grey's ambition to radically extend our lives "is likely to alienate us from the things and people who currently give our lives meaning" (pg. 122).

Agar allows that there may appear to be a way around the obsessive fear of death that SENS could bring about. To get around the risks associated with going out into the real world, he allows, negligibly senescent people could use technologies to have virtual experiences instead. But the problem with that strategy, he says, is that it fails to appreciate the extent to which human beings want "direct" contact with the "real" world. It fails to appreciate that "We think differently about these kinds of indirect contact [with the real world] than we do about 'being there.'" No one, he suggests, thinks that "seeing a Discovery Channel documentary filmed on Mount Everest substitutes for actually climbing it" (pg. 123).

Castles in the sky, and straw ones at that. I would hope that little needs to be said in response to this sort of thing - it is so self-evidently hollow, a gut feel trying to cover itself in words and failing, that it falls apart at a glance.

One of the Many Costs of Aging

The frailty and degenerations of aging impose enormous costs on sufferers and those who assist them - one of many reasons to accelerate work on repairing the biochemical damage that causes aging: "Nearly 15 million people in the United States take care of a loved one with Alzheimer's disease or another form of dementia, amounting to 17 billion hours or more than $202 billion in unpaid care ... If these caregivers all lived in one U.S. state, it would be the nation's fifth largest, according to the Alzheimer's Association's 2011 annual report on the disease. The report illustrates the growing burden of Alzheimer's disease, a fatal brain-wasting disease that erodes memory, thinking, behavior and the ability to handle daily activities. Alzheimer's affects more than 26 million people globally and can stretch on for years, slowly robbing patients of their mind and memories. And there are currently no drugs that can keep the disease from progressing. ... The group estimates that 5.4 million people in the United States are now living with Alzheimer's disease, up from 5.3 million a year ago. That includes 5.2 million people over age 65 or about one in eight senior citizens. A 65-year-old person diagnosed with Alzheimer's typically lives four to eight years after being diagnosed, but some patients live as long as 20 years after diagnosis. ... The $202 billion in unpaid care is on top of the $183 billion estimate for Alzheimer's care expected to be delivered in 2011 by healthcare workers in homes, hospitals and long-term care facilities."


p16INK4a in Calorie Restriction

Proteins generated by the gene p16INK4a are thought to be a biomarker for aging, and in this open access paper a connection with calorie restriction (CR) is explored: "Epigenetic events are among the most striking mechanisms responsible for nutrition-related longevity, which is believed to dynamically regulate gene expression by primarily impacting two epigenetic codes, DNA methylation and histone modification. As evidence of this, the yeast protein silent information regulator 2 (Sir2) [is] a key determinant in CR-induced lifespan prolongation in yeast. In mammalians, SIRT1 is one of seven mammalian orthologs of Sir2, which has been extensively studied for its roles in chromatin remodeling and lifespan elongation. SIRT1 acts as a nutrient sensor involved in the regulation of various gene expressions as well as modulation of important signal transductions either directly or indirectly through its unique epigenetic effects, which ultimately influence the regulation of longevity. Our previous studies indicated that glucose restriction-induced DNA methylation alteration in the p16 promoter contributes to cellular lifespan extension. In this regard, epigenetic mechanisms are major molecular events which play a crucial role in CR-induced longevity. Therefore, we speculated that an aging-associated gene such as p16 may have a central position in epigenetic control of inhibition of cellular senescence and lifespan elongation in response to CR."


How to Make the Vegas Group a Reality

UPDATE 05/21/2011: The Vegas Group initiative launched soon after this post, and was quickly renamed to Open Cures, with a new website and a new mailing list. Please do drop by and take a look at what we're working on.

Elsewhere, in the land of wishful thinking:

The Vegas Group came together formally sometime in 2016, though the first kick-off meeting was the year prior at one of the bi-annual conventions for longevity research held in California. ... The Vegas Group was a natural outgrowth of a decade of advocacy and anticipation for human enhancement technologies, coupled with the frustrating realization that no such technologies would be meaningfully developed, never mind made available to the public, under the regulatory regimes then in place in the US and Europe. ... by 2017 the direct action contingent of the Vegas Group consisted of about a hundred people all told. Their declared objective was a distributed collaborative effort to (a) develop human versions of the most successful longevity and metabolic enhancements demonstrated in mice, and (b) cultivate hospitable medical groups in the Asia-Pacific countries.

It is clear to me that this sort of strategy will be (and is) very necessary as a part of the process of pushing the bounds of medical technology - which is advancing nowhere near as rapidly as it might be. Stunning progress in the laboratory doesn't translate into stunning progress in the clinic, and this is because of the oppressive shroud of regulation weighing down the entire industry. Can you imagine a world in which it took ten years and a government agency to clear the latest innovations in processors and hard drives? We'd still be stuck with 70s-era computers, and paying ten times the price. Yet in medicine, this is exactly the situation we find ourselves in; a worse product, slow progress, and massive expense.

By way of a reminder, it is illegal in the US to commercially develop and market medical technologies for the purpose of slowing or reversing aging. I'll stop to let that sink in for a moment, for those of you who didn't know this. The unelected and largely unaccountable bureaucrats of the FDA do not recognize aging as a disease, therefore will not approve any treatment for aging - and so anyone who forges ahead to try it will be shut down and prosecuted. If you ever wondered why, in this age of remarkable advances and plummeting costs in biotechnology, there are not a thousand startup companies striking out to take on aging itself ... well, this is why.

Pushing change through the FDA is a glacial and very expensive process of lobbying - a political process, naturally, which must be well lubricated with money that would be far better spent on research. This is what it is: essentially corrupt, utterly hostile to progress, a system in which the incentives are for regulators to cause delay and obstruction. Absent a revolution, a broken system of governance should be avoided and worked around, not engaged. When you engage with that broken system, all you are doing is propping it up and legitimizing its existence while it has its way with you.

So I have been pondering how best to make the vision of the Vegas Group a reality: what steps do we take so that we wake up six or seven years from now to an open source biotech community whose members are working on enabling the best longevity therapies produced by the formal research community - and who have the overseas connections to enable responsible use of resulting therapies in a clinical setting. The social and regulatory change required to make this happen legally in the US is so great - and so contrary to the present downward spiral towards more government and greater regulation in every aspect of life - that from where I stand, efforts are better directed towards progress in biotechnology.

So what components are needed to move this from pipe dream to reality? In no particular order:

  • An open repository of technical information: a Wikipedia of longevity biotechnology and published research, a resource built by a community into a how-to for specific techniques in longevity science.
  • Persuading a sizable segment of the present open biotech community into finding this grand project interesting enough to support, and interesting enough to work on.
  • Bootstrapping a community of project supporters large enough to raise funding, hold conferences, and become self-sustaining.

In many ways, I see this sort of thing as the answer to "what comes next after the SENS Foundation?" When the SENS Foundation is forging through the waves five years from now, making progress and getting things done in repairing the biochemical damage of aging, what are the new and energetic research-focused organizations springing up at that time? How are they organized? What are their strategies for turning this growing sea of practical possibilities for repairing aging into therapies for humans?

I see the SENS Foundation and similarly focused organizations as covering the mainstream approach to science, which is to say it will be a slow process moving from working results in the laboratory to therapies in humans. By the very nature of the Foundation, its legitimacy in the eyes of people that matter, the ones writing the checks, depends on going through the established system of research and regulation, FDA and all. That is their fight.

I don't believe that we can afford to wait for the additional ten years or however many years it requires to win that fight, however. Not if there are other options on the table that may enable us to move faster. The Vegas Group approach is one such option: take the knowledge and techniques published by the research community into open biotech communities and overseas laboratories for further development, work them up to a level at which people are comfortable with the risks, and try them out. You get things done by getting things done.

After all, these are our lives. Ours. We are not serfs, to be the property of faceless bureaucrats in the FDA. We can choose our own risks, just as many open biotech enthusiasts would choose to work on biotechnologies of rejuvenation that will ultimately benefit all of humanity. Unless we get this sorted out, the only thing ahead of us is pain, suffering, and death.

