Fight Aging! Newsletter, September 15th 2014

September 15th 2014

Herein find a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress on the road to bringing aging under medical control, the prevention of age-related disease, and present understanding of what works and what doesn't when it comes to extending healthy life. Expect to see summaries of recent advances in medicine, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • Another Method of Restoring Activity in Old Muscle Stem Cells
  • $1 Million Palo Alto Longevity Prize Launches
  • "When Google is throwing $100 million at aging research, why fund SENS?"
  • Inducing Heat Shock Protein 70 as a Basis for Therapies
  • Near Term Outcomes in Healthcare Costs Resulting from Piecemeal Progress Towards a Cure for Aging
  • Latest Headlines from Fight Aging!
    • Less Time Sitting Correlated With Longer Telomeres
    • Mitochondrial Stress Signaling in Longevity
    • More Intestinal AMPK Extends Life in Flies via Autophagy
    • Incremental Improvement in Kidney Tissue Engineering
    • "Why am I waiting to do something about this?"
    • Applying Targeting Mechanisms to Stem Cell Therapy
    • Getting Closer to Type 2 Diabetes Raises Cancer Risk
    • A Clinical Trial of Induced Pluripotent Stem Cells for Macular Degeneration
    • Recent Work on SkQ1 and Vascular Inflammation
    • Considering Intracellular Amyloid Beta in Alzheimer's Disease


Stem cell activity progressively declines with age, leading to lapsed tissue maintenance and increasing dysfunction and frailty. The role of stem cells is after all to replenish tissues, to provide a supply of fresh cells to replace those lost by the normal turnover, as well as issuing signals that spur other cell types into repair and regenerative efforts. Why does stem cell activity diminish? It is most likely an evolved reaction to rising levels of cellular damage, and serves to reduce the risk of cancer: our long life span in comparison to other primates is a balancing act between death by cancer on the one hand and death by tissue failure on the other. This in turn may have came about due to the development of greater intelligence and culture in our species, as when old people can contribute positively to the survival of their descendants there is a selection pressure that leads to a growing number of old people - a lengthening of life spans.

The satellite cells that support muscle tissue are one of the most studied stem cell populations. Certainly it is there that most of the really interesting discoveries have been made in recent years. For example that stem cell populations are not greatly diminishing in size, though there is some debate over this point in various different types of stem cell, and that the cells themselves are not becoming incapable of action. Rather the stem cell niche, the supporting tissue environment that houses these cells, changes over time and the stem cells become increasingly quiescent in response to altered levels of circulating proteins. We can speculate as to how these and other changes in the tissue environment are linked to the cellular and molecular damage that accumulates as a side-effect of the normal operation of metabolism. Figuring that out is very much a work in progress. Researchers have identified some of the specific protein signals involved in recent years, and have demonstrated that altering these signal levels can restore aged stem cells to a more youthful level of activity. You might look back in the Fight Aging! archives at work on GDF-11 and muscle stem cell rejuvenation, for example.

Obviously this is of great interest, as putting old stem cells back to work could ameliorate a range of age-related conditions. Just look at the benefits produced today via first generation stem cell therapies used to treated the old and the damaged. As is usually the case, we should expect there to be multiple mechanisms at work and multiple ways to influence any one underlying process in cell biology, however. Nothing is simple in metabolism, and all processes are networks of linked feedback loops and mechanisms. So here researchers report another method of restoring activity in aged muscle stem cells:

Why age reduces our stem cells' ability to repair muscle

[Researchers] found that as muscle stem cells age, their reduced function is a result of a progressive increase in the activation of a specific signalling pathway. Such pathways transmit information to a cell from the surrounding tissue. The particular culprit identified by [the] team is called the JAK/STAT signalling pathway. "What's really exciting to our team is that when we used specific drugs to inhibit the JAK/STAT pathway, the muscle stem cells in old animals behaved the same as those found in young animals. These inhibitors increased the older animals' ability to repair injured muscle and to build new tissue."

What's happening is that our skeletal muscle stem cells are not being instructed to maintain their population. As we get older, the activity of the JAK/STAT pathway shoots up and this changes how muscle stem cells divide. To maintain a population of these stem cells, which are called satellite cells, some have to stay as stem cells when they divide. With increased activity of the JAK/STAT pathway, fewer divide to produce two satellite cells (symmetric division) and more commit to cells that eventually become muscle fibre. This reduces the population of these regenerating satellite cells, which results in a reduced capacity to repair and rebuild muscle tissue.

Researchers discover a key to making new muscles

There are two important processes that need to happen to maintain skeletal-muscle health. First, when muscle is damaged by injury or degenerative disease such as muscular dystrophy, muscle stem cells - or satellite cells - need to differentiate into mature muscle cells to repair injured muscles. Second, the pool of satellite cells needs to be replenished so there is a supply to repair muscle in case of future injuries. In the case of muscular dystrophy, the chronic cycles of muscle regeneration and degeneration that involve satellite-cell activation exhaust the muscle stem-cell pool to the point of no return.

"Our study found that by introducing an inhibitor of the STAT3 protein in repeated cycles, we could alternately replenish the pool of satellite cells and promote their differentiation into muscle fibers. Our results are important because the process works in mice and in human muscle cells. Our next step is to see how long we can extend the cycling pattern, and test some of the STAT3 inhibitors currently in clinical trials for other indications such as cancer, as this could accelerate testing in humans."

Inhibition of JAK-STAT signaling stimulates adult satellite cell function

Diminished regenerative capacity of skeletal muscle occurs during adulthood. We identified a reduction in the intrinsic capacity of mouse adult satellite cells to contribute to muscle regeneration and repopulation of the niche. Gene expression analysis identified higher expression of JAK-STAT signaling targets in 3-week-old relative to 18-month-old mice. Knockdown of Jak2 or Stat3 significantly stimulated symmetric satellite stem cell divisions on cultured myofibers. Genetic knockdown of Jak2 or Stat3 expression in prospectively isolated satellite cells markedly enhanced their ability to repopulate the satellite cell niche after transplantation into regenerating tibialis anterior muscle. Pharmacological inhibition of Jak2 and Stat3 activity similarly stimulated symmetric expansion of satellite cells in vitro and their engraftment in vivo. Intramuscular injection of these drugs resulted in a marked enhancement of muscle repair and force generation after cardiotoxin injury. Together these results reveal age-related intrinsic properties that functionally distinguish satellite cells and suggest a promising therapeutic avenue for the treatment of muscle-wasting diseases.

