Fight Aging!

Naked mole rats live as much as nine times longer than the members of other similarly-sized rodent species and are essentially immune to cancer, traits that may be side-effects of evolutionary adaptation to life in oxygen-poor underground burrows. Insofar as there is any consensus on the mechanisms driving naked mole rat longevity, it centers around the membrane pacemaker hypothesis: that the composition of important cell membranes in this species, such as those in mitochondria, makes them more resistant to oxidative damage. That in theory cuts down on some of the forms of stochastic damage that lead to degenerative aging.

Here researchers identify another novel feature in the low-level molecular biology of naked mole rats. This most likely indicates the opening of another line of research into the roots of their longevity:

Why Do Naked Mole Rats Live So Long?

In recent years, Gorbunova and her husband Andrei Seluanov have looked closely at the species, which lives in underground colonies in East Africa, hoping to figure out how exactly it manages to survive so long. As revealed in new research her team published today in Proceedings of the National Academy of Sciences, their team thinks they've found at least part of the answer: naked mole rats have strange ribosomes.

Every one of our cells (and, for that matter, every living organism's cells) converts the genetic instructions present in our DNA into proteins - which control a cell's overall operation - through a process called translation. Tiny microscopic structures called ribosomes handle this translation, reading genetic instructions that specify a particular recipe and churning out the protein accordingly.

The ribosomes in almost every multicellular organism on the planet is made up of two large pieces of RNA, a genetic substance similar to DNA. But last year, one of the Rochester lab's students was isolating RNA from cells taken from the naked mole rats when he noticed something unusual. When he separated the RNA pieces, instead of seeing two distinct pieces of ribosomal RNA, he saw three.

After a variety of testing confirmed that it wasn't an experimental error, they decided to look more closely at the potential effects of this unusual structure. It turned out that, compared to mouse ribosomes, these three-part structures made between four and forty times fewer errors during the translation process. At this point, it's unclear how exactly that might lead to longer lifespans, but the researchers believe it plays a key role.

Naked mole-rat has increased translational fidelity compared with the mouse, as well as a unique 28S ribosomal RNA cleavage

Molecular mechanisms responsible for differences in longevity between animal species are largely unknown. Here we show that the longest-lived rodent, the naked mole-rat, has more accurate protein translation than the mouse. Furthermore, we show that the naked mole-rat has a unique fragmented ribosomal RNA structure. Such cleaved ribosomal RNA has been reported for only one other species of mammal.

Although we cannot directly test whether the unique 28S rRNA structure contributes to the increased fidelity of translation, we speculate that it may change the folding or dynamics of the large ribosomal subunit, altering the rate of GTP hydrolysis and/or interaction of the large subunit with tRNA during accommodation, thus affecting the fidelity of protein synthesis. In summary, our results show that naked mole-rat cells produce fewer aberrant proteins, supporting the hypothesis that the more stable proteome of the naked mole-rat contributes to its longevity.

The first thing I would do with this new finding, if I had a laboratory and time to burn, is to look at the ribosomes of blind mole rats, a similar species that seems to have evolved its own mechanism for cancer resistance that is conceptually similar to that of the naked mole rat but different in detail. It would be interesting to see if they also have unusual ribosomes, with the most beneficial outcome being that they do not, meaning there may be a good opportunity for comparison studies.

Mitochondria are the power plants of the cell, known to be important in aging. They have their own DNA, inherited from the mother, and genetic variations lead to different levels of mitochondrial efficiency. This DNA becomes damaged in the course of aging, and in recent years researchers have been investigating ways to replace mitochondria and their DNA, the basis for therapies to treat this contribution to degenerative aging.

Of related interest, researchers here show that mitochondrial DNA variations impact heart disease risk. This is another incentive to complete the development of technologies that will allow replacement of mitochondrial DNA with some more optimal form, not just to repair damage that occurs over a lifetime.

"Having been in this field for decades, I remember when mitochondrial DNA variations were thought to play a role only in the rarest of genetic syndromes. Today, there is a growing consensus that variations in mitochondrial DNA alone make a substantial contribution to each person's risk for heart disease, and ours is the first study to directly confirm it in a living mammal."

The research team started with two varieties of mice; the C57 mouse known to be vulnerable to diseases associated with diet, and the C3H mouse, which is resistant. The study authors then used a technique called nuclear transfer to remove the nucleus from an embryo in each mouse line and switch them. Because mitochondria reside in the cytoplasm (not in the switched nuclei), the new embryos grew into mice whose cells had their own mitochondrial DNA and the nuclear DNA from the other line. That enabled researchers to compare mice with the same nuclear DNA, but different mitochondrial DNA, isolating the latter's distinct contribution to risk.

In general, the data showed that replacing mitochondrial DNA alone could increase or decrease a given mouse's susceptibility to a model of heart failure. Mice with efficient C57 mitochondrial DNA also generated 200 percent more oxidants than their disease-resistant counterparts with C3H mitochondrial DNA.

Another study underway [is] comparing mitochondrial DNA variations in people of African versus northern European ancestry. Evidence suggests that mitochondria carrying African mitochondrial DNA get more energy from the same amount of oxygen and sugar, perhaps reflecting an evolutionary history of food scarcity. Early migrating humans may have found more food in Europe, but would also have had to brave the cold. Thus, Euro mitochondria appear to be less efficient, perhaps because a byproduct of such inefficiency is the increased generation of body heat. More efficient mitochondria, with their greater oxidant production, may explain, in part, higher incidents of heart disease and diabetes among those of African ancestry in the face of modern, high-calorie diets.

Link: http://www.sciencedaily.com/releases/2013/09/130926204433.htm

Cryonics Magazine is published by Alcor, a cryonics service provider. Aubrey de Grey is a noted biogerontologist, advocate for research into human rejuvenation, and co-founder of the SENS Research Foundation:

Cryonics Magazine: At what age, currently, should someone feel that there is very little chance of life extension research benefiting him before the end of his (current, average projected) life expectancy?

Aubrey de Grey: There's no way to answer that in terms of chronological age, because different people aged (say) 60 have such different states of health and chances of living another (say) 30 years. All we can say is that there seems to be a good chance - I'd say at least 50% - that we will be able to control aging pretty comprehensively within 20-25 years from now, allowing those who are not too frail to be treated to benefit greatly. I think anyone who is in a good enough state of health that they can reasonably expect to avoid serious age-related disease or disability for another 10 years has a non-negligible chance of benefiting. But I should point out that the humanitarian motivation for striving to hasten the defeat of aging is much the most powerful in my view - much more powerful than the desire to benefit oneself, or to benefit any particular other person.

Cryonics Magazine: What advice can you give to cryonics organizations and activists to improve the public's perception of cryonics?

Aubrey de Grey: That's pretty hard: very smart people have been trying to perfect a pitch that works for a long time, so I'm unlikely to have any ideas that are really new. The only thing I think might be more effective is to promote certain aspects of the logic of cryonics a bit more aggressively, and especially to educate the public better concerning aspects of that logic that are already mainstream. For example, I think it would be useful if the public knew that mainstream cryobiologists, the type who publicly deride cryonics with great vigor, nevertheless typically have a very positive view of research aimed at vitrifying organs and reviving them for transplant purposes. If this were better known, the question of what makes the brain any less revivable in principle than a kidney becomes rather obvious, and the absence of any good answer from the mainstream critics of cryonics becomes rather conspicuous.

Link: http://www.alcor.org/magazine/2013/09/26/interview-with-dr-aubrey-de-grey/

The last generation whose members will be forced into death by aging is alive today. It won't be the youngest of us, born in the past few years - they, most likely, have thousands of years ahead of them. It won't be the oldest of us either, as even under the plausible best of circumstances we are twenty to thirty years away from a widespread deployment of rejuvenation therapies based on the SENS research program. As to the rest of us, just who is left holding the short straw at the end of the day depends on the speed of progress in medical science: advocacy, fundraising, and the effectiveness of research and development initiatives. Persuasion and money are far more important at this early stage than worrying about how well the researchers are doing their jobs, however.

We live in a world in which the public is only just starting to come around to the idea that aging can be treated, and demonstrations of rejuvenation in the laboratory could be achieved in a crash program lasting ten to twenty years, at a comparatively small cost. But still, most people don't care about living longer, and most people try not to think about aging, or the future of degeneration and sickness that awaits. They think it is inevitable, but that is no longer true. If you are in early middle age today in the first world, then you have a good shot at living for centuries if the world suddenly wakes up tomorrow and massive funding pours into rejuvenation research. You will age and die on a timescale little different from that of your parents if that awakening persistently fails to happen.

So, roll the dice, or help out and try to swing the odds in your favor. Your choice.

Crowdfunding on Kickstarter and related sites is still the new new thing, the shine not yet worn off. One of the truths that this activity reinforces is that it is far, far easier to raise funding for the next throwaway technological widget than for medical research projects aimed at the betterment of all humanity. Research crowdfunding is a tiny, distant moon orbiting the great mass of comics, games, and devices on Kickstarter, Indiegogo, and others. Hell, it's easier to crowdfund a short film that points out how close human rejuvenation might be to the present day than it is to crowdfund a project to actually conduct a portion of that research. Is this a reflection of rationality? You decide, though it could be argued either way regarding whether a dollar given to raising awareness is more valuable than a dollar given to the researchers at this point in time. Both research and persuasion need to happen.

The Last Generation To Die - A Short Film

Set in the future when science first begins to stop aging, a daughter tries to save her father from natural death. The story takes place roughly 30 years in the future at the moment when science has first figured out how to stop aging through genetics. It is framed around the gulf between generations that would occur with the first release of this technology. A daughter who works for a company called Aperion Life - the first to bring this new technology to the public - wants to save her aging father. She starts him on the trials but he soon stops coming. The film continues with the conflict rising between them as she wants him to live on with her while he feels a natural ending is more human.

The film centers itself around the natural conflict that would exist at this divide. Upon developing this story, I've asked many people and I've found a pretty even 50/50 divide of opinions strongly on one side or the other- either they want to die naturally and believe there is beauty in finality, or they want to see what the future holds and have more time to explore and learn more in life. I'd like to turn the question to you... Which side are you on? Would you want to live on or die naturally?

I feel this is a film that needs to be made. Asking these questions in the form of art and story will help start the discussion. Our world is changing very fast and the rate of technology is speeding up. What does all of this mean for humanity? Everything we know, from a book to a play to a song, ends... What does it mean when there is no ending? Would we be more complacent? Would life be as meaningful? Is there more of a beauty in the way it has always been with our passing or is there more beauty in our bodies and minds staying fresh and alive for many, many years to come? What about social justice and overpopulation? Would life become boring after living on indefinitely or would you find it exhilarating to have time to learn new languages, instruments, subjects - to read more books, to love more - to live several lifetimes? Would it be worth it if some of your most loved friends or relatives passed on and wouldn't live on with you? Are you interested in seeing what the future brings in technology and social evolution or are you happy to have contributed and be a part of it for a short time?

Tim Maupin's Film, 'The Last Generation to Die', to Explore Longevity and Life Extension

Chicago filmmaker Tim Maupin launched a Kickstarter for a short film titled, "The Last Generation to Die." Maupin thinks now is a great time to start a conversation about life extension. And he's right. The idea that within decades a genetic fountain of youth may plausibly reverse the aging process, even indefinitely stave off death, seems to be rising up in pop culture. Maupin's Kickstarter has so far raised over $15,000 - $6,000 more than its initial funding goal. Encouraged by the positive response, they're dreaming bigger and hope to fund a stretch goal of $25,000 in the last 10 days of the campaign.

Mitochondria are evolved remnants of symbiotic bacteria within our cells. They produce chemical energy stores used to power cellular operations, but that process also produces damaging oxidative molecules, and the mitochondria themselves bear the brunt of that. Unfortunately some rare forms of the resulting damage sabotage mitochondrial machinery in ways that propagate throughout a cell's herd of mitochondria, turning the entire cell into a malfunctioning exporter of harmful oxidative molecules. The growing numbers of such cells in the body cause increasing harm, and this is one of the contributing causes of degenerative aging.

There are natural antioxidants present in mitochondria, such as forms of superoxide dismutase, and the situation would - in theory - be far worse without them. Researchers have shown that boosting the levels of some of these antioxidants can be beneficial in mice, and targeting designed antioxidant molecules to the mitochondria can similarly produce benefits to health and life span.

Interestingly it is possible to extend life in some cases by reducing the level of natural antioxidants in the mitochondria. In this case it is thought that increased levels of oxidants produce a hormetic response in cells, driving more housekeeping and maintenance activities to create a net benefit. The inner workings of mitochondria are both very complex and very important to metabolism and aging, and the results of any change to these mechanisms can be counterintuitive:

The processes that control aging remain poorly understood. We have exploited mutants in the nematode, Caenorhabditis elegans, that compromise mitochondrial function and scavenging of reactive oxygen species (ROS) to understand their relation to lifespan.

We discovered unanticipated roles and interactions of the mitochondrial superoxide dismutases (mtSODs): SOD-2 and SOD-3. Both SODs localize to mitochondrial supercomplex I:III:IV. Loss of SOD-2 specifically (i) decreases the activities of complexes I and II, complexes III and IV remain normal; (ii) increases the lifespan of animals with a complex I defect, but not the lifespan of animals with a complex II defect, and kills an animal with a complex III defect; (iii) induces a presumed pro-inflammatory response. Knockdown of a molecule that may be a pro-inflammatory mediator very markedly extends lifespan and health of certain mitochondrial mutants.

The relationship between the electron transport chain, ROS, and lifespan is complex, and defects in mitochondrial function have specific interactions with ROS scavenging mechanisms. We conclude that mtSODs are embedded within the supercomplex I:III:IV and stabilize or locally protect it from reactive oxygen species (ROS) damage.

Link: http://dx.doi.org/10.1111/acel.12144

Cells that are old or damaged become senescent and change their behavior for the worse, emitting signals that harm surrounding tissue and increase the chance of other nearby cells becoming senescent. These cells should destroy themselves or be destroyed by the immune system, but some survive, and their growing presence is one of the root causes of degenerative aging. As this short primer notes, we might consider cellular senescence to be an evolving battlefield, a portion of the fight with cancer: cellular senescence is an anti-cancer mechanism that is partially subverted by cancer.

Senescence has been shown to prevent and promote tumorigenesis. These results are not so paradoxical. To develop and maintain, organisms rely on cellular growth and cell division. As organisms age, deregulations of these processes appear leading to hyperplastic or degenerating diseases, such as cancer and Alzheimer disease, respectively. Interestingly, these two aged-related diseases have been linked to a cellular response that yet, uncouples cellular growth from cell division: senescence.

Senescence is a natural cellular response that can be triggered by various stimuli, such as telomere shortening, oncogenic stresses or unrepaired DNA damages. Senescent cells grow but do not divide so that they are enlarged and restricted in number. In addition, as they do not proliferate due to the irreversible cell cycle arrest, they do not differentiate. Thus senescence modifies tissue homeostasis by profoundly impacting tissue architecture both physically and biologically. Such disorganisation leads to alteration of cell contacts thereby re-wiring cellular communication.

To communicate, cells use physical interactions and diffusible factors. In that context, it is interesting to observe that senescent cells often release factors such as cytokines or growth factors. This is known as senescence associated secretory phenotype (SASP). It is therefore tempting to suggest that one of the outcomes of senescence is tissue re-organisation, achieved via cell communication, to reach new homeostasis upon cellular stress. As a matter of fact, studies of senescent cancer cells suggest so. First, senescence has been shown to act as an anti-cancer barrier, both physically and biologically in preneoplastic tissue. Secondly, it has been shown to promote tumorigenesis by favoring the emergence of cancer stem-like cells (CSLCs).

CSLCs are rare quiescent cells. They niche in heterogeneous tumors and have, in contrast to the bulk tumor cells but similarly to normal stem cells, the ability to self renew and to differentiate. Thus, if tissue has to be re-organised upon senescence to gain minimal homeostasis for functioning, new cells have to emerge and differentiate. This can be achieved by stimulation of CSLCs by SASP factors released from senescent cancer cells.

