$36,000
$24,120

Looking Back at 2013

Another year flees past us, ever faster it seems. The past year was characterized by advocacy, shifts in publicity and organizations supporting longevity science, and community fundraising success. For example, we just finished raising $60,000 for the SENS Research Foundation in the last few days. Back in October Longecity raised $21,000 for another SENS research project: restoring function in mitochondrial mutants, an opportunity to use a pair of cell lines that suddenly became available, and would otherwise require a great deal of work to produce. The month prior, a film project on life extension raised $35,000 on Kickstarter. Publicity is good, but I can't help feeling that we have a way to go yet with our advocacy when it is easier to raise funds to talk about longevity science in fiction than it is to raise funds to actually build the technologies needed for human rejuvenation. Ah, priorities. We humans are so bad at priorities.

Alongside all of this community fundraising, the new crowdfunding models are starting to make some inroads into science - moving beyond comics and games and widgets. I see this as a promising sign. Making community fundraising for projects like the ones above, and providing better tools to help the organizers, can only lead to more projects being funded and a growth in the number of supporters.

In a similar vein the Methuselah Foundation recently officially launched the New Organ Liver Prize: $1 million for the production of a tissue engineered, functional, transplanted liver. Their fundraising proceeds apace as they continue to work on speeding up whole organ tissue engineering through a variety of avenues.

While we are on the subject of Foundations, this was the year in which the SENS Research Foundation launched their Reimagine Aging campaign, added scientific luminary George Church to their advisory board, hosted the SENS6 conference, reached a yearly budget of $4 million, filled out their YouTube channel with videos, and posted an excellent series on the work done by young molecular biologists in their intern program. The SENS research program to watch in the coming couple of years is the AGE-breaker project focused on glucosepane, I think, but you really should take a look at their annual reports to get an idea as to how the Foundation is growing, and be sure to read The Undoing of Aging. You should also absolutely catch the Ben Best interview of Aubrey de Grey from August.

Interestingly, one other noteworthy group in aging research has published their own manifesto on how to treat degenerative aging, clearly modeled on the SENS proposals. That looks a lot like victory from where I stand.

The big funding news for the year in mainstream aging research is that the Ellison Medical Foundation is exiting the arena, and the vaguely aging-related Genomics X Prize was cancelled. Meanwhile Google has created the Calico initiative with the determination to spend hundred of millions of dollars on extending healthy life. At this point I don't expect Calico to back anything so useful and ambitious as SENS - I think it will look a lot more like a backing of the slow road to nowhere of metabolic manipulation to reduce the pace of aging. No rejuvenation research there. I may be wrong, but we shall see.

Various campaigns such as the Longevity Dividend have made new publicity efforts this past year to attract more public funding to their vision of incremental slow progress towards drugs to ameliorate the effects of aging. In addition we've seen other signs of the spread of awareness of longevity science into the mainstream: a radical life extension policy wonk conference, a big well-publicized study on views of radical life extension from Pew Research, and an advertising campaign touting 150 year life spans from Prudential. There is movement: each year we come closer to mass support for the goal of longer, healthier lives, yet still much of the public seems strangely disinterested.

Telomeres have been floating around in the news in relation to longevity this year. This is largely a consequence of new services offering telomere measurement, rather than anything of greater utility. Startup companies tend to generate press as a side-effect of their existence, but that doesn't necessarily tell us anything. On the more interesting side, the teams working on life extension in mice through telomerase gene engineering published new results earlier in the year. This is one of those items that gives me pause on my opinion of telomeres: other than this, it seems very clear from the data that telomere length is a marker, a consequence of aging and not a cause. I look forward to learning more about how telomerase in mice is actually extending life.

Mitochondrially targeted antioxidants of several types have been a topic of interest for some years now. To the extent that they extend life - where normal antioxidants do no such thing, or block hormesis signaling to shorten life - this is a reinforcement of the importance of mitochondria to aging and the need for mitochondrial repair technologies. A new type of mitochondrially targeted antioxidant known as SS-31 showed up publications earlier in the year, and makes for interesting reading.

This was the year in which research into brain emulation became more serious. Very large sums and formal programs are now working on creating first simulations and later emulations of the brain. Relevant to life extension? Not directly, unless you are one of those who believe that a copy of you is still you - but this bears watching. In a related community, the 2045 Initiative held their Global Futures conference back in June. This is another initiative that is worth keeping an eye on, though I don't believe it relevant to actual progress in extending human longevity despite their claims - and for much the same set of reasons as for brain emulation. A copy of you isn't you.

There are some puzzling oddities floating around the edge of the field of aging research, made puzzling simply by virtue of the fact that all too few people are studying them. The results arrive slowly and intermittently as a result. These are items that are likely irrelevant to the future of human life extension, but that doesn't stop them from being interesting. One of the best, I think, is whether and how heavy water extends life in short-lived species.

Immune therapies are one of the more active areas of medical development at the present time. Guiding the immune system has very broad applications: treatment of cancer, removal of amyloid and other waste compounds, and reversal of age-related immune dysfunction. Even something as simple as generating enormous numbers of patient-matched immune cells and infusing them can be very beneficial for the old, a way to restore some of the immune capacity that they now lack.

Several groups of researchers are at present chewing through past claims of life extension in mice from various dietary components and supplements and disproving them one by one. This seems to be the trend: look at every such claim from the past few decades with suspicion, as they likely resulted from inadvertent calorie restriction and are now being refuted by more careful work. The present consensus is that aggressive supplementation does nothing or may even be harmful to life expectancy.

In the area of drugs to slow aging, there is some debate over whether rapamycin actually does slow aging in mice versus just reducing cancer rates. This is ongoing with some fairly energetic arguments on both sides, especially from those already fairly vested in mTOR as a target for slowing aging, given that this is becoming an area of increased fundraising. To my eyes this is all irrelevant, of course. It isn't damage repair, it's just more metabolic manipulation that is exceedingly unlikely to meaningfully extend life in humans, even though it manages 20-30% life extension in mice, about half to two thirds of the effects of calorie restriction. Think of it as version 2.0 of the hubbub over sirtuins and resveratrol - that all went nowhere, generating only new knowledge, and the same will come of this, I think.

I'm not going to talk about tissue engineering, stem cells, or regenerative medicine this year. So much is going on that it would be a very long list: body parts and their components are being made, and researchers are just hitting their stride in this arena. The 2020s are going to be very interesting, as that is when we'll start to see a fair number of people with bioartificial replacements, augmentations, organ patches, and other treatments.

On cancer, again too much to point out. I leave that to others. But I will point to news on granulocyte transplant therapies: this has been a topic in past years because it seemed so very promising. It still looks promising, but by the sound of it this has run into the wall of grinding slow progress towards application, and the discovery of previously unappreciated complexity. But on the bright side, here are two and a half other ways to cure cancer.

Programmed aging as a viewpoint seems to be on the rise. Perhaps there are more publications, perhaps I'm just noticing more publications. This might be seen to be as much a threat to future funding of rejuvenation research as the continued focus of the mainstream of the research community on either doing nothing or working only on ways to manipulate metabolism with drugs to slightly slow aging. In the programmed aging worldview we should be working to restore epigenetic patterns and other aspects of metabolism to youthful levels, as they see this change as the root cause of aging. To their eyes damage repair is a waste of time. But this focus on altering metabolism is the doomed path to nowhere if aging is accumulated damage, as in the SENS viewpoint and - largely - the present mainstream view.

This year had its usual crop of short essays, links below:

I missed a hundred other interesting things in this short retrospective, of course - but that's why Fight Aging! has archives, and why you have free time.

Spurring Axon Regeneration in an Injured Spinal Cord

The scientific community continues to work on ways to spur or guide nerve regeneration, something that doesn't normally occur to any great degree in human tissues. Much of that focus is on spinal injuries, and here researchers have found a way to use one cell type to guide the regrowth of others:

Transplanting self-donated Schwann cells (SCs, the principal ensheathing cells of the nervous system) that are elongated so as to bridge scar tissue in the injured spinal cord aids hind limb functional recovery in rats modeled with spinal cord injury. "Injury to the spinal cord results in scar and cavity formation at the lesion site. Although numerous cell transplantation strategies have been developed to nullify the lesion environment, scar tissue - in basil lamina sheets - wall off the lesion to prevent further injury and, also, at the interface, scar tissue impedes axon regeneration into and out of the grafts, limiting functional recovery."

The researchers determined that the properties of a spinal cord/Schwann cell bridge interface enable regenerated and elongated brainstem axons to cross the bridge and potentially lead to an improvement in hind limb movement of rats with spinal cord injury. Electron microscopy revealed that axons, SCs, and astrocytes were enclosed together within tunnels bounded by continuous basal lamina. The expression of neuroglycan (NG2; a proteoglycan found on the membrane of cells) was associated with these tunnels. They subsequently determined that a "trio" of astrocyte processes, SCs and regenerating axons were "bundled" together within the tunnels of basal lamina.

Link: http://www.eurekalert.org/pub_releases/2013-12/ctco-sfa122313.php

An Example of Engineering Bioartificial Heart Tissue

The biggest challenge in tissue engineering is still the creation of a blood vessel network sufficient to keep larger portions of tissue alive and functional. A workaround is to use decellularized donor tissues in which those blood vessels already exist: all of the cells are removed, leaving only the scaffolding of the extracellular matrix and its chemical cues, ready to be repopulated by cells derived from the recipient. As these researchers demonstrate, that donor tissue doesn't necessarily have to originate from the same organ or even the same species:

The in vitro generation of a bioartificial cardiac construct (CC) represents a promising tool for the repair of ischemic heart tissue. Several approaches to engineer cardiac tissue in vitro have been conducted. The main drawback of these studies is the insufficient size of the resulting construct for clinical applications. The focus of this study was the generation of an artificial three-dimensional (3D), contractile, and suturable myocardial patch by combining a gel-based CC with decellularized porcine small intestinal submucosa (SIS), thereby engineering an artificial tissue of 11cm in size.

The alignment and morphology of rat neonatal cardiomyocytes (rCMs) in SIS-CC complexes were investigated as well as the re-organization of primary endothelial cells which were co-isolated in the rCM preparation. The ability of a rat heart endothelial cell line (RHE-A) to re-cellularize pre-existing vessel structures within the SIS or a biological vascularized matrix (BioVaM) was determined. SIS-CC contracted spontaneously, uniformly, and rhythmically with an average rate of 200 beats/min in contrast to undirected contractions observed in CC without SIS support.

A dense network of CD31+/eNOS+ cells was detected as permeating the whole construct. Superficial supplementation of RHE-A cells to SIS-CC led to the migration of these cells through the CC, resulting in the re-population of pre-existing vessel structures within the decelluarized SIS. By infusion of RHE-A cells a re-population of the BioVaM vessel bed as well as distribution of RHE-A cells throughout the CC was achieved. Rat endothelial cells within the CC were in contact with RHE-A cells. Ingrowth and formation of a network by endothelial cells infused through the BioVaM represent a promising step toward engineering a functional perfusion system, enabling the engineering of vascularized and well-nourished 3D CC of dimensions relevant for therapeutic heart repair.

Link: http://www.ncbi.nlm.nih.gov/pubmed/24102409

Shutting Down Open Cures

The Open Cures initiative has been effectively dead for a while: I'm not doing anything with it, and I have no plans to do anything with it. So I think it's time to kill off the web site, return the domain to its original owner, and tie up any other loose ends.

Open Cures was a glimpse into how the future of medical tourism and open biotechnology will interact to work around and ultimately bring down the tall regulatory barriers put in the path of progress. As what can be accomplished in the laboratory becomes ever more advanced beyond what has finally made it into the clinic, there will an increasing pressure to bypass the massively expensive, restrictive, and uncertain process of regulatory approval. That pressure will go hand in hand with the growing ability of small groups to perform their own medical commercialization, using increasingly cheap tools and widespread knowledge, producing a dynamic that will look very similar to the way in which software development became something that anyone could do.

To my eyes this is the only way we're going to see therapies for aging arrive in good time. Attracting research funding requires the outlet of profitable markets at the end of the tunnel. The lack of such a market is one of the reasons why longevity science lacks funding: the FDA will not approve treatments for aging, so what commercial entity will fund early stage development? Thus the future of medicine will be as much about building new channels for the development of - and access to - clinical applications as it will be about the science.

There were two fundamental issues with diving in and doing this. Issue one, which is easy to forget when caught up in the idea, is that I am absolutely not the person to be leading this sort of initiative. Issue two is that despite Open Cures being a good, necessary idea, it is still the case that the highest priority in this community now and for the foreseeable future is to channel funds and interest to the SENS Research Foundation. The science needed to build rejuvenation therapies has to happen, and it is still in a comparatively early, formative stage of development: this is where efforts must go until the work is further along, with applications ready for clinical development.

I am going to post the defining essays from the Open Cures site here as a memorial to the project, and to make sure they remain online.

Open Cures: to Speed Clinical Development of Longevity Science

Let me take a moment to talk about why, in this age of biotechnology and accelerating progress, it is even necessary to build an organization to help speed matters along. What is the roadblock that stands in the way of the clinical development of longevity-enhancing biotechnology?

The Biotechnologies of Longevity, Undeveloped

When we look at work on aging and longevity in the laboratory, we can see that more than a dozen ways to use biotechnology to extend the lifespan of mice have been demonstrated over the past decade. About half of those methods appear to lack serious side-effects, delivering only longer lives, lower cancer risk, improved health and vigor, and little else. Similarly, a range of laboratory demonstrations conducted since the turn of the century have reversed specific, measurable biological changes that occur with age in mice: damaged mitochondrial DNA replaced throughout the body, the function of cellular garbage collection mechanisms restored to youthful levels in liver tissue, and so on. We live in an era of rapidly improving biotechnology - and it is delivering the goods, in the laboratory at least.

But there is one common theme to all of these advances: none are undergoing further development for clinical use in healthy humans for the purpose of slowing or reversing degenerative aging, and thereby extending healthy life span. Why is this? You would imagine, given the size of the market for medicine, that a hundred start-up biotech companies would be leaping upon these opportunities, giving rise to an era in which "anti-aging" fakes and frauds finally start to fade away in favor of a market built upon true rejuvenation science. This is not happening, however, as there is a gargantuan roadblock that stands in the way.

The Nature of the Roadblock

In the US, where much of the research most directly relevant to engineered longevity takes place, this roadblock is called the FDA: the Food and Drug Administration. Appointed FDA bureaucrats have absolute control over the commercial deployment of medical technology in the US: only those technologies formally approved by the FDA can be sold for clinical use. Further, the FDA only approves a new medical technology for narrow usage in treating a specific, defined disease in a specific, defined way. Obtaining even this narrow approval is a staggeringly expensive process. For one, that list of diseases changes only very slowly, and an entire industry of lobbyists exists solely to try to add new medical conditions to that list - burning money that would better used for research and development.

Consider sarcopenia, for example, the characteristic age-related loss of muscle mass and strength. Sarcopenia was first named as a distinct condition a decade ago or so, and expensive efforts have been ongoing for some years to convince the FDA to add it to the approved list of diseases. There seems little prospect of this happening any time soon, however, and so the lobbying efforts continue. There are potential therapies for sarcopenia, or at the least the scientific basis for potential therapies that might prove useful in humans, but little to no private funding to further develop these leads - as there is no market on which to sell any resulting treatments. Even if a storybook industrial philanthropist turned up tomorrow to devote his entire net worth to pushing through development of a therapy for sarcopenia, it would still be illegal to offer the resulting medical technology for human use in the US.

Aging itself as a medical condition is in the same boat. Aging is not a disease, per the FDA - and therefore no-one is legally permitted to treat aging in humans with biotechnology in the US. The present state of the lobbying game, as illustrated by the situation for sarcopenia, is that it will take years and millions of dollars in to carve off one tiny component of aging and have FDA bureaucrats grudgingly allow commercial development to proceed. Thus what comparatively little development of longevity science does take place - such as work on sirtuins and other possible calorie restriction mimetics - sees applications of the underlying research shoehorned into treatments for late-stage diseases of aging, whether it fits or not. Even if successful the resulting therapies will not be legally available for use by healthy or younger people for the purposes of treating aging itself.

The Mirage of Reform

Numerous organizations and advocates (such as FasterCures, for example) have been trying for years to reform the FDA, or at least make it less obstructionist - to try to make it possible for new therapies to emerge without the stifling costs in years and hundreds of millions of dollars, or to emerge at all where they are not recognized by the FDA. These initiatives are all failing: over the course of time that they have been active, and despite the funds and efforts poured into them, the FDA has only become worse, approving fewer and fewer new technologies, and continually raising the bar and the cost for approval. The fundamental incentives that shape the actions of FDA political appointees are these: they suffer very few problems due to medical technologies that are suppressed or denied approval, but take a great risk to their career in approving any new application of medicine or biotechnology. The rest of this undesirable state of affairs unfolds from that basis - bureaucrats will follow their incentives, regardless of the harm it causes.

Meanwhile, the years pass, funds are consumed by political processes rather than being spent on actual research, and we're all getting older - our bodies slowly sabotaged by the processes of aging.

All in all, working with the FDA is not a game that we win by playing. A system so entrenched and badly broken cannot be reformed through existing channels, and efforts to change it by playing within the rules do little but provide the FDA with additional legitimacy. The only way to win here is to refuse to play the game, and take an entirely different approach - which brings us back to Open Cures, which is exactly that: an entirely different approach to the roadblocks put in the path of development by the FDA and its counterparts in other highly regulated countries.

The Rise of Medical Tourism

I'll restate the primary challenge: that it is illegal to commercially offer medical treatments for aging in the US, and based on the lack of progress in effecting change to date, this situation will persist for the foreseeable future - regardless of how much money and effort is expended on lobbying within the system. In turn, that the clinical application of longevity science is forbidden means that there is little to no investment available to develop laboratory demonstrations into therapies. Thus the most promising and advanced biotechnologies shown to extend life or reverse specific biochemical aspects of aging in mice languish unexplored and undeveloped.

Yet if we look beyond America and Europe, we see regions in which clinical development of therapies based on cutting edge science is both possible and less restricted. To pick one example, stem cell therapies that will not be commercially available in the US for years yet have been offered for a number of years by responsible, skilled groups in China, Vietnam, Thailand, and other countries. You might look at Beike Biotech or Vescell, for example. It should make American citizens of a certain age sad that China has become an example of freedom outshining the US in any field of endeavor - not sad for the Chinese, but sad for what has become of medical development in America.

This is a shrinking world we live in. Air fares are cheap, tourism growing, and the internet links together cultures, movements, and businesses ever more efficiently with each passing year. When the cost of travel is low compared to the cost of newly available medical technologies, we see the growth of medical tourism. Clinical development will occur wherever capable institutions exist and local law permits it, and patients will travel from restricted regions like the US to receive treatments that are not available at home.

Medical tourism is a growing business in the US precisely because forbidding and regulating medical development is also a growth concern: medicine is only expensive and unavailable because bureaucrats make it that way. Medical tourism is still a comparatively young industry, however, feeling its way and largely focused on a few major and well-known fields of medicine (such as the early therapeutic uses of stem cell transplants). It is far from the case that people are taking advantage of the full range of cost-savings and possibilities, and this is due in part to all the standard challenges inherent in establishing important business relationships across a great distance.

When you stop to think about it, however, you'll notice that all of these problems are well solved for traditional tourism - even where comparatively large sums of money are involved, such as in the much maligned timeshare business. People comfortably travel great distances and expect to rely on critical services at their destination: this works because intricate, long-standing industries of communication, organization, and education make that possible. It will one day be the same when people routinely travel to obtain medical services from far removed locations.

Now consider this: there is no technical barrier to, for example, clinical development of a way to replace all damaged mitochondrial DNA in humans - the basic technology has existed, demonstrated in mice, for six years. The work is published, fairly well known in the small part of the field where it matters, and were it made into a therapy there would be tens of thousands lining up to pay for it. Yet in countries where it is both possible and legal to move ahead with that commercial development, and where there is already an established, albeit nascent, medical tourism industry, that development has not yet happened. Why is this?

A Material Role for Open Biotechnology Movements

When it comes to the passage of information, we do not live in a frictionless world. Scientists and medical development groups in widely separated regions do not in fact necessarily have good insight into the work of their far-removed peers, or even know that the work exists in the first place. They are separated by distance, culture, and language - far less so than in the past, thanks to the internet, but separated nonetheless.

The effects this has on a given field of research and development are a matter of degree: smaller fields are more affected than the larger ones, as more researchers, more funding, and more public interest means more transmission of information. Aging research and longevity science is not a very large field, as it happens, at least not in comparison to stem cell medicine or cancer research - and you can see the difference that makes in cooperation and organization across national boundaries in the resulting levels of medical tourism. The relationships for development and transmission of knowledge that exist for stem cell research, to pick one example, dwarf those developed for longevity research. Thus you don't see clinical projects outside the US and Europe that are analogous in scope and ambition to those that presently take place in the field of stem cell medicine.

But all is not doom and gloom: I do not expect the gaps in the transmission of knowledge to last. Institutions and cultural forces will arise to close these communication gaps, and they will arise from present-day open biotechnology movements. These movements are still young and small, but very similar in aims and ethos to the open software engineering cultures that first formed in the 1970s in the US: information and designs are freely shared, there is an emphasis on moving the ability to produce significant products out of the ivory tower and large institutions, and the result is a massive body of work that greatly lowers the barriers to entry for hobbyists and professionals alike. Software development, once an arcane art practiced only within large organizations and universities, became possible as a garage industry, and then as a hobbyist activity - which in time gave rise to a vast breadth of knowledge and practice, a staggering pace of innovation, and a community of developers that has grown in size and sophistication by leaps and bounds.

The last 40 years in the culture of developing software is a snapshot that will be repeated for the next 40 years in the development of biotechnology. Costs of equipment and processes will fall, garage developers and hobbyists will come to greatly outnumber institutional professionals, and the pace of innovation will accelerate dramatically. On the way to that end result, open biotechnology movements (such as the DIYbio groups) will play an important role in bridging the communication gaps that exist between life science professionals and clinical developers in different parts of the world.