One concern in this approach of putting old stem cells back to work is the very same that has existed for all stem cell treatments, which is the risk of cancer. If stem cells decline in their activity because it reduces cancer risk, then overriding that behavior in an old body that still has a high level of cellular damage will probably raise the risk of cancer. This is an issue that has been successfully addressed in stem cell treatments to date, and I imagine it will be successfully addressed in future treatments based on making older stem cells act as though they are in young tissue. It is a concern and an additional cost of development, not a roadblock.

Indeed, with reference to this recent work on stem cell rejuvenation you don't have to look far to see that STAT3 levels are associated with cancer stem cells in a variety of cancers, though not in any straightforward fashion. Biology is always far more complicated than we would like it to be for the purposes of medicine.


In recent years a growing network of supporters of longevity science has emerged in the Bay Area entrepreneurial and venture community. It is a highly networked environment, and visible signs such as the Health Extension meetings are really just the tiniest tip of the iceberg. It is no accident that the SENS Research Foundation and its coordination of rejuvenation biotechnology research is based in the Bay Area: venture capitalist turned philanthropist Peter Thiel was one of the early high net worth donors to SENS research, and folk in the software engineering community have always made up a sizable fraction of the donors and supporters of first the Methuselah Foundation and then the SENS Research Foundation after it was spun off as an independent organization. Medicine is engineering, and aging is an engineering problem asking for a solution: this is something that is perhaps more clearly visible to people who have written code for a living at some point in their careers.

Which is not to skip over the fact that there is a thriving medical biotech venture community in that part of the world as well. It just doesn't get as much press, and the people involved have historically tended to be just as conservative and quiet about the prospects for treating aging as the rest of the life science research community. Sometimes change must come from the outside, which is exactly what happened in this case.

Before funding SENS research the Methuselah Foundation initially focused entirely on the Mprize: a research prize aiming to spur the research community into doing more work and speaking more publicly about efforts to extend healthy life span and produce rejuvenation in the old. At the time the prize launched, the silence of the research community and their unwillingness to push the boundaries, educate the public, and get on with treating aging was a real issue and a cultural roadblock to progress. That this state of affairs has changed dramatically is due in no small part to the efforts of the Methuselah Foundation and the networking that took place as a direct consequence of the existence of a research prize.

The prize continued over the years, and still runs today to encourage researchers to put in more work on extending healthy life spans in mammals. In a different world the Mprize might still be generating meaningful levels of press and attention even now, but it was hampered by an unfortunate happenstance of research, in that one of the first methods discovered to extend life span in mice was so effective that it has yet to be surpassed or even matched, more than ten years later. It is hard to have a contest when there are no new winners emerging on a short enough time frame to interest the public. For my money, I'd wager that producing mice that live longer than growth hormone receptor knockout mutants won't happen without the implementation of SENS rejuvenation treatments, ways to extend life by repairing damage (and thus reversing aging) rather than slowing the progression of damage (and thus slowing aging).

Nonetheless, the Mprize was a successful vehicle to produce change in the aging research community: this is the interesting thing about research prizes, that they don't have to achieve their stated competitive goals or even look like they worked as a contest in order to produce the desired outcome, a revival of effort in a specific field of research and development. Success is all about networking and attention, which in turn leads to fundraising and greater activity where before there was little. The Methuselah Foundation continues to run the Mprize, but is presently more focused on speeding up organ tissue engineering through the New Organ Prize: working to ensure that patient-specific organs built from stem cells exist soon rather than twenty years to thirty years from now.

So perhaps this leaves a space for a next generation of research prizes in longevity science, and it turns out that folk in the Bay Area venture community think that is the case - and if there is one thing that these people are good at, it is networking, the lifeblood of a research prize initiative. So take a little time to peruse the Palo Alto Longevity Prize and note the panoply of advisors and research teams signed up to compete. The actual details of the prize are of technical interest, especially since they lean in the direction of supporting repair over slowing aging, but they are far less important than what is taking place behind the scenes as a result of this initiative:

Palo Alto Longevity Prize

Just six decades after Orville and Wilbur Wright launched the aviation age, President Kennedy pronounced a moonshot: fly people to the moon and back. Eight years later, the mission was accomplished. Now, six decades after James Watson and Francis Crick discovered the code of life, it is time to embark on another historic mission: hack the code of life and cure aging.

The Palo Alto Longevity Prize (the "Prize") is a $1 million life science competition dedicated to ending aging. Ours is one of a growing number of initiatives around the world pursuing this goal - the more shots on goal the better. Through an incentive prize, our specific aim is to nurture innovations that end aging by restoring the body's homeostatic capacity and promoting the extension of a sustained and healthy lifespan.

There are two prizes available and teams may compete for one or both prizes:

1) A $500,000 Homeostatic Capacity Prize will be awarded to the first team to demonstrate that it can restore homeostatic capacity (using heart rate variability as the surrogate measure) of an aging reference mammal to that of a young adult.

2) A $500,000 Longevity Demonstration Prize will be awarded to the first team that can extend the lifespan of its reference mammal by 50% of acceptable published norms. Demonstration must use an approach that restores homeostatic capacity to increase lifespan.

To enable a rapid commercial path forward for the innovations, the sponsor of the Prize will be contributing an existing pool of relevant intellectual property to the Prize effort.


There is an art to writing press releases for large joint ventures, and one part of it involves setting out the largest number you can vaguely justify in terms of dollars that will be spent in the future. You can look at the recent joint announcement of the Calico / Abbvie collaboration on longevity science as a good example of the type: of the $1.5 billion touted everything above the first $100-200 million is basically fuzzy money, a matter of conditional future outlays, a hopeful position statement made far in advance rather than any sort of real commitment. Large numbers are rolled out in this way because the declaration helps the companies involved: it produces free advertising in the media circus, aids in gaining political leverage for tax advantages, and so forth.