Of note, it remains unclear why CSLCs, unlike normal stem cells, do not senesce. In relation to their role in tissue architecture, it has been described that CSLCs preferentially develop, within the tissue mass, under hypoxic conditions. Interestingly, hypoxia has been shown to inhibit mTOR, which converts quiescent cells into senescent cells. If experimentally verified, hypoxia could reinforce the intrinsic resistance of CSLCs by maintaining their quiescent state, while inhibiting mTOR and geroconversion of CSLCs from quiescence to senescence.

It therefore appears, at least in pathological cancer tissue, that senescence, and SASP in particular, could play a pivotal role in tissue re-organisation upon cellular stress. As a consequence, depending on the cancer stage, i.e. to which extent tissue has to be re-organised upon cancer invasion, senescence could be pro or anti tumorigenic.

Link: http://www.impactaging.com/papers/v5/n9/full/100602.html

Governments in much of the world are massive and intrusive. Little of any consequence can be done without considering how government employees will intervene to make matters harder, more costly, or just plain impractical. Therefore there exists an enormous, many-layered industry that works to sway the opinion of politicians and, perhaps more importantly, the many unelected and largely unaccountable career bureaucrats in charge of large budgets or sweeping regulations. In a rational world we'd have none of this, and people would just get on with improving medicine without the need to spend as much money on lobbying as goes to actually building new and better therapies.

It is in this context that I'll point you to an ongoing effort by a lower layer of the lobbying community, one that has some overlap with both the mainstream media and the business of producing data, white papers, and projections on various topics for use by lobbyists. This one concerns the trajectory of the next few decades of human health and longevity, which of course is of great interest to a range of concerns whose agents are pushing for various changes and payouts in the highly regulated healthcare industry. A plague on all their houses from my point of view, as the machinations of politicians and special interests does little but reduce the odds of seeing radical new therapies to extend healthy life. The cost of regulation is very real, and it is measured in lives lost.

So that said, the contents below are of interest as yet another sign that opinions on medicine and longevity are changing. No longer is the status quo of little change in human longevity the only opinion presented by the mainstream. The years of advocacy for longevity science, the scientific results, and the uncertainty over upward bounds on longevity expressed by the actuarial community are starting to be heard. The possibility of radical life extension driven by new directions in medicine, such as the Strategies for Engineered Negligible Senescence and similar repair-based approaches to rejuvenation, is on the table and talked about in public.

Drooling on Your Shoes or Living Long and Prospering?

Humanity's increase in lifespan may be our greatest achievement. Most of the world's children and their parents and grandparents will live long, productive lives. Even counting the wretched of the Earth, the typical person at birth today worldwide can expect to live to nearly 70, up from her 30s in 1900. But what does the future of longevity hold in the United States? Stagnation? Lift-off? The future is impossible to predict. That's why, to think rationally, systematically and long-term about the future, you need scenarios. These are credible stories, faithful to today's facts, that aim to paint dramatically different futures.

Scenario A: Small Change

Small Change is the official Washington future regarding aging - the one many policymakers expect. In Small Change, the exponential increases in the biological, genetic, neurological, information, nano, and implant technologies have relatively minor impact on current trends in lifespan, healthspan, costs, hospitals, health insurance, Social Security, Medicare, Obamacare, and federal policy. It is a straight-line projection from the present - small but persistent incremental medical change, while costs skyrocket.

Scenario B: Drooling on Their Shoes

In Drooling on Their Shoes, the exponential advances in the GRIN technologies (genetics, robotics, information, and nanotechnology) succeed in increasing lifespan, but largely fail at increasing healthspan. In 2030, octogenarians [are] already in assisted living facilities, where they can expect to spend the next 10 or 20 years. Their long lives, such as they are, will be marked by one major medical intervention after another, at tremendous cost - even greater than in Small Change.

Scenario C: Live Long and Prosper

Live Long and Prosper is based on the assumption that the first human to robustly and even youthfully live to the age of 150 is already alive today. Variations on this scenario are the New Conventional Wisdom among some sober scientists. In Live Long and Prosper, we see marked advances in personalized medicine, tissue engineering, organ regeneration, implants, and memory enhancement, as well as novel means of peering into the body and major interventions in heart disease, diabetes, and cancer. Medicine has become an information technology, and thus follows Moore's Law.

Scenario D: Immortality

Immortality is not as crazy a scenario as it sounds. All it requires is for technology to be advancing faster than you're aging. In principle, all you have to do is turn this line into a curve a little - increase this rate by a factor of four - and you have life expectancy advancing one year for every year you age. And you have something that looks like immortality for some people.

The curve actually has to increase somewhat more than a factor of four to reach actuarial escape velocity. Life expectancy at birth gives that multiple, but life expectancy at birth has no relevance to your future life expectancy as an adult at 20, 40, 60, or 80. Life expectancy at older ages is presently creeping forward at about 1 year with every passing decade. But who cares about trends? Trends reflect what is and what was, not what will be. In eras of rapid progress in enabling technologies old trends can break upward to new heights as radical new advances are introduced, changing the whole picture. In this case the radical new advance is to actually treat the root causes of aging, repairing or slowing them, now that the research community can identify both what to do and how to do it. All progress in the upper end of adult life expectancy in the past has been incidental, fortunate accidents and side-effects of better medical technologies whose goals had nothing to do with aging per se. In contrast the sky is the limit when directed and deliberate efforts are made to extend healthy human life and rejuvenate the old.

Senescent cells are those that have existed the cell cycle of continual division, due to either age or damage. They should destroy themselves or be destroyed by the immune system, but not all are, and that number increases greatly in older age, not least because the immune system declines and fails due to aging. Senescent cells that are not destroyed emit harmful signals to surrounding tissue, degrading function and encouraging more of their neighbors to also become senescent.

This paper looks at a mechanism by which the immune system clears out senescent cells. It is entirely plausible that these activities can be enhanced via suitable therapies, helping to greatly cut down the number of senescent cells hanging around to contribute to degenerative aging. Note that the paper is open access, but the full version available for download is PDF only.

Physiologic autoantibodies, that is, those with an active physiologic role, are an important part of the normal human immune system and are essential in maintaining homeostasis. Evidence suggests that the body uses autoantibodies to prevent disease and to self-treat diseases once started. This suggests a potential therapeutic role for autoantibodies, or, even better, a way to use them to prevent disease. Their capacity to remove aged, damaged cells is well established. Immunoglobulin (Ig) G autoantibodies bind to senescent cell antigen (SCA), which is an altered band 3 anion exchanger protein found mainly on aged cells. Once bound, IgG triggers the removal of the senescent cells by macrophages.

Band 3 is altered primarily by oxidation, which in turn generates SCA. These studies demonstrated that oxidation can generate neoantigens that the immune system will recognize. Band 3 isoforms are ubiquitous: they have been found in all mammalian cells and species so far examined.

The innate immune response to band 3 membrane proteins, and their regulation of cellular lifespan and therapeutic potential will be presented. Examples of other potential innate and physiologic autoantibodies include neuroprotective antibodies to amyloidgenic toxic peptides and antibodies to oxidized LDL (OxLDL), which modify the natural progression of atherosclerosis.

Link: http://dx.doi.org/10.2174/1874609811306010008

Heterochronic parabiosis is the process of linking together the circulatory systems of an old and a young individual. This is done in mice to try to isolate the roles of various signaling proteins in age-related alterations to metabolism, stem cell activity, and so forth. The older mice tend to show improvements in various short-term measures that otherwise decline with age.

While the full details of what is going on under the hood are not yet understood, why not trial a human therapy based on regular blood transplants from a young donor to an old recipient? This would be a stopgap on the way to figuring out the laundry list of signals that need to be altered and then altering them directly - which is in turn a stopgap on the way to repairing the underlying damage of aging that causes these signaling and metabolic changes, as well as many other forms of harm.

My guess is that in the present regulatory environment such a therapy would be unlikely to emerge. There is a very strong bias against progressing without a full explanation of the underlying molecular biology these days - therapies of the past are grandfathered in, but would never be admitted to clinical trials in today's risk averse world. As and when a comprehensive explanation emerges, researchers will focus on direct manipulation of the signals in question rather than developing a blood transfusion methodology to carry them over.

The population of baby boomers (age 60-65) is rapidly increasing globally. The aging of the human body is associated with the decline of cellular function which leads to the development of a variety of diseases. The increased demand for health care for the aging population creates significant financial burden to any healthcare system. Developing strategies and health intervention methods to ameliorate this situation is paramount.

Experiments utilizing heterochronic parabiosis in mice have demonstrated that replacing the aging cellular milieu with the plasma of a young experimental animal leads to reversal of cellular senescence. This article describes a hypothetical model of intermittent heterochronic plasma exchange in humans as a modality for heterochronic parabiosis in an attempt to delay cellular senescence.

Link: http://dx.doi.org/10.1002/jca.21286

After reading around longevity science for a few years you start to develop a feel for what sounds suspect: one of the first flags is for something to be so far removed from the spotlight of the mainstream that it would be hard for any mainstream researcher to evaluate it, for example. New technologies have to come from somewhere, however, and they start with small groups of knowledgeable developers and researchers. By their nature these new advances are hard to evaluate at the outset. Mainstream researchers aren't all that interested in spending significant time on serious evaluation given that most radical departures from the norm are in fact wrong directions, or just flat out wrong. Of course sometimes the new and radical departure is the right way forward, an advance that will reshape the whole field for the better - such as the SENS vision for aging. Then progress is as much a matter of slowly gathering support and making your case over a matter of years, bootstrapping a mass of supporting evidence incrementally as you can convince funding sources and researchers that you are right.

This process applies between all groups. I may know enough about the underpinnings of SENS rejuvenation research to judge that it is a good plan, but I'm all at sea when a group starts to talk about modulating cellular activities with low-frequency electromagnetism. So let me say that if QUEC PHISIS TM was not an accepted abstract at SENS6, and not the subject of a paper in the Rejuvenation Research advance publication queue, I would have written this off as exceedingly dubious after the first paragraph. It still looks exceedingly dubious to my eye, based on its similarity to several well-entrenched lines of medical quackery that have been ongoing for decades now. See what you think:

Modulating Biological Events by Biophysics: An innovative Molecular Methodology using Ion Cyclotron Resonance

It has been known since long time that electromagnetic fields characterized by extremely low frequency (ELF) and intensity are able to trigger Molecular Cyclotronic Ion Resonance phenomena. However, only in the last decades, biophysical studies have shown that Molecular Cyclotronic Ion Resonance, thanks to the ELF waves, activates some fundamental elements (proteins, vitamins, mineral salts..) and makes them enter more easily through the cellular membrane thus guiding all the biochemical reactions essential for the normal cellular activity.

The QUEC PHISIS TM QPS1 treatment is programmed to emit specific frequencies of electromagnetic waves tailored to research the most proper approach to restore the cellular metabolism, the optimize the redox balance (rH2) and the acidity (pH) of body fluids. Preliminary clinical data suggest the significant and sudden impact of this device on cardiovascular parameters (flow mediated dilation) in healthy volunteers, a stronger and quicker antioxidant effect than antioxidant drugs, improvement in muscular coordination and performance through better recruitment of neuromotor units in neuromuscular diseases, increase in body (muscular) mass in unhealthy or frail people and enzymatic activation of the basal metabolism and of the fatty acid metabolism has been proved, in aged rats.

Am I qualified to evaluate this in any way? Absolutely not. My decade of reading around longevity science publications doesn't give me much of a footing to say how valid this research is - it is way off in left field in relation to the molecular biology and health studies I normally peruse. I'd have to go and read up on the relevant areas for a few months: it seems that investigation of cyclotronic ion resonance in the context of medical research is an ongoing concern, for example, though sparsely populated. All in all I'd want to see a few other research groups showing the same sorts of results before I'm prepared to treat this as more than a curio.

Telomeres are caps at the ends of chromosomes, and their average length, while dynamic, tends to become shorter with advancing age or illness. To my eyes this looks like a secondary effect of the damage of aging, but there are researchers who think that it might be a primary cause of degenerative aging and are working on ways to lengthen telomeres, such as through the use of the enzyme telomerase.

Natural variations in life span in humans are to some degree inherited, depending upon both genes and lifestyle choices. Here is a study that puts some numbers to telomere length inheritance:

Telomeres play a central role in cellular senescence and are associated with a variety of age-related disorders such as dementia, Alzheimer's disease and atherosclerosis. Telomere length varies greatly among individuals of the same age, and is heritable. Here we performed a genome-wide linkage scan to identify quantitative trait loci (QTL) influencing leukocyte telomere length (LTL) measured by quantitative PCR in 3,665 American Indians (aged 14 - 93 years) from 94 large, multi-generational families. All participants were recruited by the Strong Heart Family Study (SHFS), a prospective study to identify genetic factors for cardiovascular disease and its risk factors in American Indians residing in Oklahoma, Arizona and Dakota.

LTL heritability was estimated to be between 51% and 62%, suggesting a strong genetic predisposition to interindividual variation of LTL in this population. The strongest evidence of linkage for LTL in our genome-wide scan was localized to chromosome 13q12 in the Oklahoma population. [Among nearby genes, two] could represent promising candidate genes for LTL in American Indians. One is the well-known aging gene Klotho (KL) and [another] is poly (ADP-ribose) polymerase family, member 4 (PARP4). The PARP enzymes recognize DNA strand damages, and DNA binding by PARP controls telomere length and chromosomal stability by triggering its own release from DNA ends. Apart from KL and PARP4, the 13q linkage peak also includes known candidate genes for inflammation, e.g., arachidonate 5-lipoxygenase-activating protein (ALOX5AP), and cancer, e.g., breast cancer 2 early onset (BRCA2), all of which may be involved in the aging process.

Link: http://www.impactaging.com/papers/v5/n9/full/100600.html

Researchers have been investigating ways to restore sensory hair cells in the ear for some years now. These cells are lost with age, leading to a form of age-related hearing loss. Here researchers reduce this loss through raising levels of the protein islet1:

Isl1 is a LIM-homeodomain transcription factor that is critical in the development and differentiation of multiple tissues. In the mouse inner ear, Isl1 is expressed in the prosensory region of otocyst, in young hair cells and supporting cells, and is no longer expressed in postnatal auditory hair cells. To evaluate how continuous Isl1 expression in postnatal hair cells affects hair cell development and cochlear function, we created a transgenic mouse model in which the Pou4f3 promoter drives Isl1 overexpression specifically in hair cells.

Isl1 overexpressing hair cells develop normally, as seen by morphology and cochlear functions (auditory brainstem response and otoacoustic emissions). As the mice aged to 17 months, wild-type (WT) controls showed the progressive threshold elevation and outer hair cell loss characteristic [of] age-related hearing loss (ARHL). In contrast, the Isl1 transgenic mice showed significantly less threshold elevation with survival of hair cells. Further, the Isl1 overexpression protected the ear from noise-induced hearing loss (NIHL): both ABR threshold shifts and hair cell death were significantly reduced when compared with WT littermates.

Our model suggests a common mechanism underlying ARHL and NIHL, and provides evidence that hair cell-specific Isl1 expression can promote hair cell survival and therefore minimize the hearing impairment that normally occurs with aging and/or acoustic overexposure.

Link: http://www.ncbi.nlm.nih.gov/pubmed/24048839

Research into sirtuins emerged from research into the sweeping beneficial metabolic changes that take place due to the practice of calorie restriction. The mainstream research community would like to build drugs, calorie restriction mimetics, that reproduce some fraction of these changes with minimal side-effects. This involves first finding key proteins in the mechanisms that coordinate the metabolic reaction to fewer calories in the diet, and then finding or designing compounds that can change the amounts of those proteins.

So far work on sirtuins has largely meant work on sirtuin 1, and this has generated only knowledge. Despite the hopes for activators of sirtuin 1 (overinflated hopes, as is often the case in areas with significant venture capital invested) this looks like a dead end. There is no reliable extension of life shown in animal studies, and doubts are cast on the early consensus of research in this regard. Nonetheless, there is inertia in funding for this line of research and investigations continue.