How will this happen? Consider that in software development today, there are no secrets and no specialty so small that it doesn't have a hundred skilled observers in the broader open community - watching, talking, and tinkering on their own time. When an important new advance arrives, it will be echoed around the world, dissected, analyzed, and evaluated. The best new strategies rise to the top very rapidly indeed exactly because the community is very large. Unfortunately, this state of affairs is not yet realized for biotechnology and the life sciences, but that is only because the open community of demi-professionals and hobbyists is still comparatively small. It won't remain small for many more years, however, and as the community grows, it will become increasingly unlikely that any promising biotechnologies will remain buried in scientific papers, undeveloped.

So in short, it is my conjecture that the present scientific demonstrations that might possibly be applied to extend life or reverse aspects of aging in healthy humans go undeveloped because they haven't been brought out into the open by a community of thousands: they haven't been discussed, picked over, buffed up, and presented far and wide in overseas regions where provision of clinical therapies for aging is not illegal. This process would happen as a matter of course given a much larger open development community associated with the biotechnology industry, but until that community arrives, a helping hand is needed.

Information and Relationships: the Role of Open Cures

And here we come to the point of the exercise: the reason for Open Cures. The high-level goal of the Open Cures initiative is to produce the communication, examination of research, and relationship building in longevity science that would naturally emerge from a larger open biotechnology community - but which is nowhere in evidence today, and will not arrive on its own for a long time yet.

The foundational items on the Open Cures to-do list are as follows:

  • Establish a repository of how-to documentation for longevity-enhancing biotechnologies demonstrated on mice in the lab, with sufficient detail and explanation to make it comprehensible and useful for garage biotech groups, DIYbio practictioners, and overseas developers.
  • Establish a network of relationships with the open biotechnology community, overseas developers, and the movers and shakers who are building the medical tourism industry rooted in the US.

That might not seem like much, but we stand at a fulcrum point in the growth of three large movements: regulation of medicine, medical tourism, and open biotechnology, all driven in their changes by accelerating technological progress in computing and biotechnology. The initial Open Cures projects are a lever for that fulcrum, a foundation for the construction of lasting bridges between researchers who discover and demonstrate the biotechnologies of engineered longevity and overseas development groups who can translate that science into new medicine for clinical use.

The bottom line is that the groundwork for a range of potentially life-extending therapies exists already, and the development groups legally able and capable of turning this science into therapies exist already: something must be done to bring these two sides together, and ensure that they build further ties for future development. If this were a better world, therapies built upon replacement of mitochondrial DNA would already be emerging, today, for example - there is no technical reason why that could not have been the case. That this has not happened is a challenge of people and organization: regulation, relationships, fundraising, the transmission of knowledge and experience.

My vision for the future of Open Cures is a long-term process of growth in establishing a self-sustaining community around the process of rescuing longevity science from its current fate: discovered and published, yet unheralded and undeveloped for use. This is analogous to the long-term vision of the SENS Foundation, which is as much about the development of a culture and community of longevity research as it is about the development of true rejuvenation biotechnology capable of repairing the biochemical damage of aging. When the scientific research of SENS is complete in its first phase, perhaps twenty years from now, we want to be living in a world in which potential biotechnologies of longevity are routinely and eagerly developed into clinical applications, no matter where they were initially researched, and no matter what destructive games the regulators and bureaucrats have found to play.

Making this happen is as much a project as researching the technologies in the first place, and just as necessary: it is also a project that we can all help with, even those of us who are not and never will be life scientists. So take a look at Open Cures, and consider how you might be able to help make the future a better place for progress in medical science and longer, healthier lives.

Longevity Science Needs Documentation

We all express the symptoms of a fatal, inherited degenerative condition called aging-or so the joke goes. It's a dark joke, but there's truth to be found in it, as is often the case in black humor. Unfortunately, all too few people think of themselves as patients suffering aging, and fewer still would call themselves patient advocates, agitating for research leading towards therapies and cures for aging. This is a sorry state of affairs: given that our time is limited and ticking away, the tasks upon the table should always include some consideration of aging. What can we do about it? How can we engineer a research community, funding and support to make real progress within our lifetimes? If you don't spend at least some of your time on this issue, then you're fiddling while Rome burns. Time is the most precious thing we have, and we live on the cusp of technologies that will allow us to gain more of it-but those advances in medicine won't happen soon enough unless we work at it.

Working on progress in longevity science doesn't have to mean working in a laboratory. Much of what I have done to help matters along takes the form of written advocacy at Fight Aging! and elsewhere: sharing events, passing on news, putting scientific publications in context, explaining where we stand in research and development, encouraging fundraising, and so on. In effect this is a sort of loose documentation of the existence of the community of people interested in engineered longevity, and a way to provide direction and grounding to newcomers: how to become involved, how to benefit from becoming involved, and how to help advance the science of human longevity.

My latest effort, the volunteer initiative Open Cures, is more explicitly a documentation project in its early stages: an effort to clearly and extensively document the range of longevity-enhancing biotechnologies demonstrated in the laboratory over the past decade. A body of documentation is a necessary foundation for later phases of the Open Cures roadmap, but will also help broaden the community of people who are both aware of this work and understand what it might be used to achieve.

Not everyone agrees that this is useful, however. One of the challenging attitudes I've encountered of late is the idea that documentation of longevity science in this manner is largely worthless-that time and funds spent trying to make science clear to developers and laypeople should go towards other, more direct activities like further research. This sort of criticism is, I think, symptomatic of a failure to understand the necessary role of documentation in the broader scope of technological progress. This article, then, is an answer of sorts: what is the role of documentation, and why is it important enough to need dedicated organizations that do it well?

The Challenge of Complex Ideas

Most important topics relating to the future of advanced technological development are very complex: engineered human longevity, strong artificial intelligence, molecular manufacturing, and so forth. Even the general concepts (such as "why is this important?", "why is this plausible?", or "why should I support it?") are made up of many moving parts and conditional arguments that the broader public generally hasn't heard or thought about yet. Thus we advocates can't just jump in and start persuading people that life extension is a great idea: instead, when it comes time to try to explain why this goal is important-and how best to proceed with research and development-we must first walk through a whole squadron of supporting concepts that are unfamiliar to the audience. Each must be explained, and only then can they be assembled into the final persuasive conclusion.

In the area of healthy life extension and biotechnologies to repair aging, an array of foundational ideas might include the following:

  • This is a time of radical progress in biotechnology, far more so than even just a decade ago
  • Scientists can extend life in a score of different ways in laboratory animals
  • But you don't see the results of this work in the clinic because the FDA is needlessly obstructive
  • Aging is just damage, and that damage is well enough understood for work on practical repair biotechnologies to proceed
  • A large-scale research program could plausibly produce decades of life extension by 2040
  • Any effective longevity therapy will give people more time of life and health to wait for even better new therapies
  • Overpopulation is a myth, and longer lives won't greatly increase population in any case
  • Ethical objections to engineered longevity are all weak in comparison to the massive and ongoing harm caused by aging

Each of these is no small thing in and of itself, and worthy of longer treatment. So presenting all of the concepts that lead up to thinking about rejuvenation biotechnologies is time-consuming, hard to do well, and requires a willing and interested audience. Unfortunately few people in the broader public are in fact willing put in the effort to follow you, me, or anyone else with a complicated idea all the way from square one to the end point. That takes time and attention-both of which are precious commodities, hard to obtain at the best of times. Thus the ideas that do gain traction in our culture are those that can be successfully communicated in a short period of time, because they build directly upon what is already known.

The Example of Hotmail

The recent past provides many good examples of ideas that could be quickly communicated to the public at large, and as a result rapidly gained interest and support. Hotmail is one such example: when the company was founded in 1996, it was the first service to offer email over the web. The founders were petrified that they would be beaten to the punch because the idea was absolutely obvious in hindsight: take email, take websites, and merge the two. Anyone in the internet-using world could easily grasp that concept, and the service took off like wildfire when it launched.

But let's stop to think about that for a moment. Both email and the way in which most people experience the web are in and of themselves very complicated concepts. Imagine that some visionary fellow gave you the task of explaining to the public an email service used via a web site in 1970: you would be right back to having to explain many foundational, unfamiliar concepts to an audience unwilling to give you sufficient time and attention. What is a network? How do ordinary people connect to or even use a network? What is a web browser? How does an ecosystem of websites and hosting services arise? Why would I need email, or some sort of patchwork visual information service? And so forth.

Nonetheless, in 1996 Hotmail was an idea that could be conveyed and understood in a single sentence. "Email via a website." When we consider this and other similar examples, we see that there must be an ongoing process by which complex, unfamiliar, and challenging ideas become simple, familiar, and easily communicated ideas.

Layers of Knowledge, Attention, and Expertise

You might envisage the broad field of longevity science as a series of concentric circles. The innermost circle is made up of a small number of people who pay a great deal of attention to the field, and who possess the most knowledge and expertise: researchers who work on cutting edge science, for example. The outermost circle consists of a large number of people who pay just a little attention to the field, and who possess the least knowledge and expertise-such as casual advocates and interested members of the public. The progression of circles from innermost to outermost reflects an increasing number of people, but lesser expertise and attention. I'd loosely categorize the circles from inner to outer as follows:

  • Cutting edge researchers
  • Other researchers, postgraduates, and scientists in related fields
  • Dedicated patient advocates
  • Medical technology developers, funding sources
  • Physicians, clinicians and medical technicians
  • Interested members of the public

In this model of human endeavor, knowledge flows outward while funds and newly participating members of the community flow inward-or at least, that is the ideal. In practice, managing this flow of knowledge is a big and thorny problem: many of the most important movements in technology over the last few decades have focused on how to best move knowledge from inner circles to outer circles. Consider the open science movements, fights over closed journal business models, and the many efforts to try to adopt open source practices in the scientific community, to consider but a few examples.

Let me advance a definition for the purposes of this article: documentation is the name given to explanations and tutorials produced by the members of one circle that are intended for the next outermost circle. For example, review papers written by scientists present an overview of progress in one area of research rather than new data or results. These review papers are a form of documentation for the next outermost circle of researchers-scientists in other fields, or postgraduates, or other academics with less experience in the topic at hand.

To take another example, what I do at Fight Aging! is a form of documentation by this definition: ongoing efforts to explain the ins and outs of longevity science to people who are less familiar with the field, and who have less time to devote to understanding the work of researchers. Academic publicity services at the major universities also perform a similar task, producing explanations for the outer circles of doctors, interested members of the public, and the like.

Documentation thus moves raggedly and through many hands, as each circle learns from the inward circles and then in turn explains its knowledge, understanding, and work to the outer circles. That there are so many layers involved goes a long way towards explaining how science so often becomes garbled and misinterpreted on the way from researchers to the interested public. The process works over time, however, as the example of Hotmail well illustrates. The level of knowledge in the outer circles does increase, and the efforts of people involved in producing documentation make it easier for new ideas to gain traction.

Researchers, Like Most Communities, Document Poorly and Reluctantly

Anyone who spends time working in a technical field eventually forms a cynical attitude towards documentation: it is never what it might be, and the next innermost circle never does a good enough job of explaining themselves. This is simply the way of the world: most people in a given circle spend the majority of their time and effort in communicating with each other, not with the members of the next outermost circle. In the sciences, researchers write papers for one another as a part of the business of research, and this publishing of results is not intended to educate anyone other than peers at a similar level of expertise in the same field.

The process of producing documentation for outer circles is nonetheless very important, despite being undertaken by only a minority in any field. It is only through documentation that there can exist a roadway of information to connect researchers who produce new science with developers who build clinical applications of that science. If documentation is lacking, then so is the pace of development: developers work on what they know, what can be understood, and what can be sold to their investors. Ultimately, that knowledge must come from efforts made by researchers to explain their work.

Across the years I've spent following work on longevity-related research as an interested observer, I've seen a score of techniques demonstrated to significantly extend healthy life in mice, or reverse a narrowly specific manifestation of the damage of aging. Many of these results are languishing undeveloped, as the FDA forbids clinical application of biotechnologies for the treatment of aging. There is little writing on these research results, and no good sources other than the original papers-most of which are behind journal paywalls. What hope is there for the proper transmission of knowledge to the circle of clinical developers when the researchers have no incentive to explain their work, due to the FDA roadblock, and no other group seems to be picking up the slack? Potentially viable medical technologies are lying fallow, buried in the output of the scientific community, and left unexplained for the rest of us.

The Solution: Produce Documentation to Take up the Slack

Addressing the challenges of documentation and transmission of knowledge is an area in where a volunteer organization like Open Cures can make a real difference to the future of longevity science-and for a comparatively small amount of effort and money.

The flow of knowledge from the research community is vital, but as described above there exists a clearly identifiable gap in that process: science that might lead to therapies for aging exists in many different forms, but there is little to no documentation of it. Thus there is little in the way of a roadway to systematically bring this knowledge out to the circles of life science students, entrepreneurs, clinical developers, and other interested parties. Those groups, in turn, have nothing to work with when it comes to educating the medical community and public at large. This, in a nutshell, is the problem. The US may be closed to development of longevity-enhancing biotechnologies by regulatory fiat, but much of the rest of the developed world remains open for business in this field-if the developers in those countries knew more about the work that has taken place and presently lies largely buried.

The irony of the situation is that documentation isn't expensive in the grand scheme of things, and certainly not in comparison to scientific research or clinical development. It doesn't require more than a few weeks of part-time work for a life scientist, a graphic artist, and an editor to produce a long document that explains exactly how to replicate a demonstrated research result in longevity science-a way to extend life in mice, for example. That document will explain the research in plain English, at length, and in a way clearly comprehensible to people who are not cutting edge scientists: exactly what is needed open the door to a far wider audience for that research.

So in conclusion, documentation is important: it's not just words, but rather a vital structural flow of information from one part of the larger community to another, necessary to sustain progress in any complex field. We would all do well to remember this-and to see that building this documentation is an activity in which we can all pitch in to help.

Ellison Medical Foundation to Cease Funding Aging Research

The Ellison Medical Foundation has for the past fifteen years or so acted much like an extension of the National Institute on Aging, channeling philanthropic funding from Larry Ellison into investigations of the biology of aging. This has been mainstream work with little to no involvement in efforts to extend life. The Ellison Medical Foundation didn't come about because Larry Ellison has any great interest in aging research, however: the interest was in furthering molecular biology, and the study of aging just happens to be a field in which a lot of cutting edge molecular biology takes place. By the sound of it the Foundation is moving on into a new phase of existence:

Oracle Corp. founder Larry Ellison's medical foundation - one of the leading funders for research on aging over the past 15 years - has stopped making new grants and may shift its focus beyond medical research. In all, the Ellison Medical Foundation has awarded nearly $430 million in grants since its founding in late 1997. Perhaps 80 percent to 90 percent of that money went to aging researchers.

The foundation is not endowed by Ellison. Instead, Ellison varies his annual gift to the foundation, which this year will fund $53 million in new and continuing grants, the bulk of those for aging research projects. Already-awarded grants will continue to be funded, but the foundation will not make new awards. "There are some other activities planned for the foundation. It may be broader and outside the medical research sphere - not to say medical research wouldn't be a component."

The foundation's pullback from aging research is particularly perplexing, given the entrance of Calico, which is led by former Genentech Inc. chief Art Levinson, and the attention that Google's involvement has brought to the field of aging research. Some researchers have said that Calico's entré would give private foundation grants more oomph and attract other funders.

Link: http://www.bizjournals.com/sanfrancisco/blog/biotech/2013/12/larry-ellison-foundation-aging-calico.html?page=all

Another Study Showing Either No Effect or Reduced Life Span in Mice From Dietary Supplements

There is in fact little evidence for the benefits of dietary supplementation as commonly practiced in wealthier parts of the world. Past results that suggest life extension or improved health in mice tend to vanish once researchers run more careful studies that control for calorie intake. This is taking a while to sink in, however: the supplement industry is enormous, has little incentive to give up its revenue stream or advertising programs, and that voice is much louder than the scientific community in popular culture.

Present data suggest that the consumption of individual dietary supplements does not enhance the health or longevity of healthy rodents or humans. It might be argued that more complex combinations of such agents might extend lifespan or health-span by more closely mimicking the complexity of micronutrients in fruits and vegetables, which appear to extend health-span and longevity.

To test this hypothesis we treated long-lived, male, F1 mice with published and commercial combinations of dietary supplements and natural product extracts, and determined their effects on lifespan and health-span. Nutraceutical, vitamin or mineral combinations reported to extend the lifespan or health-span of healthy or enfeebled rodents were tested, as were combinations of botanicals and nutraceuticals implicated in enhanced longevity by a longitudinal study of human aging. A cross-section of commercial nutraceutical combinations sold as potential health enhancers also were tested, including Bone Restore®, Juvenon®, Life Extension Mix®, Ortho Core®, Ortho Mind®, Super K w k2®, and Ultra K2®. A more complex mixture of vitamins, minerals, botanical extracts and other nutraceuticals was compounded and tested.

No significant increase in murine lifespan was found for any supplement mixture. Our diverse supplement mixture significantly decreased lifespan. Thus, our results do not support the hypothesis that simple or complex combinations of nutraceuticals, including antioxidants, are effective in delaying the onset or progress of the major causes of death in mice. The results are consistent with epidemiological studies suggesting that dietary supplements are not beneficial and even may be harmful for otherwise healthy individuals.

Link: http://www.ncbi.nlm.nih.gov/pubmed/24370781

Fundraising Success: $60,000 Raised for Rejuvenation Science, Another $15,000 Matching Grant Announced

For the past month Fight Aging!, Jason Hope, and the Methuselah Foundation have been running a 3 to 1 match on up to $15,000 donated to the SENS Research Foundation before the end of the year. The Foundation is perhaps the only organization in the world presently working earnestly and seriously on the scientific foundations needed to produce actual, real, working rejuvenation therapies, piece by piece over the next few decades. The Foundation is very well connected in the research community, funds projects in labs around the world, and the scientific advisory board is made up of well-regarded names from numerous fields in the life sciences and medicine.

It is the grassroots that drives the growth of any organization: the more people that show support the easier it becomes to win large investments from conservative funding sources and philanthropists. Multi-million dollar donations for medical research only happen when thousands of people make it known that this cause is worth it by giving a little each. Thus more money raised and more supporters raising their voices at this comparatively early juncture will lead to accelerating progress over the years ahead, moving us towards the large-scale funding needed for the best practical rate of growth in this field of research. None of us are getting any younger, after all, and time is of the essence.

I'm very pleased to say that even after past months of generous donations to fund a number of projects relating to healthy life extension and research, the community still pulled together to find the full $15,000 in just a few weeks, pulling in the combined $45,000 in matching funds from Fight Aging!, Jason Hope, and the Methuselah Foundation.

But that isn't all: long-time Methuselah Foundation donor Michael Cooper has put up another $15,000 matching fund that has yet to be met. Further donations will be matched by this - so if you are still on the fence or late to the news, here is your chance. This was in the mail today from the SENS Research Foundation staff to announce present success and continued work to meet their original year-end goal of $100,000 put forward in November:

Everyone at SENS Research Foundation would like to thank you for your support of our work to change the way the world researches and treats age-related disease throughout 2013.

We are pleased to announce that your generous contributions have enabled us to fully realize our three matching grants from Jason Hope, the Methuselah Foundation and Fight Aging!.

To add to the good news, we have now received a new matching grant of $15,000 from Michael Cooper. We need your help to match this grant between now and the end of the year. Help us to meet our goal of raising $100,000 by visiting our donate page today. All donations to SENS Research Foundation are tax deductible.

Aging affects us all and the research needed to stop the suffering caused by Alzheimer's, heart disease, cancer, and other age-associated health problems remains in critical need of better funding. Please consider SRF as you choose your charitable contributions this season.

Thank you again for supporting SENS Research Foundation! Have a happy and healthy New Year.

Reviewing Methods of Life Extension in Flies, From a Perspective of Maintaining Homeostasis

If you consider aging to be an accumulation of cellular and molecular damage, then loss of homeostasis in tissues - a progressive failure of stability and maintenance - is a consequence of that damage, and epigenetic changes shown to occur with aging are reactions to damage or driven by damage. The way to reverse the issue is to repair the damage. If, on the other hand, you consider aging to be a genetic program, then loss of homeostasis and damage are both consequences of these epigenetic changes. The way to reverse the issue is to restore epigenetic patterns to a youthful level.

Interestingly, while the majority of the research community holds the view that aging is damage accumulation, they also tend to work on projects that better fit the programmed aging hypothesis - aiming to use drugs to alter the operation of metabolism in order to slow aging, for example. This is most likely because these projects look more like past drug development and exploration of the molecular basis for disease, and are thus more palatable to conservative funding sources and regulatory bodies. This is just one of numerous ways in which the research community proceeds in a less than rational manner, following short term incentives at the expense of longer term goals.

Aging is characterized by a widespread loss of homeostasis in biological systems. An important part of this decline is caused by age-related deregulation of regulatory processes that coordinate cellular responses to changing environmental conditions, maintaining cell and tissue function. Studies in genetically accessible model organisms have made significant progress in elucidating the function of such regulatory processes and the consequences of their deregulation for tissue function and longevity. Here, we review such studies, focusing on the characterization of processes that maintain metabolic and proliferative homeostasis in the fruitfly Drosophila melanogaster.

The primary regulatory axis addressed in these studies is the interaction between signaling pathways that govern the response to oxidative stress, and signaling pathways that regulate cellular metabolism and growth. The interaction between these pathways has important consequences for animal physiology, and its deregulation in the aging organism is a major cause for increased mortality.

Importantly, protocols to tune such interactions genetically to improve homeostasis and extend lifespan have been established by work in flies. This includes modulation of signaling pathway activity in specific tissues, including adipose tissue and insulin-producing tissues, as well as in specific cell types, such as stem cells of the fly intestine.