But still, that first $100 million is a large chunk of change in the aging research world. The annual budget of one of the noted Buck Institute for Research on Aging is a little more than $30 million, and the National Institute on Aging (NIA) budget is $1.2 billion for 2014. If we take the usual ballpark guesstimate of public funding as about a third of overall research in this field in the US, that gives some idea of the scale of things.

Here is an opinion that I've heard expressed of late: why bother with all the effort and grassroots fundraising and advocacy to fund the rejuvenation biotechnology work at the SENS Research Foundation now that Google is throwing hundreds of millions of dollars into the aging science ring? This sounds like plain old lazy thinking to me. Not all research expenditure is the same, and not everyone who talks about tackling aging is in fact performing useful work likely to have much of an impact on human life spans in the near future. Consider that the organizations coordinating SENS research on repair of the causes of aging have been bootstrapped on philanthropic donations for a decade now, and in an environment in which ten times the amount Google is likely to spend on aging research over the next few years has been expended by the NIA alone - and that is each and every year. The question could just as well be "why bother with SENS when the NIA is spending a river of dollars?"

"But look at the Calico website, right they they say they are tackling aging. That is new and different." That too is something I have heard. But this is really no different from the messaging you'll find at the NIA:

The NIA has been at the forefront of the Nation's research activities dedicated to understanding the nature of aging, supporting the health and well being of older adults, and extending healthy, active years of life for more people.

This story really isn't about dollars. It is about methodology. If everything could be solved by simply ensuring a large inflow of dollars, then the world be a much simpler and possibly much better place as a result. But how those dollars are spent matters far more than the amount. For all the rhetoric and grand budget of the NIA, outside of some cancer and stem cell research, I would be extremely surprised to learn than more than a few million each year out of that vast flow of money actually funds any of the remaining SENS-like lines of research capable of contributing meaningfully to extended healthy life spans. The same is true of the private research and development institutions. The mainstream simply isn't undertaking the needed work, and that is why we need a funded SENS research program.

SENS exists as a disruptive innovation in aging research: it is a conceptually novel way of approaching aging and its treatment, a better approach to using existing capabilities and knowledge to produce longer, healthier lives at the end of the research process. It focuses on repair and root causes, and will ultimately overtake the research community to replace the old way of doing things that is consuming vast sums to no good end. SENS will achieve this goal by producing meaningful results on measures of health and aging where other approaches do not, and at a fraction of the cost; that is the reasonable expectation based on the scientific underpinnings, to my eyes, and to the eyes of a significant minority in the research community. Disruption is a bootstrapping process, a start from nothing but an idea, followed by incremental growth, proof, and persuasion until everyone admits you were right all along and switches to do things your way. This happens constantly in the technology business, and also elsewhere in the sciences, albeit on a slower timeframe because the issues at hand are usually far more complex and - in the case of medicine - far more bound up in regulation.

The deployment of large sums of money in any industry is an extremely conservative business. It is very, very rare for large institutions to head off in new radical directions - or indeed to intentionally take any sort of similarly large risk. They follow and reinforce the mainstream. At this time in aging research the mainstream is still characterized by the NIA and Big Pharma approaches to age-related disease: only treat the complex, late stages of aging; only treat named diseases of aging; only work on proximate causes of dysfunction rather than root causes; only try to repair harm after the fact rather than prevent it; attempt to alter our highly complex metabolism to slow aging rather than repair the damage of aging to reverse aging. The disruptive adoption of a SENS approach of prevention and rejuvenation of aging and age-related disease has not yet happened, for all that it is on the way.

So when you see the emergence of an organization like Calico, well-funded, and headed by establishment figures from the research mainstream, then the odds are good that the organization will prove to be a continuation of the present work of the mainstream. It will most likely start out as a Big Pharma operation trying to make age-slowing candidate drugs work - akin to more of the same failed, expensive work on sirtuins and other aspects of the calorie restriction response, and similar lines of investigation. They are not going to work on SENS-like approaches for all the same reasons that other large groups are not yet doing so. It isn't the mainstream yet, the disruption hasn't happened yet.

As a part of the mainstream, Calico, like all the other existing large entities funding research, can be disrupted in the future, however. They will turn to devote funds to new methodologies demonstrated to be far more effective and cost-effective than the existing very poor paths forward in drug development to slow aging. The best way to have these organizations devote significant funding to rejuvenation research after the SENS model is for the SENS Research Foundation and related groups to be funded well enough over the next few years to be able to prove their case: to make one or more of the detailed proposed treatments work, and show that they results are far better and far less costly than the present dominant approaches to aging. With money that won't be too challenging, but "with money" is the hard part.

That is why we raise funds for SENS research: to ensure that it is adopted as soon as possible by the mainstream, and that in turn is because to our eyes the diverse evidence from the research community paints a very convincing picture that SENS is the best shot at actually defeating aging. There is nothing novel in any of this. This is how change happens in every field: it is an incremental process of persuasion and gathering evidence, it never goes fast enough, and at the start it is always a matter of raising a few dollars in the middle of a river of money heading towards the old, far worse, mainstream ways of doing things.


Most research into intervening in the aging process is focused on slowing aging. It is a search for ways to safely alter metabolism in order to reduce the rate at which unrepaired cellular and molecular damage accumulates. This damage is a side-effect of the normal operation of metabolism, and it in turn leads to chains of further changes and damage, and all of that together causes aging - a progressive dysfunction and rising risk of catastrophic system failure in organs and tissues based on growing levels of damage. Working on ways to slow aging is the dominant strategy in the mainstream not because it is the best way forward, but rather because it involves exactly the same research process as is employed in the established drug development pipeline: researchers work on explaining how a tiny slice of metabolism works, find a way to alter it in the existing drug library or develop a new drug for that purpose, and then see if it has a positive enough outcome to move towards trials.