A Visualization of Wealth and Health Over Time

Longevity corresponds very well with the general level of wealth and technology in society. This is well illustrated by the transformation of South Korea over past decades, as well as by historical periods such the 17th and 18th centuries in England. Here Gapminder provides an interactive visualization of how both wealth and health have advanced in lockstep over the past century - there is always inequality between and within regions of the world, but the overall direction of progress is onward and upward. Some of you have no doubt seen this before, as the topic is a common one here at Fight Aging!, but this visualization is a quality product and well worth pointing out again. I'll leave you with an appropriate quote to think on: "200 years ago, all countries were poor and life expectancy was less than 40 years. In the 1800s, health only improved in a few countries, but today no country has less than 40 years in life expectancy."


A Profile of Suspended Animation Inc

From the most recent edition of Cryonics Magazine: "Alcor Life Extension members now have access to nationwide standby, stabilization and transport services provided by teams of medical professionals through Suspended Animation, Inc., but some Alcor members may be unfamiliar with Suspended Animation, the company. Founded in 2002, Suspended Animation, Inc. (SA) serves cryonicists in the continental United States from all cryonics companies through contracts with individuals and their membership and long-term care organizations. SA is not a membership organization and does not offer long-term cryonics care, but instead focuses its efforts on research and development of superior equipment and services for cryonics. Over the years, SA has developed or modified a variety of equipment suitable for air travel and used for cryonics applications, including portable ice-baths, custom stabilization kits and two patient care and transport vehicles now deployed in California and Florida. SA's current research and development projects are an automated, air-transportable liquid ventilation device (in conjunction with Critical Care Research) for rapid cooling of cryonics patients; an automated whole body vitrification system (based on a proprietary 21st Century Medicine, Inc. system currently used in animal research), and using cell death gene expression profiling to evaluate existing and new cryonics stabilization strategies."


Cases Against Cryonics

In a recent post at Depressed Metabolism Aschwin de Wolf discusses arguments against cryonics - the low temperature storage of the deceased that aims to preserve the data contained in the brain. For example, what would be needed to make a rational, scientific case against cryonics?

What is striking about cryonics is that those who have taken serious efforts to understand the arguments in favor of its technical feasibility generally endorse the idea. Those who have not made cryonics arrangements usually give non-technical arguments (anxiety about the future, loss of family and friends, etc), lack funding or life insurance, or are (self-identified) procrastinators. In contrast, those who reject cryonics are almost invariably uninformed. They do not understand what happens to cells when they freeze, they are not aware of vitrification (solidification without ice formation), they think that brain cells "disappear" five minutes after cardiac arrest, they demand proof of suspended animation as a condition for endorsing cryonics, etc.

his does not mean that no serious arguments could be presented. [For example, it could be argued that] memory and identity are encoded in such a fragile and delicate manner that cerebral ischemia, ice formation or cryoprotectant toxicity irreversibly destroy it. Considering our limited understanding of the nature of consciousness, and the biochemical and molecular basis of memory, this cannot be ruled out.

Cryonics advocates can respond to such a challenge by producing an argument that pairs our current understanding of the neuroanatomical basis of identity and memory to a cryobiological argument in order to argue that existing cryonics procedures are expected to preserve it. An excellent, knowledgeable, response of this kind is offered in Mike Darwin's Does Personal Identity Survive Cryopreservation? Cryonics skeptics in turn could produce evidence that existing cryonics procedures fall short of this goal.

To my eyes, the weight of evidence presently favors low temperature vitrification being an adequate methodology to preserve the data of the brain. The practice could be greatly improved upon in many ways, such as by eliminating the toxicity of chemicals that must presently be used. There is always room for revolutionary improvement in any technology, but vitrification as it stands seems to be up to the bare essentials of the job: preserve the data sufficiently well for later restoration of a human mind.

Sadly most of the arguments made against cryonics are far from scientific and rational, and in this it is in a similar position to research into the biotechnologies of engineered human longevity. Most people argue against radical life extension from the gut, not the head, when they are first introduced to the concept. It is an instinctive rejection of anything that looks like change: one of the less helpful aspects of human nature at work. People are fiercely defensive of the norm, whatever the norm might happen to be, even when it involves ongoing preventable deaths on a massive, staggering scale.

The human death toll in the Year 2001 from all 227 nations on Earth was nearly 55 million people, of which about 52 million were not directly caused by human action, that is, not accidents, or suicides, or war. They were "natural" deaths.

Targeting Inflammation in Neurodegenerative Diseases

Neurodegeneration has an inflammatory component, and some research groups use that as a starting point for treatment: "Neurodegenerative diseases like Alzheimer's and Parkinson's are partly attributable to brain inflammation. Researchers [now] demonstrate [that] a well-known family of enzymes can prevent the inflammation and thus constitute a potential target for drugs. Research suggests that microglial cells - the nerve system's primary immune cells - play a critical part in neurodegenerative diseases, such as Alzheimer's and Parkinson's. The over-activation of these cells in the brain can cause inflammation, resulting in neuronal death. Scientists [have] now found a way to prevent the activation of the microglia and consequently the inflammation they cause. The key is the blocking of enzymes called caspases, which the team has shown control microglial activation. ... By studying cell cultures and mice, the researchers show that certain caspases (3, 7 and 8) activate rather than kill microglial cells, which triggers an inflammatory reaction. Mice given caspase inhibitors displayed fewer activated microglia and less inflammation and cell death in the surrounding neurons."


Manipulating Stem Cells to Treat Vascular Disease

An example of a class of stem cell medicine that involves manipulation of existing populations of cells in the body: "Circulating through the bloodstream of every human being is a rare and powerful type of cell, one that can actually create new blood vessels to bypass blockages that cause heart attacks and peripheral artery disease. Though everyone has these cells - called endothelial progenitor cells - they are often dysfunctional in people prone to vascular disease. Now researchers [have] discovered that a molecule - called Wnt1 - can improve the function of endothelial progenitor cells, increasing the blood flow to organs that previously had been cut off from the circulation. The finding could enhance clinical trials already testing these powerful cells in patients hospitalized with cardiac arrest. ... A number of studies in the past few years have suggested that genes that play an important role during early development and get 'turned off' during adulthood may also get 'turned on' or expressed again in response to injury, such as heart attack. [Researchers] found that one gene in particular, Wnt1, was expressed during development of blood vessels, shut off during adulthood and then re-expressed in angiosarcoma, a cancer of endothelial cells. ... treating these special cells with Wnt1 not only greatly increased their function but also their number. Next, [researchers] investigated what effect the protein would have on a mouse model of peripheral artery disease, an illness in humans caused by decreased blood flow to the extremities. They found that treating these animals with a single injection of the Wnt1 protein resulted in almost three fold increase in blood flow in the affected areas."


The Short End of the Gender Stick

Here is some data for you to mull over today: the not so great odds that come with being male.

[The] disparity in mortality rates for males and females does not just occur in late adolescence/young adulthood. Males have a higher mortality rate at young ages (e.g. ages 1-4 the death rate for males is 12% higher than it is for females the same age) and older ages (e.g. ages 65-74 the death rate is 33% higher than it is for females that age). Considering the inequality in mortality rates between the genders across the lifespan makes it clear that it is not "nurture" alone that explains why males are more likely to die in every single age category, from the first year of life to age 85+.

The disparity between male and female life expectancy is well known and widely studied, but not definitively understood. What this means in practice is that there exists a very wide range of theories to explain some or all of the gender longevity gap:

Differing smoking rates, stem cell effectiveness, mitochondrial effectiveness, and the possible effects of hormones on the immune system are all on the list. [As well as the theory] that hormones influence the expression and activity of known longevity genes

Which is not to mention the raft of subtly different takes on evolutionary arguments to explain shorter male life spans, such as the debate over disposable soma theories as they apply to the genders.