Some researchers have moved on to look at mTOR and its activators, as there is far better and more reliable data there for life span extension in mice. Even so, there are good reasons not to buy into another hype machine, one that will no doubt wind up for action the moment that a biotech startup in this area obtains meaningful funding. There is no reason to expect any effort involving metabolic manipulation to slow aging to produce good results for human life extension any time soon. These are enormously challenging, enormously expensive efforts, and the payoff is unlikely to be any greater than that produced by moderate exercise or the practice of calorie restriction. This is peanuts in the grand scheme of things, compared to actual rejuvenation of the old, reversal of aging, that might be obtained through a focus on repairing cellular damage rather than altering metabolism to gently slow the rate at which that damage accrues.

But this is the mainstream of longevity science: a comparatively small research community, of which most are focused on a comparatively poor approach to achieving their end goals. So we come to sirtuin 3, which has been gathering more interest in recent years. This sirtuin, unlike sirtuin 1, is a mitochondrial protein. Mitochondria occupy an important place in the roots of degenerative aging, and levels of sirtuin 3 appear to affect mitochondrial function to a great enough degree to influence health and longevity. As you can see from the title of this open access review paper, there is some enthusiasm for work on sirtuin 3. One might expect that this line of research may too at some point in the near future blossom into an overhyped, venture-funded effort to build a calorie restriction mimetic drug worthy of the name:

Forever young: SIRT3 a shield against mitochondrial meltdown, aging, and neurodegeneration

Caloric restriction (CR), fasting, and exercise have long been recognized for their neuroprotective and lifespan-extending properties; however, the underlying mechanisms of these phenomena remain elusive. Such extraordinary benefits might be linked to the activation of sirtuins. In mammals, the sirtuin family has seven members (SIRT1-7), which diverge in tissue distribution, subcellular localization, enzymatic activity, and targets.

SIRT1, SIRT2, and SIRT3 have deacetylase activity. Their dependence on NAD+ directly links their activity to the metabolic status of the cell. High NAD+ levels convey neuroprotective effects, possibly via activation of sirtuin family members. Mitochondrial sirtuin 3 (SIRT3) has received much attention for its role in metabolism and aging. Specific small nucleotide polymorphisms in Sirt3 are linked to increased human lifespan.

SIRT3 mediates the adaptation of increased energy demand during CR, fasting, and exercise to increased production of energy equivalents. SIRT3 deacetylates and activates mitochondrial enzymes involved in fatty acid β-oxidation, amino acid metabolism, the electron transport chain, and antioxidant defenses. As a result, the mitochondrial energy metabolism increases.

In addition, SIRT3 prevents apoptosis by lowering reactive oxygen species and inhibiting components of the mitochondrial permeability transition pore. Mitochondrial deficits associated with aging and neurodegeneration might therefore be slowed or even prevented by SIRT3 activation. In addition, upregulating SIRT3 activity by dietary supplementation of sirtuin activating compounds might promote the beneficial effects of this enzyme.

In recent years, researchers have shown that introducing additional mitochondrial transcription factor A (TFAM) can reverse some age-related loss of mitochondrial function. Research on mitochondrial protofection seems to have been sidetracked by this finding also - the researchers were using TFAM as a part of a means to replace damaged mitochondrial DNA, but are now more focused on TFAM itself, arguably a less useful path forward.

In this research, scientists show that TFAM levels differ in old and young rats, and life-long calorie restriction eliminates that difference. Calorie restriction slows aging and improves near every measure of metabolism examined to date, so we should expect to see it reduce any given difference between old and young tissues. As for many lines of research, this points to the importance of mitochondria in aging:

Aging affects mitochondria in a tissue-specific manner. Calorie restriction (CR) is, so far, the only intervention able to delay or prevent the onset of several age-related changes also in mitochondria. Using livers from middle age (18-month-old), 28-month-old and 32-month-old ad libitum-fed and 28-month-old calorie-restricted rats we found an age-related decrease in mitochondrial DNA (mtDNA) content and mitochondrial transcription factor A (TFAM) amount, fully prevented by CR. We revealed also an age-related decrease, completely prevented by CR, for the proteins PGC-1α, NRF-1 and cytochrome c oxidase subunit IV, supporting the efficiency of CR to forestall the age-related decrease in mitochondrial biogenesis. Furthermore, CR counteracted the age-related increase in oxidative damage to proteins, represented by the increased amount of oxidized peroxiredoxins in the ad libitum-fed animals.

To investigate further the age- and CR-related effects on mitochondrial biogenesis we analyzed the in vivo binding of TFAM to specific mtDNA regions and demonstrated a marked increase in the TFAM-bound amounts of mtDNA at both origins of replication with aging, fully prevented by CR. A novel, positive correlation between the paired amounts of TFAM-bound mtDNA at these sub-regions was found in the joined middle age ad libitum-fed and 28-month-old calorie-restricted groups, but not in the 28-month-old ad libitum-fed counterpart suggesting a quite different modulation of TFAM binding at both origins of replication in aging and CR.

Considering all together the present results, we demonstrate in rat liver a very articulated age-related decrease in mitochondrial biogenesis leading to the loss of mtDNA probably also through the increase of TFAM binding to both origins of replication. [This] gives an interesting and novel clue to evaluate the preservation of mitochondrial biogenesis as very relevant in the anti-aging action of CR. Of course, future work will be necessary to further verify such hypothesis also in consideration of the therapeutic applications that might lead, through up-regulation of PGC-1α expression and maintenance of mtDNA, to a longer-lasting mitochondrial functionality.

Link: http://dx.doi.org/10.1371/journal.pone.0074644

The practice of calorie restriction, eating fewer calories while still maintaining an optimal intake of nutrients, produces sweeping beneficial changes in metabolism. It produces larger short term changes in measures of health in humans than any presently available medical technology, and can extend maximum life span in laboratory animals such as mice by up to 40%. In longer lived species it seems that any extension of life becomes shorter, however, even while the short term changes in metabolism, health measures, and metabolic processes remain very similar - which is a puzzle.

Modeling aging and age-related pathologies presents a substantial analytical challenge given the complexity of gene-environment influences and interactions operating on an individual. A top-down systems approach is used to model the effects of lifelong caloric restriction, which is known to extend life span in several animal models. The metabolic phenotypes of caloric-restricted (CR; n = 24) and pair-housed control-fed (CF; n = 24) Labrador Retriever dogs were investigated [to] model both generic and age-specific responses to caloric restriction.

Three aging metabolic phenotypes were resolved: (i) an aging metabolic phenotype independent of diet, characterized by high levels of glutamine, creatinine, methylamine, dimethylamine, trimethylamine N-oxide, and glycerophosphocholine and decreasing levels of glycine, aspartate, creatine and citrate indicative of metabolic changes associated largely with muscle mass; (ii) an aging metabolic phenotype specific to CR dogs that consisted of relatively lower levels of glucose, acetate, choline, and tyrosine and relatively higher serum levels of phosphocholine with increased age in the CR population; (iii) an aging metabolic phenotype specific to CF dogs including lower levels of lipoprotein fatty acyl groups and allantoin and relatively higher levels of formate with increased age in the CF population.

There was no diet metabotype that consistently differentiated the CF and CR dogs irrespective of age. Glucose consistently discriminated between feeding regimes in dogs (≥312 weeks), being relatively lower in the CR group. However, it was observed that creatine and amino acids (valine, leucine, isoleucine, lysine, and phenylalanine) were lower in the CR dogs (earlier than 312 weeks), suggestive of differences in energy source utilization. [Analysis] of longitudinal serum profiles enabled an unbiased evaluation of the metabolic markers modulated by a lifetime of caloric restriction and showed differences in the metabolic phenotype of aging due to caloric restriction, which contributes to longevity studies in caloric-restricted animals.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23713866

As I'm sure you're aware, the Longecity community raises funds for modestly-sized research projects in longevity science: things that can be accomplished for a few tens of thousands of dollars and in six months to a year. In this day and age that encompasses a lot of useful, cutting edge research if you can find a group with access to an established laboratory - biotechnology costs are a fraction of what they were even a decade ago, and a single postgraduate student can achieve today what would have required an entire dedicated laboratory staff in the 1990s. For example in 2012 Longecity funded a study on transplantation of young microglia into old mice to see if this can help to slow or reverse age-related neurodegeneration.

Here is an even better goal for 2013: funding a stepping stone project for mitochondrial repair carried out by a SENS Research Foundation team. Mitochondrial damage is one of the root causes of degenerative aging, and the SENS Research Foundation is the leading coordinator of scientific work aimed at doing something about this. The funding deadline is November 28th, and Longecity will provide $2 to the project for every $1 donated by folk such as you and I:

LongeCity Research Support 2013: Mitochondrial Gene Therapy

After careful consideration of a very competitive round this year, we are delighted to have identified a research team and project that we can warmly recommend for community funding:

Development of an Innovative Gene Therapy Method to Cure Mitochondrial Aging - "Backing Up" the Mitochondrial Genome

Mitochondria, the power plants of the cell, contain their own DNA. Unlike the nucleus, mitochondria lack an efficient system to repair damaged DNA, and this damage accumulates over time. As we age, these accumulated mutations result in an increase in oxidative stress throughout the body. It is no coincidence that organisms which age more slowly consistently display lower rates of mitochondrial free radical damage. Reversing and/or preventing damage to mitochondrial DNA may be a key factor in slowing the aging process.

In this project, engineered mitochondrial genes will be used to restore function to cells that contain defective mitochondrial genes.

The SENS team is developing a unique method for targeting these genes to the mitochondria; this step has been the bottleneck in research on this topic over the last decade. In their system, the mRNA from the engineered mitochondrial gene is targeted to the mitochondrial surface before it is translated into a protein using a co-translation import strategy. Once imported, it is incorporated into the correct location in the inner mitochondrial membrane. The long-term goal of this project is to utilize this improved targeting strategy to rescue mutated mitochondrial DNA and thereby prevent and cure one of the major causes of cellular aging.

The research brief is available to logged in Longecity members, but you can download a PDF copy here if you want to take a look at the details. This is a small but valuable project within the larger SENS strategy for dealing with the contribution of mitochondrial damage to aging. In the future a great deal of science will look this way: more effort made to break down long-term research plans into goals that can be crowdfunded easily in a step by step fashion.

Our six month goal is two-fold. First, we will create cells that are null for two mitochondrial genes: CyB and ATP8. Second, we will "cure" the cells by inserting engineered versions of CyB and ATP8 into the nuclear genome, rather than the mitochondrial genome, and then target the functional protein into the mitochondria.

We are requesting a budget of $21,000 to pay for the supplies necessary to continue this project. We have a talented team of highly trained mitochondrial biologists working on mitoSENS. Right now the rate-limiting factor is the cost of the expensive reagents that we use for these experiments. Increasing our funding will allow us to double the pace of our research and bring results to the public much faster. Two areas which are costly are reagents for operating our qPCR machine and for culturing our mutant cells. The bulk of the money will be spent on reagents for those two types of work. Additionally, valuable hours are spent manually counting cells under a microscope, and the purchase of an automated cell counter would speed up this work significantly and would provide a lasting contribution to lab efficiency.

You can pose questions to the researcher at the Longecity forums, and donate at the site. The present goal for community donations is $7,000, with the rest of the funds provided through matching by Longecity: for every $1 you donate, $2 will be donated by Longecity.

Do you want to see rapid progress in the foundations of rejuvenation biotechnology? Then do something about it! Putting my money where my mouth is, I donated $1,000 to this project today. I think that it merits your attention as well: look at the research brief, read the SENS Research Foundation's page on mitochondrial repair, and give what you think will help meet the amount. This is the future, in which those of us most interested in any particular research program can collaborate to make it run faster, picking and choosing what we wish to fund first. There will only be more of this going forward, so jump in now, and show your support for rejuvenation research.

Dentistry will benefit from stem cell technologies just like the rest of medicine. While the public eye is generally focused on the tissue engineering of new teeth, the ability to regenerate gums and other supporting structures that surround the teeth is just as important.

Mesenchymal stem cells (MSC) have been considered as a potential therapy for the treatment of periodontal defects arising from periodontitis. However, issues surrounding their accessibility and proliferation in culture significantly limit their ability to be used as a mainstream treatment approach. It is therefore important that alternative, easily accessible, and safe populations of stem cells be identified.

Controlled induction of induced pluripotent stem cells (iPSC) into MSC-like cells is emerging as an attractive source for obtaining large populations of stem cells for regenerative medicine. We have successfully induced iPSC to differentiate into MSC-like cells. The MSC-like cells generated satisfied the International Society of Cellular Therapy's minimal criteria for defining multipotent MSC, since they had plastic adherent properties, expressed key MSC-associated markers, and had the capacity to undergo tri-lineage differentiation. Importantly, the resulting iPSC-MSC-like cells also had the capacity, when implanted into periodontal defects, to significantly increase the amount of regeneration and newly formed mineralized tissue present.

Our results demonstrate, for the first time, that MSC derived from iPSC have the capacity to aid periodontal regeneration and are a promising source of readily accessible stem cells for use in the clinical treatment of periodontitis.

Link: http://jdr.sagepub.com/content/92/9/833.full

Here is one example of ongoing explorations of the intersection between metabolism and longevity in lower animals. It is an open access paper, so you might take a look at the full PDF version:

Caenorhabditis elegans is widely used as a model for investigation of the relationships between aging, nutrient restriction and signalling via the DAF-2 receptor for insulin-like peptides and AGE-1 (PI 3-kinase) but the identity of the glucose transporters (GLUTs) that may link these processes is unknown. We unexpectedly find that of the eight putative GLUT-like genes only the two splice variants of one gene have a glucose transport function in an oocyte expression system. We have named this gene (fgt-1 (Facilitated Glucose Transporter, isoform 1).

We show that knockdown of fgt-1 RNA leads to loss of glucose transport and reduced glucose metabolism in wild type worms. The FGT-1 glucose transporters of C. elegans thus play a key role in glucose energy supply to C. elegans. Importantly, knockdown of fgt-1 leads to an extension of lifespan equivalent, but not additive, to that observed in daf-2 and age-1 mutant worms. Our data are consistent with DAF-2 and AGE-1 signalling to glucose transport in C. elegans and this process being associated with the longevity phenotype in daf-2 and age-1 mutant worms. We propose that fgt-1 constitutes a common axis for the life-span extending effects of nutrient restriction and reduced insulin-like peptide signalling.

Link: http://dx.doi.org/10.1042/BJ20131101

Stem cell research is an enormous field these days. Not a week goes by without the demonstration of some new advance, most of which now skate beneath the notice of the public, and yet as recently as ten years ago would have been major milestones in and of themselves. The wondrous becomes prosaic very quickly indeed in this age of rapid, revolutionary progress in biotechnology. The stem cell field is perhaps the only area of medical science important to human longevity that needs little help in meeting the goals needed to reverse the effects of aging on cell populations. Funding is easily raised, there are many researchers with the necessary skills and interest to participate, and the most obvious and lucrative applications for stem cell therapies involve treating degenerative conditions of aging. Researchers are thus set on a course that requires them to find out how to repair loss of stem cell function with age in order for these therapies to work effectively in old people.

Stem cell research is a shining example of a successful field of medical research. If we are to see meaningful progress in the other necessary portions of longevity science, however, aging research in general must grow to become as large and as energetic a field as stem cell science, and a research community that is just as motivated to find practical clinical therapies.

Here are some recent examples of progress in the ability to work with stem cells: a few steps forward among the hundreds presently underway.

Stem cell reprogramming made easier

[Researchers] looked at a certain protein, called MBD3, whose function was unknown. MBD3 had caught their attention because it is expressed in every cell in the body, at every stage of development. This is quite rare: In general, most types of proteins are produced in specific cells, at specific times, for specific functions. The team found that there is one exception to the rule of universal expression of this protein: the first three days after conception. These are exactly the three days in which the fertilized egg begins dividing, and the nascent embryo is a growing ball of pluripotent stem cells that will eventually supply all the cell types in the body. Starting on the fourth day, differentiation begins and the cells already start to lose their pluripotent status. And that is just when the MBD3 proteins first appear.

This finding has significant implications for the producing [induced pluripotent stem cells] for medical use. [Researchers] used viruses to insert the four genes but, for safety reasons, these are not used in reprograming cells to be used in patients. This gives the process an even lower success rate of only around a tenth of a percent. The researchers showed that removing MBD3 from the adult cells can improve efficiency and speed the process by several orders of magnitude. The time needed to produce the stem cells was shortened from four weeks to eight days. As an added bonus, since the cells all underwent the reprograming at the same rate, the scientists will now be able, for the first time, to actually follow it step by step and reveal its mechanisms of operation.