Based on results to date it is highly unlikely that this convenient approach will do much more than add knowledge and consume funding. It is not going to result in ways to greatly extend human life spans in the near future: a decade and at least a billion dollars spent on research of the molecular biology of life extension via calorie restriction has demonstrated just how hard it is to use drugs to replicate even this easily replicated and very well studied method. Despite the time and effort calorie restriction is still not yet fully understood, and there is no reliable drug candidate to mimic even a fraction of its effects on health and longevity at this point. Metabolism is exceedingly complex, and so is the calorie restriction response. Even if a perfect calorie restriction mimetic drug turned up tomorrow, which it won't, then would this drug help old people? From the point of view of extending healthy life, not really. There is little use in a drug that slows down the rate at which damage accrues if you are already elderly, frail, and extremely damaged.

The research community should be focused instead on rejuvenation. Repair the damage in the metabolism we have and restore it to the known good working state it exhibits in youth. Don't slow down the damage, try to fix it: help the elderly and frail by restoring youthful function to their tissues. Metabolism complex and changing it would be enormously challenging, so don't change it. The damage that accumulates in and between our cells due to the operation of metabolism is very simple by comparison. Its effects, the aging process, are only complex because we are complex: simple damage in a complex system produces complex results. Consider this: no-one would rebuild an engine to make it work better when it is very rusted, as it is obviously better to remove the rust and rust-proof that machinery. The former option is enormously complex and ultimately doomed to produce only marginal benefits, while the latter is much simpler and restores the engine to an earlier level of function and a longer expected working life span. Rust is simple, engines are complex.

There is far too much engine rebuilding going on in medical research today, and not enough of a focus on the rust. This must change if we are to see meaningful progress towards bringing aging under medical control in our lifetimes. There is a lot of inertia in the present research community and its establishments, however. I expect to see the drug discovery and metabolic alteration approach to slowing aging continue on its largely futile way for decades, even as the better approach to treating aging gathers support and overtakes it. One of the obvious targets in addition to mimicking the benefits of calorie restriction is to try to enhance cellular housekeeping processes responsible for repairing many forms of molecular and cellular damage. Evidence strongly suggests that many of the ways demonstrated to slow aging in laboratory animals are at least partially due to increased levels of cellular housekeeping. So research results like this paper below appear regularly these days:

Inducing Muscle Heat Shock Protein 70 Improves Insulin Sensitivity and Muscular Performance in Aged Mice

Heat shock proteins (HSPs), named after the observed up-regulation following heat shock, are a family of protective chaperone proteins that maintain normal cellular function when cells are under various stressors. Aging is associated with generally reduced levels of heat shock protein 70 (HSP70), which plays a conserved role in cellular homeostasis in all species. Genetic manipulation to increase generalized HSP70 levels has improved lifespan in invertebrate models, and thus it is the focus of our studies. It has been demonstrated that aged muscle tissue does not increase HSP production in adaptation to normal exercise; however, increases in muscle mass and function can be generated by pharmacological induction or overexpression of HSP70.

Aged C57/BL6 mice acclimated to a western diet were randomized into: geranylgeranylacetone (GGA)-treated (100mg/kg/d), biweekly heat therapy (HT), or control. The GGA and HT are well-known pharmacological and environmental inducers of HSP70, respectively.

HT mice had more than threefold, and GGA mice had a twofold greater HSP70 compared with control. Despite comparable body compositions, both treatment groups had significantly better insulin sensitivity and insulin signaling capacity. Compared with baseline, HT mice ran 23% longer than at study start, which was significantly more than GGA or control. Hanging ability (muscular endurance) also tended to be best preserved in HT mice. Muscle power, contractile force, capillary perfusion, and innervation were not different. Heat treatment has a clear benefit on muscular endurance, whereas HT and GGA both improved insulin sensitivity. Different effects may relate to muscle HSP70 levels. An HSP induction could be a promising approach for improving health span in the aged mice.

Will useful therapies will result from this sort of thing? Likely so: some interesting and fairly dramatic results have been obtained by boosting the operation of cellular housekeeping mechanisms over the years. But this isn't the road to bringing aging under medical control and greatly extending healthy life spans, for the reasons noted above. Slowing aging isn't good enough, being only an expensive path to poor results in terms of healthy years of life gained and the ability to rejuvenate the old.


The cure for aging is often naively envisaged as a single treatment, but this won't be the case in reality. Aging is caused by a variety of distinct parallel processes all running at the same time, producing forms of damage that accumulate in and between cells. These consequences interact with and exacerbate one another in a stochastic fashion to produce quite different individual outcomes within a process that is basically the same for everyone. It is the grand lottery: which vital system will give way first. So aging will be brought under medical control one piece at a time, because dealing with each root cause is a very different type of project, suited to different career specialists and research teams. Research doesn't run to any more of a fixed schedule than the processes of aging, and it's hard to say when and for which of the causes of aging the first effective treatments will emerge. There won't be a single cure for aging, and neither will the treatments making up the first generation rejuvenation toolkit for humans emerge all at once. There will be a period of transition, probably just two decades or so judging from the present pace of development in the life sciences, in which all of the unpleasant physical aspects of being old and causes of mortality will be eliminated slice by slice.

It is obviously the case that medical expenditures per year will drop dramatically when old people are no longer physically old. At present the vast majority of medical expenditures are needed by the old: it is hard and expensive to keep a failing system working when you are not addressing the underlying reasons for its failing state. Physically young people have little need for treatment, and the rejuvenation therapies of tomorrow will be cheap in the long run. Everyone ages for the same root causes, and the damage of aging is the same, and further you could run a good few decades between treatments with few consequences. Thus treatments will largely be mass-produced infusions, administered by bored clinicians who have to do little more than push a button. That is not a recipe for great expense: all the really expensive processes in medicine are expensive because they require a lot of time and attention from highly trained individuals, but that will not be the case for rejuvenation therapies that work by repairing the underlying cellular and molecular damage that causes aging.