On the one hand it is fascinating that we stand upon the verge of being able to repair aging, yet at the same time we cannot answer what appears to be a simple question about the nature of aging. On the other hand, this is an apt illustration that sometimes what appear to be simple questions are in fact very complex questions. In this case, the answer to why men and women exhibit different mortality rates and life expectancies must involve the summed interactions of all the systems of human biology, subject to the statistical blurring of a million different lifestyles lived concurrently by billions of people.

The path from epidemiology to clear vision of biological mechanisms is a long, tough trek - and in the end it will do no more for us than to make it easier to work on ways to change that biology. Which is all the more reason to place less of an emphasis on that and more of an emphasis on the path to repairing the forms of molecular damage that cause aging - which are already known and enumerated.

More on Hypoxia-Related Mechanisms and Longevity

It is known that the hypoxic response at a cellular level is involved in the longevity induced by calorie restriction, and works like most forms of hormesis - by stimulating cells to greater housekeeping efforts. Here is an open access paper on the subject: "A mild reduction in mitochondrial respiration extends the life span of many species, including C. elegans. We recently showed that hypoxia-inducible factor 1 (HIF-1) is required for the acquisition of a long life span by mutants with reduced respiration in C. elegans. We suggested that increased levels of reactive oxygen species (ROS) produced in the respiration mutants increase HIF-1 activity and lead to this longevity. In this research perspective, we discuss our findings and recent advances regarding the roles of ROS and HIF-1 in aging, focusing on the longevity caused by reduced respiration. ... Many interesting questions remain unanswered. Which tissues and functional target genes are important in the regulation of aging by HIF-1? How can both up-regulation and down-regulation of HIF-1 promote longevity? What is the molecular mechanism by which mitochondrial ROS stimulates HIF-1 activity? ... Since many aging-regulatory processes are conserved between C. elegans and mammals, these studies may also provide insights into the regulatory mechanisms of aging in mammals, including humans. Moreover, in addition to aging, HIF-1 and mitochondrial impairment have been implicated in various human diseases such as cancer, diabetes, and neurodegenerative diseases. Thus, we believe that these future studies will help us better understand the pathophysiology of these diseases."


Advances in Induced Pluripotency

EurekAlert! passes on an advance in the technology of reprogramming cells: "In the past few months, a slew of papers have indicated that the therapeutic potential of a promising type of stem cell, called induced pluripotent stem (iPS) cells, might be limited by reprogramming errors and genomic instability. iPS cells are engineered by reprogramming fully differentiated adult cells, often skin cells, back to a primitive, embryonic-like state. Given these problems, a team of researchers [wondered] if there might be a better way to regenerate lost tissue to treat conditions like heart disease and stroke. ... they outline a method to obtain a new kind of stem cell they call 'induced conditional self-renewing progenitor (ICSP) cells.' ... It's amazingly cool that we can dial adult cells all the way back to embryonic-like stem cells, but there are a lot of issues that still need to be addressed before iPS cells can be used to treat patients. So we wondered... if we just want to treat a brain disease, do we really have to start with a skin cell, which has nothing to do with the brain, and push it all the way back to the point that it has potential to become anything? In this study, we developed ICSP cells using a cell from the organ we're already interested in - the nervous system, in this case - and pushed it back just enough so it continued to divide, giving us a quantity that we were able to apply efficiently, safely and effectively to treat stroke injury in a rodent model. ... the [reprogramming gene] used here is conditionally expressed. This means that ICSP cells can only produce [the gene] when the researchers add a compound called tetracycline to laboratory cultures. When tetracycline is removed, the cells cease dividing and start differentiating. Then, once transplanted into to an animal model, ICSP cells are no longer exposed to tetracycline and take their growth and differentiation cues from their new environment."


Aubrey de Grey at the iLabs Singularity Summit in Milan

The iLabs Singularity Summit was held this past weekend in Milan, Italy - it's always good to see more of this sort of event happening on that side of the Atlantic. There was a strong focus on longevity science:

Biological ageing is a progressive, degenerative process. As a side-effect of the everyday metabolic activities, cells in our body are damaged: year after year, the cumulative effect of this micro-damages considerably diminishes the overall efficiency of the system, leading eventually to death. ... We die mainly because of ignorance: we do not know how to measure our health, we do not understand completely the side-effects of our therapies and we can't explain the complex interplay between mind and body.

Doing something about these technological and scientific inadequacies should be far higher on most people's to-do lists than it in fact is - we all age, we all suffer the degenerations caused by low-level biological damage. We should all be highly motivated to deal with the problem before it sucks away our ability to live, and then kills us. Alas, the present state of affairs is far from this ideal, and most people do not know or believe that the defeat of aging really is within reach. But it won't happen soon enough unless a great many more people work hard to make it happen.

Amongst the presenters at the summit was the familiar face of Aubrey de Grey, biomedical gerontologist, SENS Foundation cofounder, and outspoken advocate for the development of rejuvenation biotechnology. Here is a video interview made by David Orban and thoughtfully uploaded to YouTube:

I caught up with Aubrey de Grey at the iLabs Singularity Summit in Milan, Italy on March 5. In this video he talks about the progress SENS made in securing funding sources, the latest scientific results, and the need to further its perception as a sound research program all over the world.

Singularity Hub on Artificial Retinas

Another in a series of articles on this topic from Singularity Hub: "The blind in Europe have reason to rejoice, the world's most advanced artificial retina has just received the CE Mark, approved for use in new patients. The Argus II, developed by Lawrence Livermore National Laboratory and marketed by Second Sight, is on sale in the EU, but still awaiting FDA approval here in the US. Luckily, clinical trials are already underway and we could get the amazing device here soon. With the Argus II, blind patients use an external camera to pick up video that is wirelessly transmitted to an electrode array surgically implanted in the eye. While full vision is not restored, the 60+ electrodes allow for some distinction of outlines and other basic shapes. Definitely an improvement over blindness. ... a camera embedded in a pair of glasses records the world in front of the patient. A wearable computer takes that image and transforms it into a basic series of impulses. That pattern is transmitted to the Argus II implant which rests inside the eye, and which is attached to the back of the eye through an electrode array. ... Although software improvements may arrive first, hardware upgrades are also on the horizon. The Argus II operates with about 60 electrodes in its array. That's 60 points of data for your eye to interpret. The Argus III, currently under development at LLNL, should have 200+ electrodes. Perhaps considerably more. It will take a thousand or so to make out human faces accurately, but the Department of Energy is pushing LLNL towards that goal, and beyond. As slow as the progress in artificial retinas has been, it shows no sign of stopping. There are other projects outside of the Argus series, at least two (one in MIT, another in Germany) show serious promise, and even have superior qualities to the Argus in some respects. I have no doubt that we could, eventually, reach a resolution that equals that of the human eye. Perhaps, with a different kind of interface, we could even see in greater detail than nature intended."


Enhancing Memory in Mice

Via ScienceDaily: "Even long after it is formed, a memory in rats can be enhanced or erased by increasing or decreasing the activity of a brain enzyme. ... Our study is the first to demonstrate that, in the context of a functioning brain in a behaving animal, a single molecule, PKMzeta, is both necessary and sufficient for maintaining long-term memory. ... Unlike other recently discovered approaches to memory enhancement, the PKMzeta mechanism appears to work any time. It is not dependent on exploiting time-limited windows when a memory becomes temporarily fragile and changeable - just after learning and upon retrieval - which may expire as a memory grows older. ... This pivotal mechanism could become a target for treatments to help manage debilitating emotional memories in anxiety disorders and for enhancing faltering memories in disorders of aging. ... In their earlier studies, [researchers] showed that even weeks after rats learned to associate a nauseating sensation with saccharin and shunned the sweet taste, their sweet tooth returned within a couple of hours after rats received a chemical that blocked the enzyme PKMzeta in the brain's outer mantle, or neocortex, where long-term memories are stored. In the new study, they paired genetic engineering with the same aversive learning model to both confirm the earlier studies and to demonstrate, by increasing PKMzeta, the opposite effect. They harnessed a virus to infect the neocortex with the PKMzeta gene, resulting in overexpression of the enzyme and memory enhancement. Conversely, introducing a mutant inactive form of the enzyme, that replaced the naturally occurring one, erased the memory - much as the chemical blocker did."