Link: http://jeb.biologists.org/content/217/1/109.long

A Method of Delivering Genes to Mitochondria

One of the causes of aging is mitochondrial DNA damage. The mitochondria, the cell's herd of bacteria-like power plants, contain their own DNA, separate from that in the cell nucleus. It is more vulnerable to damage: mitochondrial DNA repair mechanisms are not as good as those operating in the nucleus, and mitochondria generate reactive free radical molecules in the course of their operation.

DNA provides the blueprints for protein machinery, and some forms of damage to mitochondrial DNA can lead to crippled mitochondria that can nonetheless out-compete their undamaged brethren. Cells become taken over by broken mitochondria and themselves begin to malfunction and harm surrounding tissue: by the time you are old this is a very significant issue that contributes to a range of fatal age-related conditions. Yet this can all be reversed provided that the necessary proteins are provided to the mitochondria. There are numerous strategies, some more permanent than others: the SENS Research Foundation favors a one-time life-long fix that puts copies of mitochondrial genes into the cell nucleus, for example. But more temporary solutions include delivering the proteins directly, or delivering extra copies of undamaged mitochondrial DNA to swamp out the damaged copies and provide the necessary protein blueprints.

A number of ways are either proposed or demonstrated to deliver new DNA to mitochondria, and here is another of them. As is usually the case, the focus here is on comparatively rare genetic disorders rather than the ubiquitous problem of aging, however:

Mitochondrial genetic disorders are a major cause of mitochondrial diseases. It is therefore likely that mitochondrial gene therapy will be useful for the treatment of such diseases. Here, we report on the possibility of mitochondrial gene delivery in skeletal muscle using hydrodynamic limb vein (HLV) injection. The HLV injection procedure, a useful method for transgene expression in skeletal muscle, involves the rapid injection of a large volume of naked plasmid DNA (pDNA) into the distal vein of a limb.

We hypothesized that the technique could be used to deliver pDNA not only to nuclei but also to mitochondria, since cytosolic pDNA that is internalized by the method may be able to overcome mitochondrial membrane. We determined if pDNA could be delivered to myofibrillar mitochondria by HLV injection by PCR analysis. These findings indicate that HLV injection promises to be a useful technique for in vivo mitochondrial gene delivery.

Link: http://dx.doi.org/10.1016/j.jconrel.2013.09.029

Visualizing the Global Burden of Aging

Today I was pointed to the Institute for Health Metrics and Evaluation, an organization that - among other things - provides a set of interesting visualization tools for exploring changing health and mortality data by country and cause. Part of the focus here is the traditional one on infectious disease and developing world health, but the data is global in extent, and at least two thirds of the burden of disease in the world is in fact the burden of aging: the progressive failure of the body due to damage that accumulates as a natural consequence of the operation of metabolism.

Unlike most of the presentations I've glanced at in the past, these visualizations also cover years spent in ill health, not just the bottom line of mortality. You can spent quite a lot of time walking through this data and finding things you might not have known about trends and risks.

So very much of this suffering and death due to aging - hundred of millions with disability and disease, and more than 100,000 deaths every day - is now beginning to verge on preventable. We are just a handful of years away from first generation rejuvenation therapies, were the right research strategies fully funded at this time. That full funding is minuscule in the grand scheme of things: perhaps one to two billion dollars over the next ten to twenty years. The lower end of that range is about 5% of the budget of the National Institute on Aging over the same period of time, or about what is spent on pushing a single drug to market in the Big Pharma ecosystem, or less than than the sums wasted on US politics in a presidential election year, or less than the cost per machine for some military aircraft. Priorities.

Evidence for Longer Telomeres in Women

Women tend to live longer than men for reasons that remain much debated, an example of the way in which identifying cause and effect for natural variations in longevity can be very challenging. Telomeres, the caps of repeating DNA sequences at the end of chromosomes, tend to become shorter on average with age and illness. Some forms of telomere length measurement in some tissues may be useful as a biomarker of aging, but so far this hasn't proven to be straightforward. Given these two line items we might expect to find that women have longer telomeres than men, once the details are sorted out:

It is widely believed that females have longer telomeres than males, although results from studies have been contradictory. We carried out a systematic review and meta-analyses to test the hypothesis that in humans, females have longer telomeres than males and that this association becomes stronger with increasing age. Searches were conducted in EMBASE and MEDLINE and additional datasets were obtained from study investigators. Eligible observational studies measured telomeres for both females and males of any age, had a minimum sample size of 100 and included participants not part of a diseased group. We calculated summary estimates using random-effects meta-analyses. Heterogeneity between studies was investigated using sub-group analysis and meta-regression.

Meta-analyses from 36 cohorts (36,230 participants) showed that on average females had longer telomeres than males. There was little evidence that these associations varied by age group or cell type. However, the size of this difference did vary by measurement methods, with only Southern blot but neither real-time PCR nor FlowFISH showing a significant difference. This difference was not associated with random measurement error. Further research on explanations for the methodological differences is required.

Link: http://www.ncbi.nlm.nih.gov/pubmed/24365661

Reversing Glial Scars in Brain Injuries

Researchers here are working on a way to remove a type of scarring that occurs in brain injuries and forms of neurodegeneration:

When the brain is harmed by injury or disease, neurons often die or degenerate, but glial cells become more branched and numerous. These "reactive glial cells" initially build a defense system to prevent bacteria and toxins from invading healthy tissues, but this process eventually forms glial scars that limit the growth of healthy neurons. "There are more reactive glial cells and fewer functional neurons in the injury site, so we hypothesized that we might be able to convert glial cells in the scar into functional neurons at the site of injury in the brain."

[The researchers] began by studying how reactive glial cells respond to a specific protein, NeuroD1, which is known to be important in the formation of nerve cells in the hippocampus area of adult brains. They hypothesized that expressing NeuroD1 protein into the reactive glial cells at the injury site might help to generate new neurons - just as it does in the hippocampus. To test this hypothesis, his team infected reactive glial cells with a retrovirus that specifies the genetic code for the NeuroD1 protein.

In a first test, [researchers injected] NeuroD1 retrovirus into the cortex area of adult mice. The scientists found that two types of reactive glial cells - star-shaped astroglial cells and NG2 glial cells - were reprogrammed into neurons within one week after being infected with the NeuroD1 retrovirus.

In a second test, [researchers] used a transgenic-mouse model for Alzheimer's disease, and demonstrated that reactive glial cells in the mouse's diseased brain also can be converted into functional neurons. Furthermore, the team demonstrated that even in 14-month-old mice with Alzheimer's disease - an age roughly equivalent to 60 years old for humans - injection of the NeuroD1 retrovirus into a mouse cortex can still induce a large number of newborn neurons reprogrammed from reactive glial cells.

Link: http://news.psu.edu/story/298921/2013/12/19/research/breakthrough-could-one-day-help-sufferers-brain-injury-alzheimers

Amyloid Buildup in Aging Brains is Decreasing

We are living longer than our predecessors. Much of that is due to improvements in prevention of early life mortality relating to diet, control of infectious disease, sanitation, and similar items. A person who suffers many more infections and other health challenges in younger life, while eating a poor diet, will be more frail in later life. Thus methods of reducing early life mortality have the additional effect of extending life expectancy at older ages as well.

This first phase of technological improvement in overall wealth, medicine, and sanitation is largely done, the big initial gains secured. The present trend of interest is a slow upward movement in adult life expectancy driven by (a) continued smaller gains in control of disease and other forms of medicine for young adults, and (b) improvements in the treatment and control of age-related disease. The pace is slow in the latter case because age-related diseases are late stage manifestations of spiraling damage and dysfunction in the body, well past the point at which the web of biological consequences and relationships are easy to understand or treat.

Aging is an accumulation of damage: broken DNA, damaged molecular machinery, malprogrammed cells, metabolic waste products gumming up necessary functions, and more. Our biology can and does repair some of these issues on an ongoing basis, but as the damage accumulates even normally very efficient damage repair systems start to fail, driving a downward spiral of ever-faster dysfunction. Nonetheless, we are living longer and so we must expect that at any given age we are, on balance, less damaged than our ancestors. Since we are living measurably longer than people did even half a century ago (by something like ten years of life expectancy at birth, and more like five for adult life expectancy), this decline in damage must be visible over even such a short time frame.

Below you'll fine an example of such a measure. Amyloid is a precipitation of misfolded proteins that forms in old tissues in fibrils and other structures. There are numerous different types of amyloid, not all definitively tied to specific forms of age-related degeneration at this time, but if you have heard of amyloid then it is probably in connection with Alzheimer's disease (AD), in which amyloid buildup is thought to play an important role. The presence of amyloid is a noteworthy difference between young and old tissue, and levels of amyloid tend to correlate with levels of dysfunction and disease.

Amyloid deposition is decreasing in aging brains

We compared amyloid deposition in autopsied cases aged 65 years and older who died between 1972 and 2006. We included consecutive cases for 1972-1975, 1980, 1985, 1990, 1995, and 2000-2006. We used linear regression models to assess period effects after adjustment for age, cognitive status, and neurofibrillary tangle (NFT) staging. We calculated amyloid/NFT stage ratios to account for possible changes in AD prevalence/severity over time.

Mean amyloid stage was significantly related to year of death in the total population (1,599 cases, mean age 82 ± 8 years) and decreased 24% in 1,265 individuals without dementia. This decrease was particularly marked in the oldest age groups; people 85 years and older in 2006 had less amyloid deposition compared with those aged 75 to 84 years in 1972. Recent cohorts had lower amyloid deposition. The amyloid/NFT stage ratio [decreased], confirming that more recent cases had less amyloid despite higher NFT densities.

The strong cohort effect we describe [provides] preclinical evidence supporting recently described decreases in AD incidence.

Data to Bolster the Usual Explanation as to Why Conscientious People Live Longer

In a better world, researchers who presently spend their time figuring out how and why personality traits correlate to life expectancy would instead be working on rejuvenation treatments. Alas, most of the study of aging is just that - study, with little to no interest in producing treatments. Here, scientists provide additional data to support the usual explanation as to why conscientious people live longer: they are taking better care of their health by refraining from smoking, engaging in regular exercise, not carrying excess fat tissue, and so forth. No doubt they are also making better use of available preventative and other medical services, but that isn't examined in this study.

Personality traits predict both health behaviors and mortality risk across the life course. However, there are few investigations that have examined these effects in a single study. Thus, there are limitations in assessing if health behaviors explain why personality predicts health and longevity. Utilizing 14-year mortality data from a national sample of over 6,000 adults from the Midlife in the United States Study, we tested whether alcohol use, smoking behavior, and waist circumference mediated the personality-mortality association.

After adjusting for demographic variables, higher levels of Conscientiousness predicted a 13% reduction in mortality risk over the follow-up. Structural equation models provided evidence that heavy drinking, smoking, and greater waist circumference significantly mediated the Conscientiousness-mortality association by 42%. The current study provided empirical support for the health-behavior model of personality - Conscientiousness influences the behaviors persons engage in and these behaviors affect the likelihood of poor health outcomes.

Link: http://www.ncbi.nlm.nih.gov/pubmed/24364374

A Glance at Reflexive Opposition to Radical Life Extension

This columnist sees the signs of progress, thinks that extended longevity is plausible, but rejects radical life extension on the flimsy grounds that only death gives life meaning and removes the possibility of stasis. This seems particularly silly given that, I'm sure, this isn't someone who would advocate moving life expectancy back to where it was a century or two ago. So would he argue that life is less meaningful now, more of a "featureless expanse" as he puts it?

Death doesn't give life meaning - it strips meaning, and everything else, from us. Being alive is what allows us to inject meaning into life, and for so long as you are alive you can be a font of meaning if that's what drives you. We can draw lines and calculate totals and change careers and directions wherever we want, and then start over to work on something new and interesting. This already happens constantly throughout life, just the same as it did a century or two ago, and just the same as it will when people live far longer in good health.

The buzz around radical life extension is such that the dot-com gurus who brought us the likes of Google and PayPal now find themselves laser-focused on an Age of Longevity, as if transforming our lives was not enough whereas doubling them through moonshot thinking would be an incontrovertible contribution to human progress. Connectivity was O.K., but conjuring super-centenarians will be better. Larry Page, the chief executive of Google, and Peter Thiel, the Silicon Valley billionaire, early investor in Facebook and co-founder of PayPal, are among those who, in separate ventures, have aging in their cross hairs.

"If people think they are going to die, it is demotivating," Thiel told me. "The idea of immortality is motivational." He described his ideas as "180 degrees the opposite" of Steve Jobs's, who once said: "Remembering that you are going to die is the best way I know to avoid the trap of thinking you have something to lose. You are already naked. There is no reason not to follow your heart." It is probably wise to take Thiel's idea of an end to aging (or at least its radical postponement) seriously. Any extrapolation from technological progress over the past quarter-century makes the notion plausible. At least seriously enough to ask the question: Do we want this Shangri-La?

This year, the Pew Research Center found that in the United States, where current life expectancy is 78.7 years, 56 percent of American adults said they would not choose to undergo medical treatments to live to 120 or more. This resistance to the super-centenarian dream demonstrates good sense. Immortality - how tempting, how appalling! What a suffocating trick on the young! Death is feared, but it is death that makes time a living thing. Without it life becomes a featureless expanse. I fear death, up to a point, but would fear life without end far more: All those people to see over and over again, worse than Twitter with limitless characters.

Link: http://www.nytimes.com/2013/12/25/opinion/cohen-when-im-sixty-four.html

Aubrey de Grey Explains the Role of Mitochondrial Mutations in Aging, and What to Do About It

The SENS Research Foundation (SRF), cofounded by biogerontologist and advocate Aubrey de Grey, funds work on the foundation science needed for tomorrow's rejuvenation therapies. We age and die because the operation of our metabolism generates various forms of cellular and molecular damage, some fraction of which goes unrepaired. Like rust, it accumulates and degrades the operation of organs and tissues to cause age-related disease and, ultimately, death. Work aimed at treating and repairing the root causes of aging is arguably the most important research presently taking place today: even if we combine every other cause of human suffering and death into one total, that toll is only half of the harm caused by aging.

In addition to funding research, the SENS Research Foundation staff and supporters also engage in advocacy relating to rejuvenation research: education, raising awareness, and fundraising. Too few scientists are engaged, there is far too little funding considering the gains that might be obtained comparatively soon with a suitable large-scale research program, and the public is largely ignorant and indifferent, even as they age to death, with more than hundred thousand lives lost to aging every day.

One aspect of the Foundation's outreach efforts is a growing YouTube video library of lectures and presentations by researchers in the field. A recent addition has Aubrey de Grey walking through the role of mitochondrial DNA damage, the present state of knowledge in the field, and what might be done to reverse this contribution to degenerative aging:

In this video, SRF Chief Science Officer Dr. Aubrey de Grey discusses mitochondrial mutations, their role in aging, and the SENS approach to combating their deleterious effects. Dr. de Grey opens his lecture by describing the structure of mitochondrial DNA (mtDNA) in humans. In particular, he explains that only thirteen protein-encoding mitochondrial genes actually reside in mitochondria. Throughout the course of human evolution, over a thousand other mitochondrial genes have migrated to the nuclear genome.

Next, he explains the major theories developed between the 1970 and the present that aimed to explain the role of mtDNA mutations in aging. During his discussion of the most recent theoretical ground, Dr. de Grey explains his own contribution to the field: an alternative hypothesis to explain how clonal expansion of mutant mitochondria might occur. He then turns to therapeutic strategies and discusses the three main mechanisms by which scientists might intervene in mitochondrial aging.

Dr. de Grey closes by describing the mechanism SRF finds most promising: inserting the thirteen protein-encoding mitochondrial genes into the nucleus modified in such a way that the corresponding RNA transcripts or protein-products can be imported into the mitochondria.

Embrace Your Eminently Sensible Fear of Death

Coming to terms with a personal future of disability, pain, and then death due to aging is very human. But coming to terms is one step removed from complacency, and the world is complacent about aging and the staggering toll of death and suffering it causes. Thus research into prevention of aging and treatments that might remove this death and suffering languish with little funding and interest, and the populace go about their days doing their best to ignore the fact that they are corroding away inside. If aging were treatable, no-one would want to go back to when it was not - that would be a nonsensical proposition, like restoring smallpox and famine. Yet all too few people today care to help us move forward into a better world.

Is there a person alive today who does not fear dying? Well yes, if they are asleep or in a coma. But most of us, while we are awake and going about our business, harbour a deep-seated fear of dying. ("Thanatophobia", in case anyone was wondering, being Greek for "fear of death".) . Now the question is what to do about it, the two opposing extremes being: try to repress it as much as possible, or embrace it with all your being. Repressing it was my first strategy. I had no idea what to do with this fear, except that I wanted it to go away. And my strategy for making it go away was essentially to not think about it. And that worked, most of the time.

One very good reason for repressing thanatophobia is that if we don't it can drive us nuts. Nobody can tolerate being scared the whole time, and the risk - even, arguably, the certainty - of dying is always there. So we must suppress it. We wouldn't have it, however, if it wasn't serving a useful purpose, and it is also thanatophobia that makes us look before we cross the road. So while there are times when we must suppress it, there are other times when we do and must embrace it.

So far this is nothing that should be particularly shocking for anyone. What is shocking for many people, however, is the possibility that we might develop technology that extends life well beyond our current life-spans. And the reason it is shocking, in my view, is that it interferes with people's delicate strategies for managing their thanatophobia. Anything that reminds people that they are not only likely (perhaps even certain) to die, but that they are terrified of this prospect, tends to horrify them. So they enter what Aubrey de Grey has described as the "pro-aging trance", in which they convince themselves that since aging (and eventual death) is inevitable it must be desirable, and that because it is desirable it must also be inevitable.

What this means, in my view, is that whatever we think of the pros and cons of radical life extension, if we are to steer ourselves as individuals and as a species through the "bottleneck" of the next few decades, we need to make greater efforts to embrace our fear of death. We need to allow ourselves to be aware of that fear, and allow it to motivate us, without completely taking over.

Link: http://ieet.org/index.php/IEET/more/wicks20131222

A Heart That Beats for 500 Years

The ocean quahog species of Arctica islandica can live for at least 500 years and individuals appear to undergo comparatively little in the way of obvious degeneration across that span. Many species of bivalve live only a couple of years, and this very large range of life spans in similar animals has attracted researchers who wish to uncover the molecular biology that determines longevity.

Study of negligibly senescent animals may provide clues that lead to better understanding of the cardiac aging process. To elucidate mechanisms of successful cardiac aging, we investigated age-related changes in proteasome activity, oxidative protein damage and expression of heat shock proteins, inflammatory factors, and mitochondrial complexes in the heart of the ocean quahog Arctica islandica, the longest-lived noncolonial animal (maximum life span potential: 508 years).

We found that in the heart of A. islandica the level of oxidatively damaged proteins did not change significantly up to 120 years of age. No significant aging-induced changes were observed in caspase-like and trypsin-like proteasome activity. Chymotrypsin-like proteasome activity showed a significant early-life decline, then it remained stable for up to 182 years. No significant relationship was observed between the extent of protein ubiquitination and age. In the heart of A. islandica, an early-life decline in expression of HSP90 and five mitochondrial electron transport chain complexes was observed. We found significant age-related increases in the expression of three cytokine-like mediators (interleukin-6, interleukin-1β, and tumor necrosis factor-α) in the heart of A. islandica.

Collectively, in extremely long-lived molluscs, maintenance of protein homeostasis likely contributes to the preservation of cardiac function. Our data also support the concept that low-grade chronic inflammation in the cardiovascular system is a universal feature of the aging process, which is also manifest in invertebrates.

Link: http://dx.doi.org/10.1093/gerona/glt201

A New Approach to Myostatin-Related Muscle Growth

Blocking myostatin has been shown to boost muscle growth and regeneration in various species. There are even a few natural human myostatin mutants, but that is a rare genetic occurrence. For some years now researchers have been investigating means to manipulate myostatin levels and related signaling as a therapy for age-related loss of muscle mass and strength, as well as for various other medical conditions in which wasting of muscles plays a role. This, like many forms of modern medical research, aims to produce a form of compensatory change, potentially beneficial but in no way addressing root causes to prevent progression of the underlying condition.

Researchers here have moved on past myostatin and further down the chain of signals and molecular mechanisms to find a novel place to intervene in order to boost muscle growth in mice and humans. So far results are promising: if this treatment turns out to produce few to no side-effects, it is the sort of thing that everyone could benefit from. That said, again, it doesn't address root causes of degenerative muscle loss with aging - something that needs to be accomplished in order to reliably and most effectively extend healthy life.

New Compound Could Reverse Loss of Muscle Mass in Cancer and Other Diseases

The new compound (BYM338) acts to prevent muscle wasting by blocking a receptor that engages a cellular signaling system that exists to put the brakes on muscle development when appropriate. But sometimes those brakes are activated inappropriately, or are stuck on.

A variety of signals can activate the receptor. Prior to development of BYM338, compounds developed to block these molecules were blunt instruments, either trapping all incoming signals (which stimulated muscle growth but also caused harmful side effects) or blocking just a single receptor activator (providing only tepid growth stimulation.) BYM338 was designed to be in the Goldilocks zone (just right.)

In the study the compound boosted muscle mass 25 to 50 percent and increased strength in animal models. Those gains were significantly superior to those of compounds that blocked a single receptor activator. Clinical trials are currently underway. Preliminary data on the antibody was promising enough to have it designated a breakthrough therapy by the US Food and Drug Administration for sporadic inclusion body myositis, a rare muscle wasting disease with no approved therapies.

Here is a link to the paper - the PDF format full version is also presently available if you'd like to wade in to the details.

An Antibody Blocking Activin type II Receptors Induces Strong Skeletal Muscle Hypertrophy and Protects from Atrophy

The myostatin/Activin type II receptor (ActRII) pathway has been identified as critical in regulating skeletal muscle size. Several other ligands, including GDF11 and the Activins, signal through this pathway, suggesting that the ActRII receptors are major regulatory nodes in the regulation of muscle mass.