Equally it is obviously the case that if you live for thousands of years as a physically young individual your lifetime medical expenditures for insurance alone, while small year by year, will eventually outweigh the expense of a short aging life span of a century. But so what? You don't hear people complaining about lifetime costs of food going up if they were to live longer. Life is opportunity, a process. You earn, you spend. It only stops being that way when you become too sick to earn - which is for most people only the case due to aging.

In the transitional period between today and a future in which the last piece of the rejuvenation toolkit is in place, piecemeal progress will produce interesting and sometimes counterintuitive effects on medical costs. To my eyes living an extra year without suffering an pain is an opportunity, and if it means you spend more to do it, so be it. You could always choose the alternative. Never forget that we live lives of privilege in comparison to the billions who have gone before, people who didn't have the luxury of the medicine we have now, never mind the medicine we might have tomorrow.

Sadly much of the public discussion of medical costs is distorted by the present baroque system of entitlements and regulation. Few people in wealthier regions of the world pay for medical care directly, money often comes from government funds, and thus the incentives are aligned against progress and efficiency. Prices have no connection to reality, competition is muted, and providers have little direct incentive to deliver good services, or improve upon their offerings. Everyone involved recognizes that the system is terrible, but their short-term incentives are to go along with it, even as it becomes progressively worse and more harmful to progress and quality over time. This is largely why there is a lot of attention paid to measures of life time medical costs, as there are people who want that number to be lower because it is paid for by entitlements, or because it is inflated by a broken system of regulation that stifles price competition, and so forth.

Here is a fairly coherent paper on the subject of cost and piecemeal medical progress. It is useful from the point of view of forming a mental model of what is likely to happen in the years ahead as aging is brought under control one slice at a time. Many of us will live through the transition decades from a point of no treatments for the causes of aging to a point of comprehensive rejuvenation therapies, so it is perhaps worth thinking ahead just a little:

Disease Prevention: Saving Lives or Reducing Health Care Costs?

Disease prevention has been claimed to reduce health care costs. However, preventing lethal diseases increases life expectancy and, thereby, indirectly increases the demand for health care. Previous studies have argued that on balance preventing diseases that reduce longevity increases health care costs while preventing non-fatal diseases could lead to health care savings. The objective of this research is to investigate if disease prevention could result in both increased longevity and lower lifetime health care costs.

Mortality rates for Netherlands in 2009 were used to construct cause-deleted life tables. Data originating from the Dutch Costs of Illness study was incorporated in order to estimate lifetime health care costs in the absence of selected disease categories. We took into account that for most diseases health care expenditures are concentrated in the last year of life.

Elimination of diseases that reduce life expectancy considerably increase lifetime health care costs. Exemplary are neoplasms that, when eliminated would increase both life expectancy and lifetime health care spending with roughly 5% for men and women. Costs savings are incurred when prevention has only a small effect on longevity such as in the case of mental and behavioural disorders. Diseases of the circulatory system stand out as their elimination would increase life expectancy while reducing health care spending.

The stronger the negative impact of a disease on longevity, the higher health care costs would be after elimination. Successful treatment of fatal diseases leaves less room for longevity gains due to effective prevention but more room for health care savings.


Monday, September 8, 2014

Average telomere length in blood cells tends to decline with advancing age, but it is a dynamic measure that should probably be regarded as an indirect reflection of health and robustness. Consider that telomeres shorten with each cell division, acting as a part of the mechanisms that limit somatic cell life span, so the average telomere length in any given tissue is a function of how rapidly cells divide and how often they are replenished from the supporting population of stem cells in which telomerase activity maintains long telomeres. It isn't clear at all that telomere erosion is an important cause of aging, versus simply a secondary effect of damage taking its toll on stem cell activity and other necessary aspects of tissue maintenance. Given that, it is interesting that telomerase based treatments extend life in mice: the mechanism has yet to be established, however, and there are hints that it may have something to do with the effects of telomerase on mitochondria.

Separately, in recent years researchers have demonstrated that greater time spent sitting, independent of other factors relating to exercise and sedentary behavior, correlates with worse health and a shorter life expectancy. Various researchers are exploring mechanisms that might explain these results. Here this group shows a correlation with telomere length, which would be expected if sitting time does indeed correlate with worse health:

[Researchers] analysed the length of chromosomal telomeres in the blood cells of 49 predominantly sedentary and overweight people in their late 60s, on two separate occasions, six months apart. All 49 participants had been part of a previously reported clinical trial in which half of them had been randomly assigned to a tailored exercise program over a period of six months, and half had been left to their own devices. Levels of physical activity were assessed using a seven day diary and a pedometer to measure the number of footsteps taken every day, while the amount of time spent sitting down each day was gleaned through a validated questionnaire. The time spent exercising as well as the number of steps taken daily increased significantly in the group following the exercise program, while the amount of time spent seated fell in both groups.

Various risk factors for heart disease and stroke also improved in both groups, particularly those on the exercise program, who also lost a great deal more weight than their counterparts left to their own devices. But increases in physical activity seemed to have less of an impact than reductions in sitting time, the findings showed. The number of daily steps taken was not associated with changes in telomere length, while an increase in moderate intensity physical activity was linked to a shortening in telomere length, although this was not significant. But a reduction in the amount of time spent sitting down in the group on the exercise program was significantly associated with telomere lengthening in blood cells.

Monday, September 8, 2014

Mitochondria are the power plants of the cell, a bacteria-like herd of organelles that have an important role in aging. They become damaged as a result of their everyday activities, and that damage ultimately creates malfunctioning cells that harm surrounding tissues. Many of the methods demonstrated to slow aging in laboratory animals involve alterations to mitochondrial function that may impact the pace at which their damage progresses or degree to which it is ameliorated by cellular housekeeping mechanisms. We would like to see a comprehensive way to entirely eliminate this damage, however, a way to completely repair mitochondrial damage and reset the clock on this contribution to degenerative aging. Fortunately there are a range of possible approaches to this goal, such as replacement of mitochondria, replacement of their DNA, moving their DNA into the cell nucleus, and so forth.