Revisiting Naked Mole Rats and their Lack of Cancer

As you might recall, naked mole rats are interesting to researchers not just because they live nine times longer than similarly sized rodents of other species, but because they don't seem to suffer cancer. At all. There's a primer or two on naked mole rats and cancer back in the Fight Aging! archives:

Naked Mole Rats Do Not Suffer From Cancer

No naked mole rat has been observed to suffer from cancer, a fact that is attracting interest from the cancer research community as this species becomes more widely studied. If the biochemistry that leads to this feat can be understood, it is possible there exists an economical way to port that cancer immunity to humans.

Mechanisms of Naked Mole Rat Cancer Immunity

Like many animals, including humans, the mole rats have a gene called p27 that prevents cellular overcrowding, but the mole rats use another, earlier defense in gene p16. Cancer cells tend to find ways around p27, but mole rats have a double barrier that a cell must overcome before it can grow uncontrollably.

It will be interesting to see whether this line of research pans out into something that looks like a gene therapy for humans. On this topic I see that there's a general interest article on mole rats and their cancer immunity in yesterday's Washington Post:

In the past few years, researchers have been teasing out the biological bases for this cancer resistance, which they say may help explain how naked mole rats manage to live almost 10 times longer than their house mouse and street rat cousins. When Old Man, the oldest known naked mole rat on the planet, died at the University of Texas Health Science Center in San Antonio in November, he was 32 years old.


Getting old without the usual diseases and diminishments of the aging process has always been an intriguing idea. Vera Gorbunova, a biologist and cancer researcher at the University of Rochester in New York, is among those scientists trying to find out how naked mole rats do it.


For many of the experiments her team wanted to do, they needed to grow naked mole rat cells in laboratory dishes, but this proved to be difficult. Whenever the cells touched one another, they stopped replicating. This was frustrating, but it also presented Gorbunova with a clue. She knew that normal mouse and human cells exhibit a less pronounced type of "contact inhibition" and that cancer cells grow into masses because they lack this inhibition.

"In naked mole rat cells," Gorbunova surmised, "we are seeing super contact inhibition." She wondered if there might be a linkage with the mole rats' immunity to cancer.


As Gorbunova sees it, living a long time and disease-thwarting mechanisms such as super contact inhibition go hand in hand. Mice are valuable animal models for studying cancer precisely because they get the disease so easily, she notes, and naked mole rats should become just as important for cancer research precisely because they never get the disease.

A similar line of thinking can be applied to the study of whales, species that must also be highly resistant to cancer, given their massive size and life spans that stretch out to more than 200 years in some cases:

Blue whales can weigh over a thousand times more than a human being. That's a lot of extra cells, and as those cells grow and divide, there's a small chance that each one will mutate. A mutation can be harmless, or it can be the first step towards cancer. As the descendants of a precancerous cell continue to divide, they run a risk of taking a further step towards a full-blown tumor. To some extent, cancer is a lottery, and a 100-foot blue whale has a lot more tickets than we do.

There is potentially much that can be learned from the mammalian species - like naked mole rats and the great whales - that share similar cellular biologies but nonetheless manage to be far more resilient or far longer lived than we humans.

Tissue Engineering of New Urethras

From CNN: "Engineering organs begins with something missing - a phantom organ in the body that causes a patient incredible discomfort, dysfunction or pain. It ends with a Star Trek-esque feat of engineering where missing organs are replaced using cells culled from a patient's own body. In a small pilot [study] scientists reported successfully reconstructing urethras in five young patients, using their own cells. ... We were able to create patients' own tissue that actually belongs there. If the tissue is supposed to be there, hopefully we will do better by the patient. ... Patients had their engineered urethras implanted between March 2004 and July 2007 at the Federico Gomez Children's Hospital in Mexico City. Their urethras continued to function after several years' follow-up. The urethra is a narrow tube that connects the bladder with the genitals, providing a conduit to usher waste out of the body. When it is damaged - sometimes congenitally, or as result of disease, pelvic fractures or other traumas - it is usually replaced using tissue harvested from the lining of a patient's cheeks or using skin grafted from another area of the body. ... Unfortunately for the narrow structures in the body (like urethras), they are kind of complex because they tend to collapse. Every organ has its own challenges. ... The challenge with traditional urethra replacement is creating a viable tube, one that will not easily collapse. And that is where engineering urethras may offer some benefit. The first step for engineering a new urethra is to take a very small piece of the patient's own tissue (around half the size of a postage stamp) from the bladder area. Cells are scraped from the biopsied tissue, allowed to multiply, after which muscle cells are separated from urethral cells. It is the next few steps in the process that sound like science fiction. When there are a sufficient number of cells, scientists 'seed' them - much like you would seed a new lawn - onto a mesh scaffold that is shaped like a urethra. The inside of the mesh is coated with urethral cells while the outside gets muscle cells. ... The seeded structure is placed in an incubator for about two weeks, in a 'cooking' process that [simulates] how cell growth occurs inside the body. After that, the newly engineered urethra is ready to be implanted into the patient."


Boosting Garbage Disposal in Brain Cells

The processes of cellular housekeeping appear to be important in aging, and here is an example of what can be achieved by selectively boosting their operation: "Gene therapy that boosts the ability of brain cells to gobble up toxic proteins prevents development of Alzheimer's disease in mice that are predestined to develop it ... the treatment - which is given just once - could potentially do the same in people at the beginning stages of the disease. ... giving brain cells extra parkin genes promotes efficient and effective removal of amyloid particles believed to be destroying the neurons from the inside. This revved up protein disposal process prevents the cells from dying and spewing amyloid proteins into the brain, where they stick together and clump into plaque. ... Many neurodegenerative diseases are characterized by a toxic build-up of one protein or another, and this approach is designed to prevent that process early-on. ... providing brain cells with about 50 percent more parkin protein activates two parallel garbage-removal processes within the brain. One is ubiquitination, in which errant proteins are targeted for destruction and recycling within the cell. The other process is autophagy, in which membranes form around damaged mitochondria (the cell's power plants) and these membranes fuse with lysosomes that destroys the contents. This is particularly important [because] damaged mitochondria have been found to clog the insides of neurons affected by Alzheimer's disease, and the extra parkin seems to help clear them. That allows the cells to produce new and healthy mitochondria. ... With a normal amount of parkin, the cells are overwhelmed and cannot remove molecular debris. Extra parkin cleans everything." This should have much wider application, possibly even for the slowing of aging, given the broad role of autophagy; it's the sort of therapy that everyone would want done, regardless of their present state of health.


Closer, But Still So Very Far Away

I noticed a recent New York Times article on the interests of one of the world's few hundred billionaires:

Because [David Murdock] is 87, it makes an unusually robust specimen, which is what he must be if he is to defy the odds (and maybe even the gods) and live as long as he intends to. He wants to reach 125, and sees no reason he can't, provided that he continues eating the way he has for the last quarter century: with a methodical, messianic correctness that he believes can, and will, ward off major disease and minor ailment alike.


His affluence has enabled him to turn his private fixation on diet and longevity into a public one. I went to see him first in North Carolina in late January. It is there, outside of Charlotte, in a city named Kannapolis near his lodge, that he has spent some $500 million of his fortune in recent years to construct the North Carolina Research Campus, a scientific center dedicated to his conviction that plants, eaten in copious quantities and the right variety, hold the promise of optimal health and maximal life span.

Profiles and even interviews as they appear in a paper are no way to gauge the finer details of what a fellow does and doesn't believe. A superficial reading of the article would cast Murdock as someone who has spent a lifetime of benefiting from exercise and mild calorie restriction - and the related benefits of veganism - while having little interest in the actual science of calorie restriction. In that he would be much like the late Jack Lalanne, if it is an accurate rendition of his views.