Pancreatic Stem Cells Isolated from Mice

Scientists have succeeded in growing stem cells that have the ability to develop into two different types of cells that make up a healthy pancreas. The research team [have] isolated and grown stem cells from the pancreases of mice using a 3-D culture system previously developed by the scientists. The results [could] eventually lead to ways to repair damaged insulin-producing beta cells or pancreatic duct cells.

In the study, the pancreases of mice were altered in a way that makes duct cells proliferate and differentiate. Some cells in this new population were stem cells that were capable of self-renewal. The scientists were able to culture these cells to give rise to large numbers of pancreatic cells or tiny clumps of tissue referred to as organoids.

Scientists grow new stem cells in a living mouse

Scientists have succeeded in generating new stem cells in living mice and say their success opens up possibilities for the regeneration of damaged tissue in people with conditions ranging from heart failure to spinal cord injury. The researchers used the same "recipe" of growth-boosting ingredients normally used for making stem cells in a petri dish, but introduced them instead into living laboratory mice and found they were able to create so-called reprogrammed induced pluripotent stem cells (iPS cells). "This opens up new possibilities in regenerative medicine. In principle, these partially dedifferentiated cells could [be] induced to differentiate to the cell type of choice inducing regeneration in vivo without the need of transplantation."

Generation of functionally competent and durable engineered blood vessels from human induced pluripotent stem cells

Efficient generation of competent vasculogenic cells is a critical challenge of human induced pluripotent stem (hiPS) cell-based regenerative medicine. Biologically relevant systems to assess functionality of the engineered vessels in vivo are equally important for such development. Here, we report a unique approach for the derivation of endothelial precursor cells from hiPS cells [and] an efficient 2D culture system for hiPS cell-derived endothelial precursor cell expansion.

With these methods, we successfully generated endothelial cells (ECs) from hiPS cells obtained from healthy donors and formed stable functional blood vessels in vivo, lasting for 280 days in mice. In addition, we developed an approach to generate mesenchymal precursor cells (MPCs) from hiPS cells in parallel. Moreover, we successfully generated functional blood vessels in vivo using these ECs and MPCs derived from the same hiPS cell line.

These data provide proof of the principle that autologous hiPS cell-derived vascular precursors can be used for in vivo applications, once safety and immunological issues of hiPS-based cellular therapy have been resolved. Additionally, the durability of hiPS-derived blood vessels in vivo demonstrates a potential translation of this approach in long-term vascularization for tissue engineering and treatment of vascular diseases.

TechCrunch occasionally has its uses:

The sad truth is that, if everyone on the Forbes 400 list simultaneously (and tragically) got cancer, or Parkinson's (or any given disease for that matter), the world would probably be well on its way to finding a cure for these illnesses, thanks to the enormous wealth that would be incentivized to back those efforts. Finding a cure for an intractable disease requires time, enormous amounts of human and financial capital, cooperation and research - and at least a few public-private partnerships. It's costly, and it's messy. This is why Calico, Google's newest mad science project, is potentially so exciting.

Google CEO Larry Page implied that dramatically extending human life is one of Calico's main goals; not making people immortal per se, but, according to a source familiar with the project, increasing the lifespan of people born 20 years ago by as much as 100 years. Interestingly, Calico doesn't seem to be a Google company per se, more of an investment in a new company that will be affiliated with Google and become an extension of the company's mad science lab, Google X.

Sources tell us that us that Calico is still very much in the exploratory phases and is seeking neither near term profits nor have much of any idea about how to actually increase lifespans. So, there's that. It's one thing to say "we're going to increase the human lifespan by 20 years!" and another entirely to actually do that. For now, sources tell us that Calico will primarily function as an R&D group, exploring the latest in longevity science. However, it won't rule out the possibility of manufacturing their own products down the line. At some level, Larry Page, the company - someone in Mountain View - has become convinced that Google needs to help figure out the aging problem. As Bette Davis and most 90-year-olds will tell you, "old age is no place for sissies." It's tough. After all, longevity isn't any fun if one spends the last decade of life wheezing in a hospital bed.

I don't see how anyone familiar with the science can reasonably expect to manage radical life extension to the tune of doubling human life expectancy without backing SENS or SENS-like development programs that focus on periodic repair of cellular damage. But I have no insight into the thinking here, and TechCrunch is in a similar position, sources or no.

Link: http://techcrunch.com/2013/09/19/wtf-is-calico-and-why-does-google-think-its-mysterious-new-company-can-defy-aging/

The thing I noted about this article is that Prudential is prominently sponsoring it, as a part of a larger advertising effort to make people think about longer lives in the context of their future finances - that there is a good chance they will live longer than they expect to. You might recall that the company was putting up provocative billboards about radical life extension not so long ago. This approach is both clever and timely on their part, and, given that it will sway public opinion and raise the profile of longevity science, I think it will aid research and fundraising. It is also one of many signs that the zeitgeist on aging and medicine is going through a phase change, right now, all around us.

There is in fact great uncertainty in the degree to which healthy life will be extended over the next few decades, and this stems entirely from the fact that rejuvenation biotechnology is in its early stages. One investor more or less, one research group joining or leaving, could swing the future timeline a decade or two in either direction. The actuarial community has been aware of this uncertainty in projections for years now, and the massive industry of insurance and pensions is one of the channels by which the public will become more knowledgeable about the prospects for developing rejuvenation therapies soon enough to matter for you and I.

How long do you think you'll live? Seventy years? Seventy-five? Most Americans don't see themselves living all that long past retirement age - and why would they want to, anyway? Old age is often thought of as a drag, a tedious and unpleasant slide into sickness. Even if everybody could make it to 100, would they want to? "For years, we've heard this myth: The older you get, the sicker you get," says Dr. Thomas Perls, a specialist in aging and longevity. "And at some point, we're all going to have to recognize that it's just not true. We should take an enabling and positive view of aging, because most Americans generally have the genetic makeup, the blueprint, to live at least into their late 80s. It just depends on what they do with that blueprint."

After developing his hypothesis about our bodies' potential for a healthy old age, Perls decided to launch a new study to confirm his theories, this time focusing on Seventh Day Adventists. According to the dictates of their religion, Adventists are forbidden to smoke, drink, or eat meat, and they are encouraged to exercise regularly and pray frequently. (For believers, prayer often relieves stress.) And almost all of them live into their 80s and 90s.

The Adventists' astonishing longevity was made even more intriguing by disparate genetics. As a group, they are geographically and ethnically heterogeneous; in other words, they don't have any obvious genetic predisposition to longevity. That fact seems to contradict another common myth: that only people with certain protective genes can live an extremely long life. "Many people assume that without those protective genes, we don't have a good shot at longevity," Perls says. "But the Adventist study shows that that's just not true."

Link: http://www.slate.com/articles/health_and_science/prudential/2013/09/a_longer_lifespan_if_we_can_afford_it.html

The consensus view on Alzheimer's disease is that the immediate agent of destruction in the disease process is beta amyloid, one of a number of misfolded proteins that aggregate in various organs and tissues in increasing amounts as a person ages. Why some people accumulate this metabolic waste product more rapidly than others, and why amyloid deposition accelerates in later life, is a topic for another day: there is plenty of room for theorizing, as the full details of degeneration and damage in the interaction between metabolism and aging are not yet known.

The Strategies for Engineered Negligible Senescence (SENS) approach to amyloid is to find ways to get rid of it on a periodic basis - such as some form of immune therapy that directs immune cells to attack and destroy amyloid wherever it occurs. If a therapy can clear amyloids such as beta amyloid from tissues, then it doesn't matter why it is building up, or why some people see more of it than others, as treatments will ensure that no-one ever suffers from a pathological level of amyloid. It is probably the case that beta amyloid deposition accelerates in later life due to other forms of damage at the level of cells and tissues. But in the SENS vision that other damage should also be reverted and repaired. This model of repairing all the primary, fundamental differences between old and young tissue is very powerful: it enables researchers to sidestep the enormous costs and time involved in gaining a complete understanding of all of the processes involved.

The mainstream research community tends to focus on obtaining a full understanding before taking action, however: that is very much the scientific process. In recent years great strides have been made in understanding the molecular biology of beta amyloid and the ways in which it harms brain cells. The dominant strategy here is to find some part of this process that is amenable to sabotage: don't try to remove the amyloid, but instead disable the identified ways by which it causes harm. I believe that this is a less robust approach in comparison to removal, and one that will probably prove more costly in the long run: what if there are multiple processes by which amyloid harms tissues, for example? Each requires identification and full understanding in order to have a good shot at sabotaging it. Removal just requires one research and development effort, and through removal researchers can eliminate all other potential harms.

This research is a good example of the full understanding and molecular sabotage approach to developing a therapy for Alzheimer's disease:

Stanford scientists reveal how beta-amyloid may cause Alzheimer's

Beta-amyloid begins life as a solitary molecule but tends to bunch up - initially into small clusters that are still soluble and can travel freely in the brain, and finally into the plaques that are hallmarks of Alzheimer's. Using an experimental mouse strain that is highly susceptible to the synaptic and cognitive impairments of Alzheimer's disease, [researchers] showed that if these mice lacked a surface protein ordinarily situated very close to synapses, they were resistant to the memory breakdown and synapse loss associated with the disorder. The study demonstrated for the first time that this protein, called PirB, is a high-affinity receptor for beta-amyloid in its "soluble cluster" form, meaning that soluble beta-amyloid clusters stick to PirB quite powerfully. That trips off a cascade of biochemical activities culminating in the destruction of synapses.

[The researchers] wondered whether eliminating PirB from the Alzheimer's mouse strain could restore that flexibility. So [they bred] Alzheimer's-genes-carrying strain with the PirB-lacking strain to create hybrids. Experimentation showed that the brains of young "Alzheimer's mice" in which PirB was absent retained as much synaptic-strength-shifting flexibility as those of normal mice. PirB-lacking Alzheimer's mice also performed as well in adulthood as normal mice did on well-established tests of memory, while their otherwise identical PirB-expressing peers suffered substantial synapse and memory loss. "The PirB-lacking Alzheimer's mice were protected from the beta-amyloid-generating consequences of their mutations." The question now was, why?

In another experiment, [researchers] compared proteins in the brains of PirB-lacking Alzheimer's mice to those in the brains of PirB-expressing Alzheimer's mice. The latter showed significantly increased activity on the part of a few workhorse proteins, notably an enzyme called cofilin. Subsequent studies also found that cofilin activity in the brains of autopsied Alzheimer's patients is substantially higher than in the brains of people without the disorder. Here the plot thickens: Cofilin works by breaking down actin, a building-block protein essential to maintaining synaptic structure. And, as the new study also showed, beta-amyloid's binding to PirB results in biochemical changes to cofilin that revs up its actin-busting, synapse-disassembling activity. "No actin, no synapse."

Beta-amyloid binds to PirB (and, the researchers proved, to its human analog, LilrB2), boosting cofilin activity and busting synapses' structural integrity. Although there may be other avenues of destruction along which synapses are forced to walk, [researchers doubt] there are very many, [and suggest] that drugs that block beta-amyloid's binding to PirB on nerve-cell surfaces - for example, soluble PirB fragments containing portions of the molecule that could act as decoy - might be able to exert a therapeutic effect.

The current mainstream position in aging research is still a silent majority who work on investigating aging only: no attempts to actually do anything about degenerative aging, only attempts at producing late-stage treatments for its consequences, the various named age-related diseases. The nascent new mainstream position is a research strategy based on attempts to slow aging and postpone age-related disease; this is in the process of gaining central and widespread support.

This is a step forward, but sadly it is still unlikely to produce meaningful results in terms of extended human life - though it will generate a far greater understanding of aging and metabolism at the detail level. Treatments to modestly slow aging will take decades to produce and become widely available, as it is a very challenging problem to safely alter the operation of our exceedingly complex evolved metabolic machinery: billions have gone into trying to replicate the most obvious beneficial metabolic shift, that of calorie restriction, and there is little to show for that yet.

The better path forward is to focus on repair of the damage that causes aging. That doesn't require any alteration to metabolism, but rather just addresses the known fundamental differences between old tissues and young tissues, one by one, until old becomes young. This is probably easier than metabolic manipulation, a great deal more is presently known about what needs to be done, and the resulting treatments will produce rejuvenation rather than just a slowing of aging. Still, this strategy is presently a minority position in the field, with little funding. That must change if we are to see meaningful progress in our lifetime.

Here is an example of the present zeitgeist of aging research and its intersection with medicine, illustrating the ascendance of the camp who want to slow aging over the old status quo of doing nothing and never talking about aging in the context of medicine:

"[Aging is] a huge economic problem that impacts the bottom line of corporations as well as governments, and every country we can think of," said Dr. William A. Haseltine, chairman and president of ACCESS Health International, who was a professor at Harvard Medical School and Harvard School of Public Health from 1976 to 1992. "Whether it's a country like Sweden that deals with health as a state issue, or the United States that deals with it more or less as a private issue, aging is hitting the bottom line and people are upset," said Dr. Haseltine.

So far, what the medical community has come up with is disappointing, noted several of the conference speakers. "At the moment, the current healthcare system is all about keeping people sick longer, not keeping people healthy," argued Dr. Brian K. Kennedy, CEO of Buck Institute of Aging, who is internationally known for his research in the basic biology of aging and whose focus is on translating research discoveries into new ways of detecting, preventing and treating age-related conditions. These conditions include Alzheimer's and Parkinson diseases. Cancer. Stroke, diabetes, and heart disease.

"We have to rethink how we do healthcare, and one of the ways is to extend people's health span and intervene early on to slow aging and prevent diseases," said Dr. Kennedy. To develop new approaches to alleviate aging-associated diseases in humans, Dr. Kennedy has been working to move discoveries from simple organism into mammalian animal models as quickly as possible.

Link: http://www.forbes.com/sites/genemarcial/2013/09/18/regenerative-medicine-global-aging-were-hot-topics-at-life-science-conference-in-stockholm/

Here is another article in a popular science series on the history of human longevity and related topics. This looks at a mainstream disagreement in aging research, among researchers who do not see radical life extension as a near-term possibility:

One of the most fascinating debates in life science these days is between S. Jay Olshansky and James Vaupel of the Max Planck Institute for Demographic Research in Rostock, Germany. They disagree fundamentally about whether and how average life expectancy will increase in the future, and they've been arguing about it for 20 years. Olshansky, a lovely guy, takes what at first sounds like the pessimistic view. He says the public health measures that raised life expectancy so dramatically from the late 1800s to today have done about as much as they can. We now have a much older population, dying of age-related diseases, and any improvements in treatment will add only incrementally to average life expectancy, and with vanishing returns.

On the other side of the ring is Vaupel, who says that people are living longer and healthier lives all the time and there is no necessary end in sight. His message is cheerier, but he takes the debate very seriously; he won't attend conferences where Olshansky is present. His charts are heartening; he takes the records of the longest-lived people in the longest-lived countries for each year and shows that maximum lifespan has been zooming up linearly from 1800 to today. One wants to mentally extend the line into all of our foreseeable futures.

Olshansky says the only way to make major improvements in life expectancy is to find new ways to prevent and treat the diseases of aging. And the most efficient way to do that is to delay the process of aging itself. That's something that some people already do - somehow. Olshansky says, "The study of the genetics of long-lived people, I think, is going to be the breakthrough technology." Scientists can now easily extend lifespan in flies, worms, and mice, and there's a lot of exciting research on genetic pathways in humans that might slow down the aging process and presumably protect us from the age-related diseases that kill most people today. "The secret to longer lives is contained in our own genomes," Olshansky says.

Olshansky favors the mainstream high level research strategy that I believe is largely futile: a slow, expensive process of building treatments to alter human metabolism to look more like that of long-lived people, or replicate the effects of calorie restriction. It will produce a great deal of knowledge, but little effect on life spans: this is an approach that will slow aging slightly, not create rejuvenation, and not directly address the root causes of aging. If we want to see real progress in human life span in our lifetimes, decades or more of healthy life added even for those already old, then we have to back repair-based research such as the Strategies for Engineered Negligible Senescence (SENS).