This open access paper covers what is known of the numerous ways in which mitochondria are thought to influence the behavior of other important biological systems also linked to aging:

Mitochondria are principal regulators of cellular function and metabolism. In addition, mitochondria play a key role in cell signaling through production of reactive oxygen species that modulate redox signaling. Recent findings support an additional mechanism for control of cellular and tissue function by mitochondria through complex mitochondrial-nuclear communication mechanisms and potentially through extracellular release of mitochondrial components that can act as signaling molecules. The activation of stress responses including mitophagy, mitochondrial number, fission and fusion events, and the mitochondrial unfolded protein response requires mitochondrial-nuclear communication for the transcriptional activation of nuclear genes involved in mitochondrial quality control and metabolism.

The induction of these signaling pathways is a shared feature in long-lived organisms spanning from yeast to mice. As a result, the role of mitochondrial stress signaling in longevity has been expansively studied. Current and exciting studies provide evidence that mitochondria can also signal among tissues to up-regulate cytoprotective activities to promote healthy aging. Alternatively, mitochondria release signals to modulate innate immunity and systemic inflammatory responses and could consequently promote inflammation during aging. In this review, established and emerging models of mitochondrial stress response pathways and their potential role in modulating longevity are discussed.

Tuesday, September 9, 2014

Intestinal function is especially important in fly aging, and of late a number of ways of extending life in fly studies have involved interventions targeted to intestinal tissue, including altered levels of PGC-1 and improved stem cell function via altered insulin signaling. Further, it was recently established that INDY, an early longevity gene discovery in flies, also works via improved intestinal stem cell function.

The gene AMPK turns up in many studies of methods known to slow aging in laboratory species: you might peruse the Fight Aging! archives for a fair sized selection. AMPK is centrally placed in numerous core mechanisms of metabolism that are altered by these existing ways to slow aging, but it is especially important as an activator of the cellular housekeeping processes of autophagy. More autophagy generally leads to longer life in animal studies for all of the obvious reasons: less damage means less dysfunction. Here researchers show that increased AMPK levels in fly intestines extend healthy life:

Working with fruit flies, the life scientists activated a gene called AMPK that is a key energy sensor in cells; it gets activated when cellular energy levels are low. Increasing the amount of AMPK in fruit flies' intestines increased their lifespans by about 30 percent - to roughly eight weeks from the typical six - and the flies stayed healthier longer as well. "We have shown that when we activate the gene in the intestine or the nervous system, we see the aging process is slowed beyond the organ system in which the gene is activated."

The findings are important because extending the healthy life of humans would presumably require protecting many of the body's organ systems from the ravages of aging - but delivering anti-aging treatments to the brain or other key organs could prove technically difficult. The study suggests that activating AMPK in a more accessible organ such as the intestine, for example, could ultimately slow the aging process throughout the entire body, including the brain. Humans have AMPK, but it is usually not activated at a high level.

"Instead of studying the diseases of aging - Parkinson's disease, Alzheimer's disease, cancer, stroke, cardiovascular disease, diabetes - one by one, we believe it may be possible to intervene in the aging process and delay the onset of many of these diseases. We are not there yet, and it could, of course, take many years, but that is our goal and we think it is realistic. The ultimate aim of our research is to promote healthy aging in people."

"A really interesting finding was when [we] activated AMPK in the nervous system, he saw evidence of increased levels of autophagy in not only the brain, but also in the intestine. And vice versa: Activating AMPK in the intestine produced increased levels of autophagy in the brain - and perhaps elsewhere, too." Many neurodegenerative diseases, including both Alzheimer's and Parkinson's, are associated with the accumulation of protein aggregates, a type of cellular garbage, in the brain. "[We] moved beyond correlation and established causality. [We] showed that the activation of autophagy was both necessary to see the anti-aging effects and sufficient; that [we] could bypass AMPK and directly target autophagy."

Tuesday, September 9, 2014

One small step at a time, researchers continue to improve in their attempts to build patient-matched organs for transplantation. An organ constructed with the patient's own cells should have a much lower chance of transplant rejection, and greater odds of success overall. Here work focuses on assembling the necessary techniques to make xenotransplantation feasible:

"Until now, lab-built kidneys have been rodent-sized and have functioned for only one or two hours after transplantation because blood clots developed. In our proof-of-concept study, the vessels in a human-sized pig kidney remained open during a four-hour testing period. We are now conducting a longer-term study to determine how long flow can be maintained." If proven successful, the new method to more effectively coat the vessels with cells (endothelial) that keep blood flowing smoothly, could potentially be applied to other complex organs that scientists are working to engineer, including the liver and pancreas.

The current research is part of a long-term project to use pig kidneys to make support structures known as "scaffolds" that could potentially be used to build replacement kidneys for human patients with end-stage renal disease. Scientists first remove all animal cells from the organ - leaving only the organ structure or "skeleton." A patient's own cells would then be placed in the scaffold, making an organ that the patient theoretically would not reject.

The cell removal process leaves behind an intact network of blood vessels that can potentially supply the new organ with oxygen. However, scientists working to repopulate kidney scaffolds with cells have had problems coating the vessels and severe clotting has generally occurred within a few hours after transplantation.

The [scientists] took a two-pronged approach to address this problem. First, they evaluated four different methods of introducing new cells into the main vessels of the kidney scaffold. They found that a combination of infusing cells with a syringe, followed by a period of pumping cells through the vessels at increasing flow rates, was most effective. Next, the research team coated the scaffold's vessels with an antibody designed to make them more "sticky" and to bind endothelial cells. Laboratory and imaging studies - as well as tests of blood flow in the lab - showed that cell coverage of the vessels was sufficient to support blood flow through the entire kidney scaffold.