We have developed a novel, human anti-ActRII antibody ("Bimagrumab", aka BYM338) to prevent binding of ligands to the receptors, and thus inhibit downstream signaling. BYM338 enhances differentiation of primary human skeletal myoblasts, and counteracts the inhibition of differentiation induced by myostatin or Activin A.

BYM338 dramatically increases skeletal muscle mass in mice, beyond sole inhibition of myostatin as detected by comparing the antibody with a myostatin inhibitor. A mouse version of the antibody induces enhanced muscle hypertrophy in myostatin-mutant mice, further confirming a beneficial effect on muscle growth through blockade of ActRII ligands beyond myostatin inhibition alone.

A Complex Relationship Between Mitochondrial Haplogroups and Natural Variations in Longevity

Mitochondria, the power plants of the cell, bear their own mitochondrial DNA (mtDNA) that is inherited from the mother. There are a range of common variants of human mitochondrial DNA known as haplogroups, and given that mitochondria are important in aging there is an expectation that some of the natural variation in human longevity can be explained via haplogroup differences. Indeed, there is evidence to suggest that some haplogroups are better than others when it comes to life expectancy, all other things being equal.

These effects are not large in the grand scheme of things, however, and as for everything involving the genetics of longevity the underlying mechanisms and relationships are complicated:

To re-examine the correlation between mtDNA variability and longevity, we examined mtDNAs from samples obtained from over 2200 ultranonagenarians (and an equal number of controls) collected within the framework of the GEHA EU project. The samples were categorized by high-resolution classification, while about 1300 mtDNA molecules (650 ultranonagenarians and an equal number of controls) were completely sequenced.

Sequences, unlike standard haplogroup analysis, made possible to evaluate for the first time the cumulative effects of specific, concomitant mtDNA mutations, including those that per se have a low, or very low, impact. In particular, the analysis of the mutations occurring in different OXPHOS complex showed a complex scenario with a different mutation burden in 90+ subjects with respect to controls.

These findings suggested that mutations in subunits of the OXPHOS complex I had a beneficial effect on longevity, while the simultaneous presence of mutations in complex I and III (which also occurs in J subhaplogroups involved in LHON) and in complex I and V seemed to be detrimental, likely explaining previous contradictory results. On the whole, our study, which goes beyond haplogroup analysis, suggests that mitochondrial DNA variation does affect human longevity, but its effect is heavily influenced by the interaction between mutations concomitantly occurring on different mtDNA genes.

Link: http://dx.doi.org/10.1111/acel.12186

Examining the Opening Stages of Alzheimer's Disease

Researchers here add data to the picture of the early stages of Alzheimer's disease:

"It has been known for years that Alzheimer's starts in a brain region known as the entorhinal cortex. But this study is the first to show in living patients that it begins specifically in the lateral entorhinal cortex, or LEC. The LEC is considered to be a gateway to the hippocampus, which plays a key role in the consolidation of long-term memory, among other functions. If the LEC is affected, other aspects of the hippocampus will also be affected."

The study also shows that, over time, Alzheimer's spreads from the LEC directly to other areas of the cerebral cortex, in particular, the parietal cortex, a brain region involved in various functions, including spatial orientation and navigation. The researchers suspect that Alzheimer's spreads "functionally," that is, by compromising the function of neurons in the LEC, which then compromises the integrity of neurons in adjoining areas.

A third major finding of the study is that LEC dysfunction occurs when changes in tau and amyloid precursor protein (APP) co-exist. "The LEC is especially vulnerable to Alzheimer's because it normally accumulates tau, which sensitizes the LEC to the accumulation of APP. Together, these two proteins damage neurons in the LEC, setting the stage for Alzheimer's."

"Now that we've pinpointed where Alzheimer's starts, and shown that those changes are observable using fMRI, we may be able to detect Alzheimer's at its earliest preclinical stage, when the disease might be more treatable and before it spreads to other brain regions." In addition, say the researchers, the new imaging method could be used to assess the efficacy of promising Alzheimer's drugs during the disease's early stages.

Link: http://www.eurekalert.org/pub_releases/2013-12/cumc-ssw121713.php

A Brace of Papers from the Longevity Genetics Community

You'll find quite a few papers on longevity and genetics in the preprint queue of Current Vascular Phamacology at the moment. This is a portion of the output of that part of the research community focused on developing a full understanding of the molecular biology of how aging progresses and varies between individuals and species. Biology is fantastically complex, and obtaining that full understanding will be a much, much more challenging endeavor than merely successfully treating or reversing aging.

Treating and even curing aging are goals that might be achieved without a full understanding of exactly how aging progresses. Consider this: you don't need anything even close to a full molecular model of the progression of rust to greatly extend the life of metal equipment through scrubbing and protective coating. Exactly the same argument about knowledge and action can be applied to biology and medicine. Knowing what the damage is and having a complete understanding of how that damage progresses to cause the visible symptoms of aging are two very different things, the latter much more complex than the former, and only the former actually needed to produce useful therapies.

Nonetheless, most of the present work and funding in the aging science community is focused on developing an understanding of how degenerative aging progresses, not on damage repair and treatment of aging. So most of the output of the research community looks much along the lines of these first few papers I'm going to point out today.

The Challenges in Moving from Ageing to Successful Longevity

During the last decades survival has significantly improved and centenarians are becoming a fast-growing group of the population. Genetic factors contribute to the variation of human life span by around 25%, which is believed to be more profound after 85 years of age. It is likely that multiple factors influence life span and we need answers to questions such as: 1) What does it take to reach 100?, 2) Do centenarians have better health during their lifespan compared with contemporaries who died at a younger age?, 3) Do centenarians have protective modifications of body composition, fat distribution and energy expenditure, maintain high physical and cognitive function, and sustained engagement in social and productive activities?, 4) Do centenarians have genes which contribute to longevity?, 5) Do centenarians benefit from epigenetic phenomena?, 6). Is it possible to influence the transgenerational epigenetic inheritance (epigenetic memory) which leads to longevity?, 7) Is the influence of nutrigenomics important for longevity?, 8) Do centenarians benefit more from drug treatment, particularly in primary prevention?, and, 9) Are there any potential goals for drug research?

Genes Of Human Longevity: An Endless Quest?

Human longevity is a complex trait which genetics, epigenetics, environmental and stochasticity differently contribute to. To disentangle the complexity, our studies on genetics of longevity were, at the beginning, mainly focused on the extreme phenotypes, i.e. centenarians who escaped the major age-related diseases compared with cross sectional cohorts.

In association studies on candidate genes many SNPs, positively or negatively correlated with longevity have been identified. On the other hand, the identification of longevity-related genes does not explain the mechanisms of healthy aging and longevity, but it opens a huge amount of questions on epigenetic contribution, gene regulation and the interactions with essential genomes, i.e. mitochondrial DNA and microbiota.

Centenarian Offspring: a model for Understanding Longevity

A main objective of current medical research is the improving of life quality of elderly people as priority of the continuous increase of ageing population. Accordingly, the research interest is focused on understanding the biological mechanisms involved in determining the positive ageing phenotype, i.e. the centenarian phenotype.

Centenarians have been used as an optimal model for successful ageing. However, it is characterized by several limitations, i.e. the selection of appropriate controls for centenarians and the use itself of the centenarians as a suitable model for healthy ageing. Thus, the interest has been centered on centenarian offspring, healthy elderly people. They may represent a model for understanding exceptional longevity for the following reasons: to exhibit a protective genetic background, cardiovascular and immunological profile as well as a reduced rate of cognitive decline than age-matched people without centenarian relatives.

Phenotypes and Genotypes of High Density Lipoprotein Cholesterol in Exceptional Longevity

A change in the lipoprotein profile is a metabolic hallmark of aging and has been the target for modern medical developments. Although pharmaceutical interventions aimed at lipid lowering substantially decrease the risk of cardiovascular disease, they have much less impact on mortality and longevity. Moreover, they have not affected death from other age-related diseases.

In this review we focus on high density lipoprotein (HDL) cholesterol, the levels of which are either elevated or do not decrease as would be expected with aging in centenarians, and which are associated with lower prevalence of numerous age-related diseases; thereby, suggesting a potential HDL-mediated mechanism for extended survival. We also provide an update on the progress of identifying longevity-mediating lipid genes, describe approaches to discover longevity genes, and discuss possible limitations. Implicating lipid genes in exceptional longevity may lead to drug therapies that prevent several age-related diseases, with such efforts already on the way.

It has to be said, however, that some areas of research are close enough to the development of actual rejuvenation treatments - those addressing at least some of the root cause damage of aging rather than downstream consequences - that even the scientific mainstream is coming around to the idea. The impact of cellular senescence on aging is one such field, as several obvious and existing applications of medical technology may aid in removal of the senescent cells that accumulate with age, and early work in mice confirms that such treatments should prove helpful:

Cellular Senescence in Ageing, Age-Related Disease and Longevity

Cellular senescence is the state of permanent inhibition of cell proliferation. There is mounting evidence that senescent cells contribute to ageing and age-related disease by generating a low grade inflammation state (senescence-associated secretory phenotype-SASP). Even though cellular senescence is a barrier for cancer it can, paradoxically, stimulate development of cancer via proinflammatory cytokines. There is evidence that senescent vascular cells, both endothelial and smooth muscle cells, participate in atherosclerosis and senescent preadipocytes and adipocytes have been shown to lead to insulin resistance.

Thus, modulation of cellular senescence is considered as a potential pro-longevity strategy. It can be achieved in several ways like: elimination of selected senescent cells, epigenetic reprogramming of senescent cells, preventing cellular senescence or influencing the secretory phenotype. Some pharmacological interventions have already been shown to have promising activity in this field.

Life Extension in Mice Via p66Shc Refuted

There are many years of studies showing that p66Shc deficiency in mice produces resistance to a number of age related conditions, lowered inflammation, and extended life. Here, however, researchers undertake a more rigorous study and rule out life extension. This is a not infrequent event in the genetics of longevity: a result goes unchallenged for the better part of a decade only to be later refuted when more funding arrives due to increased interest.

The signaling molecule p66Shc is often described as a longevity protein. This conclusion is based on a single life span study that used a small number of mice. The purpose of the present studies was to measure life span in a sufficient number of mice to determine if longevity is altered in mice with decreased Shc levels (ShcKO). Studies were completed at UC Davis and the European Institute of Oncology (EIO).

At UC Davis, male C57BL/6J wild type and Shc knockout (ShcKO) mice were fed 5% or 40% calorie-restricted (CR) diets. In the 5% CR group, there was no difference in survival curves between genotypes. There was also no difference between genotypes in prevalence of neoplasms or other measures of end-of-life pathology. At 40% calorie restriction group, 70th percentile survival was increased in ShcKO, while there were no differences between genotypes in median or subsequent life span measures.

At EIO, there was no increase in life span in ShcKO male or female mice on C57BL/6J, 129Sv, or hybrid C57BL/6J-129Sv backgrounds. These studies indicate that p66Shc is not a longevity protein. However, additional studies are needed to determine the extent to which Shc proteins may influence the onset and severity of specific age-related diseases.

Link: http://dx.doi.org/10.1093/gerona/glt198

Proposing a Microvascular Theory of Aging

It seems that everyone has their own theory of aging these days, something that might be taken as a sign of increased interest in the field:

One of the main features of human aging is the loss of adult stem cell homeostasis. Organs that are very dependent on adult stem cells show increased susceptibility to aging, particularly organs that present a vascular stem cell niche. Reduced regenerative capacity in tissues correlates with reduced stem cell function, which parallels a loss of microvascular density (rarefraction) and plasticity. Moreover, the age-related loss of microvascular plasticity and rarefaction has significance beyond metabolic support for tissues because stem cell niches are regulated co-ordinately with the vascular cells. In addition, microvascular rarefaction is related to increased inflammatory signals that may negatively regulate the stem cell population. Thus, the processes of microvascular rarefaction, adult stem cell dysfunction, and inflammation underlie the cycle of physiological decline that we call aging.

Observations from new mouse models and humans are discussed here to support the vascular aging theory. We develop a novel theory to explain the complexity of aging in mammals and perhaps in other organisms. The connection between vascular endothelial tissue and organismal aging provides a potential evolutionary conserved mechanism that is an ideal target for the development of therapies to prevent or delay age-related processes in humans.

Link: http://online.liebertpub.com/doi/full/10.1089/rej.2013.1440

Increasing NAD to Reduce HIF-1 Reverses Age-Related Inflammation and Insulin Resistance in Muscle Tissue

There has been a fair amount of research into the effects of manipulating hypoxia-inducible factor 1 (HIF-1) in lower animals, mostly nematode worms I believe. Interestingly this is one of the few manipulations in which either reducing or increasing levels of the protein in question can increase longevity. This is a sign that there is probably significant complexity involved in this outcome, such as in relationships with other mechanisms or that the effects of changes are tied to specific tissues in the body or locations within cells.

Researchers are today announcing - and, I think, overhyping - new research into a way to manipulate HIF-1 that is apparently an offshoot of past and ongoing research into sirtuins and aging. When considering the source of the work, the overhyping is perhaps less of a surprise than it might otherwise be: this is a group with a very large sunk cost behind them and little to show for it. Deep pockets nonetheless still back continued efforts, and they have a lot of experience with the press. This is a formula that leads to breathless press materials touting rejuvenation. The people who are really, actually working on rejuvenation are more restrained these days.

So let's start by noting that I disagree with the title of the article quoted below. I think that (a) these researchers have found an interesting set of interactions to help explain why manipulation of HIF-1 can affect longevity, and (b) the changing levels of that and various related proteins with advancing age are responses to accumulated cellular damage. Perhaps the most relevant damage is mitochondrial, given that cycling of NAD is involved in the chain of unpleasant results that unfold when mitochondrial DNA becomes damaged, or perhaps it is something else.

So to my eyes what they focus on isn't a cause, it's a consequence. The fastest way to see what causes what at this point is to work on repairing the known forms of damage rather than tracing back all of the myriad complexity of relationships and feedback loops in the cell - a task that would take substantially longer than just building means of biological repair for our cells and other small-scale structures.

A New - and Reversible - Cause of Aging

Ana Gomes, a postdoctoral scientist in the Sinclair lab, had been studying mice in which [the] SIRT1 gene had been removed. While they accurately predicted that these mice would show signs of aging, including mitochondrial dysfunction, the researchers were surprised to find that most mitochondrial proteins coming from the cell's nucleus were at normal levels; only those encoded by the mitochondrial genome were reduced.

As Gomes and her colleagues investigated potential causes for this, they discovered an intricate cascade of events that begins with a chemical called NAD and concludes with a key molecule that shuttles information and coordinates activities between the cell's nuclear genome and the mitochondrial genome. Cells stay healthy as long as coordination between the genomes remains fluid. SIRT1's role is intermediary, akin to a security guard; it assures that a meddlesome molecule called HIF-1 does not interfere with communication.

For reasons still unclear, as we age, levels of the initial chemical NAD decline. Without sufficient NAD, SIRT1 loses its ability to keep tabs on HIF-1. Levels of HIF-1 escalate and begin wreaking havoc on the otherwise smooth cross-genome communication. Over time, the research team found, this loss of communication reduces the cell's ability to make energy, and signs of aging and disease become apparent.

While the breakdown of this process causes a rapid decline in mitochondrial function, other signs of aging take longer to occur. Gomes found that by administering an endogenous compound that cells transform into NAD, she could repair the broken network and rapidly restore communication and mitochondrial function. If the compound was given early enough - prior to excessive mutation accumulation - within days, some aspects of the aging process could be reversed.

Examining muscle from two-year-old mice that had been given the NAD-producing compound for just one week, the researchers looked for indicators of insulin resistance, inflammation and muscle wasting. In all three instances, tissue from the mice resembled that of six-month-old mice. In human years, this would be like a 60-year-old converting to a 20-year-old in these specific areas.

Natural Human Longevity is Accompanied by Increased Healthspan

There has been an increasing level of research into natural variations in human longevity in recent years, largely focused on genetics and metabolism in long-lived families and populations. This produces a fair amount of epidemiological data too, which allows for this sort of analysis to be conducted:

Hypothesizing that members of families enriched for longevity delay morbidity compared to population controls and approximate the health-span of centenarians, we compared the health-spans of older generation subjects of the Long Life Family Study (LLFS) to controls without family history of longevity and to centenarians of the New England Centenarian Study (NECS).

We estimated hazard ratios, the ages at which specific percentiles of subjects had onsets of diseases, and the gain of years of disease-free survival in the different cohorts compared to referent controls. Compared to controls, LLFS subjects had lower hazards for cancer, cardiovascular disease, severe dementia, diabetes, hypertension, osteoporosis, and stroke.

The age at which 20% of the LLFS siblings and probands had one or more age-related diseases was approximately 10 years later than NECS controls. While female NECS controls generally delayed the onset of age-related diseases compared with males controls, these gender differences became much less in the older generation of the LLFS and disappeared amongst the centenarians of the NECS. The analyses demonstrate extended health-span in the older subjects of the LLFS and suggest that this aging cohort provides an important resource to discover genetic and environmental factors that promote prolonged health-span in addition to longer life-span.

Link: http://www.frontiersin.org/Journal/10.3389/fpubh.2013.00038/full

Towards Printed Retinal Tissue

Researchers are working on tissue printing for structures in the retina, and this is an early proof of principle:

A group of researchers [have] used inkjet printing technology to successfully print cells taken from the eye for the very first time. The breakthrough [could] lead to the production of artificial tissue grafts made from the variety of cells found in the human retina and may aid in the search to cure blindness. At the moment the results are preliminary and provide proof-of-principle that an inkjet printer can be used to print two types of cells from the retina of adult rats - ganglion cells and glial cells. This is the first time the technology has been used successfully to print mature central nervous system cells and the results showed that printed cells remained healthy and retained their ability to survive and grow in culture.

"The loss of nerve cells in the retina is a feature of many blinding eye diseases. The retina is an exquisitely organised structure where the precise arrangement of cells in relation to one another is critical for effective visual function. Our study has shown, for the first time, that cells derived from the mature central nervous system, the eye, can be printed using a piezoelectric inkjet printer. Although our results are preliminary and much more work is still required, the aim is to develop this technology for use in retinal repair in the future."

Link: http://www.iop.org/news/13/dec/page_62164.html

December 2013 Issue of Rejuvenation Research

The latest issue of Rejuvenation Research is out this month. In the editorial, Aubrey de Grey of the SENS Research Foundation returns once more to a topic that puzzles many of us: the pervasive public disinterest when it comes to medical research to enable longer lives accompanies by extended health and youth.

Selling Anti-Aging Research: The Perils of Mixed Messages

A truth universally acknowledged within gerontology, as within any scientific discipline, is that the funding necessary for research in a given field is forthcoming from public sources only to the extent that the goals of such research are favored by the general public. As such, it has been a persistent source of frustration that biogerontology research remains rather far from the holy grail of delivering truly effective medical intervention, and thus that decision-makers over governmental research funding tend to deprioritize such research.

I strongly believe, based on my own quite extensive interaction with people from all walks of life who (for example) attend my talks, that the "Tithonus error" (that postponing aging would extend ill-health rather than health span) underpins most of the public's ambivalence concerning our field, despite gerontologists' vocal attempts to correct it. But be that as it may, the facts are these: fully 56% of the US public are unenthusiastic about living longer.

Maybe it's mostly the Tithonus error, but I must not overstate that case: in my experience, even those who are disabused of that misconception are uncannily prone to fall back on some other objection to such work (whether it be overpopulation, boredom, immortal dictators, whatever).

Over the decade I've been writing on this topic, I haven't come up with any better ideas on how to address this issue than to keep on bootstrapping and persuading: growing the number of supporters, writing more material, spreading knowledge, raising funds to further the production of research results that will help to persuade more people. It's a grind, but sooner or later the old, wrong ideas will suddenly wither away in the face of a significant number of people willing to call them out. All advocacy goes this way: when a cause seems to emerge from nowhere in the course of a few years, you can be certain that advocates were plugging away for the prior ten or twenty years, laying the groundwork, building arguments and support, and persuading a critical mass of people to join in, slowly but surely.

We've seen significant progress in attitudes to longevity science and extended lives over the years since the Methuselah Foundation and SENS Research Foundation have been in existence. But I still wish I had a better magic argument to open the eyes of those who hold to their disinterest in living longer. I don't think it exists, however: it really isn't a matter of facts. We have plenty of those, and they all support longer lives and the medical research needed to create greater human longevity. It is the stubborn resistance to even acknowledge the message of the research community that proves frustrating: for some years now researchers have been straightforwardly presenting healthy life extension as a plausible result of near future research - and yet all too few people care to listen.

Considering the Data on Mitochondrial DNA Damage in Aging

These researchers are concerned about the state of data for mitochondrial DNA damage in aging, suggesting that the research community doesn't in fact have enough data to demonstrate that work in mice is fully relevant to the human molecular biology of aging in this case:

A significant body of work, accumulated over the years, strongly suggests that damage in mitochondrial DNA (mtDNA) contributes to aging in humans. Contradictory results, however, are reported in the literature, with some studies failing to provide support to this hypothesis. With the purpose of further understanding the aging process, several models, among which mouse models, have been frequently used. Although important affinities are recognized between humans and mice, differences on what concerns physiological properties, disease pathogenesis as well as life-history exist between the two; the extent to which such differences limit the translation, from mice to humans, of insights on the association between mtDNA damage and aging remains to be established.

In this paper we revise the studies that analyze the association between patterns of mtDNA damage and aging, investigating putative alterations in mtDNA copy number as well as accumulation of deletions and of point mutations. Reports from the literature do not allow the establishment of a clear association between mtDNA copy number and age, either in humans or in mice. Further analysis, using a wide spectrum of tissues and a high number of individuals would be necessary to elucidate this pattern.