Link: http://www.slate.com/articles/health_and_science/science_of_longevity/2013/09/maximum_adult_lifespan_debate_over_how_long_humans_can_live.single.html

It was only a matter of time before more big players started to dip their toes into funding longevity science. The bigger the player, the more important the very existence of their position of support becomes: much of the struggle to raise funding and public support for the goal of extending the healthy human life span involves generating credibility and legitimacy in the public eye. It's unfair, and completely disconnected from merit and utility, but that's the way things work. Greater support for longevity science from the California venture and technology community has been building for some years: it is no accident that the SENS Research Foundation has its base in the Bay Area, for example. That choice is not just a matter of several of the most noted aging research laboratories being nearby, with another in LA, but also that a strong base of funding and grassroots support exists in that part of the world.

It is pleasing to see that the folk running Google have decided to direct some of their philanthropic muscle towards the problem of aging, not least because they have access to one of the largest soapboxes in this modern world of ours. That Google openly backs longevity science is a tremendous boon for everyone who advocates for greater research funding in this field, and for everyone seeking to raise funding in this field.

Announcement by Larry Page

I'm excited to announce Calico, a new company that will focus on health and well-being, in particular the challenge of aging and associated diseases. Art Levinson, Chairman and former CEO of Genentech and Chairman of Apple, will be Chief Executive Officer. Art and I are excited about tackling aging and illness. These issues affect us all - from the decreased mobility and mental agility that comes with age, to life-threatening diseases that exact a terrible physical and emotional toll on individuals and families. And while this is clearly a longer-term bet, we believe we can make good progress within reasonable timescales with the right goals and the right people.

Google vs. Death

At the moment Google is preparing an especially uncertain and distant shot. It is planning to launch Calico, a new company that will focus on health and aging in particular. The independent firm will be run by Arthur Levinson, former CEO of biotech pioneer Genentech, who will also be an investor. Levinson, who began his career as a scientist and has a Ph.D. in biochemistry, plans to remain in his current roles as the chairman of the board of directors for both Genentech and Apple, a position he took over after its co-founder Steve Jobs died in 2011. In other words, the company behind YouTube and Google+ is gearing up to seriously attempt to extend human lifespan.

Google isn't exactly bursting with credibility in this arena. Its personal-medical-record service, Google Health, failed to catch on. But Calico, the company says, is different. It will be making longer-term bets than most health care companies do. "In some industries," says Page, "it takes 10 or 20 years to go from an idea to something being real. Health care is certainly one of those areas. We should shoot for the things that are really, really important, so 10 or 20 years from now we have those things done."

Aubrey de Grey: Finally, the War on Aging Has Truly Begun

To paraphrase Churchill's words following the Second Battle of El Alamein: Google's announcement about their new venture to extend human life, Calico, is not the end, nor even the beginning of the end, but it is, perhaps, the end of the beginning.

As little as 20 years ago, when I joined the pitifully small band of academics who call themselves biogerontologists, the prospects for defeating aging were so bleak that it was widely considered unscientific even to discuss it: according to the respectable view, our only option was to continue discovering more about the nature of aging until, by some miracle in the distant future, our body of knowledge took sufficient shape to reveal a route to intervention. A string of advances in the late 1990s, mostly made by researchers not focused on aging per se, changed that: it allowed, for the first time, the formulation of a realistic divide-and-conquer strategy against mankind's most formidable foe. Many components of this strategy were at a dauntingly early stage of development, but all could be described in sufficient detail to offer hope for foreseeable success. As so often in science, many established luminaries voiced skepticism, and some still do; but the plan progressively attracted the support of world-leading experts in all the relevant disciplines, and as it has done so, funding - albeit far too little to maximise the rate of progress - has materialized too.

Now is the right time for a commercial entity to get heavily involved. One of the key activities of SENS Research Foundation, as a non-profit, is proof-of-concept research on key components of the anti-aging arsenal that are still too early-stage to constitute an attractive business proposition for all but the most visionary investors. But we've always made clear that our ultimate goal is to kick-start a real anti-aging industry: not the essentially cosmetic industry that goes by that name today, but a bona fide rejuvenation biotechnology industry, providing people with truly comprehensive restoration and preservation of youthful mental and physical function however long they live. And yes, one side-effect of this advance - a side-effect that we should all celebrate - is that most people will live a great deal longer than today, and will do so in the prime of health.

With Google's decision to direct its astronomical resources to a concerted assault on aging, that battle may have been transcended: once financial limitations are removed, curmudgeons no longer matter. That's why I think it is no exaggeration to state that the end of the beginning may have arrived. I won't go so far as to say that my crusading job is done, but for sure it just got a whole lot easier.

One example of the sort of groundswell of support for longevity science in the California technology culture I'm talking about can be seen in the Hacker News thread on this announcement by Google. Hacker News is a slice of the technology entrepreneur community with an emphasis on the Bay Area startup scene. People commenting there immediately made the connection with the work of the SENS Research Foundation and Aubrey de Grey, despite that not being mentioned anywhere in the press materials. There is a web of connections between entrepreneurs-turned-investor such as Peter Thiel, the SENS Research Foundation, researchers in California laboratories, and a range of people in the technology and venture capital communities, and that network has been growing quietly in the background for years now. Health Extension is one small example of the sort of organized efforts that arise from that community.

Aging is a terrible thing, and parts of the research community have for some years been able to show that there are real prospects for creating rejuvenation therapies. Sooner or later people with a great deal more money than they could ever manage to spend on luxuries are going to wake up and realize that they can buy more years, decades even, of healthy life by funding longevity research. Obviously if you are rich and you can do that, it would be foolish not to. What do you have to lose?

But let us not get too far ahead of ourselves. This effort by Google has just started, and we have no idea how it will turn out. Google doesn't have a good track record for going above and beyond the safe, staid norm when it comes to philanthropy. Their initiatives in that respect have generally been very mainstream, very similar to what other factions of Big Philanthropy are up to, and very unlikely to change the world. So it is entirely possible that this could turn out to be another version of the Ellison Medical Foundation, wherein funding follows the National Institute on Aging model, and is thus highly conservative, largely focused on investigation rather than intervention, and very unlikely to produce any meaningful extension of healthy life. That would be a grand waste of an opportunity, but it's a plausible outcome.

Another possibility is that the outcome here will look very much like the Glenn Foundation initiatives that have established laboratories for longevity science around the country. Most of those funds and the resulting work presently goes towards the slow, ineffective path to extending human life: manipulating metabolism, searching for ways to replicate the benefits of calorie restriction, and so forth. Slightly slowing aging isn't rejuvenation, it's arguably harder than creating rejuvenation, and it won't make any great different to the life span of anyone in middle age today. What use are medicines that can slightly slow aging if you are already old when they emerge? This, too, would be a waste of an opportunity, but is a plausible prediction.

On balance, I will be pleasantly surprised if money flows from Google towards SENS research and similar work on human rejuvenation any time soon: I don't expect that to happen now. I expect Google to back the mainstream, and the mainstream today is not SENS, but rather the slow, painful, expensive attempt to build drugs that slightly slow aging. That said, I will also be surprised if significant money fails to flow from Google to SENS by 2018 or so, as the trajectory for SENS is for it to become a major faction within the aging research community. I expect that trajectory to accelerate as attempts to slow aging via drugs continue to produce poor or no results, and as incremental progress accrues in the foundation technologies needed for rejuvenation: mitochondrial replacement; cleaning up the lysosome; immunotherapies to clear amyloid; and so forth. Sooner or later, people start backing the winning horse, even if it takes them time to recognize that said horse is obviously, self-evidently better than the alternatives.

Chronic inflammation is not a good thing, but it becomes worse with age even for those in the best of health, a result of the decline of the immune system into progressively worse states of malfunction. There are plenty of ways to accelerate this decline into inflammation, however, such as by becoming overweight, as visceral fat tissue generates inflammation via a range of signaling processes.

The importance of chronic inflammation as a determinant of aging phenotypes may have been underestimated in previous studies that used a single measurement of inflammatory markers. We assessed inflammatory markers twice over a 5-year exposure period to examine the association between chronic inflammation and future aging phenotypes in a large population of men and women.

We obtained data for 3044 middle-aged adults (28.2% women) who were participating in the Whitehall II study and had no history of stroke, myocardial infarction or cancer at our study's baseline (1997-1999). Interleukin-6 was measured at baseline and 5 years earlier. Cause-specific mortality, chronic disease and functioning were ascertained from hospital data, register linkage and clinical examinations. We used these data to create 4 aging phenotypes at the 10-year follow-up (2007-2009): successful aging (free of major chronic disease and with optimal physical, mental and cognitive functioning), incident fatal or nonfatal cardiovascular disease, death from noncardiovascular causes and normal aging (all other participants).

Of the 3044 participants, 721 (23.7%) met the criteria for successful aging at the 10-year follow-up, 321 (10.6%) had cardiovascular disease events, 147 (4.8%) died from noncardiovascular causes, and the remaining 1855 (60.9%) were included in the normal aging phenotype. After adjustment for potential confounders, having a high interleukin- 6 level (greater than 2.0 ng/L) twice over the 5-year exposure period nearly halved the odds of successful aging at the 10-year follow-up and increased the risk of future cardiovascular events and noncardiovascular death. Chronic inflammation, as ascertained by repeat measurements, was associated with a range of unhealthy aging phenotypes and a decreased likelihood of successful aging.

Link: http://dx.doi.org/10.1503/cmaj.122072

Mitochondria are the power plants of the cell, producing chemical energy stores used to power cellular activities. They come equipped with their own DNA, separate from that in the cell nucleus. Damage to that DNA that occurs as a side-effect of the processes necessary to generating chemical energy stores is thought to be one of the root causes of degenerative aging. The SENS Research Foundation funds research to work around this problem by putting copies of the most important mitochondrial genes into the cell nucleus, where they are better protected and will provide a backup source of the protein machinery needed for correct mitochondrial operation, thus eliminating this contribution to aging.

Other approaches are possible, however: replace the mitochondrial DNA or mitochondria entirely on a regular basis, for example, or as in the research noted here use a variant form of gene therapy to deliver individual replacement genes into the mitochondria:

We injected a modified self-complementary (sc) AAV vector [into] the mouse vitreous to deliver the human ND4 gene under the control of a mitochondrial heavy strand promoter (HSP) directly to the mitochondria of the mouse retina. Control viruses consisting of scAAV lacking the COX8 targeting sequence and containing human ND4, or scAAV containing green fluorescent protein (GFP), were also vitreally injected. Using next-generation sequencing of mitochondrial DNA extracted from the pooled mouse retinas of experimental and control eyes, we tested for the presence of the transferred human ND4, and any potential recombination of the transferred human ND4 gene with the endogenous host mitochondrial genome.

We found hundreds of human ND4 DNA reads in mitochondrial samples of MTS AAV-ND4-injected eyes, a few human ND4 reads with AAV-ND4 lacking the MTS, and none with AAV-GFP injection. Putative chimeric read pairs at the 5′ or 3′ ends of human ND4 showed only vector sequences without the flanking mouse sequences expected with homologous recombination of human ND4 with the murine ND4. Examination of mouse mitochondrial ND4 sequences for evidence of intra-molecular small-scale homologous recombination events yielded no significant stretches greater than three to four nucleotides attributable to human ND4. Furthermore, in no instance did human ND4 insert into other non-homologous sites of the 16 kb host mitochondrial DNA.

Our findings suggest that human ND4 remains episomal in host mitochondria and is not disruptive to any of the endogenous mitochondrial genes of the host genome. Therefore, mitochondrial gene transfer with an MTS-AAV is non-mutagenic and likely to be safe if used to treat Leber hereditary optic neuropathy patients with mutated ND4.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712668/

Telomeres are caps of repeating DNA sequences at the end of chromosomes. A little of their length is lost with each cell division, dropped in the process of copying the cell's genome. This acts as a clock in some types of cell population, those in which there is a lot of cell turnover and in which cells divide frequently to replace losses: shortening telomeres count down to the point at which the cell should self-destruct or at least stop dividing. The system is more complex than just a clock, however, as telomeres can be lengthened by the activity of the enzyme telomerase. When measuring average telomere length, or the proportion of very short telomeres in a cell population, you must also think about how much work is being done by stem cells: how often are the stem cells supporting a given tissue creating fresh new cells with comparatively lengthy telomeres?

In this system of dynamically lengthening and shortening telomeres, researchers have found that average telomere length - or the proportion of very short telomeres - in at least some tissues correlates moderately well with health and aging. Blood cells are those most often used for these measurements. If you are stressed or ill or damaged by aging then the proportion of short telomeres tends to be higher, and this can change on a short-term basis.

There is some debate over whether progressive shortening of telomeres over the years is one of the primary causes of aging or whether it is a secondary reaction to levels of cellular damage and other environmental factors. Even if it is a secondary reaction, it might still go on to cause further harm. Researchers have shown that mouse life span can be extended by boosting levels of telomerase, but there is still the question of whether this is happening because of lengthened telomeres, or because of some other effect of telomerase - such as the possibility that it might help protect mitochondria from damage, where mitochondrial damage is a much more convincing primary cause of aging. It is also worth noting that mouse telomere biology is quite different from that of humans.

What is needed in the process of obtaining more definitive answers is a way to globally lengthen telomeres without telomerase, and ideally without altering anything else in cells in the course of doing so - a challenging goal for any specific piece of cellular machinery, given the interconnected nature of cellular systems and the extensive reuse of proteins in multiple types of machinery. A way to repair forms of cellular damage thought to contribute to aging would also be useful: if rejuvenation therapies, once created, have the side-effect of lengthening telomeres then that will strongly suggests that telomere erosion is not a meaningful cause of aging. In the meanwhile, research results tend to reinforce interest in telomeres, but not add a great deal to the debate on whether age-related shortening is a cause or an effect.

Telomeres May Hold Clues To Effects Of Aging

KNOX: Ornish and his colleagues, including a scientist who won the Nobel Prize for her work with telomeres, studied two groups of older men. One didn't do anything special. The other adopted healthier habits that will sound familiar. Five years later, the telomeres of the men who did these things were different.

ORNISH: The more people changed their lifestyle, the more their telomeres got longer.

NIR BARZILAI: Certainly everybody in our field will agree that the telomere length is telling us something.

KNOX: But it's not clear what. And he says the new study doesn't answer that either.

BARZILAI: At the end of the day, this hasn't stopped any argument. You know? Either you're healthy, so you have longer telomeres. Or you have longer telomeres, and that's why you're healthy. You can pick and choose what you believe in and make an argument.

KNOX: Apart from this fundamental disagreement, there's something that troubles scientists. It's not only healthy cells that have longer telomeres - so do cancer cells. That may be what keeps them dividing out of control.

AUBREY DE GREY: My sense is that the cancer problem is a really, really big problem. The implicit hope is that cancer either will not be stimulated in the manner that many people think it will. Or else that even if it is, we'll find ways to get around cancer somehow.

Here is the paper that prompted the article quoted above:

Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study

This follow-up study compared ten men and 25 external controls who had biopsy-proven low-risk prostate cancer and had chosen to undergo active surveillance. Eligible participants were enrolled between 2003 and 2007 from previous studies and selected according to the same criteria. Men in the intervention group followed a programme of comprehensive lifestyle changes (diet, activity, stress management, and social support), and the men in the control group underwent active surveillance alone. We took blood samples at 5 years and compared relative telomere length and telomerase enzymatic activity per viable cell with those at baseline, and assessed their relation to the degree of lifestyle changes.

Relative telomere length increased from baseline [in] the lifestyle intervention group, but decreased in the control group. When data from the two groups were combined, adherence to lifestyle changes was significantly associated with relative telomere length after adjustment for age and the length of follow-up.

Here is an example to follow, an individual who decided to take the extra step beyond just reading about progress in longevity science and made a donation in support of ongoing research. I of course would prefer to see donations going to the SENS Research Foundation (SRF) rather than the older established laboratories such as the Buck Institute for Research on Aging, as to my eyes the work underway at the SRF is much more likely to lead to significant progress, but nonetheless taking the decision to materially support this field of research is important and should be encouraged.