Murdock will, I think, be disappointed in his goal of 125 years of life: with the medical technology of today, and the predicted medical technology of the next ten years, he has very little chance of living to be 100 no matter how healthy he is now. No man is verified to have lived much past 115, and those who made it past 110 are a minuscule fraction of the billions who are presently alive. That is true regardless of anything Murdock might do with his life insofar as diet and exercise go: the statistics of human mortality are what they are.

The simple, unfortunate truth of the matter is this: if eating exceedingly well really could let people live to 100 and beyond with any reliability, then this would be well known, and the world population would include thousands upon thousands upon thousands of centenarians. But people who do the very best largely die far earlier than that - few of them make it into their 80s, let alone 90s. Living well has great worth: clearly there is much that can be done to optimize your own person life expectancy under present day medical technology. But don't expect to live to 100 under those conditions, because the odds are that you won't. The only thing that will bring much longer life to all of us is the advance of medical technologies into the realm of repairing the biological damage of aging.

It might be disappointing or frustrating for some in the longevity advocacy community to know that at least two billionaires - David Murdock and John Sperling - have enough of an interest in longevity to do something about it, have enough funds to realize a rejuvenation biotechnology program such as the Strategies for Engineered Negligible Senescence (SENS), but will never take that path as their convictions lie in a completely different - and ultimately futile - direction. That emotion is the natural human inclination to know better how to spend another fellow's money, but try to suppress it. It's pure poison, like the green-eyed monster of jealousy, and suffering it is no way to lead a stress-free life.

Really this is - and should be - no more frustrating than the fact that any billionaire has a personal and vested interest in fixing aging, the fiscal ability to develop out SENS to function in mice over the next ten years (and build a thriving research community along the way) and probably won't do it. This is what it is, and will be until we change it.

Billionaires are best viewed as a process rather than a person: they are a churning cloud of forward momentum, companies, and thousands of people, including dozens or hundreds of inner circle advisors. When thinking about how to persuade a billionaire to see things your way, you should be thinking along the lines of how you persuade a company of people to see things your way. The traditional path is to build an organization - to gather supporters, advocates, press, and donated dollars. All these are forms of validation that companies - and high net worth individuals - pay attention to.

In this sense, you should look at initiatives like the Methuselah Foundation and the SENS Foundation as being in essence long levers used to gain the attention of wealthy concerns. Alternately, you might see them as components of the very long lever that is the entire longevity science community. It is to the credit of the SENS and Mprize communities that so far these groups have been able to gather multi-millionaires to the fold and talk them into supporting the broader mission of defeating aging. To pull billionaires to the table will require reaching the next level in growth and size of community - ten or a hundred times as large and loud as it is today. It can be done, and it can be done in a very similar fashion to either cancer advocacy or AIDS advocacy. It's just a matter of work and time.

The clock is ticking. What are you doing to help?

Critiquing SENS on Nuclear DNA Damage

Ben Best here offers a critique of SENS, the Strategies for Engineered Negligible Senescence assembled by Aubrey de Grey, based on the absence of nuclear DNA damage from the list of things to repair: "Dr. de Grey asserts that repairing aging damage is a more effective approach than attempting to slow or prevent aging, and I agree with him. Being an ardent supporter of SENS has not stopped me from simultaneously being a critic of aspects of his program that I think are flawed or deficient. I will attempt to outline some of my criticisms in simple language, assuming that my readers have some knowledge of basic science. ... [a] fundamental concern that I have that a significant form of aging damage may be being ignored by SENS. ... There are many types of DNA damage, but for the purposes of this essay I will focus on breakage of both DNA strands - resulting in a gap in a chromosome. There are two mechanisms for repairing double-strand DNA breaks: Homologous Recombination (HR) and Non-Homologous End-Joining (NHEJ). HR usually results in perfect repair, but HR can only operate when cells are dividing. NHEJ is the more frequent form of double-strand break repair, but it is error-prone. NHEJ is the only DNA repair mechanism available for non-dividing cells. Even in cells that divide, 75% of double-strand breaks are repaired by NHEJ. ... It is hard to believe that it could be a coincidence that the most notorious 'accelerated aging' diseases are due to defective DNA repair. ... Nuclear DNA damage typically leads to mutation or DNA repair - or apoptosis or cellular senescence when DNA repair fails (a mechanism that is believed to have evolved for protection against cancer). But not all DNA damage is repaired, and NHEJ repair is often defective. Accumulating DNA damage and mutation can lead to increasingly dysfunctional cells." Everyone in the community should have a go at critiquing SENS - because doing so forces you to do some digging and think it through for yourself, at which point you'll find that many aspects of biotechnology and human cellular biology are not as intimidating or as hard to understand as they might appear at a distance.


Communications Technology and Scientific Progress Towards Longevity

Thoughts on large systems, communications, scientific progress, and evolutionary theory from h+ Magazine: "What do the Global Brain (GB) and human biological immortality have in common? At first, this appears to be a strange question. However, I believe that the realisation of the Global Brain will, perhaps inevitably, result in humans achieving extreme life extension, and eventually abolishing death due to aging. The GB is an emergent worldwide entity of distributed intelligence, one facilitated by communication and the meaningful interconnections between billions of humans, via technology such as the internet. ... When fully operational, the GB must rely on its individual constituents - individual human brains interconnected through technology. Without human input, the GB cannot exist. Furthermore, it cannot exist without technology. This is similar to the human brain - a neuron contributes to the whole, but without suitable connections, the individual neuron does not survive. This is not a magical or fictional process. The sequence of events will happen according to natural laws. Human brains, as individual units of the GB, will be subjected to increased pressures that facilitate longer survival. This is not a teleological argument. The GB does not have any intent or purpose. It is just an instrument of nature, forming part of the general direction of evolution from simple to complex. Within our specific niche, dependent on technology, society and communication, we must adapt and evolve quickly in order to be successful. A hierarchical progress from simple to higher intelligence is a natural consequence (or requirement) of this. It follows that nature will favor mechanisms that lead to higher intelligence quickly, abandoning slow, non-specific mechanisms, such as traditional natural selection. Resources will be shifted from primarily maintaining the germline at the expense of the body (the slow process of natural selection), to maintaining the brain (a fast process for achieving higher intellectual complexity)."


Is Prevention of Aging Within Our Grasp?

Yes, prevention of aging is within our grasp - in the sense that a package of foreseeable medical technologies could enable repair of the low-level biochemical damage that causes aging, and those technologies might take only twenty years or so to develop. Unfortunately, that timeline is dependent on a large amount of funding and a dedicated research community, neither of which presently exists for many of the essential parts of this research program. While the regenerative medicine and cancer research communities are populous, well funded, and achieving progress, very few researchers are presently working on other goals necessary to halt the aging process - such as repair of mitochondrial DNA.

So when I say "within our grasp," I mean "if we all get up and do our part to make it happen." It takes a wave of public interest and advocacy to steer the scientific community and large funding institutions - and they presently need steering towards repair-based strategies to deal with aging, otherwise the first working rejuvenation therapies will arrive too late for those in middle age today.

Here is an article from Ageing Research with a different take on "within our grasp":

Slowly but steadily knowledge about the human body has progressed and new ideas of animal ageing have immerged. The classic model of ageing, based on "accumulation of errors" has become an outdated notion. Instead, evidence suggests that ageing, at least in part, is likely the result of a failure in the function of cells (such as stem cells) required for cellular regeneration. Replacing impaired stem cells with fully functional stem cells should thus prevent/treat age-associated pathologies allowing us to live healthier longer lives.

This sort of viewpoint I see as a dangerous path of complacence. While it is true that (a) regenerative medicine and stem cell science are racing ahead, and (b) the ability to replace tissue, whole organs, or damaged stem cell populations will do much to help, you can't fix aging with stem cells alone.