Likewise humans, mice demonstrated a clear pattern of age-dependent and tissue-specific accumulation of mtDNA deletions. Deletions increase with age, and the highest amount of deletions has been observed in brain tissues both in humans and mice. On the other hand, mtDNA point mutations accumulation has been clearly associated with age in humans, but not in mice. Although further studies, using the same methodologies and targeting a larger number of samples would be mandatory to draw definitive conclusions, the revision of the available data raises concerns on the ability of mouse models to mimic the mtDNA damage patterns of humans, a fact with implications not only for the study of the aging process, but also for investigations of other processes in which mtDNA dysfunction is a hallmark, such as neurodegeneration.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3843651/

Blocking miR-712 to Treat Atherosclerosis

This work is characteristic of much of modern medical development in that it does nothing to address underlying root causes of an age-related condition, but rather finds a way to partially patch over this one end result at a fairly late point in the chain of consequences.

[Researchers] have developed a potential treatment for atherosclerosis that targets a master controller of the process. In a twist, the master controller comes from a source that scientists had thought was leftover garbage. It is a micro RNA molecule, which comes from an unused template that remains after punching out ribosomes - workhorse protein factories found in all cells.

The treatment works by stopping the inflammatory effects of disturbed blood flow on cells that line blood vessels. In animal models of atherosclerosis, a drug that blocks the micro RNA can stop arteries from becoming blocked, despite the ongoing stress of high-fat diet. The micro RNA appears to function similarly in human cells. "We've known that aerobic exercise provides protection against atherosclerosis, partly by improving patterns of blood flow. Now we're achieving some insight into how. Healthy flow tunes down the production of bad actors like this micro RNA. Targeting it could form the basis for a therapeutic approach that could be translated with relative ease compared to other drugs."

Micro RNAs were recently discovered to be able to travel from cell to cell, and thus could orchestrate processes such as atherosclerosis. Out of all the micro RNAs the researchers examined, one in particular, called miR-712, was the micro RNA most strongly induced by disturbed blood flow in the atherosclerosis model system. In response to disturbed or unhealthy blood flow, endothelial cells produce miR-712, the researchers found. miR-712 in turn inhibits a gene called TIMP3, which under healthy flow conditions restrains inflammation in endothelial cells.

Link: http://www.eurekalert.org/pub_releases/2013-12/ehs-gat121613.php

Extending Life by Manipulating Metabolism Only Produces Dramatic Results in Short-Lived Species

I'm sure that you noticed recent research results demonstrating a five-fold increase in life span in nematode worms. That's actually only half as long as the present record for that species, but both approaches involved tinkering with genes associated with insulin-like signaling, one of the better studied areas of intersection between metabolism, genetics, and aging. The press picks up on this sort of thing and uses it to wave around wild comparisons with hypothetical 500-year human life spans; wild comparisons in the headline attract attention regardless of merit, and the press is in the attention business, not the truth, sense, and accuracy business. There isn't any merit of course: one thing that is pretty clear from the data of the past couple of decades is that ways of manipulating metabolism to slow aging only have dramatic outcomes in very short-lived species.

A good example is manipulation of growth hormone metabolism, such as by removing the growth hormone gene, or interfering with gene expression of growth hormone, or by blocking or removing growth hormone receptor. In mice the best of these methods extends life by 60-70%. There is, however, an analogous natural mutation in the human growth hormone receptor that leads to Laron dwarfism. Those with the condition do not appear to live any longer than the rest of us, but may be resistant to some age-related disease. That is quite a climb-down in comparison to the results in mice.

But we can see the same sort of trend when comparing effects in worms with effects in mice: the best of the methods of slowing aging explored to date produce much greater results in nematodes, which of course normally live for a fraction of a mouse life span.

This should all make sense if considered from the perspective of evolution. Why would species evolve the ability to extend life in response to circumstances, or evolve a toolkit that allows for easier subsequent evolution of altered life span, or evolve a general adaptability of life span? The usual answer stems from consideration of the metabolic response to calorie restriction: for a short-lived species surviving a famine to reproduce later requires a great lengthening of life. For a long-lived species that survival doesn't require any lengthening of life, but it does require other types of short-term resistance to privation. So the evolutionary pressures that emerge from environmental changes that proceed on a timescale of seasons are very different for short-lived species, but they are sufficiently ubiquitous across all of evolutionary time to have very deep roots in our ancestry.

The evidence to date obtained from myriad ways of slowing aging in mice, flies, and worms suggest that we shouldn't be terribly excited by even a tenfold extension of healthy life through present genetic engineering or similar approaches when it occurs in very short-lived animals. There is no good reason at this time to expect any of these strategies to achieve results of great consequence in humans. Researchers may find therapies that improve upon present-day marginal treatments for age-related conditions, but that is about it - a very poor showing in the grand scheme of things.

The future of human life extension is very different from this work: it will be based on direct repair of damage rather than altering metabolism to slow the accumulation of damage. Aging is damage, and removing that damage should constitute a reversal of aging. However, we have at this point very little data to use to understand how damage repair will differ in its outcome between short-lived and long-lived species. It wouldn't be unreasonable to expect partial repair - such as, say, partial clearance of AGEs or replacement of mitochondrial DNA or removal of some fraction of senescent cells - to have more of an effect on mouse life span than on human life span. But more data is needed: clearly it is the case that ongoing perfect damage repair should have exactly the same effect in mice and people, the result being agelessness and indefinite healthy life span.

Healthcare Costs Increase With Excess Weight

Past studies have shown that carrying around excess fat tissue harms you in all sorts of ways. One indirect way to measure the level of that harm is to look at medical costs - and indeed researchers have shown that lifetime medical costs increase when you are overweight, even though your life expectancy is reduced. Here is more of the same:

Health care costs increase in parallel with body mass measurements, even beginning at a recommended healthy weight. The researchers found that costs associated with medical and drug claims rose gradually with each unit increase in body mass index (BMI). Notably, these increases began above a BMI of 19, which falls in the lower range of the healthy BMI category. "Our findings suggest that excess fat is detrimental at any level."

Using health insurance claims data for 17,703 Duke employees participating in annual health appraisals from 2001 to 2011, the researchers related costs of doctors' visits and use of prescription drugs to employees' BMIs. Measuring costs related to doctors' visits and prescriptions, the researchers observed that the prevalence of obesity-related diseases increased gradually across all BMI levels. In addition to diabetes and hypertension - the two diseases most commonly associated with being overweight or obese - the rates of nearly a dozen other disease categories also grew with increases in BMI. Cardiovascular disease was associated with the largest dollar increase per unit increase in BMI.

The average annual health care costs for a person with a BMI of 19 was found to be $2,368; this grew to $4,880 for a person with a BMI of 45 or greater. Women in the study had higher overall medical costs across all BMI categories, but men saw a sharper increase in medical costs the higher their BMIs rose.

Link: http://www.eurekalert.org/pub_releases/2013-12/dumc-hcc121613.php

Generating Functional Kidney Tissue From Stem Cells

Researchers continue to make progress in producing small amounts of functional organ tissue from stem cells. This is an early step on the way to creating whole organs from a patient's own cells, but producing larger amounts of tissue is still limited by the need for engineered blood vessel networks - something that is proving to be a challenge. Here, researchers show off progress in producing small but functional kidney structures:

[Scientists] have grown the world's first kidney from stem cells - a tiny organ which could eventually help to reduce the wait for transplants. The breakthrough, published in the journal Nature Cell Biology, followed years of research and involved the transformation of human skin cells into an organoid - a functioning "mini-kidney" with a width of only a few millimetres.

Scientists are hoping to increase the size of future kidneys and believe the resulting organs will boost research and allow cheaper, faster testing of drugs. Within the next three to five years, the artificial organs could be used to allow doctors to repair damaged kidneys within the body, rather than letting diseases develop before proceeding with a transplant.

The process for developing the kidney was "like a scientific approach to cooking". The scientists methodically examined which genes were switched on and off during kidney development and then manipulated the skin cells into embryonic stem cells which could "self-organise" and form complex human structures. "The [researchers] spent years looking at what happens if you turn this gene off and this one on," he said. "You can eventually coax these stem cells through a journey - they [the cells] go through various stages and then think about being a kidney cell and eventually pop together to form a little piece of kidney."

Link: http://www.telegraph.co.uk/news/worldnews/australiaandthepacific/australia/10520058/Kidney-grown-from-stem-cells-by-Australian-scientists.html

Longevity Induces Virtue

When you have more to lose, you behave in a more civilized fashion. This is a fair theory to explain why - despite the industrialization of war and nationalism - violence has in fact decreased over recorded history, even over the past century. We have on balance become much wealthier, and that includes a wealth of healthy years in comparison to our ancestors. This alters the balance of risk and reward in favor of trade, cooperation, patience, peace, and long-term over short-term gains.

Can we expect this trend to continue? I don't see why not. We are nowhere near the point at which a near-certainty of future longevity stretches ahead for so far that it is pointless to plan: there are still retirement funds and a structure of life that focuses relentlessly on a beginning, an industrious middle, and an end. Talk to me again when centuries are on the table, and we'll see how people approach things then from the perspective of foresight and organization.

Here is an article that argues for the benefits of longevity from the point of view of civics and the practical philosophy of living one's live as best one can - with an look at what lies beneath everyday to decisions to be humane and cultivated:

Life Extension and Risk Aversion

A major benefit of longer lifespans is the cultivation of a wide array of virtues. Prudence and forethought are among the salutary attributes that the lengthening of human life expectancies - hopefully to the point of eliminating any fixed upper bound - would bring about. Living longer renders people more hesitant to risk their lives, for the simple reason that they have many more years to lose than their less technologically endowed ancestors.

​This is not science fiction or mere speculation; we see it already. In the Western world, average life expectancies increased from the twenties and thirties in the Middle Ages to the early thirties circa 1800 to the late forties circa 1900 to the late seventies and early eighties in our time. As Steven Pinker writes in his magnum opus, The Better Angels of Our Nature, the overall trend in the Western world (in spite of temporary spikes of conflict, such as the World Wars) has been toward greater peace and increased reluctance of individuals to throw their lives away in armed struggles for geopolitical gain. Long-term declines in crime rates, automobile fatalities, and even smoking have accompanied (and contributed to) rises in life expectancy. Economic growth and improvements in the technologies of production help as well. If a person has not only life but material comfort to lose, this amplifies the reluctance to undertake physical risks even further.

When life is long and good, humans move up on the hierarchy of needs. Not starving today ceases to be a worry, as does not getting murdered tomorrow. The true creativity of human faculties can then be directed toward addressing the grand, far more interesting and technologically demanding, challenges of our existence on this Earth.

The less likely a failure is to rob one of opportunities forever, the more likely humans will be to pursue the method of iterative learning and to discover new insights and improved techniques through a beneficent trial-and-error process, whose worst downsides will have been curtailed through technology and ethics. Life extension will lead us to avoid and eliminate the risks that should not exist, while enabling us to safely pursue the risks that could benefit us if approached properly.

Of the virtues brought by greater longevity, greater prosperity and more rapid progress will do the most to shape our future for the better. We are a young species in the grand scheme of things, and there is much left to accomplish. Given success in rejuvenation biotechnology development of the sort undertaken by the SENS Research Foundation many of us alive today will live on to see a golden future in which we expand from this world to form a society of ageless trillions, wealthy beyond measure, and blessed with a near complete understanding of physics, chemistry, and biology. In the long term all that matters is knowledge and technology: everything else is fleeting, including our lives if we don't move rapidly enough towards practical rejuvenation treatments.

A Look at the Damage Done By 7-ketocholesterol

One important component of aging is an inability of the body to break down some metabolic waste products that accumulate slowly over life. Small amounts are largely harmless, but by old age these accumulations become large enough and prevalent enough to cause disease. Atherosclerosis, for example, is associated with the buildup of oxidized cholesterols known as oxysterols, such as 7-ketocholesterol.

The SENS approach to removing this contribution to aging is medical bioremediation: find enzymes in wild bacteria species that can be adapted for use in human tissues to safely break down the problem waste products. Research has been ongoing at a low level of funding for a few years now, with 7-ketocholesterol as one of the early targets.

Here, researchers examine in more detail just how 7-ketocholesterol causes harm:

The damage of barrier tissues, such as the vascular endothelium and intestinal epithelium, may lead to disturbances of local immune homeostasis. The aim of the study was to assess and compare the effect of oxidized cholesterols (7-ketocholesterol and 25-hydroxycholesterol) on the barrier properties of human primary aortic endothelium (HAEC) and intestinal epithelium cells.

7-ketocholesterol [caused] extensive damage to the endothelial monolayer, while 25-hydroxycholesterol caused partial damage and did not affect the epithelial monolayer. 7-ketocholesterol, but not 25-hydroxycholesterol, increased endothelial cell apoptosis and decreased the viability of endothelial cells.

Oxidized cholesterols destroy the HAEC, but not the epithelial barrier, via cell apoptosis dependent on the site of oxidation. Damage to the endothelium by oxidized cholesterol may disrupt local homeostasis and provide open access to inner parts of the vascular wall for lipids, other peripheral blood-derived agents, and immune cells, leading to inflammation and atherogenesis.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826051/

Targeting Tau With Antibodies in Alzheimer's Disease

Researchers here apply an immune therapy approach to clearing out misfolded or otherwise damaged tau proteins implicated in the pathology of Alzheimer's disease:

Tau aggregation occurs in neurodegenerative diseases including Alzheimer's disease and many other disorders collectively termed tauopathies. Trans-cellular propagation of tau pathology, mediated by extracellular tau aggregates, may underlie pathogenesis of these conditions.

P301S tau transgenic mice express mutant human tau protein and develop progressive tau pathology. Using a cell-based biosensor assay, we screened anti-tau monoclonal antibodies for their ability to block seeding activity present in P301S brain lysates. We infused three effective antibodies or controls into the lateral ventricle of P301S mice for 3 months.

The antibodies markedly reduced hyperphosphorylated, aggregated, and insoluble tau. They also blocked development of tau seeding activity detected in brain lysates using the biosensor assay, reduced microglial activation, and improved cognitive deficits. These data imply a central role for extracellular tau aggregates in the development of pathology. They also suggest that immunotherapy specifically designed to block trans-cellular aggregate propagation will be a productive treatment strategy.

Link: http://dx.doi.org/10.1016/j.neuron.2013.07.046

An Evolutionary Programmed Aging Viewpoint

Josh Mitteldorf blogs fairly regularly on the topic of aging and longevity science. I believe that he and I are on much the same page when it comes to the necessity for greater funding and more rapid progress towards therapies to treat degenerative aging, and the plausibility of achieving radical life extension through medical technology. When it comes to the details of how to proceed, however, we are at opposite ends of the pool. Based on my reading of the field, I see aging as accumulated damage and the reactions to that damage, which means that SENS-like research focused on damage repair is the way to create rejuvenation. Mitteldorf, on the other hand, sees aging as a genetic program that creates damage. In his view damage repair will be ineffectual, and the research community should focus on adjusting the operation of metabolism such that its epigenetic patterns are restored to youthful levels - reversing the program, in other words. So he is in favor of the expansion of programs such as work on drugs to change TOR signaling, for example.

The types of life extension research that the two of us back couldn't be more different, and the predicted outcomes stand in opposition to one another. To a programmed aging advocate damage repair is a slow road to nowhere, while the aging as damage camp in turn see manipulation of metabolism and epigenetic patterns as a slow road to marginal treatments. Interestingly, the mainstream of the research community largely holds an aging as damage consensus, but they also largely work on ways to slow aging through metabolic manipulation, rather than aiming for damage repair. This I blame on the costly and extensive regulations associated with medical research and clinical application of medicine: if your work isn't a drug that can be targeted to a specific named disease, then getting it approved for use will be somewhere between an exceedingly expensive uphill battle and impossible. This reality is recognized and percolates back up the research chain to make it very hard to raise funding for even early stage research into anything that is new, radical, and different.

In any case, I see the programmed aging view as interesting but wrong. Everyone in the community, whether hypothesizing programmed aging or aging as damage, largely agrees on the facts in evidence, the differences between old and young tissue and other data. The interpretation of those facts is where the action is. Mitteldorf's views are similar in some ways but also a little different from those of the Russian gerontology community I've pointed out in past posts, and so seem worth reading through.

The Selfish Gene vs Multi-level Selection: Aging Doesn't Fit

Genes are evolved to promote their own replication, and also copies of themselves that exist in relatives. In the 1970s, the theory was extended by George Price to deal rigorously with groups that may or may not be related. This is now known as multi-level selection (MLS). There is an ongoing dialog in the evolutionary community about whether MLS is significant in nature, which is still the minority view. The majority continues to hold that everything should be explainable in terms of the selfish gene.

But aging cannot be explained by the selfish gene; and even with the considerably broader perspective of MLS, the evolution of aging remains problematic. What is missing from both systems is ecology. When species' interdependence is taken into account, it becomes possible to understand aging and many other cases where individuals sacrifice their own fitness to the community.

The Selfish Gene can't explain aging - but neither can Multi-level Selection

Last week, I discussed the gene-eyed view of evolution that came to dominate evolutionary theory of the 20th century. In the 1960s, this view hardened into a dogma, and provoked a reaction, in recognition of the many cooperative networks in nature that are difficult to explain in terms of "kin selection," the only recourse of the Selfish Gene.

I continue [here] with the science of multilevel selection (MLS), and talk about why aging is a tough nut to crack. Clearly the selfish gene paradigm is inadequate to explain aging. MLS provides a formal test for deciding whether a given trait can evolve via group selection, and according to these criteria, aging should not be able to evolve.

Where do we go from here? What is missing from both systems is ecology. When species' interdependence is taken into account, it becomes possible to understand aging and many other cases where individuals sacrifice their own fitness to the community.

Glycans as a Potential Biomarker of Aging

Researchers here uncover a set of characteristic molecular changes that correlate well with chronological and biological age. This is not the only such discovery in recent years: DNA methylation patterns are another candidate for biomarker of aging, and it may yet be the case that some form of telomere measurement might also do the job. It is important to have a good way to measure biological age, how damaged an individual is, as how else is the research community to effectively evaluate the first generation of prospective rejuvenation treatments when they arrive? The wait and see approach of life span studies is already far too expensive in time and money when carried out in laboratory mice, and certainly impractical in humans on an ongoing basis.

Fine structural details of glycans attached to the conserved N-glycosylation site significantly not only affect function of individual immunoglobulin G (IgG) molecules but also mediate inflammation at the systemic level.

By analyzing IgG glycosylation in 5,117 individuals from four European populations, we have revealed very complex patterns of changes in IgG glycosylation with age. Several IgG glycans (including FA2B, FA2G2, and FA2BG2) changed considerably with age and the combination of these three glycans can explain up to 58% of variance in chronological age, significantly more than other markers of biological age like telomere lengths. The remaining variance in these glycans strongly correlated with physiological parameters associated with biological age.

Thus, IgG glycosylation appears to be closely linked with both chronological and biological ages. Considering the important role of IgG glycans in inflammation, and because the observed changes with age promote inflammation, changes in IgG glycosylation also seem to represent a factor contributing to aging.

Link: http://dx.doi.org/10.1093/gerona/glt190

Proposing Alzheimer's as a Mitochondrial Disease

This is an interesting viewpoint on the underlying causes of Alzheimer's disease, but one with little to no support in the research community at the present time. They are not the only group to think that removing beta amyloid will do little to address Alzheimer's symptoms, however, and there has been a shift in recent years to begin to focus on amyloid precursor protein instead:

Ten years ago we first proposed the Alzheimer's disease (AD) mitochondrial cascade hypothesis. This hypothesis maintains that gene inheritance defines an individual's baseline mitochondrial function; inherited and environmental factors determine rates at which mitochondrial function changes over time; and baseline mitochondrial function and mitochondrial change rates influence AD chronology. Our hypothesis unequivocally states in sporadic, late-onset AD, mitochondrial function affects amyloid precursor protein (APP) expression, APP processing, or beta amyloid (Aβ) accumulation and argues if an amyloid cascade truly exists, mitochondrial function triggers it.

We now review the state of the mitochondrial cascade hypothesis, and discuss it in the context of recent AD biomarker studies, diagnostic criteria, and clinical trials. Our hypothesis predicts that biomarker changes reflect brain aging, new AD definitions clinically stage brain aging, and removing brain Aβ at any point will marginally impact cognitive trajectories. Our hypothesis, therefore, offers unique perspective into what sporadic, late-onset AD is and how to best treat it.

Link: http://dx.doi.org/10.1016/j.bbadis.2013.09.010

Fivefold Extension of Life Span in Nematode Worms

The next logical step for researchers after discovering a range of different ways to slow aging in laboratory animals is to try these methodologies in combination. Many in fact work to extend healthy life through overlapping mechanisms, and so much of the incentive for the researchers is not in fact to produce greater extension of longevity, but rather to get a better handle on which of these methods of life extension are just different ways of triggering the same underlying processes.

Some years ago, researchers demonstrated a tenfold increase in life span in nematode worms. Short-lived lower animals have so far shown a much greater potential extension of life than longer-lived higher animals; for example the record in mice is only a 60-70% extension of life span, even though very similar approaches are presently used to alter metabolism to enhance longevity in species such as worms, flies, and mice. In humans we'd expect the benefits to be much smaller again: the equivalent natural mutants in human populations don't appear to live longer than the rest of us, although studies suggest that they are more resistant to some age-related disease.

That tenfold increase in nematode life spans was achieved through a single gene mutation in the insulin / insulin-like growth factor 1 pathway. Here, however researchers achieve a fivefold increase by combining methods that individually produce smaller gains:

Five-Fold Lifespan Extension in C. Elegans by Combining Mutants

What are the limits to longevity? New research in simple animals suggests that combining mutants can lead to radical lifespan extension. [Scientists] combined mutations in two pathways well-known for lifespan extension and report a synergistic five-fold extension of longevity in the nematode C. elegans.

The mutations inhibited key molecules involved in insulin signaling (IIS) and the nutrient signaling pathway Target of Rapamycin (TOR). Single mutations in TOR usually result in a 30 percent lifespan extension, while mutations in IIS (Daf-2) often result in a doubling of lifespan in the worms - added together they would be expected to extend longevity by 130 percent. "Instead, what we have here is a synergistic five-fold increase in lifespan. The two mutations set off a positive feedback loop in specific tissues that amplified lifespan."