"My name is Michelle and I'm from Wausau, WI (USA). I'm not a scientist, and I'm not very wealthy, but I'm in this group because I care about the future and curing aging. I want to be useful instead of just sitting at my computer chair reading articles on researchers trying to make us live longer and healthier lives. So I tried to talk to my family and friends, you know, to help raise awareness, but I was surprised that most of them didn't agree with me, and said they wanted to die. My entire extended family is Catholic (with me being the only Atheist in the family), and they all think they are going to go to heaven so there is no point in extending life. This made me quite sad, but then I realized there are other things I can do that will make a difference right now. There are a lot of researchers out there working hard on projects but lack funding. There are 4,661 members in this group. If each of us donated even just $10 a person, that would be over $46,000 we could give to help speed the research along, and achieve our common goal faster. I donated $20 to the Buck Institute. Will you join me and do the same? What do you think?"

Even if you are not particularly wealthy, that's alright, because every dollar counts in aging research. Michelle chose Buck Institute for Research on Aging, and there are other places where one can donate and make a huge difference for themselves and for the rest of the society, for example SENS Research Foundation, Institute for Aging Research at the Albert Einstein College of Medicine and other particular labs. There are also a couple of aging research-related crowd funding projects like the I am a little mouse and I want to live longer! campaign. So, be the change you wish to see in the world - donate to aging research.

Link: http://mariakonovalenko.wordpress.com/2013/09/16/we-should-all-follow-michelles-example/

Advanced glycation end-products (AGEs) build up in our tissues over time and cause a range of issues, such as by gluing together important proteins, or triggering abnormal cell behavior. This is one of the contributing causes of degenerative aging, in fact. Many different types of AGE exist, some of which are hardier and longer-lasting than others, and levels of the various types swing up and down to different degrees in response to diet and other circumstances. There is some debate over the degree to which dietary AGE intake is important versus the creation of AGEs through metabolic processes taking place within the body. Here at least researchers show that higher levels of AGEs in the diet of flies leads to shorter lives:

Advanced glycation end product (AGEs)-modified proteins are formed by the non-enzymatic glycation of free amino groups of proteins and along with lipofuscin (a highly oxidized aggregate of covalently cross-linked proteins, sugars and lipids) have been found to accumulate during ageing and in several age-related diseases.

As the in vivo effects of diet-derived AGEs or lipofuscin remain elusive, we sought to study the impact of oral administration of glucose (Glc)-, fructose (Frc)-, or ribose (Rib)-modified albumin or of artificial lipofuscin (LF) in a genetically tractable model organism.

We report herein that continuous feeding of young Drosophila flies with culture medium enriched in AGEs or in lipofuscin resulted in reduced locomotor performance, in accelerated rates of AGEs-modified proteins and carbonylated proteins accumulation in the somatic tissues and the haemolymph of flies, as well as in a significant reduction of flies healthspan and lifespan. These phenotypic effects were accompanied with reduced proteasome peptidase activities in both the haemolymph and in somatic tissues of flies and higher levels of oxidative stress and proteasome expression levels.

Finally, RNAi-mediated cathepsin D knockdown reduced flies longevity and significantly augmented the deleterious effects of AGEs and lipofuscin indicating that lysosomal cathepsins reduce the toxicity of diet-derived AGEs or lipofuscin. Our in vivo studies demonstrate that chronic ingestion of AGEs or lipofuscin disrupt proteostasis and accelerate the functional decline that occurs with normal ageing.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23999505

A recent survey on radical life extension reinforced a point that regular readers here know all too well: that most people are not all that interested in living longer, and their vision really doesn't extend to a future that looks all that much different from the present. It is a puzzle to watch generations live through decades of constant, dynamic change and technological progress, and yet think that twenty years ahead will look just like today. It is fortunate that we don't have to persuade more than a sizable minority to be able to raise sufficient funds for optimal progress towards rejuvenation therapies, as there's still a way to go to achieve even that end.

It is perfectly possible to find populations that are generally supportive of work on human rejuvenation and lengthening the healthy human life span, however. The transhumanist community is the obvious example, given that they put in much of the effort to launch the present generation of advocacy and rejuvenation research. But also you'll find a lot of support for longer lives through medical science in the engineering and software development fields: creating greater human longevity is an engineering problem, after all. It seems that the subset of economists who blog regularly are another such group, judging from this material:

Life Extension: Economists vs. the Public

Earlier this year, Pew surveyed Americans' beliefs about life extension. I was appalled by their nihilistic responses. Americans' awful answers made me wonder: Are economists any better? Tim Kane's latest survey of leading econ bloggers (PDF) has some answers.

As you can see, a supermajority of economists accepts the truism that longer, healthier lives are "a good thing for society." True, 10% of economists appear to be fans of death and misery. But by and large, ours is a life-affirming profession.

As usual, my fellow economists aren't perfect. How could any economically literate person deny that the "economy would be more productive"? The hypothetical specifically states that we don't just keep people alive longer; we actually "slow the aging process." Under what scenarios does the implied fall in the dependency ratio fail to raise living standards? I can think of a few, but none are plausible.

As usual, economists have much to learn. Yet compared to the U.S. public, economists once again prove themselves to be an island of common sense in a sea of misanthropic folly. I don't expect many of us will live to 120. But if will obviously be a glorious thing if we do. If I'm still alive in 2091, party at my house. Hope to see each and every one of you there, fit as fiddles!

The slow progress in adult life expectancy that has been the state of affairs for a lifetime is not a stable trend, not something that can be counted on to remain slow in the future. We are now entering a new period of research and development in the medical sciences, one very different from the immediate past. Prior to the present time, there was no initiative to extend life by addressing aging - all life extension was an incidental side-effect of the deployment of incrementally better medical technology. There will be an enormous difference in results between healthy life extension as an accident and healthy life extension as a deliberate outcome of research programs specifically designed with that goal in mind. This is the age of opportunity, an era in which enormous gains in human life span and rejuvenation of the old are there to be seized. Medicine over the next few decades will be anything but business as usual.

Metabolism is enormously complicated, even in very simple creatures such as nematode worms. So there are any number of ways in which genetic and other changes can confound the conventional wisdom, or produce results that run contrary to the well-established pattern. In this case the well-established pattern is that loss of DNA repair capabilities shortens life: a whole class of rare diseases that have the appearance of accelerated aging result from forms of DNA repair deficiency in humans.

Nonetheless, the particular loss of function mutation noted here manages to extend life in nematodes, possibly by spurring overcompensation in other forms of cellular housekeeping, despite the fact that it has most of the other expected effects in reducing viability of cells and the organism as a whole:

Human-nucleotide-excision repair (NER) deficiency leads to different developmental and segmental progeroid symptoms of which the pathogenesis is only partially understood. To understand the biological impact of accumulating spontaneous DNA damage, we studied the phenotypic consequences of DNA-repair deficiency in Caenorhabditis elegans.

We find that DNA damage accumulation does not decrease the adult life span of post-mitotic tissue. Surprisingly, loss of functional ERCC-1/XPF even further extends the life span of long-lived daf-2 mutants, likely through an adaptive activation of stress signaling.

Contrariwise, NER deficiency leads to a striking transgenerational decline in replicative capacity and viability of proliferating cells. DNA damage accumulation induces severe, stochastic impairment of development and growth, which is most pronounced in NER mutants that are also impaired in their response to ionizing radiation and inter-strand crosslinks. These results suggest that multiple DNA-repair pathways can protect against replicative decline and indicate that there might be a direct link between the severity of symptoms and the level of DNA-repair deficiency in patients.

You might consider this in the context of the debate over whether nuclear DNA damage is actually relevant to aging over the course of a human life span, or whether it only contributes to cancer risk.

Link: http://dx.doi.org/10.1038/cdd.2013.126

One of the hurdles in the way of better understanding the root causes of aging is that it is extremely challenging to change any one piece of cellular machinery in isolation. Evolution has produced structures and processes that promiscuously reuse one another's building blocks, so alter a gene or add a protein and it will affect all sorts of different mechanisms inside the cell, which will in turn cascade to cause further changes.

In the case of telomeres there is some debate over whether the diminished telomere length associated with aging and ill health is a primary cause of aging or a secondary effect. Using telomerase to lengthen telomeres extends life in mice, but telomerase has other effects as well. Average telomere length can vary up and down over the short term in any given tissue in the body, and these telomere dynamics are quite different in different species.

The ways forward towards a better understanding of the role of telomere length in aging include implementing rejuvenation biotechnologies such as SENS to see what the effects are on telomere length, or finding ways to extend telomeres without producing any other changes in a cell:

It is well known in the scientific community that telomeres shorten every time a cell divides and eventually become so short that they can no longer protect the chromosomes. The unprotected chromosome ends send signals that stop the cell from dividing further, a state referred to as "senescence". Senescent cells occur more frequently as we age, which can contribute to tissue loss and organ failure.

[Researchers have] now discovered that turning transcription on or off at telomeres can have drastic effects on their length. Transcription is the process of making an RNA molecule from DNA. It has only recently been shown to occur at telomeres, but the functional significance of this discovery has remained a mystery. Molecular biologists [were] now able to show that the RNA itself is the key regulator that drives telomere length changes, especially when it sticks to telomeric DNA to make a so-called "RNA-DNA hybrid molecule".

"We experimentally changed the amount of RNA-DNA hybrids at the chromosome ends. We can thus either accelerate or diminish the rate of cellular senescence directly by affecting telomere length." This could be a first step towards telomere-based therapies for tissue loss or organ failure. With respect to diseases, it remains to be determined whether altering transcription rates at telomeres does indeed improve health status. This approach is also significant for cancer cells, which do not senesce and are thus considered immortal. "Transcription-based telomere length control may therefore also be applicable to cancer treatment."

Link: http://www.sciencedaily.com/releases/2013/09/130911092915.htm

The sixth SENS conference took place last week, and like the 2011 SENS5 was a fairly quiet event from the point of view of online media. The SENS conferences focus on the foundations of rejuvenation biotechnology outlined in the Strategies for Engineered Negligible Senescence (SENS) research plans, but a lot of other research is presented, not all of which is directly relevant to building the means to rejuvenate old humans. The public isn't really the immediate audience for these conferences: it's part and parcel of the SENS Research Foundation's continuing and successful efforts to build support and networks of allied researchers within the aging research community.

Once the spark takes hold, the need for the SENS Research Foundation will fade as many other organizations will arise to raise funding and perform similar work on the foundation technologies needed for future human rejuvenation therapies. That process is still underway at a comparatively early stage yet despite the tremendous successes in advocacy that have taken place over the past decade - it's the old story, working hard to open the door for the next round of working hard some more. Climb the hill to get to the mountain. Conference series like SENS are one of the more visible signs of all of this work.

You can take a look at the abstracts archive for SENS6 to see a selection of the topics that were on the program this year. Videos of the presentations from SENS5 in 2011 emerged online over the course of 2012. With luck that will be a faster process this year. Most are interesting and well worth the time taken to view.

In any case, despite the many scientists present and much networking taking place, SENS6 like SENS5 was a quiet conference with little of an online footprint while underway. Here is the only set of notes from SENS6 I've seen emerge from the folk who were present:

Strategies for Engineering Negligible Senescence - Report from SENS-6

Aubrey de Grey has rallied the world's scientific community and its funders to attack the biological basis of aging, which underlies the majority of disease and suffering in the developed world. Since 2003, he has organized bi-annual conferences, bringing together innovative biologists, medical researchers and a few policy wonks to share knowledge and perspectives, to coordinate and support each others' efforts. Below I report highlights from this year's meeting, SENS 6, which I attended last week at Queens College, Cambridge.

Exercise vs Caloric Restriction

For the last ten yeas, Luigi Fontana of Washington University St Louis has been conducting an ongoing study of two groups of people who exercise fanatically (by middle-class US standards) and who seriously restrict their food intake (same standard). Both groups have dramatically improved biomarkers compared to the average American couch potato.

DRACO - kills all virus-infected cells

Todd Rider of MIT is quietly witty on-stage and charmingly self-effacing, but his program is radically ambitious. He wants to cure all infectious disease. DRACO is an acronym for Double-stranded RNA-Activated Caspase Oligomizer. The bottom line is that DRACO molecules can find cells that are infected with any virus, distinguish them from uninfected cells, and selectively signal the cell to destroy itself. It's been tested in test tubes and in mice it cures, for example, the flu. Rider's lab is producing only tiny quantities of DRACO at present, but by year's end he hopes to ramp up production for much wider testing.

Growing a liver on a lymph node

Eric Lagasse [has] had success growing new livers from stem cells in the patient's body. Liver progenitor cells are implanted in a lymph node, which seems to provide a favorable environment for growth. In mouse models, 70% are able to grow a functional liver "ectopically", meaning in a part of the body where it does not belong.

Adult life expectancy is a little more interesting than life expectancy at birth as a measure of modern medical progress towards healthy life extension. Much of the innovation now is in ways to treat age-related conditions rather than in ways to reduce childhood mortality and control the more obvious infectious diseases. Removing childhood from the picture when considering the data narrows the focus to the effectiveness of medical technologies deployed in later life.

Here is a recent study that measures gains obtained in the past couple of decades, none of which is really due to any attempt to deliberately extend human life or tackle aging. Progress here stems from the deployment of incrementally better medical technology across the board. Once the research community begins to address aging in earnest, I'd expect the pace of growth in life expectancy to accelerate considerably - especially if the better path of SENS, rejuvenation, and repair of cellular damage is chosen over efforts to slow aging via metabolic manipulation.

Thanks to medical advances, better treatments and new drugs not available a generation ago, the average American born today can expect to live 3.8 years longer than a person born two decades ago. Despite all these new technologies, however, is our increased life expectancy actually adding active and healthy years to our lives? That question has remained largely unanswered - until now. In a first-of-its-kind study, [researchers] have found that the average 25-year-old American today can look forward to 2.4 more years of a healthy life than 20 years ago while a 65-year-old today has gained 1.7 years.

Synthesizing data from multiple government-sponsored health surveys conducted over the last 21 years [researchers] were able, for the first time, to measure how the quality-adjusted life expectancy (QALE) of all Americans has changed over time. The data shows that Americans are living longer, reporting fewer symptoms of disease, have more energy and show fewer impairment in everyday tasks such as walking than a generation ago. According to the study authors, a 25-year-old person today can expect to live 6 percent or 2.4 quality years longer than their 1987 counterpart.

Bear in mind that life expectancy is effectively a measure of what would happen if all change and progress was frozen where it is today. It measures past progress, not future outcomes. We are in the midst of a revolutionary period of change and acceleration in biotechnology and medicine, comparatively little of which has yet percolated into available medical technologies. So adjust your expectations for the future accordingly.

Link: http://www.eurekalert.org/pub_releases/2013-09/uomm-all091213.php

Large scale research requires widespread support to raise the necessary funds and gather a sizable scientific community, and this is just as true of work on human rejuvenation as anything else. When it comes to the persuasion needed to gain that support, there is some debate over whether the incremental softly-softly approach of advocacy for a living a little longer and tackling age-related disease is better or worse than talking about the end goals of agelessness and radical life extension of centuries or more of health and vigor. Here are comments from someone more in favor of toning down the rhetoric:

One of the biggest challenges we face as transhumanists, is conveying our philosophy to the uninitiated in a manner that is successful and productive. For the purpose of this article, I will be speaking of cryonics and transhumanism in the same context. Cryonics really isn't a separate idea, but in my view, a tool in the transhuman ordinance to attain one of its most fundamental goals, which is radical life extension. Essentially it is a Plan B.

I have advocated for cryonics for 17 years. In that time I have encountered very few people who on first glance, found it to be something they could imagine for themselves. Very recently, I have devoted much time to the study of transhumanism, and have found the same barriers. People don't tend to like what we have to offer. I have struggled for a long time to come to terms with this fact, and have spent a great deal of energy trying to understand why.

One of the first things I feel we are doing wrong is speaking to the public about immortality. We are jumping to the end of the story, and expecting others to buy it without ever having learned about all of the other steps. Immortality is an unrealistic expectation that makes us sound like fundamentalist zealots. We can never prove to be immortal, no matter how long we live, so why come out of the gate running with it? It's not the right approach to take with the Everyman and seems to be a poor sales tactic. I think that simply going with the concept of extending one's life - for a decade or a century - seems to be an easier concept to sell. Let's worry about immortality later.