I've had to make this point with a number of folk who are enthusiastic about progress in regenerative medicine and think that it will enable great extension of human life. Unfortunately this is not the case, as a great deal of degenerative aging is built atop a build-up of waste biochemicals and the body is an integrated system - the health of each of its subsystems impact the others. You can't fix problems in isolation; you can't drop new stem cells into age-damaged stem cell niches, and you can't put a new heart into a body with corroded arteries and expect it to be just fine. If you replace some failing tissue with fresh tissue, that fails to solve a range of other eventually fatal problems.

This is another aspect of the well known factoid regarding cancer research - if you cured cancer and made no other advance in medicine, that state of affairs would add only a couple of years to overall human life expectancy. The people who survived cancer thanks to the miracle therapy would soon be cut down by other conditions of aging. All of the life-span-limiting forms of biological damage have to be repairable before we can greatly extend our lives. There are no short cuts: it doesn't matter how well regenerative medicine is progressing, the other branches of longevity science must also progress rapidly if we are to live longer.

Given that those branches are for the most part not well funded, nor the focus of large and vigorous research communities, this means that we have work to do.

Work on Building New Neurons

One strand of stem cell research is learning how to construct exactly the type of cell needed: "researchers for the first time have transformed a human embryonic stem cell into a critical type of neuron that dies early in Alzheimer's disease and is a major cause of memory loss. This new ability to reprogram stem cells and grow a limitless supply of the human neurons will enable a rapid wave of drug testing for Alzheimer's disease, allow researchers to study why the neurons die and could potentially lead to transplanting the new neurons into people with Alzheimer's. ... These critical neurons, called basal forebrain cholinergic neurons, help the hippocampus retrieve memories in the brain. In early Alzheimer's, the ability to retrieve memories is lost, not the memories themselves. There is a relatively small population of these neurons in the brain, and their loss has a swift and devastating effect on the ability to remember. ... Now that we have learned how to make these cells, we can study them in a tissue culture dish and figure out what we can do to prevent them from dying. ... This technique to produce the neurons allows for an almost infinite number of these cells to be grown in labs, allowing other scientists the ability to study why this one population of cells selectively dies in Alzheimer's disease. ... The ability to make the cells also means researchers can quickly test thousands of different drugs to see which ones may keep the cells alive when they are in a challenging environment. ... [Researchers] demonstrated the newly produced neurons work just like the originals. They transplanted the new neurons into the hippocampus of mice and showed the neurons functioned normally. The neurons produced axons, or connecting fibers, to the hippocampus and pumped out acetylcholine, a chemical needed by the hippocampus to retrieve memories from other parts of the brain."


Alzheimer's Plaque and the Liver

Interesting research reported via ScienceDaily: "Unexpected results from a [recent study] could completely alter scientists' ideas about Alzheimer's disease - pointing to the liver instead of the brain as the source of the 'amyloid' that deposits as brain plaques associated with this devastating condition. The findings could offer a relatively simple approach for Alzheimer's prevention and treatment. ... The product of [the mouse gene corresponding to a gene known to predispose humans carrying particular variations of it to develop early-onset Alzheimer's disease], called Presenilin2, is [involved] in the generation of pathogenic beta amyloid. Unexpectedly, heritable expression of Presenilin2 was found in the liver but not in the brain. Higher expression of Presenilin2 in the liver correlated with greater accumulation of beta amyloid in the brain and development of Alzheimer's-like pathology. ... This finding suggested that significant concentrations of beta amyloid might originate in the liver, circulate in the blood, and enter the brain. If true, blocking production of beta amyloid in the liver should protect the brain. ... mice were administered imatinib [which] has poor penetration of the blood-brain barrier in both mice and humans. ... Because it doesn't penetrate the blood-brain barrier, we were able to focus on the production of amyloid outside of the brain and how that production might contribute to amyloid that accumulates in the brain, where it is associated with disease. ... the drug dramatically reduced beta amyloid not only in the blood, but also in the brain where the drug cannot penetrate. Thus, an appreciable portion of brain amyloid must originate outside of the brain, and imatinib represents a candidate for preventing and treating Alzheimer's."


Money-Making Websites and the Cause of Longevity Science

Moderately skilled and experienced operators can make money by creating and maintaining a website on a particular topic. The degree to which money can be made by doing this is, at the highest level, a function of the level of interest in that topic - complicated by how much money flows in associated industries, but in general it is a measure of public interest and engagement.

Out there in the very fluid ecosystem comprised of small-scale entrepreneurs, online advertising networks, and the browsing population, you'll find an ever-changing and adapting group of websites associated with almost any topic that you find interesting. You have the basement level of automated spam blogs and tiny content sites, bottom feeders produced with minimal effort to generate a tiny amount of revenue each - but there are millions of them. Above that there are the institutional versions of those automated spam systems: companies that churn out terrible, banal content according to metrics that measure present interest in particular topics. Above that, the mix of old and young online journalism that does much the same thing, only more slowly and with a more idiosyncratic flavor.

Then you have the entrepreneurs who build and sell websites over the course of years in much the same way that some people buy, renovate, and sell houses. There is a well-established formula: you work on good (or rather good enough) content, pull in an audience, demonstrate worth, and then sell to another player in that marketplace. None of this implies that the entrepreneur has any interest whatsoever in the topic covered by the website - it helps if they do, but it isn't necessary.

This ecosystem, coupled with the vast sums of money that flow through the "anti-aging" marketplace, explains why 99% of the material out there on the topic of human longevity is junk, nonsense, machine-generated, or only present in the hopes that you'll click on a high-value ad. It is worthless garbage, produced by people who have no interest whatsoever in actually attaining the goal of longer lives through medical science. Over the past few years it seems the search engines have largely given up, their indexes clogged with useless pages created by ignorant outsiders for gain that push down the relevance of useful pages created by knowledgeable insiders.

This state of affairs is been a plague upon our houses, a blanket of lies and misdirection that has long made it extremely hard for newcomers to find any sane starting point in learning about longevity science. Discussion of fundraising and serious research can't get a word in edgeways around the jabbering of supplement-pushers and machine-generated sales pitches for the "anti-aging" products of magical thinking.

I mention all of this as I've noticed a slight shift in the strategy of the site-building entrepreneurs over the past year or so. I should mention that it is often the case that it is hard to tell the difference between one of their sites and a spam system, and their modus operandi in matters of aging and longevity has typically been to follow on the coattails of the "anti-aging" marketplace to push whatever expensive, unproven, and ultimately useless supplement is all the rage. Even sites run by people who are genuinely interested in radical life extension have largely made money through supplements - as that, so far as I can see, is the only game in town.

This becomes at some point a self-fulfilling prophecy: the vast majority of the ecosystem spews forth discussion of supplements and "anti-aging" nonsense - and so this is what the community hears, expects, and looks for. The for-profit websites are just as much a tool for education and advocacy as this site is, and sad to say they are generally far more effective at propagating the message they eventually settle on.

But of late, I've been seeing more site-building that incorporates the messages of rejuvenation biotechnology and modern, serious longevity science. Pulling in quotes from well known aging researchers, for example, talking about the Strategies for Engineered Negligible Senescence, and cutting back on the supplement-pushing. I'm not sure where the various entrepreneurs are going with this, but it seems to be a sign that the right sort of message is further spreading thanks to the efforts of advocates in the healthy life extension community. It is, after all, hard to talk up a $20 pitch while selling a $1 technology that looks pretty weak beside the ongoing work that the scientist next door is busy explaining.

Here are a couple of sites I've noticed of late - see if you can decipher the longer-term motivations of the builders. In each case, these are small-scale commercial ventures at various stages of their inception and progress; and I provide no assurances that any of the content you'll find is true, straightforward, or anything other than a hook aimed at your wallet.

Ageless Zoom

For most of my adult life I've had the sense that I was to participate in bringing in the future. But I never clearly knew what that meant. Now we are able, if we choose, to live longer than any life-span humans have ever imagined. That's not mere possibility, it's real and at hand. I think of it as a second lifetime. And for me it's a very real opportunity to move from chance to choice.