The positive feedback loop (DAF-16 via the AMPK complex) originated in the germline tissue of worms. The germline is a sequence of reproductive cells that may be passed onto successive generations. "The germline was the key tissue for the synergistic gain in longevity - we think it may be where the interactions between the two mutations are integrated. The finding has implications for similar synergy between the two pathways in more complex organisms."

The germline connection is interesting, as other researchers have shown that life can be extended in nematodes via removal of the germline, or genetic manipulations primarily focused on germline cells.

These pioneering demonstrations of life extension in the laboratory by slowing aging have, I think, little direct relevance to the future of human life extension. They are principally important for the continued accumulation of knowledge regarding metabolism and aging. Development of means to slow aging in humans isn't a good path from a practical point of view: it is very challenging, very expensive, and the safe adjustment of metabolism will require far more knowledge than is presently available to the research community, even when the goal is only to replicate known beneficial metabolic alterations such as the response to exercise or calorie restriction. The result at the end of the day - therapies to slow the course of aging - will be of little use to old people, despite the fantastic cost it will require to get to that point.

This is why it is important to look past much of this work on slowing aging, and the media attention it obtains, and focus instead on repair-based strategies such as SENS research. We will only be able to meaningfully help the aged - ourselves in a few decades, in other words - by developing rejuvenation therapies, not just means to slightly slow down the aging process. To rejuvenate the old, to reverse aging, requires a focus on repair of the known and cataloged forms of damage that cause degeneration: the research community can do that with the metabolism we have, with no need to engineer a new one. Further, far more is known of what has to be done than is the case for the metabolic manipulation approach to slow aging.

Autophagy Required for Zebrafish Regeneration

Zebrafish are studied for their exceptional regenerative capacity, as researchers are attempting to determine whether we mammals have similar, dormant abilities to regenerate limbs and organs, or whether there is any other way to port this ability into human tissues. The first step on this path is to catalog the molecular biology of zebrafish regeneration: how exactly it works under the hood. This research is a part of these efforts:

Regeneration is the ability of multicellular organisms to replace damaged tissues and regrow lost body parts. This process relies on cell fate transformation that involves changes in gene expression as well as in the composition of the cytoplasmic compartment, and exhibits a characteristic age-related decline. Here, we present evidence that genetic and pharmacological inhibition of autophagy - a lysosome-mediated self-degradation process of eukaryotic cells, which has been implicated in extensive cellular remodelling and aging - impairs the regeneration of amputated caudal fins in the zebrafish. Thus, autophagy is required for injury-induced tissue renewal.

We further show that upregulation of autophagy in the regeneration zone occurs downstream of mitogen-activated protein kinase/extracellular signal-regulated kinase signalling to protect cells from undergoing apoptosis and enable cytosolic restructuring underlying terminal cell fate determination. This novel cellular function of the autophagic process in regeneration implies that the role of cellular self-digestion in differentiation and tissue patterning is more fundamental than previously thought.

Link: http://dx.doi.org/10.1038/cdd.2013.175

The Potency of Exercise

Exercise and calorie restriction provide greater beneficial effects than much of the array of therapies making up modern medicine; this is a measure of just how much work is left to do in medical research. There remain many conditions for which only marginal, palliative treatments exist. It is a strange era we live in: that this can be the case on the one hand, and yet on the other the research community is just a few decades away from being able to cure all cancer, grow organs from a patient's cells, and create rejuvenation therapies that will greatly extend healthy life.

To determine the comparative effectiveness of exercise versus drug interventions on mortality outcomes [we] combined study level death outcomes from exercise and drug trials using random effects network meta-analysis.

We included 16 (four exercise and 12 drug) meta-analyses. Incorporating an additional three recent exercise trials, our review collectively included 305 randomised controlled trials with 339,274 participants. Across all four conditions with evidence on the effectiveness of exercise on mortality outcomes (secondary prevention of coronary heart disease, rehabilitation of stroke, treatment of heart failure, prevention of diabetes), 14,716 participants were randomised to physical activity interventions in 57 trials.

No statistically detectable differences were evident between exercise and drug interventions in the secondary prevention of coronary heart disease and prediabetes. Physical activity interventions were more effective than drug treatment among patients with stroke. Diuretics were more effective than exercise in heart failure. Inconsistency between direct and indirect comparisons was not significant.

Although limited in quantity, existing randomised trial evidence on exercise interventions suggests that exercise and many drug interventions are often potentially similar in terms of their mortality benefits.

Link: http://dx.doi.org/10.1136/bmj.f5577

Reviewing the Work of More of the SENS Research Foundation 2013 Interns

The SENS Research Foundation is the leading coordinator of rejuvenation research: funding and organizing scientific programs with the aim of reversing degenerative aging and preventing age-related disease. This can be achieved through the development of biotechnologies capable of repairing the identified forms of cellular and molecular damage that cause aging. Some of these biotechnologies are within just a few years of proof of concept treatments deployed in the laboratory, given fully funded research programs. Sufficient resources for such rapid progress are lacking, however: rejuvenation research of this sort is entirely funded by philanthropy at the present time, ignored by more mainstream sources of research funding.

One of the programs run by the SENS Research Foundation assembles talented young graduate researchers from around the world each year, offering them the chance to further their careers in the molecular biology of aging and longevity by performing cutting-edge research at the Foundation's research center, or in allied laboratories also focused on aging. We are all still aging today, and the researchers who lead the deployment of the first generation of clinical rejuvenation treatments will not be those presently at the peak of their careers. Creating the next generation of the research community is just as important as persuading the present generation to focus on repair-based approaches to treating aging.

Still, much can be accomplished with comparatively little nowadays. The state of biotechnology today is very different from that of even just ten or twenty years ago: tasks that would have required a fully staffed institution and tens of millions of dollars - if they were even possible at all - can now be achieved by a single researcher and tens of thousands of dollars. The cost of life science research is plummeting, even as the capabilities of laboratory technologies expand just as rapidly.

The SENS Research Foundation has been showing off the work of the 2013 interns over the past few months:

Here is the latest installment of posts:

Evidence that Cell Senescence is a Factor in Chronic Obstructive Pulmonary Disease -- SRF intern Shahar Bracha

Chronic obstructive pulmonary disease (COPD) is a lung disease which is currently the 4th leading cause of death in the world, affecting the lives of hundreds of millions every year. In this disease, an excessive inflammatory response to noxious particles or gases causes airflow to become restricted. A deadly combination of chronic inflammation in the small airways and destruction of the alveoli slowly limits the lungs' ability to do their job transmitting oxygen to the blood.

The two main risk factors for COPD are smoking and age. Senescence of cells in the airway due to environmental stress, such as smoking, or due to advanced age may explain these risk factors. Senescence is a non-proliferative state which a normal, dividing cell may enter to prevent excessive cell growth. Although the senescent response limits tumorigenesis in these cells, it may also contribute to the pathogenesis of COPD by both limiting the proliferative capacity necessary for tissue repair and by promoting chronic inflammation.

To determine if senescence plays a role in COPD, I studied transgenic mice that possessed lung cells with an impaired ability to undergo senescence. The senescence-impaired cells are a special type of epithelial cell found in small airways in the lungs, called Clara cells. By inactivating the tumor suppressor gene p53 in these cells, one of the main regulatory pathways of cellular senescence was impaired. I also developed a protocol for inducing COPD-like symptoms by treating the mice with aerosolized lipopolysaccharide (LPS). This allowed me to compare the response of these transgenic mice to normal mice when faced with COPD-inducing conditions. The correlation between fewer senescent cells and lower levels of inflammation suggests that the senescence of Clara cells indeed might play an important role in the pathogenesis of COPD. Further study of the role senescence plays in the pathogenesis of COPD could reveal new targets for COPD therapies.

A Study of the Effect of Histone Acetylation on ATM Activation and the SASP by SRF Intern Meredith Giblin

Cellular senescence is a process in which a cell ceases to proliferate in response to oncogenic stimuli. Ironically, although senescence helps protect the cell in question from becoming cancerous, the senescence-associated secretory phenotype (SASP) has been shown to contribute to age-related diseases, in particular cancer. The Campisi lab has previously demonstrated that several proteins involved in the DNA damage response (DDR) pathway are also necessary for the SASP. Inhibition of histone deacetylases (HDACs) and activation of the ataxia telangiectasia mutated (ATM) protein in turn activate the SASP. This suggests that the state of the chromatin rather than the physical breaks in DNA is responsible for initiating the SASP response in senescent cells. My project sought to characterize the role specific HDACs play in ATM activation and SASP induction.

Investigating the Mechanism of Lithium Treatment of a Parkinson's Disease Model with SRF Intern Sean Batir

Previous research in Dr. Anderson's laboratory revealed that lithium, a drug commonly used to treat bipolar disorder, also may prevent neurodegeneration in an animal model of Parkinson's disease. Working with postdoctoral researcher Dr. Christopher Lieu, I tried to determine what molecular pathway is associated with the previously observed effects of lithium on the symptoms of a Parkinson's disease animal model.

Two possible mechanisms were investigated: autophagy (the process by which a cell can recycle and remove metabolic cellular debris, protein aggregates, and damaged organelles) and inflammation. One theory argues that dysfunction in the neurocellular autophagy pathway is responsible for the neuronal degeneration and resulting loss of motor control observed in Parkinson's disease. If so, reactivation of the autophagy mechanism may be responsible for the neuroprotective properties of lithium in a Parkinson's disease model. We also tested the possibility that the neuroprotective properties of lithium may be a result of lithium's effect on neuronal inflammation.

Inhibition of Breast Cancer Cell Metastasis by SRF Intern Eric Zluhan

Actin fibers are a key component of the proteolytic invadopodia used by breast cancer cells during metastasis. A formin protein known as FMNL1 plays a crucial role in actin assembly during macrophage migration and has been implicated in proteolytic invadopodia as well. My summer project tested whether or not inhibition of FMNL1 function in breast cancer cells [would] limit their metastatic capabilities.

I attempted to lower FMNL1 protein levels [in] cells by using a process known as RNA interference (RNAi), a technique that can be used to selectively remove a specific RNA transcript from cells. Once I confirmed that FMNL1 protein levels were reduced, I tested the invasive capability of the cells. RNAi-treated cells were placed on an artificial basement membrane, and I measured the number of cells that were able to move through the membrane. Fewer FMNL1 siRNA-treated cells were able to penetrate the membrane compared to cells treated with a control siRNA construct.

In Search of Drugs That Modulate Aging

Where the mainstream of aging research is thinking about extending healthy life, these researchers are near entirely focused on traditional drug discovery and development with the aim of gently slowing the rate of aging. This will no doubt result in a great deal of new knowledge in the course of better understanding the molecular biology of nature means of life extension, such as calorie restriction, but it doesn't stand much of a chance of producing technologies that will allow you and I to live significantly longer. A drug to slightly slow aging that emerges 20 years from now will of little use to people already old, and only of marginal use for everyone else.

An important task to undertake today is convincing the mainstream of aging research to adopt the SENS view on aging: to work on rejuvenation therapies that repair the known underlying damage of aging, a much more effective approach that will result in treatments that do help the elderly and do significantly extend healthy life spans.

Once a backwater in medical sciences, aging research has emerged and now threatens to take the forefront. This dramatic change of stature is driven from 3 major events. First and foremost, the world is rapidly getting old. Never before have we lived in a demographic environment like today, and the trends will continue such that 20% percent of the global population of 9 billion will be over the age of 60 by 2050. Given current trends of sharply increasing chronic disease incidence, economic disaster from the impending silver tsunami may be ahead.

A second major driver on the rise is the dramatic progress that aging research has made using invertebrate models such as worms, flies, and yeast. Genetic approaches using these organisms have led to hundreds of aging genes and, perhaps surprisingly, strong evidence of evolutionary conservation among longevity pathways between disparate species, including mammals. Current studies suggest that this conservation may extend to humans.

Finally, small molecules such as rapamycin and resveratrol have been identified that slow aging in model organisms, although only rapamycin to date impacts longevity in mice. The potential now exists to delay human aging, whether it is through known classes of small molecules or a plethora of emerging ones. But how can a drug that slows aging become approved and make it to market when aging is not defined as a disease? Here, we discuss the strategies to translate discoveries from aging research into drugs. Will aging research lead to novel therapies toward chronic disease, prevention of disease or be targeted directly at extending lifespan?

Link: http://dx.doi.org/10.1016/j.trsl.2013.11.007

Digging in to the Biochemistry of Glucosepane

Advanced glycation end-products (AGEs) are forms of waste produced by the ordinary operation of metabolism, in which sugars attach to proteins to form hardy compounds that in some cases are a challenge to remove. In humans glucosepane is by far the most prevalent form of AGE, and its growing presence with age causes increased levels of chronic inflammation, and a loss of elasticity and function in many tissues.

Very few researchers are presently working on ways to remove glucosepane, which is why the SENS Research Foundation funds a program aimed at making progress towards this goal. A therapy to clear glucosepane would remove this contribution to degenerative aging, and is thus a needed part of any future toolkit of rejuvenation treatments.

Ageing and diabetes share a common deleterious phenomenon, the formation of Advanced Glycation Endproducts (AGEs), which accumulate predominantly in collagen due to its low turnover. Though the general picture of glycation has been identified, the detailed knowledge of which collagen amino acids are involved in AGEs is still missing. In this work we use an atomistic model of a collagen fibril to pinpoint, for the first time, the precise location of amino acids involved in the most relevant AGE, glucosepane.

The results show that there are 14 specific lysine-arginine pairs that, due to their relative position and configuration, are likely to form glucosepane. We find that several residues involved in AGE crosslinks are within key collagen domains, such as binding sites for integrins, proteoglycans and collagenase, hence providing molecular-level explanations of previous experimental results showing decreased collagen affinity for key molecules. Altogether, these findings reveal the molecular mechanism by which glycation affects the biological properties of collagen tissues, which in turn contribute to age- and diabetes-related pathological states.

Link: http://dx.doi.org/10.1016/j.matbio.2013.09.004

Exploring Heat Shock Proteins and Longevity Via Hormesis

Many mild forms of environmental stress extend healthy life in laboratory species: yeast, flies, worms, and mice. None of the really interesting processes are fully understood at this point, but enough has been learned to think that there are numerous overlapping mechanisms involved. Thus we should expect to see that there is at least some overlap in the biochemical details of responses to calorie restriction, mild heat stress, exercise, and others including low toxin doses, despite the fact that they overall produce what look to be very different shifts in metabolism.

The activity of heat shock proteins is one shared mechanism seen in a number of different forms of life extension. As the name might imply these are proteins first cataloged in connection with the metabolic response to excessive heat, but they also turn out for cold, oxygen deprivation, and some other circumstances that stress cells. Heat shock proteins play a role in cellular housekeeping, helping to prevent harmful accumulations of misfolded proteins, among other tasks.

Hormesis is the name given to circumstances whereby beneficial results occur as a result of mild levels of damage and stress. Some of the benefit of calorie restriction, exercise, and so forth, arises due to the triggering of hormetic processes: a little damage spurs all sorts of cellular maintenance for an extended time, resulting in a net gain in integrity and less damage than would otherwise exist. Extended healthy longevity is the observable result. Heat shock proteins are just one of the mechanisms involved here - there are numerous others.

In the near future I imagine that some fraction of the researchers presently investigating drugs that might slow aging will move on to try to produce pharmaceutical means to trigger the beneficial side of hormesis. This seems like a plausible goal, especially in the case of heat shock proteins, given what is known today, but there doesn't seem to be a great deal of movement in this direction at the present time.

Here are a couple of recent papers from research groups looking into the mechanisms and connections associated with heat shock proteins and their effect on aging and longevity.

The long-term effects of a life-prolonging heat treatment on the Drosophila melanogaster transcriptome suggest that heat shock proteins extend lifespan

Heat-induced hormesis, i.e. the beneficial effect of mild heat-induced stress, increases the average lifespan of many organisms. This effect, which depends on the heat shock factor, [decreases] mortality rate weeks after the stress has ceased. To identify candidate genes that mediate this lifespan-prolonging effect late in life, we treated flies with mild heat stress (34°C for 2 hours) 3 times early in life and compared the transcriptomic response in these flies versus non-heat-treated controls 10-51 days after the last heat treatment.

We found significant transcriptomic changes in the heat-treated flies. Several hsp70 probe sets were up-regulated 1.7-2-fold in the mildly stressed flies weeks after the last heat treatment. This result was unexpected as the major Drosophila heat shock protein, Hsp70, is reported to return to normal levels of expression shortly after heat stress. We conclude that the heat shock response, and Hsp70 in particular, may be central to the heat-induced increase in the average lifespan in flies that are exposed to mild heat stress early in life.

Integrin-linked kinase modulates longevity and thermotolerance in C. elegans through neuronal control of HSF-1

Integrin-signaling complexes play important roles in cytoskeletal organization and cell adhesion in many species. Components of the integrin-signaling complex have been linked to aging in both Caenorhabditis elegans and Drosophila melanogaster, but the mechanisms underlying this function are unknown.

Here, we investigated the role of integrin-linked kinase (ILK), a key component of the integrin-signaling complex, in lifespan determination. We report that genetic reduction of ILK in both C. elegans and Drosophila increased resistance to heat stress, and led to lifespan extension in C. elegans without majorly affecting cytoskeletal integrity. In C. elegans, longevity and thermotolerance induced by ILK depletion was mediated by the heat-shock factor-1 (HSF-1), a major transcriptional regulator of the heat-shock response (HSR).

Death is Wrong: a Child's Primer on Life Extension

Crafting short illustrated books to explain the straightforward views of the life extension community seems like a good idea, and not just for an audience of younger children. The people who will most likely be leading the deployment of the first practical technologies of rejuvenation - in laboratories, in young companies - are in their teens and twenties today, with time enough to choose other paths instead:

If you have ever asked, "Why do people have to die?" then this book is for you. The answer is that no, death is not necessary, inevitable, or good. In fact, death is wrong. Death is the enemy of us all, to be fought with medicine, science, and technology. This book introduces you to the greatest, most challenging, most revolutionary movement to radically extend human lifespans so that you might not have to die at all.

You will learn about some amazingly long-lived plants and animals, recent scientific discoveries that point the way toward lengthening lifespans in humans, and simple, powerful arguments that can overcome the common excuses for death. If you have ever thought that death is unjust and should be defeated, you are not alone. Read this book, and become part of the most important quest in human history. It is here to show you that, no matter who you are and what you can do, there is always a way for you to help in humanity's struggle against death.

Link: http://www.rationalargumentator.com/index/blog/2013/12/death-is-wrong-announcement/

More on Genetic Transposition in Aging

Some researchers believe that transposable elements in DNA are involved in the aging process, though definitive links to damage or dysfunction are presently lacking. The behavior certainly changes with increasing age, however:

Transposable elements (TEs) were discovered [in] maize and have since been found to be ubiquitous in all living organisms. Transposition is mutagenic and organisms have evolved mechanisms to repress the activity of their endogenous TEs. Transposition in somatic cells is very low, but recent evidence suggests that it may be derepressed in some cases, such as cancer development.

We have found that during normal aging several families of retrotransposable elements (RTEs) start being transcribed in mouse tissues. In advanced age the expression culminates in active transposition. These processes are counteracted by calorie restriction (CR), an intervention that slows down aging. Retrotransposition is also activated in age-associated, naturally occurring cancers in the mouse. We suggest that somatic retrotransposition is a hitherto unappreciated aging process. Mobilization of RTEs is likely to be an important contributor to the progressive dysfunction of aging cells.

Link: http://www.impactaging.com/papers/v5/n12/full/100621.html

A Few Recent Publications in Calorie Restriction Research

The practice of calorie restriction involves eating fewer calories while still obtaining optimal levels of dietary micronutrients. This results in extended healthy life spans and extended maximum life spans in near all species tested to date, though the data is currently inconclusive for primates, and it is expected that the extension of life span in long-lived animals such as humans will be much smaller than that observed in short-lived animals such as mice.

From an evolutionary perspective, the response to calorie restriction is thought to have arisen as an protective adaptation for the existence of short-lived famine conditions. The length of natural reductions in food supply due to weather, seasons, and so forth, is the same whether you are a man or a mouse - so mice evolved a comparatively long life extension (up to 40% or more) while humans are probably left with just a few additional years. If we did have the ability to extend our lives by decades through eating less, you can be certain that this would have been discovered long ago and be a well-known phenomenon.

Interestingly the effects of calorie restriction on general health and metabolism in primates and mice are very similar despite the large divergence in expected outcomes for longevity. Calorie restriction is just about the best presently available methodology for ensuring good long-term health, and the data from human studies is eye-opening. You should definitely look into it if not already practicing.

Here are some recent publications from the calorie restriction research community, just a cross-section of recent research that caught my eye while browsing. This is fairly low-level work, scientists digging into details in search of new lines of research to pursue.

What are the roles of calorie restriction and diet quality in promoting healthy longevity?

Epidemiological and experimental data indicate that diet plays a central role in the pathogenesis of many age-associated chronic diseases, and in the biology of aging itself. Data from several animal studies suggest that the degree and time of calorie restriction (CR) onset, the timing of food intake as well as diet composition, play major roles in promoting health and longevity, breaking the old dogma that only calorie intake is important in extending healthy lifespan.

Data from human studies indicate that long-term CR with adequate intake of nutrients results in several metabolic adaptations that reduce the risk of developing type 2 diabetes, hypertension, cardiovascular disease and cancer. Moreover, CR opposes the expected age-associated alterations in myocardial stiffness, autonomic function, and gene expression in the human skeletal muscle. However, it is possible that some of the beneficial effects on metabolic health are not entirely due to CR, but to the high quality diets consumed by the CR practitioners, as suggested by data collected in individuals consuming strict vegan diets.