Link: http://ieet.org/index.php/IEET/more/gaspar20130911

Aging is near universal most likely because it provides considerable evolutionary advantages: aging species are more likely to survive changes in their environment, despite the fact that aging is a tremendous disadvantage from the perspective of the individual. The world changes, and so we and near all of our ancestors age and suffer. I did say near universal, however. The more primitive the types of organism surveyed, the more likely it is that you will see signs of agelessness: a few species of creature that, given sufficient peace, quiet, and nutrients, can repair themselves indefinitely.

Hydra may fall into this category, for example. When a species doesn't have a brain or any sort of very complex organ and configuration that is essential to the self, then aggressive regeneration is a viable strategy. That apparently stops being the case as complexity increases: there is some point at which evolution selects for a loss of regeneration in favor of ever more complicated structures. As a species we are a long, long way past that point. The most complex species capable of feats of complete regeneration of organs and limbs are small animals such as salamanders and zebrafish, and even they are nowhere near as good at it as the hydra.

Looking further down the tree of life, it was thought at one time that bacteria do not age. They do age, however, a fact uncovered not so very many years ago. Aging in bacteria is a matter of accumulating damaged materials and waste products, and the various strategies by which breakage and waste can be removed or diluted. Because the situation is comparatively simple it is possible for bacteria to stay ahead of aging just by dividing fast enough:

A microbe's trick for staying young

The team has shown that, unlike other species, the yeast microbe called S. pombe, is immune to aging when it is reproducing and under favourable growth conditions.

In general, even symmetrically diving microbes, do not split into two exactly identical halves. Detailed investigations revealed that there are mechanism in place that ensure that one half gets older, often defective, cell material, whereas the other half is equipped with new fully-functional material. So like humans microbes, in a sense, produce offspring that is younger than the parent.

But aging is not inevitable for the common yeast, S.pombe. The newly-published work shows that this microbe is immune to aging under certain conditions. When the yeast is treated well, it reproduces by splitting into two halves that both inherit their fair share of old cell material. "However, as both cells get only half of the damaged material, they are both younger than before". At least in a sense, the yeast is rejuvenated a bit, every time it reproduces.

We should not be surprised to see rejuvenation in practice in nature. All species are capable of rejuvenation: it's how old parents produce young children. Somewhere in that process is a step in which a lot of cleaning and repair takes place, prior to the point at which the embryo is too complex to support the necessary aggressive rejuvenation programs. If those same programs were turned on in an adult, the result probably wouldn't all that pretty. Lower species like hydra can get away with constant regeneration because it doesn't greatly inconvenience them to throw away or rebuild an entire section of an individual's body. We are only in that same boat for the very earliest period following conception.

Here's the scientific paper for the research mentioned above:

Fission Yeast Does Not Age under Favorable Conditions, but Does So after Stress

Many unicellular organisms age: as time passes, they divide more slowly and ultimately die. In budding yeast, asymmetric segregation of cellular damage results in aging mother cells and rejuvenated daughters. We hypothesize that the organisms in which this asymmetry is lacking, or can be modulated, may not undergo aging. We conclude that S. pombe does not age under favorable growth conditions, but does so under stress. This transition appears to be passive rather than active and results from the formation of a single large aggregate, which segregates asymmetrically at the subsequent cell division. We argue that this damage-induced asymmetric segregation has evolved to sacrifice some cells so that others may survive unscathed after severe environmental stresses.

This sort of research provides some insight into the very early evolutionary origins of degenerative aging, and as such it is interesting to follow even though there is nothing here that will greatly affect the course of programs aimed at producing human rejuvenation.

In the course of improving health and extending life - to a lesser degree in long-lived species, unfortunately - the practice of calorie restriction produces sweeping changes in near every aspect of metabolism. The deeper you look the more there is to find. Here is one of many examples:

Age-related alterations in the composition of skeletal muscle are linked to functional limitations, disability and metabolic disorders. Alterations in muscle damage and repair during aging can have deleterious consequences that lead to muscle degeneration and inflammation; most of the age-related declines in muscle homeostasis and function can be prevented by caloric restriction (CR) in laboratory animals. Changes in gene expression critically govern the age-related alterations in muscle mass and function.

MicroRNAs (miRNAs) regulate gene expression by recruiting the RNA‐induced silencing complex (RISC) to a target messenger RNA with which it shares partial complementarity, causing a reduction in the stability of the messenger RNA and/or its rate of translation. The relevance of miRNAs in disease development, muscle aging, and progression and prognosis of skeletal muscle diseases is not fully understood.

The profiling of miRNAs in aged tissues can provide direct links between aging, age-dependent regulation of miRNA abundance, and the involvement of miRNAs in normal aging and age-related diseases. In this study, changes in miRNAs in skeletal muscle from rhesus monkeys of different ages were assessed using RNA sequencing. Our results showed clear differences in muscle miRNA levels when comparing old and young animals, and that CR influences these age-induced changes in miRNA expression. Novel miRNAs were also identified in muscle of old and young rhesus monkeys, which could potentially be expressed in human skeletal muscle. Together, our study provides further support for the role of miRNAs in skeletal muscle aging and reveals the impact of CR on miRNA expression.

Link: http://www.impactaging.com/papers/v5/n9/full/100598.html

A European and Russian group of researchers are attempting to crowdfund a modest amount for a short-term mouse life span study, using mice that are already old to see if various compounds have much of an effect on slowing aging in old mice. This sort of study design has the advantage of being comparatively cheap as it only runs for half a year or so:

Life is precious. Health too. This is why communities of researchers and citizens dedicate our lives to discover new ways to gain additional years of healthy life. As research progresses, more and more compounds are believed to be good to maintain health over long periods of time. But wouldn't that take decades of clinical trials to verify it? A key step is to do such a clinical trial... in mice : that is what we call a mouse lifespan test. Mouse lifespan tests are infrequent because of their length, their costs and the required environments; but it is crucially needed to continue adding years of healthy life.

Here, we step on the shoulders of giants : by contributing you can help us test a combination of drugs shown to extend healthy lifespan in mice. This experiment has something unique. It is the first time in the world that crowdfunding is used to test a combination of the most potent nongenetic-interventions known to extend the lifespan.

There are *right now* in the lab a sufficient number of aged mice (~20 months old) - male and female - which belong to the C57BL/6 strain to start a lifespan test. The mice will be divided into 2 test groups (females and males) and 2 control groups (24 animals per each group). The test will be blind. The food of the treated mice will contain: 1) An α-adrenergetic receptor blocker (metoprolol). Potential action: Prevents too fast heart beats. 2) An mTOR inhibitor (everolimus, similar action as rapamycin). Potential action: Puts cells in an active and resistant mode. 3) Metformin. Potential action: Normalizes blood and IGF-1 values at low levels. It also has potential similarities with everolimus. 4) Simvastatin. Action: Decreases the amount of LDL cholesterol (considered as 'bad' by some) in the blood. 5) Ramipril: an ACE inhibitor. Action: Prevents hypertension. 6) Aspirin. When small doses are used, it is believed to have reduced side effects while improving blood flow and therefore reducing cardiovascular risks, and potentially also preventing incidence of some cancers.

Link: http://www.indiegogo.com/projects/i-am-a-little-mouse-and-i-want-to-live-longer/

Research into sirtuins comprised the bulk of the last decade's wave of interest and funding for calorie restriction research. Sirtuin levels were found to be associated with the metabolic alterations produced by calorie restriction quite early on, and so scientists proceeded from there to work with compounds known to alter sirtuin levels in the body. Numerous research groups aimed to produce a drug candidate to recapitulate at least some of the benefits to health and longevity produced through the practice of calorie restriction. As is often the case, nothing of any great practical value has resulted for these years of work and probably in excess of a billion dollars in funding, through a lot more is known of the metabolism and genetics of calorie restriction as a result.

So sirtuins look like something of a dead end at the current point in time, or at least a place where more years of work are required to understand why early promise didn't carry through into mammals. Nonethless, sirtuin research continues apace with ambiguous results: some signs of life extension and improved long-term health in laboratory animals such as flies, but nothing that is reliably shown to extend life in mammals. There remain many optimists in the research community, people who think that there is some useful therapy in the future of sirtuin studies. Better and brighter drug candidates for slowing aging are emerging nowadays, however, such as rapamycin and similar items, and I would expect that interest and funding will tend to migrate to fields in which there are more reliable signs of extension of healthy life in mammals.

That said, we shouldn't expect anything better than the past decade of sirtuin and resveratrol research to emerge from present studies of mTOR and rapamycin. Trying to build drugs to slightly slow aging is inherently hard, and yet will produce only marginal therapies even if successful. The researchers who take this path do so because they don't believe that repair based strategies such as SENS are in actual fact a much more efficient path towards extending healthy life and eliminating the diseases of aging. I think that they are wrong in that view, of course.

A recently published edition of Methods in Molecular Biology is entitled "Sirtuins," and contains more than most of us ever wanted or needed to know about the nuts and bolts of sirtuin research. Obviously it is to a large extent written by sirtuin optimists:

Introduction: Sirtuins in Aging and Diseases

Over the past 15 years, the number of papers published on sirtuins has exploded. The initial link between sirtuins and aging comes from studies in yeast, in which it was shown that the life span of yeast mother cells (replicative aging) was proportional to the SIR2 gene dosage. Subsequent studies have shown that SIR2 homologs also slow aging in C. elegans, Drosophila, and mice. An important insight into the function of sirtuins came from the finding that yeast Sir2p and mammalian SIRT1 are NAD+-dependent protein deacetylases. In mammals, there are seven sirtuins (SIRT1-7). Their functions do not appear to be redundant, in part because three are primarily nuclear (SIRT1, 6, and 7), three are mitochondrial (SIRT3, 4, and 5), and one is cytoplasmic (SIRT2). The past decade has provided an avalanche of data showing deacetylation of many key transcription factors. In this chapter, I will address the evidence that sirtuins mediate the effects of CR on physiology and will then turn to the evidence of a relationship between sirtuins and aging and life span. Finally, I will discuss the roles of sirtuins in diseases of aging and the prospects of translating these findings to novel therapeutic strategies to treat major diseases.

The Emerging Links Between Sirtuins and Autophagy

Evidence suggests a role for acetylation and deacetylation in regulating autophagy. In this chapter, we describe the methods useful for understanding this important connection. In particular, we discuss methods for the measurements of sirtuin deacetylase activity, in vivo acetylation detection, and the common assays used to monitor both autophagy and the more selective process of mitophagy.

Utilizing Calorie Restriction to Evaluate the Role of Sirtuins in Healthspan and Lifespan of Mice

Calorie restriction is the most powerful method currently known to delay aging-associated disease and extend lifespan. Use of this technique in combination with genetic models has led to identification of key metabolic regulators of lifespan. Limiting energy availability by restricting caloric intake leads to redistribution of energy expenditure and storage. The signaling required for these metabolic changes is mediated in part by the sirtuins at both the posttranslational and transcriptional levels, and consequently, sirtuins are recognized as instigating factors in the regulation of lifespan.

This family of class III protein deacetylases is responsible for directing energy regulation based on NAD+ availability. However, there are many effectors of NAD+ availability, and hence sirtuin action, that should be considered when performing experiments using calorie restriction. The methods outlined in this chapter are intended to provide a guide to help the aging community to use and interpret experimental calorie restriction properly. The importance of healthspan and the use of repeated measures to assess metabolic health during lifespan experiments are strongly emphasized.

Unlike the case ten to fifteen years ago, it is now mainstream and acceptable within the research community to talk openly about slowing aging. That is half of a very necessary change that has to take place in order to speed work on extending healthy human life. The other half is for the scientific community to move their focus and the public discussion from merely slowing aging to the aim of actual rejuvenation of the old and an acknowledgement that maximum human life span will grow greatly. That is still a work in progress, and researchers remain reluctant to talk about radical life extension. But talk they must if there is to be a good change of raising large-scale funding and creating dedicated research programs at scale to achieve this goal. Large-scale research only comes into being in an environment of widespread public support and understanding.

Here is an article that wouldn't have existed in the late 1990s, because the people in higher level positions in a noted research institute would not have openly talked about slowing human aging, for fear of a negative impact on their fundraising:

The University of Florida's Institute on Aging is dedicated to research on slowing or reversing certain aging processes that can sour the golden years. The institute itself started eight years ago and has expanded to include more research on cognitive decline and not just physical decline related to aging. "If we can slow the process (of aging) it will be a great success ... and expand active life expectancy," said Marco Pahor, the institute's director, at its fourth annual research day. Pahor added that much of the institute's research focuses on compressing the "disabled years" in which people often live with chronic inactivity and pain - conditions that are both physically unpleasant and costly. "This is a major burden on the health care system. So far most of the interventions are reactive. But we want to prevent physical and cognitive decline," just as there have been successful preventive measures for cancer and heart disease.

Roger Fillingim, a professor at the UF College of Dentistry and director of UF's newly formed Pain Research and Intervention Center of Excellence (PRICE), spoke about the prevalence of pain among the elderly. About 100 million people in the U.S. suffer from pain, which costs the health care system about $635 billion annually, Fillingim said, citing Institute of Medicine data. That's more than the expenditures for cancer, AIDS and heart disease combined. "Our goal is to reduce pain-related suffering with cutting-edge research. Pain is a major public health issue so we need all the help we can get."

Link: http://www.gainesville.com/article/20130909/ARTICLES/130909561/-1/news?p=all&tc=ar

The membrane pacemaker hypothesis suggests that the composition of cell membranes - such as those that wrap mitochondria - is an important determinant of species longevity because of consequent differences in resistance to oxidative damage. Here researchers find correlations between membrane composition and longevity within one species, but not for the same reasons:

Various compositions of fatty acids can produce cell membranes with disparate fluidity and propensity for oxidation. The latter characteristic, which can be evaluated via the peroxidation index (PI), has a fundamental role in the development of the "membrane-pacemaker theory" of aging. This study tried to evaluate differences between the membrane phospholipid fatty acid (PLFA) profile of longevity-selected (L) and corresponding control (C) lines of Drosophila melanogaster with age (3, 9, 14 and 19 days) and its consequences on phase transition temperature as a function of membrane fluidity.

Despite an equal proportion of polyunsaturated fatty acids, PI and double bond index over all ages in both experimental groups, monounsaturated fatty acids showed significant variation with advancement of age in both L and C lines. A significant age-associated elevation of the unsaturation vs. saturation index in parallel with a gradual reduction of the mean melting point was observed in longevous flies. PLFA composition of the L vs. C lines revealed a dissimilarity in 3-day old samples.

The findings of this study are not in agreement with the principle of the "membrane pacemaker theory" linking PI and longevity. However, the physiochemical properties of PLFAs in longevity lines may retard the cells' senescence by maintaining optimal membrane functionality over time. Identical susceptibility to peroxidation of both types of lines underlines the involvement of other mechanisms in protecting the bio-membrane against oxidation, such as the reduced production of mitochondrial reactive oxygen species or improvement of the antioxidant defense system in longer-lived phenotypes. Concurrent assessments of these mechanisms in relation to cell membrane PLFA composition may clarify the cellular basis of lifespan in this species.

Link: http://www.ncbi.nlm.nih.gov/pubmed/24012994

Like calorie restriction, regular exercise can reduce mortality and extend healthy life in laboratory animal populations. Unlike calorie restriction, it doesn't appear to extend maximum life span, but rather raises the average and lowers the incidence of age-related disease in study groups. It is hard to prove cause and effect in human life span studies, which instead use statistical methods to discover associations. Exercise is certainly associated with greater average human longevity, perhaps two to ten years at most, but again not with greater maximum life span. Despite the difficulties inherent in examining life span in your own species, it is far easier to obtain data on exercise in human populations: many more people exercise than practice calorie restriction, and many long-running studies have gathered exercise data over past decades, beginning long before the modern resurgence of interest in calorie restriction research. So if you go looking you'll find many more studies on the associations between exercise and life expectancy than exist for calorie restriction.