Extreme Longevity

Extreme Longevity is an Internet publication dedicated to finding and presenting the latest developments in human longevity research. ... Each day thousands of scientists and researchers around the world are working to gain a greater understanding of what processes make living things age and seek to determine methods to slow down, stop, or even reverse this process. ... At Extreme Longevity you can expect the latest research to be presented regularly in concise easy-to-understand articles which emphasisze how best to put these learnings in to practice.

Immortal Humans

The latest news and developments about humankind's drive towards biological immortality.

That last one is a good example of a site that can be hard to tell apart from a spam blog - but the entrepreneur responsible for it emerged to comment back a ways when I first noted its existence.

There are others I could point out, but a representative set of three is more than enough. Take them for what they are, and ponder what their existence indicates in terms of the present strength and propagation of the message on scientific longevity.

More on HDL Levels and Human Longevity

You might recall that studies of centenarians turned up an association between reaching that age and levels of HDL, high density lipoprotein, a form of cholesterol transport mechanism. Here is another study demonstrating the same correlation for younger old people: "No previous researchers have sought to determine whether high-density lipoprotein (HDL) cholesterol levels are associated with survival to 85 years of age in a prospective cohort of aging men. We selected 652 men (mean age 65 years) enrolled in the VA Normative Aging Study who had [at least one] HDL cholesterol level documented during the study and who were old enough on the date of HDL cholesterol measurement to reach 85 years of age by [2008]. ... We used proportional hazards to determine hazard ratios (HRs) for mortality before age 85 years for each category of initial HDL cholesterol compared to the reference adjusting for co-morbidities, calculated low-density lipoprotein cholesterol, medications, smoking, body mass index, and alcohol consumption. Treating HDL cholesterol as a continuous predictor, we also determined the HR for each 10-mg/dl increment in HDL cholesterol. ... Each 10-mg/dl increment in HDL cholesterol was associated with a 14% [decrease] in risk of mortality before 85 years of age. In conclusion, after adjusting for other factors associated with longevity, higher HDL cholesterol levels were significantly associated with survival to 85 years of age." Which leads to the thought that if HDL is so good, why not test to see if artificially creating more of it in the body is beneficial?


On Very Small Embryonic-Like Stem Cells

One group of researchers believe that every tissue in the body is supported by a left-over population of fully pluripotent stem cells that might be easily accessible for use in therapies: "From the point of view of regenerative potential, the most important cells are pluripotent stem cells (PSCs). Such cells must fulfill certain in vitro as well as in vivo criteria that have been established by work with PSCs isolated from embryos, which are known as embryonic stem cells (ESCs). According to these criteria, pluripotent stem cells should: (i) give rise to cells from all three germ layers, (ii) complete blastocyst development, and (iii) form teratomas after inoculation into experimental animals. Unfortunately, in contrast to immortalized embryonic ESC lines or induced PSCs (iPSCs), these last two criteria have thus far not been obtained in a reproducible manner for any potential PSC candidates isolated from adult tissues. There are two possible explanations for this failure. The first is that PSCs isolated from adult tissues are not fully pluripotent; the second is that there are some physiological mechanisms involved in keeping these cells quiescent in adult tissues that preclude their 'unleashed proliferation', thereby avoiding the risk of teratoma formation. In this review we present an evidence that adult tissues contain remnants from development; a population of PSCs that is deposited in various organs as a backup for primitive stem cells, plays a role in rejuvenation of the pool of more differentiated tissue-committed stem cells (TCSCs), and is involved in organ regeneration. These cells share several markers with epiblast/germ line cells and have been named very small embryonic-like stem cells (VSELs). We suggest that, on one hand, VSELs maintain mammalian life span but, on the other hand, they may give rise to several malignancies if they mutate. We provide an evidence that the quiescent state of these cells in adult tissues, which prevents teratoma formation, is the result of epigenetic changes in some of the imprinted genes."


A Review of "The Future of Aging"

Over at Depressed Metabolism, you'll find a review of The Future of Aging, a book that covers the high points of longevity research and development pretty much from end to end. That includes viewpoints on transhumanist ideals of an ageless society, present work on rejuvenation biotechnology, the cryonics industry, as well as mainstream work on understanding calorie restriction and slowing aging through metabolic manipulation.

Editor-in-chief, cryobiologist, and aging researcher Gregory M. Fahy and his associate editors Michael D. West, L. Stephen Cole and Steven B. Harris have compiled what might be the most impressive collection of articles on interventive gerontology to date in their 866 page collection The Future of Aging: Pathways to Human Life Extension. The book is divided into 2 parts. The first part includes general, scientific, social and philosophical perspectives on life extension. The second part is a collection of proposed interventions, which are organized in chronological order, starting with the (projected) earliest interventions first. Of course, such an organization of the materials necessitates a subjective estimation of when such technologies will be available and is bound to be controversial. The collection closes with a number of appendices about contemporary anti-aging funding and projects (SENS, Manhattan Beach Project).

I wanted to draw your attention to this line of thinking:

One thing that remains a mystery to me is how such an accelerating pace of anti-aging technologies could be validated considering the relatively long life expectancy of humans. Presumably we are expected to adopt a lot of these technologies based on their theoretical merits, success in animal studies, or short-term effects in humans. ... Reading all these inspiring examples, however, I found myself faced with the same kind of despair as when reading about all the neuroprotective interventions in stroke and cardiac arrest. There is great uncertainty how such interventions would fare in humans (or other animals) and, more specific to the objective of human life extension, how we ourselves can ascertain that there are no long-term adverse consequences. ... As reiterated throughout this review, the gold standard and most rigorous determination of the efficacy of anti-aging therapies and interventions is to empirically determine whether they increase maximum human lifespan.

Everyone alive today who ultimately has the chance to benefit from future rejuvenation medicine or methods to significantly slow aging will be using what is at first essentially unproven technology. It will be developed with the best knowledge and insight of the time, but proof is a very high bar when reaching the gold standard involves waiting for decades after the introduction of new therapies. We have a very good grasp of what should extend life and reverse the damage of aging in humans, and it is simply not an option to hold off to see if the first generation of therapies based on this knowledge do in fact extend life in humans. Just as is the case for the practice of calorie restriction today, we will adopt - and are best served by adopting - the use of those technologies that early on in their development can demonstrate (a) extended life in mice, (b) impressive short term changes in the biochemistry of humans, and (c) an acceptable level of observed side-effects and safety.

This all very reasonable given the circumstances: we lack the luxury of time. Facing the choice between calculated risk and the certain suffering that leads to death, sane people will choose risk. Unfortunately, fighting for the right to be able to take that risk - both in medical development and in the use of the resulting biotechnologies - is very necessary, given the present regulatory environment:

Looking back from the perspective of 2035, I guess we should all be surprised that it took so long. The Vegas Group came together formally sometime in 2016, though the first kick-off meeting was the year prior at one of the bi-annual conventions for longevity research held in California. By that time, more than a dozen gene manipulations and other biotechnologies had been shown to significantly extend life in mice, but no progress was being made to develop these technologies for human use. The Vegas Group was a natural outgrowth of a decade of advocacy and anticipation for human enhancement technologies, coupled with the frustrating realization that no such technologies would be meaningfully developed, never mind made available to the public, under the regulatory regimes then in place in the US and Europe.

There were initial fractures in the Vegas Group around the course of political change versus direct action - which led to the formation of another influential movement discussed elsewhere - but by 2017 the direct action contingent of the Vegas Group consisted of about a hundred people all told. Their declared objective was a distributed collaborative effort to (a) develop human versions of the most successful longevity and metabolic enhancements demonstrated in mice, and (b) cultivate hospitable medical groups in the Asia-Pacific countries. When these technologies were developed, the founding members would cast lots and carefully test upon themselves, in rotation, and through the agency of medical centers in Asia. In doing this the hope was to spur change in the public view and greater progress in the commercialization of these technologies - and of course to gain access to manipulations that were greatly extending life in mice.