Combined treatment of rapamycin and dietary restriction has a larger effect on the transcriptome and metabolome of liver

Rapamycin (Rapa) and dietary restriction (DR) have consistently been shown to increase lifespan. To investigate whether Rapa and DR affect similar pathways in mice, we compared the effects of feeding mice ad libitum (AL), Rapa, DR, or a combination of Rapa and DR (Rapa + DR) on the transcriptome and metabolome of the liver. The principal component analysis shows that Rapa and DR are distinct groups.

Over 2500 genes are significantly changed with either Rapa or DR when compared with mice fed AL; more than 80% are unique to DR or Rapa. A similar observation was made when genes were grouped into pathways; two-thirds of the pathways were uniquely changed by DR or Rapa. The metabolome shows an even greater difference between Rapa and DR; no metabolites in Rapa-treated mice were changed significantly from AL mice, whereas 173 metabolites were changed in the DR mice. Interestingly, the number of genes significantly changed by Rapa + DR when compared with AL is twice as large as the number of genes significantly altered by either DR or Rapa alone.

In summary, the global effects of DR or Rapa on the liver are quite different and a combination of Rapa and DR results in alterations in a large number of genes and metabolites that are not significantly changed by either manipulation alone, suggesting that a combination of DR and Rapa would be more effective in extending longevity than either treatment alone.

Thermoregulatory, cardiovascular, and metabolic responses to mild caloric restriction in the Brown Norway rat

Caloric restriction (CR) has been demonstrated to prolong the life span of a variety of species. CR-induced reduction in core temperature (Tc) is considered a key mechanism responsible for prolonging life span in rodents; however, little is known about the regulation of CR-induced hypothermia as a function of the circadian cycle. We assessed how mild CR that resulted in a 10% reduction in body weight affected the 24 h patterns of Tc as well as heart rate (HR) and motor activity (MA) of the Brown Norway rat.

Telemetered rats were allowed to feed for 20 weeks ad libitum (AL) or given a CR diet. Tc, HR, and MA of CR rats exhibited nocturnal reductions and diurnal elevations, opposite to that of AL rats. The effects of CR appeared to peak at ~4 weeks. Metabolic rate (MR) and respiratory exchange ratio (RER) were measured overnight after 18 weeks of CR. MR and RER were elevated markedly at the time of feeding in CR rats and then declined during the night.

We found that the pattern of Tc was altered with CR, characterized by elimination of high nocturnal Tc's typically observed in AL animals. In terms of mechanisms to prolong life span in CR animals, we suggest that the shift in the pattern of Tc during CR (i.e., elimination of high Tc's) may be as critical as the overall mean reduction in Tc. Future studies should address how the time of feeding may affect the thermoregulatory response in calorically restricted rats.

Calorie restriction attenuates lipopolysaccharide (LPS)-induced microglial activation in discrete regions of the hypothalamus and the subfornical organ

Calorie restriction (CR) has been shown to increase longevity and elicit many health promoting benefits including delaying immunosenescence and attenuating neurodegeneration in animal models of Alzheimer's disease and Parkinson's disease. CR also suppresses microglial activation following cortical injury and aging.

We previously demonstrated that CR attenuates lipopolysaccharide (LPS)-induced fever and shifts hypothalamic signaling pathways to an anti-inflammatory bias. The current study investigated regional changes in LPS-induced microglial activation in mice exposed to 50% CR for 28 days. Exposure to CR attenuated LPS-induced fever, and LPS-induced microglial activation in a subset of regions [and] microglial activation [was] positively correlated with body temperature.

These data suggest that CR exerts effects on regionally specific populations of microglia; particularly, in appetite-sensing regions of the hypothalamus, and/or regions lacking a complete blood brain barrier, possibly through altered pro- and anti-inflammatory signaling in these regions.

Sampling the Diversity of Aging

Aging can be defined as a rise over time in mortality rate due to intrinsic causes. This doesn't tell us much about what exactly might be happening under the hood, beyond a general failure in function, but it has proven to be a useful working definition for a broad range of research. Not all species exhibit this rise in mortality rate, however:

Not all species weaken and become more likely to die as they age. Some species get stronger and less likely to die with age, while others are not affected by age at all. Increasing weakness with age is not a law of nature. [Researchers] have studied ageing in 46 very different species including mammals, plants, fungi and algae, and they surprisingly find that there is a huge diversity in how different organisms age. Some become weaker with age - this applies to e.g. humans, other mammals, and birds; others become stronger with age - this applies to e.g. tortoises and certain trees, and others become neither weaker nor stronger - this applies to e.g. Hydra, a freshwater polyp.

While there is plenty of scientific data on ageing in mammals and birds, there is only sparse and incomplete data on ageing in other groups of vertebrates, and most invertebrates, plants, algae, and fungi. For several species mortality increases with age - as expected by evolutionary scientists. This pattern is seen in most mammal species including humans and killer whales, but also in invertebrates like water fleas. However, other species experience a decrease in mortality as they age, and in some cases mortality drops all the way up to death. This applies to species like the desert tortoise (Gopherus agassizii) which experiences the highest mortality early on in life and a steadily declining mortality as it ages. Many plant species, e.g. the white mangrove tree (Avicennia marina) follow the same pattern.

Amazingly, there are also species that have constant mortality and remain unaffected by the ageing process. This is most striking in the freshwater polyp Hydra magnipapillata which has constant low mortality. In fact, in lab conditions, it has such a low risk of dying at any time in its life that it is effectively immortal. "Extrapolation from laboratory data show that even after 1400 years five per cent of a hydra population kept in these conditions would still be alive."

Link: http://www.eurekalert.org/pub_releases/2013-12/uosd-sdi120613.php

Arguing That Mitochondrial Mutations Are Only Important to Aging in Long-Lived Species

Researchers here produce models to argue that the role of accumulating mitochondrial mutations in aging can only play out significantly in long-lived species. If this in fact turns out to the be the case it would be a hindrance to efforts to develop mitochondrial repair technologies as a rejuvenation therapy, as they would have little effect in laboratory mice. That would make it harder to drum up the enthusiasm to proceed further towards clinical applications.

The fastest way to find out whether the models presented in this paper actually reflect reality is to develop a working implementation of mitochondrial DNA (mtDNA) repair, but like many areas of research that are potentially applicable to extending healthy life there is comparatively little funding for this sort of work. With much greater funding, an actual implementation is only a few years away.

The mitochondrial theory of ageing is one of the main contenders to explain the biochemical basis of the ageing process. An important line of support comes from the observation that mtDNA deletions accumulate over the life course in post-mitotic cells of many species. A single mutant expands clonally and finally replaces the wild-type population of a whole cell.

One proposal to explain the driving force behind this accumulation states that the reduced size leads to a shorter replication time, which provides a selection advantage. However, this idea has been questioned on the grounds that the mitochondrial half-life is much longer than the replication time, so that the latter cannot be a rate limiting step. To clarify this question, we modelled this process mathematically and performed extensive deterministic and stochastic computer simulations to study the effects of replication time, mitochondrial half-life and deletion size.

Our study shows that the shorter size does in principle provide a selection advantage, which can lead to an accumulation of the deletion mutant. However, this selection advantage diminishes the shorter is the replication time of wt mtDNA in relation to its half-life. Using generally accepted literature values, the resulting time frame for the accumulation of mutant mtDNAs is only compatible with the ageing process in very long lived species like humans, but could not reasonably explain ageing in short lived species like mice and rats.

There are proposals for other mechanisms to explain how damaged mitochondria can overtake cells and replace the undamaged type: for example, through greater resistance to being cleared out by quality control mechanisms such as mitophagy.

Link: http://dx.doi.org/10.1016/j.jtbi.2013.09.009

Muscle Stem Cell Aging: "From Death, Lead Me to Immortality"

The crafting of histrionic titles for research papers is a small artistic sideline in the research community. They catch the eye, and it's only human to have a little fun from time to time while working with important topics. The important topic in this case is stem cell aging, a decline in stem cell activity that leads to increasingly frail and dysfunctional tissue due to reduced maintenance activities. Much of the work on this topic presently focuses on muscle tissue and the associated stem cells known as satellite cells: researchers will probably produce a usefully complete model of the important aspects of the epigenetics and other biochemistry of aging in satellite cells before similar investigations draw to a close for any other population of cells.

In recent years it has become apparent that much of the decline in satellite cell activities is a response to the environment of aged tissue. If you take old satellite cells and put them into young tissue they go back to work as though youthful. Similarly there have been demonstrations in which researchers restore some of the youthful activities of old stem cells by reverting one or more differences in chemical signaling noted between young and old environments.

I see the existence of this sort of work as a positive sign for the future. We need the researchers of the large and very well funded stem cell research community to become more interested in reversing age-related degeneration of stem cells. It is a big project, and will require a great deal of work. Fortunately most of the prospective therapies that can be created through the fruits of stem cell research are aimed at the treatment of age-related conditions. In order for these therapies to be effective, researchers are somewhat forced into understanding why stem cells decline in old tissue, and find ways to at least temporarily stop this from happening.

At the present time it is somewhat ambiguous as to whether damage to stem cells or signaling and epigenetic responses to broader cellular damage in tissue are the major cause of stem cell aging in all populations. But I don't expect that ambiguity to persist for too much longer, not if the funding keeps ramping up for regenerative medicine, tissue engineering, and other outgrowths of the stem cell field. Let us return to the histrionics, however:

'From Death, Lead Me to Immortality' - Mantra of Ageing Skeletal Muscle

The relationship between satellite stem cell function and muscle regeneration and repair in ageing has yet to be rigorously addressed in mammals. Initial in vitro studies of satellite cells from young and old animals suggested that there was intrinsic ageing of this stem-cell population, as aged cells generated far fewer progeny. The finding that regeneration mediated by aged satellite cells was highly effective when the cells were transplanted into young animals as whole-muscle grafts suggest reversible modifications of aged muscle stem cells, an interpretation supported by recent data showing that aged muscle stem cells, when exposed to a youthful systemic milieu by virtue of parabiotic pairings of aged and young mice, activate and repair muscle nearly as well as young satellite cells. These modifications may be associated with intrinsic epigenetic changes within the satellite stem cell population supported by our studies in myoblast cellular ageing demonstrating increased methylation of the myogenin gene [that] reduced the capacity to form myotubes which was reversed by addition of methyltransferase inhibitor 5-azacytidine.

The coordinated control of DNA methylation by methyltransferases and chromatin states by histone modifiers will be a fascinating avenue for further investigation and will particularly benefit from genome-wide examination in young and old stem cell populations. As technologies for genomic analysis and sequencing continually improve profiling potential correlation between stem cell function and epigenetic changes become increasingly feasible. As the mechanisms underlying age dependent stem cell decline are better understood that leads to a decline in muscle function, studying the effects of manipulating satellite cell function on skeletal muscle maintenance over a organismal lifespan and healthspan will be an attainable goal - 'from death, lead me to immortality'.

An Interview With Michael Rose in Cryonics Magazine

Researcher Michael Rose has interesting views on aging and longevity that diverge from much of the rest of the present research community. He is possibly best known for his work showing a late-life mortality plateau in flies - if you define aging as a rising risk of death per unit time, then there is very clearly a point at which aging stops in that species. Mortality is still high and the flies still die, but for a while they are what Rose terms "immortal," a term he adopts to mean no further rise in mortality rate. So far the data is either ambiguous or in opposition to the existence of a mortality plateau in humans, however.

My work on the evolution of aging in response to changes in the first age of reproduction has been emulated with mice by Nagai, Lin, and Sabour (1995, Growth Dev Aging), who showed that you get the same qualitative results with rodents as with flies. This and other experiments manipulating the timing of reproduction in other species show that Hamilton's 1966 Forces of Natural Selection are the fundamental controls on aging. As for the full range of experiments in the Rose and Mueller labs on the evolution and cessation of aging, no one else has come up with such a complete range of experiments to test the hypothesis that Hamiltonian theory explains the onset, rate, and cessation of aging.

Hamilton's forces start to fall after the start of reproduction, which is when aging starts. But Hamilton's forces eventually stop falling at late adult ages. If aging only occurs during or a bit after these forces are falling, then aging must eventually stop too. This means that mortality rates, fertility, and virility should all eventually reach plateaus at which they change only gradually. That is what we have found in our lab data with fruit flies.

SENS and most other thinking about aging is dominated by the hypothesis originally due to Aristotle that aging is produced by some type of physiological process, whether that process involves damage or a death program. In Hamiltonian thinking, aging is the de-tuning of adaptation during the first part of adulthood. As such, we see aging as a problem as complicated as that of evolutionary adaptation itself. Thus we expect that aging is due to many problematic nucleotide frequencies, distributed genome-wide, which in turn generate pleiotropic and epistatic effects of great complexity throughout the biology of aging organisms.

Link: http://www.alcor.org/magazine/2013/12/02/interview-with-dr-michael-rose/

Preserving Vision With Stem Cells in Retinal Degeneration

An example of recent work on stem cell treatments for forms of age-related degenerative blindness:

The advances in stem cell biology hold a great potential to treat retinal degeneration. Importantly, specific cell types can be generated efficiently with small molecules and maintained stably over numerous passages. Here, we investigated whether neural stem cell (NSC) derived from human embryonic stem cells (hESC) by small molecules can preserve vision following grafting into the Royal College Surgeon (RCS) rats; a model for retinal degeneration.

A cell suspension containing NSCs or NSCs labeled with green fluorescent protein (GFP) was injected into the subretinal space or the photoreceptors and visual function. Functionally, NSC treated eyes had significantly better visual acuity and lower luminance threshold than controls. Morphologically, photoreceptors and retinal connections were well preserved. There was an increase in expression of cillary neurotrophic factor (CNTF) in Müller cells in the graft-protected retina.

This study reveals that NSCs derived from hESC by small molecules can survive and preserve vision for long term following subretinal transplantation in the RCS rats. These cells migrate extensively in the subretinal space and inner retina; there is no evidence of tumor formation or unwanted changes after grafting into the eyes.

The NSCs derived from hESC by small molecules can be generated efficiently and provide an unlimited supply of cells for the treatment of some forms of human outer retinal degenerative diseases. The capacity of NSCs migrating into inner retina offers a potential as a vehicle to delivery drugs/factors to treat inner retinal disorders.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763886/

$1 Million New Organ Liver Prize Launched at the World Stem Cell Summit

The Methuselah Foundation has launched the New Organ Liver Prize as a part of the World Stem Cell Summit (WSWC) taking place this week. The aim of the prize is to spur one or more research groups to create functional tissue engineered livers from a patient's own cells and demonstrate their utility in animal studies by the end of 2018, five years from now.

Research prizes like this one work by through a combination of raising awareness, convincing more scientists to work on a particular problem, and motivating greater investment from both new and established funding sources in order to meet the prize goals. This is a long-proven method of invigorating and speeding fields in which progress is comparatively slow: there are many examples of successful research prizes both in recent years and past centuries.

The following missive from the Foundation arrived in the mail today to accompany the New Organ Liver Prize official launch:

This prize has been in the works for a long time, and we couldn't have done it without your enthusiastic support. Thank you! This launch is a victory for all of us, and we warmly invite you to share and celebrate the good news with everyone in your networks.

After much consideration with our scientific advisors, we decided to start with a liver-focused prize, and we intend to follow this up with a prize series that covers all the major solid organs, including the heart, kidney, and lungs. We're also working to mobilize other granting institutions to allocate additional funds in support of teams competing for the prize.

Here's what WSCS founder Bernie Siegel had to say: "Growing a whole, healthy organ is one of the ultimate goals of regenerative medicine. The world stem cell community enthusiastically supports the ambitious aim of the Methuselah Foundation in launching the New Organ Liver Prize and the mobilization of this competitive challenge for researchers to cure disease and alleviate human suffering through tissue engineering."

As you might notice, the Methuselah Foundation and New Organ websites are revamped for the occasion, and looking very modern. There is also an official press release (PDF):

The New Organ Liver Prize is the first in a series of whole organ challenges and awards designed to help solve the global organ shortage, which affects millions of people around the world. There are presently over 120,000 on the organ wait list in the U.S alone, many of whom will die before finding a compatible donor. Even those fortunate enough to receive an organ in time face ongoing medical difficulties, often for the rest of their lives.

New prospects for whole organ regeneration, engineering, and preservation offer potentially powerful solutions to this health crisis, but tissue engineering research is currently underfunded, receiving less than $500 million annually in the U.S. compared to $5 billion for cancer and $2.8 billion for HIV/ AIDS. Neither the NIH nor the NSF provide significant funding for whole organ tissue engineering, and the field also suffers from difficult regulatory hurdles as well as broader shortfalls in biotechnology investment for pre-clinical research.

New Organ has been endorsed by prominent doctors and scientists across the field of regenerative medicine, including Dr. Anthony Atala of Wake Forest, Dr. Stephen Badylak of the University of Pittsburgh, and the Founding Fellows of TERMIS (Tissue Engineering and Regenerative Medicine International Society).

"Regenerative medicine and tissue engineering are at the cusp of conquering the final frontier, the fabrication of vital organs to definitively solve the organ donor shortage," said Dr. Joseph Vacanti of Massachusetts General Hospital. "New Organ will help catalyze the efforts to solve the remaining problems to bring this life saving technology to all of the people who desperately need it."

Due to the complexity of defining strong competition criteria for each of the solid organs, including the heart, kidney, and lungs, this prize will focus exclusively on tissue engineering solutions that replace the liver. Ultimately, the Methuselah Foundation intends to develop a prize series that covers all of the major solid organs, and that spans multiple strategies, including organ regeneration, repair, replacement, and preservation. Through its New Organ Alliance, Methuselah also hopes to mobilize other granting institutions to allocate additional funds in support of teams competing for the prize.

The New Organ Liver Prize rules (PDF) are also worth looking over, especially if you've been following the development of this initiative over the past couple of years.

Type of Host:

Large mammal (specifically pig, cow, rabbit, dog, cat, sheep, baboon, or rhesus); excluding all rodents (rats, mice, etc.).

Duration:

A minimum of 90 days survivability.

Tissue:

Any bioengineered tissue solution is allowed.

Immunosuppression:

No immunosuppression is allowed if using animal cells; immunosuppression will only be allowed if using human cells.

Multiple Successes:

A minimum of 3 successful trials are required.

Success Rate:

A minimum of 3 out of 4 trials must be successful (75% success).

Functionality:

The animal must survive the duration of the 3-month survival trial and during the last month of the trial must exhibit specific liver functions and "lifestyle" functions.

Deadline:

The trials must be completed by December 31st, 2018.

Judging:

The team's trials will be evaluated by a technically-proficient and fully-independent judging committee.

Awards

The first team to meet all requirements will win the $1,000,000 award.

Responses to Daniel Callahan's Opposition to Human Longevity

Daniel Callahan is among those who oppose efforts to extend human life. He holds mistaken views on the outcome of longevity-enhancing therapies, thinking that they will extend the period of frailty and illness rather than extend healthy, vigorous life. In this he is determinedly ignoring what scientists in the field have been saying - loudly in many cases - for many years. Unfortunately he is not alone in this selective deafness: the average fellow on the street also thinks that extending life through medical science means being older for longer, not being younger for longer. This is a major hurdle still to be overcome on the way to gaining more support for medical research and development aimed at slowing or reversing aging.

Here are a few responses from interested researchers to Callahan's latest article, including some involved in the Longevity Dividend initiative:

Mainstream aging research neither promises radical immortality nor seeks to keep old people sick longer. Aging is a driving factor in the most prevalent and costly chronic diseases. Research indicates that interventions slowing aging delay the onset of these diseases. Therefore, they extend not only life span but also health span, the disease-free and functional period of life.

Fundamentally, the goals of aging research are not dissimilar from efforts to prevent or treat Alzheimer's or other chronic diseases in that they both seek to improve quality of life in the elderly. The difference is that interventions in aging may prevent not just one but a range of debilitating diseases simultaneously.

Mr. Callahan's concern about older people crowding out younger people for jobs is also unfounded. We saw warnings of this kind before when women began to join the work force. A result was that women added nearly $3 trillion to the economy, and businesses owned by women employ nearly 16 percent of the work force.

If health at any age is highly valued, then a healthier older population is worth its weight in gold. Aging science is likely to be the next revolution in public health; it should be embraced, not feared. Anti-aging research is not, as Daniel Callahan apparently believes, about prolonging the wheelchair-and-walker phase of life but about preserving youthful health and vigor so that there will be far fewer of the elderly in poor health.

I'm always amazed at the number of people who vigorously support the search for better prevention and treatment of heart disease, cancer and Alzheimer's but who find moral difficulties in the search for better prevention and treatment of those plus a host of other maladies, all simultaneously. That is what anti-aging research is about.

Link: http://www.nytimes.com/2013/12/05/opinion/when-life-goes-on-and-on.html

An Opposition to Longevity That is Almost a Caricature of Itself

The quoted material below is a condensed example of sort of thing we see from many opponents who flail away at the prospects for extending health life. They say that it couldn't possibly work; that even it if did no-one would be better for living longer; that we're all selfish for trying; that the advocates and researchers are all working on it for the wrong reasons; and so on and so forth. Really it says a lot more about the author than the topic at hand. It must take an effort of will to so blind oneself to the essentially positive nature of medical research that aims to remove pain, suffering, and death, of seeking longer life for the pleasure of living, so as to do more and achieve more, and to see the next day dawn because you are curious.

It is instructive to read most of the opposition to longevity science while replacing the objective at hand with, say, therapies for heart disease, or improvements in organ transplantation. All modern advances in medicine of the past few decades are intended to push back pain, suffering, and death. All change the nature of the human condition - and all can be argued against used the same terms as are brought out for efforts to treat, slow, and reverse aging itself. Yet none of these opponents try to argue against heart disease treatments. It shows just how hollow their positions are.

Medical development to extend healthy, vigorous life spans is completely and absolutely beneficial: it will make life better, extending all that is good while suppressing the worst physical aspects of the human condition. The work is being accomplished by people who are drawn to this field of research for the ability to make a meaningful difference: to cure, to build new ways to improve health and longevity, to stop the terrible ongoing flood of pain and death caused by degenerative aging. That some people can so twist reality as to present medical progress as some sort of selfish pursuit towards self-destruction is a tribute to misapplied ingenuity.

