Fight Aging! Newsletter, September 23rd 2013

September 23rd 2013

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

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  • Economists in Favor of Extending the Healthy Human Lifespan
  • Telomere Length Studies So Far Say Little On Cause and Effect
  • Exciting Times: Google to Back Longevity Science
  • In Search of Ways to Sabotage the Contribution of Beta Amyloid to Alzheimer's Disease
  • Recent Progress in Stem Cell Research
  • Latest Headlines from Fight Aging!
    • Manipulating Telomere Length More Precisely
    • A DNA Repair Loss of Function Mutation that Extends Life
    • Impact of Dietary AGEs on Life Span in Flies
    • An Example to Follow: Donate to Help Fund Longevity Science
    • An Early Demonstration of Mitochondrial Gene Transfer
    • Chronic Inflammation Associated With Worse Outcomes in Aging
    • Disagreements on the Current Trajectory of Life Expectancy
    • Another Sign of the Zeitgeist in Aging Research
    • An Interesting Advertising Dynamic, Illustrative of the Ongoing Change in Attitudes Towards Aging and Longevity
    • Inspecting the Calico Tea Leaves


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

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

Life Extension: Economists vs. the Public

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

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

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

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

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


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

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

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

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

Telomeres May Hold Clues To Effects Of Aging

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

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

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

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

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

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

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

Here is the paper that prompted the article quoted above:

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

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

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


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

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

Announcement by Larry Page

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

Google vs. Death

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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

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

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

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

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

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

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


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

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

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

Stem cell reprogramming made easier

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

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

Pancreatic Stem Cells Isolated from Mice

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

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

Scientists grow new stem cells in a living mouse

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

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

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

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

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


Monday, September 16, 2013

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

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

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

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

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

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

Monday, September 16, 2013

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

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

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

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

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

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

Tuesday, September 17, 2013

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

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

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

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

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

Tuesday, September 17, 2013

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

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

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

Wednesday, September 18, 2013

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

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

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

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

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

Wednesday, September 18, 2013

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

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

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

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

Thursday, September 19, 2013

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

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

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

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

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

Thursday, September 19, 2013

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

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

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

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

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

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

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

Friday, September 20, 2013

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

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

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

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

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

Friday, September 20, 2013

TechCrunch occasionally has its uses:

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

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

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

I don't see how anyone familiar with the science can re


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