Wednesday, September 10, 2014

Here is a little more context for yesterday's launch of the Palo Alto Longevity Prize. Like myself all of the regular readers of Fight Aging! had an awakening at some point in time, a moment in which we suddenly realized that aging could and should be cured with future advances in medicine. With progress in advocacy and research a larger number of fellow travelers will join us, ever more of whom will possess the means to make large strides ahead and the vision to realize that we are entering an age in which wealth can purchase time and an end to suffering if wisely spent:

"We spend more than $2 trillion per year on health care and do a pretty good job helping people live longer, but ultimately you still die," says Dr. Joon Yun, a doctor, investor and the main backer of the prize. "The way we are innovating in health care addresses the consequences of aging, but we're not addressing the root cause. So as a result of that, we ultimately can't save people. Your intrinsic homeostasis erodes at 40. Hangovers that used to last a day now last three days. Coughs drag on for months. You come off a roller coaster, and you feel awful, because you can't self center and your blood vessels don't recalibrate fast enough." The goal with the prize would be to find a way to reverse these degrading processes and return the body to a more youthful state.

Yun says his father-in-law recently passed away at the age of 68, and this, combined with conversations with his friends, inspired him to tackle aging. "I come from an old school Korean farming family where you were just expected to till the farms and die. There was something grand and dignified in that. But after my wife's father died of something pretty preventable, I asked myself, 'Why am I waiting to do something about this?'"

"Based on the rapid rate of biomedical breakthroughs, we believe the question is not if we can crack the aging code, but when will it happen," says Keith Powers, the producer of the prize group. Yun has set aside a large chunk of money to fund not just this initial prize but subsequent attempts at solving the aging puzzle. "The prize is winnable, but I don't think we will hit a grand slam on the first one," he says. "I expect to be writing lots of checks."

Wednesday, September 10, 2014

The cancer research community has developed a wide range of mechanisms that can be used to more accurately target a delivered therapy to specific locations in the body or specific types of cell. Many of these methods are largely independent of the payload being delivered, so why not use them to improve the effectiveness of stem cell treatments?

[Researchers] infused antibody-studded iron nanoparticles into the bloodstream to treat heart attack damage. The combined nanoparticle enabled precise localization of the body's own stem cells to the injured heart muscle. The study, which focused on laboratory rats, [addresses] a central challenge in stem cell therapeutics: how to achieve targeted interactions between stem cells and injured cells. Although stem cells can be a potent weapon in the fight against certain diseases, simply infusing a patient with stem cells is no guarantee the stem cells will be able to travel to the injured area and work collaboratively with the cells already there. "Infusing stem cells into arteries in order to regenerate injured heart muscle can be inefficient. Because the heart is continuously pumping, the stem cells can be pushed out of the heart chamber before they even get a chance to begin to heal the injury."

In an attempt to target healing stem cells to the site of the injury, researchers coated iron nanoparticles with two kinds of antibodies, proteins that recognize and bind specifically to stem cells and to injured cells in the body. After the nanoparticles were infused into the bloodstream, they successfully tracked to the injured area and initiated healing. "The result is a kind of molecular matchmaking. Through magnetic resonance imaging, we were able to see the iron-tagged cells traveling to the site of injury where the healing could begin. Furthermore, targeting was enhanced even further by placing a magnet above the injured heart."

Thursday, September 11, 2014

Type 2 diabetes is for the majority of sufferers a self-inflicted problem. It is usually a consequence of becoming fat and sedentary: if you avoid both of those, then it is unlikely to happen to you. Even in the comparatively late stages type 2 diabetes can be reversed by nothing more than increasingly dramatic diet alterations and consequent loss of excess fat tissue. Here researchers show that the progressive dysfunction leading to diabetes is also raising cancer risk:

Prediabetes is a general term that refers to an intermediate stage between normoglycaemia and overt diabetes mellitus. It includes individuals with impaired glucose tolerance (IGT), impaired fasting glucose (IFG) or a combination of the two. Results to date from prospective cohort studies investigating the link between prediabetes and risk of cancer are controversial. Thus in this new study, the authors did a meta-analysis to evaluate the risk of cancer in association with the impaired fasting glucose and impaired glucose tolerance population.

The researchers found that prediabetes was associated with a 15% increased risk of cancer overall. The results were consistent across cancer endpoint, age, duration of follow-up and ethnicity. There was no significant difference for the risk of cancer with different definitions of prediabetes (IGT or IFG). The authors note that it has been reported that obesity, an important risk factor for diabetes, is also linked to the development of cancer. For this reason, they performed a sensitivity analysis that only included studies that adjusted for BMI in the meta-analysis. They say: "We found that, after controlling for BMI, the presence of prediabetes remained associated with an increased risk of cancer of 22%."

The authors say several possible mechanisms could explain the results. First, chronic hyperglycaemia and its related conditions, such as chronic oxidative stress and the accumulation of advanced glycated endproducts (that are made in conditions of excessively high blood sugar) may act as carcinogenic factors. Second, increased insulin resistance leads to increased insulin secretion, which can in turn allow cancer cells to grow and divide. Third, there could be genetic mutations which predispose individuals to an increased risk of cancer, with one recent study showing that a malfunction in a tumour suppressor gene exposed individuals to increased risk of both cancer and prediabetes.

Thursday, September 11, 2014

Induced pluripotent stem (iPS) cells have been moving towards practical use in medicine quite rapidly since their discovery eight years ago, and here researchers will run a first test in a human patient:

A Japanese patient with a debilitating eye disease is about to become the first person to be treated with induced pluripotent stem cells. Unlike embryonic stem cells, iPS cells are produced from adult cells, so they can be genetically tailored to each recipient. They are capable of becoming any cell type in the body, and have the potential to treat a wide range of diseases. [The] trial will be the first opportunity for the technology to prove its clinical value.

In age-related macular degeneration, extra blood vessels form in the eye, destabilizing a supportive base layer of the retina known as the retinal pigment epithelium. This results in the loss of the light-sensitive photoreceptors that are anchored in the epithelium, and often leads to blindness. [Researchers] took skin cells from people with the disease and converted them to iPS cells. [They] then coaxed these cells to become retinal pigment epithelium cells, and then to grow into thin sheets that can be transplanted to the damaged retina.

[Researchers] have shown in monkey studies that iPS cells generated from the recipients' own cells do not provoke an immune reaction that causes them to be rejected. There have been concerns that iPS cells could cause tumours, but [the] team has found that to be unlikely in mice and monkeys. To counter further fears that the process of producing iPS cells could cause dangerous mutations, [the] team performed additional tests of genetic stability. Guidelines covering the clinical use of stem cells require researchers to report safety testing on the cells before conducting transplants.