While any detailed examination of the science invoked will promptly dispel the idea that such an ambitious extension to our lives is likely at all, and even a moment's reflection will generate a host of reasons as to why it may be even less desirable that it is likely, it is still a compelling narrative. Who really wants to die - when they could just keep living? Of course mortality is necessary, and the species needs it - but not for me. Surely my survival, my ever-accumulating wisdom, will be a noble exception, a major benefit to society? We could all advance such self-serving arguments, but if we really take the idea seriously, we have to see it as an attempt to impose stasis on the inevitable flux that is reality.

Given that death is inevitable, that mortality and finitude is blindingly and undeniably the frame in which we live our lives - why engage in these grand acts of self-delusion? Of course, some life extension may be possible, but death will not be denied, and, even if delayed a little en route by healthy living and medical advances, is coming for us all soon enough. I can only see a single psychological motive underpinning the longevity movement, and this is the same reason it sells newspapers and fascinates so many of us. This motive is our absolute and total fear and dread. The more we have suppressed death, the more we may fail to express our anxiety - but it has gone nowhere. I would contest that underneath the cheery hopes of living for centuries is a screeching, desperate flailing panic at the knowledge of our own, personal, death. The fact of death is, alas, still a fact; and longevity and immortality are as useless as the cheap trinkets of 'heaven' and post-death-life. What little we can do, surely, consists of the staring down, and confronting of the truth of death. This choice promises no escape, but at least offers us the chance to live a life where death's long shadow does not taint every thought via poorly-repressed anxiety.

Link: http://dispirited.org/2013/12/05/life-extension-and-fear-of-death/

Methuselah Foundation Expands the Year End SENS Rejuvenation Research Donation Match

I'm happy to say that Methuselah Foundation is joining the presently ongoing year-end matching of donations to the SENS Research Foundation. All donations are tax-deductible and will go towards expanding the SENS rejuvenation research programs presently taking place in laboratories around the world: building the foundation biotechnologies capable of repairing the accumulated low-level cellular and molecular damage that causes aging and age-related disease.

Methuselah Foundation joins philanthropist Jason Hope and Fight Aging! in this matching fund, each contributing $15,000 to match the next $15,000 contributed to SENS research before the end of 2013. Thus your donations will be matched 3:1!

  • Matching fund from Fight Aging!: $15,000
  • Matching fund from Jason Hope: $15,000
  • Matching fund from Methuselah Foundation: $15,000
  • Your donations, matched 3 to 1: $15,000
  • The total: $60,000

Methuselah Foundation is of course the precursor organization to the SENS Research Foundation, founded by David Gobel and Aubrey de Grey based on their shared interest in materially changing the course of aging research, to shift the scientific community from merely investigating aging to actually doing something about it. The Methuselah Foundation staff and volunteers contributed greatly to the shift in culture and goals that occurred within the aging research field over the past decade. Further, SENS research and fundraising first started under the Methuselah Foundation umbrella, alongside the Mprize for longevity science - a research prize that continues today to encourage researchers to demonstrate better and more effective means of extending healthy life through rejuvenation in laboratory mice.

Now that SENS has its own dedicated organization, the Methuselah Foundation focuses on accelerating goals in the tissue engineering of organs made from a patient's own cells: the Foundation funds breakthrough startups such as Organovo, and runs the New Organ initiative - a crowdfunding approach to generating a research prize to motivate faster development of replacement organs created to order. You'll be hearing more on that later this week, as there's a big launch presently ongoing at the World Stem Cell Summit.

There is only one roadblock standing between us and rapid progress towards the biotechnologies of rejuvenation outlined in the SENS research plans: that obstacle is money. The researchers are ready and interested, the research is planned and clear, the goals obvious - it just needs more funding than presently flows into this field. Aging research is the poor cousin of the medical life sciences, and rejuvenation research is the poor cousin of aging research: at the large scale research funding always goes towards the priorities of the past decade or two, not the forward-looking work that will form the basis for the future of medicine.

This is where you and I come in. We can see what needs to be done, and we can kickstart the necessary research projects through the SENS Research Foundation. Rarely is there such an obvious opportunity to do good in the world: to help eliminate the suffering, pain, and frailty of old age, and greatly extend healthy life.

So donate! Help make the world a better place for all of us.

A Skeptic's Guide to Cryonics

Cryonics is a small industry that provides low-temperature storage (via vitrification, not freezing) of the body and brain on death. The mind is just structure, and that structure can be preserved for a future in which advanced medical engineering can restore a vitrified mind to life. This will most likely involve a mature nanorobotics industry and the ability to accurately and efficiently manipulate low-level cell structures: things that are a long way out but not beyond reach or impossible.

Sadly the propositions of cryonics are sufficiently forward-looking that most people reject it out of hand without even looking at the wealth of supporting evidence or considering the odds in an unbiased fashion. We live in a world in which it is economically feasible to preserve the mind of near everyone who dies: there could be a massive cryonics industry, with cryonics as the default end of life choice. Yet the status quo is to do nothing, and people evaporate into oblivion. Once the structure of the mind is destroyed there is definitely no coming back from that. If our culture were more rational the choice of cremation or the grave would be the one that is looked at askance, mocked, or rejected out of hand.

Can a case for cryonics be made on skeptical grounds? If we'd have to believe self-identified skeptics this is not only unlikely but cryonics, in fact, is a "logical" target for skeptical scrutiny. The most obvious approach for a skeptic is to demand "proof" for cryonics. Upon closer inspection, this apparently reasonable demand is rather odd. Let's start with a non-controversial definition of cryonics: cryonics is a form of critical care medicine that stabilizes critically ill patients at ultra-low temperatures to allow the patient to benefit from future advances in medicine. Now, what could this demand for "proof" consist of? Does the cryonics advocate need to provide proof that future developments in medicine will indeed be capable of treating the patient? How could such a proof be even remotely possible? The most scientifically responsible answer would be to say "I don't know." And this answer reveals something important about cryonics. The decision to make cryonics arrangements is a form of decision making under uncertainty. Asking for "proof" for such a decision makes little sense.

Why has cryonics traditionally gotten such a poor reception by people who see themselves as "skeptics?" I suspect that some of it has to do with the fact that cryonics is traditionally associated with (religious) concepts such as immortality, very optimistic projections about the accelerating growth of science and technology, the technical feasibility of specific repair technologies (such as molecular nanotechnology), or mind uploading. But none of these ideas is an intrinsic part of the idea of cryonics. In its most basic form cryonics is just the recognition that what might be beyond the scope of contemporary medicine may be treatable in the future. No specific timeframe or technology is implied, or necessary. There are a lot of things that people in liquid nitrogen don't have, but one thing they do have is time.

Link: http://www.evidencebasedcryonics.org/2013/11/22/a-skeptics-guide-to-cryonics/

Inhibiting IGF1 Signaling Reduces Misfolded Protein Aggregation in Aging

The signaling pathways associated with insulin-like growth factor 1 (IGF-1) are one of the better studied parts of the intersection between metabolism and aging. So we might expect some marginal treatments to emerge here over the next decade, based on altering metabolism to produce modest beneficial effects by slowing the rate at which some forms of age-related damage occur. In this case the slowed damage involves build up of misfolded proteins associated with neurodegenerative conditions:

TyrNovo's novel and unique compound, named NT219, selectively inhibits the process of aging in order to protect the brain from neurodegenerative diseases, without affecting lifespan. Human neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases share two key features: they stem from toxic protein aggregation and emerge late in life.

[Researchers] discovered, working with worms, that reducing the activity of the signaling mechanism conveyed through insulin and the growth hormone IGF1, a major aging regulating pathway, constituted a defense against the aggregation of the Aβ protein which is mechanistically-linked with Alzheimer's disease. Later, [they] found that the inhibition of this signaling route also protected Alzheimer's-model mice from behavioral impairments and pathological phenomena typical to the disease. In these studies, the path was reduced through genetic manipulation, a method not applicable in humans.

[TyrNovo researchers] discovered a new set of compounds that inhibit the activity of the IGF1 signaling cascade in a unique and efficient mechanism, primarily for cancer treatment, and defined NT219 as the leading compound for further development.

Link: http://new.huji.ac.il/en/article/18460

Jason Hope Partners With Fight Aging! to Match SENS Rejuvenation Research Donations This December

I am very pleased to announce that philanthropist and entrepreneur Jason Hope is joining in to expand the Fight Aging! 2013 year end matching fund for SENS rejuvenation research donations. Donations are tax deductible and help to expand important research aimed at extending our healthy life spans, reversing the downward slope of age-related disease and degeneration by repairing its root causes.

Through to the end of December 2013, Fight Aging! and Jason Hope will each match the next $15,000 donated to the SENS Research Foundation. Both Fight Aging! and Jason are each putting up $15,000 in matching funds, so every dollar donated will be matched by two dollars from this fund: in this way we hope to see the community raise an additional $45,000 for SENS research by the end of the year.

  • Matching fund from Fight Aging!: $15,000
  • Matching fund from Jason Hope: $15,000
  • Your donations, matched 2 to 1: $15,000
  • The total: $45,000

So jump on in and donate! Your gifts will help to fund ongoing cutting edge SENS research programs, undertaken in laboratories in the US and Europe, in which molecular biologists develop the means to repair the known forms of damage to cells and tissues that cause degenerative aging. This work is entirely funded by philanthropic donations, filling the gaps left where the mainstream medical research community is leaving important new work undone.

Jason Hope has previously provided $500,000 to the SENS Research Foundation, a gift that established the Cambridge SENS laboratory and founded a new research program that aims to break down advanced glycation end-products (AGEs) in human tissue. Age-related loss of elasticity and function in skin and other tissues is driven in part by a buildup of AGEs, largely of one type known as glucosepane. Glucosepane is a difficult chemical to work with and has been largely ignored by the mainstream research community despite the growing evidence of its importance to the course of degenerative aging. The SENS Research Foundation and Jason Hope are kick-starting this field of research, building the foundation that will allow many other laboratories to later step in and make effective AGE clearance treatments a reality, reversing this contribution to degenerative aging.

This is one of numerous research programs undertaken by the SENS Research Foundation, whose staff and allied network of researchers work to accelerate progress towards a future toolkit of rejuvenation therapies that actually, really work to reverse the course of aging. This is an era in which we can move beyond merely hoping and wishing when it comes to age-related frailty and disease. We can work to prevent it: the researchers are interested and ready, the research plans are in place, and all that is lacking is the funding for the proof of concept and foundation projects that will show the world what can be done.

Sufficient progress in the work of the SENS Research Foundation will allow many research groups around the world to step in, raise funds from more traditional, conservative sources, and carry forward the work of human rejuvenation to clinical trials and therapies. Everyone who helps this process through donations becomes a part of the broad community that is presently changing the entire face of aging research, shifting it from an investigative field to one that actually produces meaningful therapies and treatments: ways to prevent age-related disease and extend healthy life, and ways to rejuvenate the old, by repairing the low-level biological damage that makes them old.

Help us make a better, longer, healthier future for everyone! Donate!

Generating Unlimited Numbers of Intestinal Stem Cells

Researchers have been making more progress of late in identifying and using stem cells that support intestinal tissue. A few years ago a research group managed to grow small amounts of intestinal tissue, and other similar demonstrations have been achieved since then. Here is an example of present work that should make it much easier to generate the type of cells needed for further research and development:

[Researchers] have shown that they can grow unlimited quantities of intestinal stem cells, then stimulate them to develop into nearly pure populations of different types of mature intestinal cells. Using these cells, scientists could develop and test new drugs to treat diseases such as ulcerative colitis.

The small intestine, like most other body tissues, has a small store of immature adult stem cells that can differentiate into more mature, specialized cell types. Until now, there has been no good way to grow large numbers of these stem cells, because they only remain immature while in contact with a type of supportive cells called Paneth cells.

In a new study [the] researchers found a way to replace Paneth cells with two small molecules that maintain stem cells and promote their proliferation. Stem cells grown in a lab dish containing these molecules can stay immature indefinitely; by adding other molecules, including inhibitors and activators, the researchers can control what types of cells they eventually become.

If scientists could obtain large quantities of intestinal epithelial stem cells, they could be used to help treat gastrointestinal disorders that damage the epithelial layer. Recent studies in animals have shown that intestinal stem cells delivered to the gut can attach to ulcers and help regenerate healthy tissue, offering a potential new way to treat ulcerative colitis.

Link: http://web.mit.edu/newsoffice/2013/new-means-of-growing-intestinal-stem-cells-1127.html

Frailty is a Medical Condition

Somewhere lurking in the roots of medical progress is the urge to declare portions of degenerative aging to be medical conditions. At one point all degeneration was accepted as an inevitable part of the inevitable process of aging - a matter of "it is what it is." Then dementia was declared a condition, and then heart disease, and so on through the presently accepted set of age-related diseases. These have been split off from aging and declared to be treatable.

The division between named diseases of aging and aging is artificial, nothing more than taxonomy. Eventually there will be no aging in the popular eye, just a very long laundry list of medical conditions. This is the way it should be, because aging is just a very long laundry list of medical conditions, caused by known forms of underlying damage that are open to treatment and repair. The more that this is accepted, the more support there will be for research and development of rejuvenation treatments.

As a medical resident 30 years ago, Ava Kaufman remembers puzzling over some of the elderly patients who came to the primary-care practice at George Washington University Hospital. They weren't really ill, at least not with any identifiable diseases. But they weren't well, either. They were thin and weak. They had no energy. They tired easily. Their walking speed was agonizingly slow. "We couldn't put our finger on a specific diagnosis or problem,'' Kaufman says. "We didn't have a word for it then.''

Today we do. It's called frailty. There have always been frail people, but only in recent years has the term "frailty" become a medical diagnosis, defined by specific symptoms and increasingly focused on by those who deal with the medical issues of the elderly. Clinicians now are looking at ways to prevent or delay frailty, sometimes even reverse it. "Frailty is not an age, it's a condition," says Kaufman, a Bethesda internist and geriatrician. "We know it when we see it, and it's always been with us."

Link: http://www.livescience.com/41602-frailty-is-medical-condition.html

Differences Among the Naysayers

A fair number of people stand opposed to efforts to extend human life. A wide variety of reasons are given, including variants of the mistaken belief that life extension must mean some form of maintaining old people in increasing infirmity and pain for longer. In other words that improvements in human longevity will look just like those obtained from the past few decades of progress in medicine, expensive and ultimately futile attempts to patch over age-related conditions without doing much - or anything - to address their root causes. Daniel Callahan, who regular readers will recall has opposed efforts to extend longevity for some time, apparently holds this view.

On Dying After Your Time

Modern medicine is very good at keeping elderly people with chronic diseases expensively alive. At 83, I'm a good example. I'm on oxygen at night for emphysema, and three years ago I needed a seven-hour emergency heart operation to save my life. Just 10 percent of the population - mainly the elderly - consumes about 80 percent of health care expenditures, primarily on expensive chronic illnesses and end-of-life costs. Historically, the longer lives that medical advances have given us have run exactly parallel to the increase in chronic illness and the explosion in costs. Can we possibly afford to live even longer - much less radically longer?

This is not exactly correct. From an individual perspective the outcome of modern medicine is a longer life spent with less chronic illness. A rise in counts of age-related dysfunction is the result of many more people living longer - and this is a good thing. Those people enjoyed more years of active, healthy life before becoming sick. But the opening sentence is true: modern medicine is indeed good at keeping people alive when they would have died in past decades or centuries, and maintaining a heavily damaged system of any sort is an expensive proposition.

But that is today, not tomorrow. The root of Callahan's erroneous view of the future of medicine lies in thinking that future attempts to extend life, deliberately and by targeting the root causes of aging, will in any way be the same as past medical development. In the past, no efforts were made to address the underling causes of age-related degeneration, and all therapies ameliorated or patched over damage after it occurred, with treatment usually taking place in the very late stages of dysfunction. As an approach this is doomed to be both a failure and expensive. Yes, it provides considerable benefits in comparison to doing nothing, but it is a world removed from actually going after and removing the root causes of aging and age-related disease, such as by repairing the cellular and molecular damage that causes aging. This shift in focus from merely patching over to effectively addressing root causes is the greatest and most important change of our time in strategies for medical research and development. Comparing it to the importance of the advent of germ theory is not an exaggeration.

Callahan looks at what is and projects it into the future: the same fundamental failure that bedevils most prognosticators. You have to have a better grasp of what is taking place in the aging research community in order to see that the next generation of medical development to treat aging will be fundamentally different from what has come before. The scientists have been saying this for years, but all too many people are not listening.

Wesley J. Smith is another writer opposed to life extension - and indeed to pretty much all transhumanist projects aimed at overcoming the present limitations of the human condition. He critiqued the above piece by Callahan, pointing out a little of the double standard inherent when someone who is taking full advantage of modern medicine encourages others to die on a shorter time frame. It is probably the only thing Smith will scribe any time soon where I actually agree with some of what he is saying. This seemed a rare enough event to point it out.

Time to Prevent Elderly From Living Too Long?

Contrary to the transhumanist eschatology, Callahan doesn't believe that extending the length of lives will also mean extending their vitality. I tend to agree. But he doesn't exactly practice what he preaches. Callahan could have refused that expensive treatment. I don't say he should have, but no one forced him to spend all that (presumably) public money on care.

He does ask a valid question, I think, about the wisdom of pouring resources into radical life-extending research (at least public money). However he also seems to assert that the elderly be somehow prevented from living longer. What does that mean? Some kind of Logan's Run scenario? Callahan isn't that type. But he should have specified what he meant. As I read him, he seems to be proclaiming some kind of a moral duty of the elderly to die.

Or it could mean refusing efficacious medical care to the elderly that the younger would be able to obtain. In less genteel hands than Callahan's, it could mean something even more insidious.

There are factions who are quite willing to be up-front about plans to limit medical care for the elderly, though this is usually a dialog that takes place in the context of the huge mess that is government-funded provision of medicine. The most effective way to turn an economic benefit (longer lives, with more time spent in health) into an economic liability (destruction of currencies, economies, and rational behavior through inflation while promising future obligations that cannot be met) is to create a free commons of entitlements with a decoupling of services from costs. The inevitable results are rationing, poor service, research and development grinding to a halt as the incentives to improve vanish, and, ultimately, running out of other people's money to the point at which you see a collapse of the sort that ended the Soviet Union, or which is ongoing now in Venezuela.

Even aside from this, however, there are those who oppose even free and open efforts to extend healthy human life. Environmentalist movements are perhaps the most prevalent of these. All in all there are few topics beyond life extension that are so able to bring otherwise sensible, ordinary people to espouse hideous philosophies, such as demanding that the current toll of suffering and death, 100,000 lives lost to aging every day, while hundreds of millions suffer age-related pain and dysfunction, continue without any attempt made to improve the situation.

Creating Lung and Airway Cells From Stem Cells

It was only a couple of years ago that researchers starting making progress in identifying and cataloging the stem cell populations in lung tissue. Last year researchers mapped out some of the cellular path of development for lungs in embryos. Here they are building on that to grow lung cells from embryonic and induced pluripotent stem cells, which opens the doors to the next stage of lung tissue engineering development.

"Researchers have had relative success in turning human stem cells into heart cells, pancreatic beta cells, intestinal cells, liver cells, and nerve cells, raising all sorts of possibilities for regenerative medicine. Now, we are finally able to make lung and airway cells. This is important because lung transplants have a particularly poor prognosis. Although any clinical application is still many years away, we can begin thinking about making autologous lung transplants - that is, transplants that use a patient's own skin cells to generate functional lung tissue."

The research builds on [the] 2011 discovery of a set of chemical factors that can turn human embryonic stem (ES) cells or human induced pluripotent stem (iPS) cells into anterior foregut endoderm - precursors of lung and airway cells. In the current study, [researchers] found new factors that can complete the transformation of human ES or iPS cells into functional lung epithelial cells (cells that cover the lung surface). The resultant cells were found to express markers of at least six types of lung and airway epithelial cells, particularly markers of type 2 alveolar epithelial cells. Type 2 cells are important because they produce surfactant, a substance critical to maintain the lung alveoli, where gas exchange takes place; they also participate in repair of the lung after injury and damage.

Link: http://newsroom.cumc.columbia.edu/blog/2013/12/01/human-stem-cells-converted-functional-lung-cells/

Linking RAGE Variations to Longevity

Advanced glycation end-products (AGEs) build up with age in our tissues, gumming together protein machinery and causing chronic inflammation and other bad behavior on the part of cells through the receptor for AGEs, or RAGE. Thus we should probably not be completely surprised to see associations between variations in RAGE and natural variations in longevity. This reinforces the need for AGE-breakers: treatments that can effectively break down and wash out AGEs, removing the harm that they do. Unfortunately few groups are working on this, despite the fact that there is apparently only one important type of AGE in human tissue.

Demographic and social changes in the last decades have resulted in improvements in health and longevity. The survival of elderly people has improved significantly and thus centenarians are becoming the fastest growing population group. Environmental, genetic, and accidental factors have influenced the human life span. Researchers have gained substantial evidence that advanced glycation end products may play an important role in the processes of physiological aging. The aim of the present study was to investigate any differences in the frequencies of -374T/A polymorphism [of the RAGE gene] in subjects aged 90 years or older and in middle-aged individuals.

We observed association between the A allele and genotype homozygous for this allele (AA) with a longer life expectancy in the male population. In particular, there was a prevalence of AA genotype and A allele in long-living subjects and a prevalence of the allele T in middle-aged subjects, indicating a possible protective role of the allele A to aging. In conclusion, our results support the hypothesis that longevity is the result of a good functioning of the immune system and a presumable hyper-expression of variants of anti-inflammatory genes of immunity. The differences in the genetic regulation of inflammatory processes may influence the presence of age-related disorders.

Link: http://dx.doi.org/10.3390/ijms141123203