In contrast to the situation for epidemiological studies, there is far more work taking place on the molecular biology of calorie restriction than on the molecular biology of exercise: epigenetics, gene expression, alterations in signaling pathways, and so forth. Perhaps the most obvious measure of this state of affairs is that there are no looming drug candidates touted as exercise mimetics, akin to the several strong candidate calorie restriction mimetic compounds. I expect that parity here is just a matter of time, however. Research into the mechanisms and metabolic alterations by which exercise improves health and life expectancy will in due course catch up to the present level of interest in calorie restriction.

Now as I've said in the past, if it wasn't the case that near all of us can obtain all the benefits of exercise and calorie restriction for free, I'd ascribe more value to all of this research. As it is, I think the greatest benefit will be knowledge: greater knowledge of metabolism and the details of the progression of aging. But in comparison to the possibilities offered by rejuvenation research strategies such as SENS, the development of exercise or calorie restriction mimetic drugs is a dead end of little potential. It'll swallow up time and money and there will be very little to show for it at the end of the day, when we're all old and frail and needing something far more effective than a drug that just slightly slows down the aging process.

Here are some recent papers from the exercise research community: one epidemiological, the other a look at some of the possibly detrimental effects of antioxidants on exercise:

150 minutes of vigorous physical activity per week predicts survival and successful ageing: a population-based 11-year longitudinal study of 12 201 older Australian men

Physical activity has been associated with improved survival, but it is unclear whether this increase in longevity is accompanied by preserved mental and physical functioning, also known as healthy ageing. We designed this study to determine whether physical activity is associated with healthy ageing in later life.

We recruited a community-representative sample of 12,201 men aged 65-83 years and followed them for 10-13 years. We assessed physical activity at the beginning and the end of the follow-up period. Participants who reported 150 min or more of vigorous physical activity per week were considered physically active. We monitored survival during the follow-up period and, at study exit, assessed the mood, cognition and functional status of survivors. Cox regression and general linear models were used to estimate hazard rate (HR) of death and risk ratio (RR) of healthy ageing. Analyses were adjusted for age, education, marital status, smoking, body mass index and history of hypertension, diabetes, coronary heart disease and stroke.

Two thousand and fifty-eight (16.9%) participants were physically active at study entry. Active men had lower HR of death over 10-13 years than physically inactive men (HR=0.74). Among survivors, completion of the follow-up assessment was higher in the physically active than inactive group (RR=1.18). Physically active men had greater chance of fulfilling criteria for healthy ageing than inactive men (RR=1.35). Men who were physically active at the baseline and follow-up assessments had the highest chance of healthy ageing compared with inactive men (RR=1.59).

Sustained physical activity is associated with improved survival and healthy ageing in older men. Vigorous physical activity seems to promote healthy ageing and should be encouraged when safe and feasible.

Trade-offs between Anti-aging Dietary Supplementation and Exercise

In otherwise healthy adults, moderate aerobic exercise extends lifespan and likely healthspan by 2-6 years. Exercise improves blood sugar regulation, and resistance exercise increases or maintains muscle mass, and is associated with improved cognitive function. On the other hand, evidence for antioxidant supplements increasing longevity in humans is lacking. On the contrary, transient hormetic increases in ROS, for example associated with exercise, are actually associated with increased mammalian healthspan and lifespan.

Recent studies in humans suggest that antioxidants such as vitamins C, E , resveratrol, and acetyl-N-cysteine blunt the beneficial effects of exercise on glucose sensitivity and blood sugar regulation, likely through direct inhibition of ROS signaling. Together these results suggest that there are significant tradeoffs in the use of dietary supplementation for prevention and treatment of diseases associated with aging. Such tradeoffs may result from underlying intertwined homeostatic mechanisms. For most individuals, moderate exercise is of significant benefit.

Much of the future of medicine will involve altering the mix of protein machinery and signals that drive our metabolism, instructing cells to take specific actions, and delivering new protein machines that can perform tasks that our existing biology cannot, such as clearing out otherwise resistant metabolic waste products. The current model in medicine is for the work of mixing up the necessary new materials to take place outside the body, which are then delivered in the form of infusions, injections, pills, and so on. In the future, we will probably see the creation of therapeutics move inside the body, in the form of increasingly sophisticated, reactive, and programmable implanted medical factories.

The work noted here is an early step in this direction: a single-function implant that alters the behavior of immune cells on an ongoing basis, an alternative to periodically drawing cells from a patient, altering them in culture, and then returning them to the body.

A cross-disciplinary team of scientists, engineers, and clinicians announced today that they have begun a Phase I clinical trial of an implantable vaccine to treat melanoma, the most lethal form of skin cancer. Most therapeutic cancer vaccines available today require doctors to first remove the patient's immune cells from the body, then reprogram them and reintroduce them back into the body. The new approach, which was first reported to eliminate tumors in mice [in 2009], instead uses a small disk-like sponge about the size of a fingernail that is made from FDA-approved polymers. The sponge is implanted under the skin, and is designed to recruit and reprogram a patient's own immune cells "on site," instructing them to travel through the body, home in on cancer cells, then kill them.

The technology was initially designed to target cancerous melanoma in skin, but might have application to other cancers. In the preclinical [study], 50 percent of mice treated with two doses of the vaccine - mice that would have otherwise died from melanoma within about 25 days - showed complete tumor regression.

Link: http://www.sciencedaily.com/releases/2013/09/130906141833.htm

This is a line of research that will come to be increasingly important as it new technologies make it ever easier and more cost effective to both identify specific components of the protein machinery of biology and manufacture replacements or augmented alternative versions. It is not just important for genetic diseases, in which specific proteins are missing or malformed, but also in patching over the changes of aging and enhancing the human body to better resist aging:

"Artificial limbs replace the function of an arm or leg that's missing due to injury. Some diseases occur because proteins in the body are missing or not working properly. Molecular prosthetics envisions treating those diseases with medicines that replace the functions of the missing proteins."

[Researchers] described advances to simplify and speed up the synthesis of the small molecules needed for molecular prosthetics. More than 90 percent of today's medicines use active ingredients that are small molecules. These substances can be processed into tablets and capsules and taken by mouth. They can dissolve in the gastrointestinal tract, go into the blood and travel to and work in almost every part of the body. The rest of today's medicines are large molecules or "biologics" that like insulin cannot be taken by mouth.

"For molecular prosthetics to become a reality, we must overcome two major challenges. First, it can take months or even years to synthesize just one molecule. With our new platform, we could reduce that to a few days. The second challenge is to fundamentally understand the capacity for small molecules to operate like proteins in the context of living systems. That understanding is critical to being able to design the most effective molecules."

Amphotericin B, currently used to treat fungal infections, [inserts] itself into the membrane that surrounds and encloses cells in the body. Once in the membrane, amphotericin B forms channels that enable the transport of ions into and out of the cell, an activity that mirrors many proteins whose function is critical in health and disease. A whole group of human diseases, sometimes called channelopathies, result from malfunction of ion channel proteins. Among them: migraine, epilepsy and cystic fibrosis. The team is working to use amphotericin B as a basis for making small molecules that replace the missing or malfunctioning ion channel proteins and thereby treat these diseases.

"We realized early in our studies that the lack of efficiency and flexibility with which small molecules can be prepared in the lab represented a major bottleneck in our efforts to develop small molecules with protein-like functions. We are now excited to find that our new synthesis platform can help relieve this important bottleneck and thereby enable us to focus more of our time on the key functional studies. Drug companies also have this problem with the long timelines needed to synthesize small molecules. That's part of the reason why it takes so long to develop new medicines. This is a broad problem, and our goal is to help speed up this process and thereby have an important impact on science and medicine."

Link: http://www.eurekalert.org/pub_releases/2013-09/acs-ttd081213.php

A great deal of time and money in the aging research community is invested into gaining a full understanding of the mechanisms of calorie restriction: how exactly it extends life in most species and improves health. This is still a small field in comparison to the broader life sciences or medical research in general, of course. Nonetheless it is probably the case that billions of dollars have gone into these efforts in the past couple of decades, with the goal being the development of calorie restriction mimetic drugs, some way to safely and reliably replicate the benefits of calorie restriction without the dieting. So far a lot of new knowledge of metabolism and little of practical value has emerged, but that's the way that research goes - if it was certain to produce a given set of results, then it wouldn't be research.

I, and others, think that this is a sideshow, and there are far better lines of research that are far more likely to result in meaningful extension of human life, and at a lesser cost in time and money. Change on that front is slow in coming, however.

Calorie restriction has large health benefits: along with exercise, it produces effects in basically healthy people that far outweigh those of any presently widely available medical technology. So if it wasn't already the case that a person can obtain all of those benefits just by, you know, restricting calories, I'd probably be more in favor of work focused on calorie restriction mimetics and metabolic manipulation. But you can obtain the benefits just through a modicum of willpower and planning, and while significant in the scheme of what can be done today, this is a tiny, tiny set of benefits in comparison to what billions of dollars of research into the basis for human rejuvenation should attain. You can't diet your way to living to 100 with any great chance of success, but future medical technology will achieve that end and more - just not by replicating the beneficial effects of dieting.

Here are a couple of open access papers typical of the sort of work presently taking place on the genes and proteins known to be associated with calorie restriction:

Deletion of microRNA-80 Activates Dietary Restriction to Extend C. elegans Healthspan and Lifespan

Dietary restriction, limitation of calorie intake with maintained vitamin and mineral support, can extend lifespan and protect against diseases of age across many species. Elaboration of molecular mechanisms that control dietary restriction in simple animal models may therefore inform on strategies to activate health-promoting metabolism to help address clinical challenges associated with aging and age-associated disease.

We characterize a single Caenorhabditis elegans microRNA gene that keeps dietary restriction programs off when food is abundant. A mir-80 deletion exhibits beneficial features of dietary restriction regardless of food availability, including extended maintenance of mobility and cardiac-like muscle function later into life as well as lifespan extension. We identify three key longevity genes that are required for these benefits. We hypothesize that miR-80 is a core regulator by which diverse and intersecting metabolic pathways are coordinately regulated to respond to nutrient availability.

Increased expression of Drosophila Sir2 extends life span in a dose-dependent manner

Sir2, a member of the sirtuin family of protein dacetylases, deacetylates lysine residues within many proteins and is associated with lifespan extension in a variety of model organisms. Recent studies have questioned the positive effects of Sir2 on lifespan in Drosophila. Several studies have shown that increased expression of the Drosophila Sir2 homolog (dSir2) extends life span while other studies have reported no effect on life span or suggested that increased dSir2 expression was cytotoxic.

To attempt to reconcile the differences in these observed effects of dSir2 on Drosophila life span, we hypothesized that a critical level of dSir2 may be necessary to mediate life span extension. Using approaches that allow us to titrate dSir2 expression, we describe here a strong dose-dependent effect of dSir2 on life span. Using the two transgenic dSir2 lines that were reported not to extend life span, we are able to show significant life span extension when dSir2 expression is induced between 2 and 5-fold. However, higher levels decrease life span and can induce cellular toxicity. [Our] results help to resolve the apparently conflicting reports by demonstrating that the effects of increased dSir2 expression on life span in Drosophila are dependent upon dSir2 dosage.

Some of the cells in the body are never replaced across a life span, which leads to forms of system failure and degeneration due to accumulating damage and metabolic waste products not found elsewhere. Interestingly it appears that some of the individual proteins within those cells might not be replaced either. It is unclear as to how much of a long-term challenge that will present once researchers are past the first hurdles in extending healthy human life.

Among these long-lived proteins are those that form nuclear pores, a structure that appears to become damaged in old cells in the nervous system and may contribute to age-related degeneration. Here researchers further investigate, finding that the situation is not as static as first thought:

Most proteins live only two days or less, ensuring that those damaged by inevitable chemical modifications are replaced with new functional copies. [Researchers] have now identified a small subset of proteins in the brain that persist for longer, even more than a year, without being replaced. These long-lived proteins have lifespans significantly longer than the typical protein, and their identification may be relevant to understanding the molecular basis of aging.

The new study [provides] a system-wide identification of proteins with long lifespans in the rat brain, a laboratory model of human biology. The scientists found that long-lived proteins included those involved in gene expression, neuronal cell communication and enzymatic processes, as well as members of the nuclear pore complex (NPC), which is responsible for all traffic into and out of the nucleus. Furthermore, they found that the NPC undergoes slow but finite turnover through the exchange of smaller sub-complexes, not whole NPCs, which may help clear inevitable accumulation of damaged components.

[Researchers] previously found that NPC deterioration might be a general aging mechanism leading to age-related defects in nuclear function. Other laboratories have linked protein homeostasis, or internal stability, to declining cell function and, thus, disease. The new findings reveal cellular components that are at increased risk for damage accumulation, linking long-term protein persistence to the cellular aging process. "Now that we have identified these long-lived proteins, we can begin to examine how they may be affected in aging and what the cell does to compensate for inevitable damage. We're starting to think about how to get functionality back to that younger version of the protein."

Link: http://www.sciencedaily.com/releases/2013/09/130903151802.htm

Following on from the recent Pew Research poll on radical life extension, the Canadian organization CARP ran their own similar poll on a selection of older people. It makes for an interesting comparison, but again it is clearly the case that advocates for longevity science - extending healthy life and eliminating the diseases and degenerations of aging - have a lot of work left to do:

It has to be pointed out that Pew poll was taken among a general population sample, weighted to reflect current US census data, and therefore containing all ages. The CARP sample is made up of members, whose average age is about 70. This will lead to significant differences in attitudes to health care and longevity between the two samples. CARP members are aware that there are radical life extension possibilities but are unlikely to embrace it for themselves. They are much less supportive than their American counterparts - even allowing for age differences in the sample - and cite resource pressures, think it is fundamentally unnatural and would not lead to a more productive economy.

When asked in detail, most CARP members think radical life extension is a bad thing, because it will lead to resource depletion and seniors will run out of savings. CARP members are half as interested in taking part in these life extension techniques as Americans, and much less convinced than Americans that others would like to take part. If they did take part in these treatments, CARP members are most concerned that their extra years would be healthy, not necessarily well-provided for.

CARP members expect to live as long as Americans wish to live, but they wish to live even longer, which may be reflection of greater confidence in our health care system. In a similar vein, CARP members are more confident humans will routinely live to be 120 years old by the year 2050 than Americans are. In a curious and counter-intuitive finding, CARP members are less likely than Americans to say these treatments would be available to everyone, and are more likely to say they will be reserved for the wealthy when they are available.

CARP members are more likely than Americans to agree these techniques would strain natural resources, are equally likely to find them fundamentally unnatural and are much less likely to think they will lead to a more productive economy. Most CARP members say they would not change what they are doing if they had an additional 20 years, while others say they will travel or volunteer.

Link: http://www.carp.ca/2013/09/06/carp-radical-life-extension-poll-report/

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

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

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

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

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

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

...

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

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

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

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

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

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

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

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

Link: http://www.ncbi.nlm.nih.gov/pubmed/24036417

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

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

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

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

Link: http://www.the-scientist.com/?articles.view/articleNo/37149/title/A-Hair-Raising-Solution-/

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

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

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

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

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

New Take on Free Radicals

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

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

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

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

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

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

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

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

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

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

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

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

Link: http://www.slate.com/articles/health_and_science/science_of_longevity/2013/09/life_expectancy_history_public_health_and_medical_advances_that_lead_to.single.html

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

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

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

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

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

Link: http://www.eurekalert.org/pub_releases/2013-09/yu-aml083013.php

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Link: http://www.eurekalert.org/pub_releases/2013-09/cg-shi083013.php

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

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

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

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

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

Link: http://www.sciencedaily.com/releases/2013/09/130903123041.htm

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

Here's the latest update:

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

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

A New Partnership with Organovo

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

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

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

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

Two Grants for Promising Genetic Research

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

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

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

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

Developing the New Organ Prize

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

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

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

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

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

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

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

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

Link: http://www.impactaging.com/papers/v5/n8/full/100594.html

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

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

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

Link: http://www.amazon.com/Longevitize-Philosophy-Politics-Longevity-ebook/dp/B00EX6BCSG

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Link: http://sens.org/research/research-blog/research-report-lysosomal-aggregates

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

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

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

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

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

Link: http://www.sciencedaily.com/releases/2013/08/130831110923.htm