Friday, September 12, 2014

SkQ1 is a mitochondrially targeted antioxidant, and there is evidence to show that it can modestly extend life in mice. Mitochondria are important in the aging process, and one of the ways in which they interact with surrounding cell biology is by generating damaging reactive oxygen species (ROS). Too much ROS creation can harm a cell, a state called oxidative stress. Just a little more than usual can be beneficial, as the cell reacts with increased housekeeping for a net benefit - this is probably one of the mechanisms by which exercise improves health, for example.

This signaling is a parallel mechanism to the most important harm likely caused by mitochondrial ROS, however, which is to damage mitochondrial DNA at their point of origin. This can lead to all sorts of persistent dysfunction in a small population of cells, which export harmful molecules to surrounding tissues. Mitochondrial antioxidants probably produce benefits to long term health by reducing the rate of this mitochondrial damage, but that isn't completely certain at this point because of the ROS signaling to other important aspects of cell metabolism. Biology is complex, and as for all small effects on longevity, the actual mechanism could be any one of a number of things.

So these researchers are making use of SkQ1 as a way to better identify what exactly it is that changes in response to ROS levels, with a focus on dysfunction in blood vessel wall tissue (the vascular endothelium) that leads to age-related conditions such as atherosclerosis:

Cardiovascular diseases (CVDs) have a great impact in morbidity and mortality all over the world. One of the major risk factors for development of CVDs is aging. In recent years a vast amount of information has been obtained pointing to a crucial role of endothelium in the development of age-related CVDs. A healthy endothelium fulfils numerous functions in vascular biology including inflammatory responses, as well as vascular tone and permeability. Endothelial dysfunction is typical for many pathological conditions including atherosclerosis, type I and II diabetes, inflammatory processes, and aging. Aging is associated with increased oxidative stress and a proinflammatory endothelial cell phenotype. Excessive or prolonged endothelium activation due to the action of the proinflammatory cytokines underlies endothelium dysfunction.

The "inflammaging theory" postulates that aging phenotype can be explained by an imbalance between inflammatory and antiinflammatory networks, which results in low-grade chronic proinflammatory status. The inflammatory vascular reactions are mediated by complex interactions between circulating leukocytes and the endothelium. Proinflammatory cytokines including TNF increase expression of cell adhesion molecules (CAMs) and leukocyte adhesion followed by invasion through the vascular endothelium.

We have shown that old mice have increased levels of the vascular inflammatory markers in plasma (TNF and IL-6) and in aorta tissues (ICAM1, VCAM, TNF, and MCP1). A significant body of evidence indicates that mitochondrial dysfunction and excessive mtROS production are involved in vascular inflammation and age-related CVDs. Long-term administration of the mitochondria-targeted antioxidant SkQ1 to old mice completely prevented the age-related increase in aortic ICAM1 mRNA expression and attenuated the increase in expression of the other proinflammatory genes. However, SkQ1 did not affect circulatory TNF and IL-6 levels, thus indicating that mtROS are critical for inflammatory signaling downstream from cytokine expression.

Increased expression of CAMs is implicated in early steps of atherosclerosis. The suppression of leukocyte adhesion to endothelial cells by reducing CAM expression prevented development of atherosclerosis and had positive effects on many aseptic inflammatory pathologies. According to our data, mtROS scavenging may attenuate age-related increase in CAM expression and related endothelial dysfunction.

Friday, September 12, 2014

There is a growing diversity of views in the Alzheimer's research community regarding mechanisms and future directions, which is probably to be expected given the slow path to results on the consensus approach of removing amyloid β. Here is a representative opinion piece:

Two decades have passed since the discovery of the first proteases that degrade the amyloid β-protein (Aβ), the primary constituent of the amyloid plaques that characterize Alzheimer disease (AD). While significant progress has been made, this is an appropriate juncture to reflect on what has been accomplished and ask which research directions are most likely to bear fruit going forward. Herein, I argue that a renewed focus on intracellular Aβ-degrading proteases (AβDPs) is a highly promising direction for future studies, one that is not only likely to advance our understanding of the fundamental molecular pathogenesis of AD, but also to critically inform the development of effective therapies for use clinically.

To date, most studies of AβDPs have focused predominantly on proteases that act extracellularly. This is not surprising - Aβ is, after all, a secreted peptide, and amyloid plaques form extracellularly. However, there is a growing body of evidence implicating intracellular pools of Aβ in the pathogenesis of AD. Generally speaking, it has been challenging to study specific pools of Aβ in conventional animal models of AD, since most models rely upon overexpression of the β-amyloid precursor protein (APP), which necessarily increases the levels of all pools of Aβ simultaneously. The study of AβDPs, by contrast, offers a unique window into the pathogenic role of Aβ, in no small part because individual AβDPs have unique subcellular localizations and pH profiles, which can be exploited to selectively target different pools of Aβ (e.g., extracellular, lysosomal, etc.). This can be readily achieved by overexpression, genetic deletion or pharmacological manipulation of appropriate AβDPs, either alone or in tandem with APP overexpression.

In conclusion, there is a compelling theoretical and empirical rationale for the field to undertake a renewed focus on intracellular AβDPs. The knowledge we can expect to derive from the study of extracellular AβDPs appears to be, at best, approaching an asymptote and, at worst, revealing that extracellular pools of Aβ may not be involved in the pathogenesis of AD to the extent so widely assumed for so long. The study of intracellular AβDPs, by contrast, seems poised to yield insights into questions that are not merely academic or theoretic, but highly practical - for example, the relative merits of immunotherapies, which only target extracellular Aβ, versus secretase inhibitors or modulators, which affect intracellular Aβ as well. Considering the growing interpersonal, financial and societal impact of AD, and the current lack of therapies, it is wise to pursue any and all avenues that may lead to effective treatments, and the study of intracellular AβDPs seems an especially promising direction for future investigation.


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