The Flip Side of Studies on Stress

Stress appears to affect long-term health and biochemistry in some fundamental ways, some of which are connected to the aging process - such as telomere length, chronic inflammation, and immune system function. So what happens when a person is the opposite of stressed? There is reason to believe that being happy over the long term has just as much of a beneficial effect as stress does a negative effect: "A review of more than 160 studies of human and animal subjects has found 'clear and compelling evidence' that - all else being equal - happy people tend to live longer and experience better health than their unhappy peers. ... Its lead author [analyzed] long-term studies of human subjects, experimental human and animal trials, and studies that evaluate the health status of people stressed by natural events. ... We reviewed eight different types of studies, and the general conclusion from each type of study is that your subjective well-being - that is, feeling positive about your life, not stressed out, not depressed - contributes to both longevity and better health among healthy populations. ... A study that followed nearly 5,000 university students for more than 40 years, for example, found that those who were most pessimistic as students tended to die younger than their peers. An even longer-term study that followed 180 Catholic nuns from early adulthood to old age found that those who wrote positive autobiographies in their early 20s tended to outlive those who wrote more negative accounts of their young lives. There were a few exceptions, but most of the long-term studies the researchers reviewed found that anxiety, depression, a lack of enjoyment of daily activities and pessimism all are associated with higher rates of disease and a shorter lifespan."


Learning From the Ageless Animals

Some species do not age in any easily detected way - lobsters, for example. Others are just far more resilient to the passage of years than we humans, living longer or losing little of their vitality over the course of their lives. What can be learned from a study of their biochemistry? "The first photo is from 1973, when a dark-haired and spry Nisbet was banding chicks of the small sea bird off the rocky Cape Cod coast. The second photo was taken 33 years later and shows a grizzled, silver-haired Nisbet holding a 29 year old tern, one of the oldest on record. Nisbet's body shows common signs of wear and tear - gray hair, wrinkles, achy joints. The tern, however, shows none of these outward signs, despite being the equivalent of a human centenarian. ... Terns don't even demonstrate diminished physical abilities as they age. They aren't the only animals that have combined a long lifespan with minimal signs of aging; other seabirds, alligators, crocodiles, and some tortoises also seem to sip from the Fountain of Youth. Although medical advances have extended the human lifespan, these same advances haven't been able to prevent the inimical onslaught of old age. Scientists hope that by studying the secrets of ageless critters, humans will one day be able to pause the hands of time. ... The main difference between humans and organisms like common terns is how growing older affects the risk of dying. ... In some animals, like freshwater hydras, risk of death remains pretty constant during life. For other animals, like the tern, the risk of death actually decreases with age. It seems almost counter-intuitive: an older tern is less likely to die than a younger one. 'My 29-year-old tern was still breeding,' Nisbet said. The oldest terns produced the healthiest offspring and were actually more likely to survive the year than younger terns."


Lipids and Longevity

Investigating the biochemistry of aging in long-lived species and study of the impact of mitochondrial damage on aging are two quite distinct lines of research. They start to overlap on the matter of lipids, however, and the types and relative proportions of lipids that make up the membranes of cells and cellular components.

If you look back in the Fight Aging! archives, you'll find introductory entries on this topic:

You might recall that different fatty acid or lipid composition in cell membranes was floated as a reason for the ninefold longevity of naked mole-rats over related rodent species. Plenty of oxidative stress in the older mole-rats, but little sign of biochemical damage resulting from it - in comparison to those other rodents long since aged to death, that is. Better, more damage-resistant building blocks down at the molecular level might be the cause.

Better and more damage resistant building blocks: the mitochondrial free radical theory of aging paints mitochondria as the original source of damaging free radicals that react with and destroy cellular machinery - a process that ultimately contributes to age-related conditions such as atherosclerosis. If the machinery is more resistant to free radicals, then we would expect this contribution to aging to have a lesser effect, and thus lead to a longer life span.

If you dig further, you'll see that mitochondrial membrane damage is important in the mitochondrial free radical theory of aging, and the composition of mitochondrial DNA - the blueprint for the proteins that make up mitochondrial structure, such as the membranes - correlate strongly with species maximum life span.

I recently noticed an open access commentary that revisits this area of research:

Scientific investigation of mechanisms that determine lifespan can be divided into three general approaches. The first approach (the comparative method) began over a century ago comparing species differing greatly in maximum longevity and implicated a role for the speed of metabolism in determining the length of life


The recent insight from the comparative approach has been to link membrane fatty acid composition to maximum lifespan. This link grew from the finding that membrane fatty acid composition varied systematically with body-size among mammals and the suggestion this caused different cellular metabolic rates in mammals. Membrane fatty acid was then also linked to maximum lifespan (MLSP) variation among mammals. The reason why membrane fatty acid composition is correlated with MLSP is because fatty acids differ greatly in their susceptibility to lipid peroxidation.

Peroxidation of lipids in the body is effectively a form of damage: it is the reaction between a lipid and a free radical, changing the molecular structure of the lipid and rendering it unable to perform its assigned task in the cellular machinery of which it is a part. More resistant lipids means more damage-resistant mitochondria - and damage-resistant mitochondria should translate fairly directly into enhanced life span. So far the evidence supports this way of looking at matters.

That there is such a strong correlation between the building blocks of mitochondrial membranes and species life span is another strong sign that mitochondrial damage is very important in aging - and thus we should prioritize present efforts to support the development of biotechnologies that can repair or replace mitochondria throughout the body. These therapies are tantalizingly close to realization, but progress is slow and will remain slow until such time as funding and public interest are much larger than they are today.

A Russian Open Letter on Aging

This is another project of the Science for Life Extension Foundation, here translated by Google's automated tools: "All of us [are] waiting in front of old age. And along with it - illness, sickness and loneliness. [We all] fear old age. But do not do anything to delay its onset. Meanwhile, there is hope for the extension of active life and [slowing of] aging. Hope this gives the results of research being conducted in many countries around the world. In Russia the problem of aging [is that no-one cares to do anything about it] - neither society nor the researchers nor the state. The purpose of this letter [is] to get people to think about the need for scientific methods to combat aging. By signing it, you'll make a small step to solving this global problem. ... Aging [is] the main issue in the lives of everyone. Aging reduces the protective functions of the organism and its ability to resist disease, inevitably leading to death. The main causes of mortality of Russians - cardiovascular diseases and cancer - are age-related diseases. In our country the death rate exceeds the birth rate of 250,000 people annually. And for a state extension of active life should be problem number 1. To solve this problem [funding] should be prioritized in favor of scientific research of the mechanisms of aging and the search for effective methods of radical life extension."


A Surgeon's Perspective on Medical Nanotechnology

From h+ Magazine: "A [trend] towards nanotechnology is evident in the miniaturization of surgical tools. Experimental microrobots are already available, and being tested in live tissues ... It seems likely that in one or two decades, microrobots will be in common use in surgery, before their eventual replacement by nanorobots. Microrobots will resemble minute machines from the macroscale. But what will nanorobots look like? They won't be akin to artistic representations of miniature submarines placed beside erythrocytes. Most likely, they will bear some resemblance to the body's existing nanomachines, such as mitochondria. ... Nanorobots will be scavengers for atherosclerotic plaque, just like artistic representations you may find online, but not with exactly the same mechanics. We will witness a gradual transition from surgical repair, to prevention. Atherosclerosis, which is in fact the gradual stenosis of the arteries due to plaque formation, will be solved at the genomic and proteomic level, and this will lead to a great enhancement of the human life span. Minimally invasive microrobots will be used instead of stents inside arteries, for repairs that are currently being performed laparoscopically. ... Last but not least, one of the greatest achievements of nanotechnology in surgery will be what we call the 'ideal graft'; that is, biocompatible and durable 'repairs' of parts of the body like arteries, joints or even organs. At first, these repairs will be used for healing, but soon afterwards, they will be used for transcendence: to enhance current human abilities."