Fight Aging! Newsletter, July 14th 2014

July 14th 2014

The Fight Aging! Newsletter is a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: both the road to future rejuvenation and the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medicine, news from the longevity science community, advocacy and fundraising initiatives to help advance rejuvenation biotechnology, links to online resources, and much more.

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!

To subscribe or unsubscribe to the Fight Aging! Newsletter, please visit the newsletter site:


  • Fight Aging! Newsletter Delivery Issues to Gmail Accounts
  • Recent Research Data on Lack of Exercise and Obesity
  • Stem Cell Decline and Loss of Organ Mass with Aging
  • Aiming to Remove the Senescent Cell Contribution to Aging and Age-Related Disease
  • The Strategic Future of the SENS Research Foundation
  • Latest Headlines from Fight Aging!
    • A Telomere-Centric View of the Biochemistry of Aging
    • The Lack of Ambition that Characterizes Much of the Discussion of Aging and Longevity
    • Stochastic Mutations in Mitochondrial DNA are Commonplace
    • TDP43 and Autophagy in Frontotemporal Dementia and ALS
    • An Article on the Work of the Gerontology Research Group
    • Trapped by the Conviction that an Extended Life Means Older For Longer, Not Younger For Longer
    • Quantifying the Value of a Healthy Lifestyle
    • Aging, Klotho, and Skeletal Muscle
    • The Rejuvenation Research Advocacy of Aubrey de Grey
    • Promoting October 1st as Longevity Day


Ensuring that the thousands of emails sent out each week for the Fight Aging! newsletter all end up where they should is an ongoing battle with the forces of entropy. Every mail service has its own quirks, and there are dozens of services large enough to require attention. Anti-spam automation is a complex ecosystem, prone to errors and false positive identifications, and one in which small organizations have little influence or recourse to correct such errors. Much of the categorization of spam is completely automated and networked, machines identifying and publishing analyses in real time. Other networks of machines then build their own conclusions based on each layer of processed data. It is like an immune system, and just like the real immune system it can sometimes produce poor outcomes for reasons that are challenging to determine.

A case in point is that in recent weeks Gmail subscribers have been missing out on the Fight Aging! newsletter. At some point Google's internal systems decided that one past newsletter was spam or a promotional email, not a legitimate mail requested by a list subscriber. This could have happened for any number of obscure and complicated causes, but probably has a lot to do with the fact that I have been talking about fundraising of late. Sending a newsletter that discusses longevity science is already sailing close to the wind from the point of view of the global anti-spam ecosystem, given the amount of junk the frauds and marketing departments of the "anti-aging" industry generate. Mix in mentioning money with that, and apparently I'm just asking for it. Spam automation has always had problems distinguishing between real science and fake science relating to aging and longevity, which may be yet another reflection of the fact that most people - a category that includes most people who work on anti-spam automation - still don't think that there is real science there to be discussed.

Google's anti-spam automation is self-reinforcing. If one newsletter ends up in the spam folder or Promotions tab at Gmail, then all similar following emails will as well. Google's systems cheerfully build upon any mistake, and worse, they propagate that mistake out into the broader anti-spam ecosystem to make it more likely that other systems identify Fight Aging! newsletters as spam and blacklist the Fight Aging! mail server. As anyone who has ever had issues with Google's free products know, there is no way to reach an actual human being at Google unless you happen to represent a large business concern, or you have a large audience and can make Google look bad by complaining. Errors don't get fixed, there is no customer service, and you simply have to deal with whatever breakage they create.

So I am doing what I can at my end, but there are really very few ways to influence this course of events beyond moving the mail server, a task that is presently in progress. Even there the actual thread of identification in Google's systems is the email address and the content of the newsletter, not the mail server's location. Moving the server just helps to minimize some of the other damaging consequences resulting from this issue.

The best solution under the circumstances is for Gmail subscribers to find the recent Fight Aging! newsletters in the spam folder or the Promotions tab in their account and then inform Gmail that (a) these emails are are not spam, and (b) that they want to receive future similar emails in the Primary tab. If enough people do this, then it will go some way towards teaching Gmail's automation not to miscategorize these newsletters.

So if you are subscribed to the Fight Aging! newsletter at a Gmail address, please check your spam folder for copies of the Fight Aging! newsletter from the past few weeks. For each, select the mail and click the "Not Spam" button. This will probably move it to the Promotions tab of your inbox. Then please open the Promotions tab of your inbox, find the newsletter emails there and drag them to the Primary tab. You will see a popup asking you whether all future similar emails should be delivered to the Primary tab. Choose that option. I'd greatly appreciate it.


For an allegedly industrious species, we are quite indolent as individuals - or at least just as soon as we achieve a modicum of wealth and success in life. Being wealthier beats the pants off being poorer at every level of improvement, but for most people it comes with some costs as well as a universal array of benefits. You can afford better healthcare, but you are going to need it because you exercise less and eat more. The self-sabotage of an averagely unhealthy lifestyle is enabled by the trappings of modern technology, such as advances in transport, comfort, and entertainment, even as that very same technology is heading towards the establishment of science-fiction-like medicine that will defeat all disease and even aging itself in the decades ahead. For now we're stuck somewhere in the fat and unhealthy middle ground, however: enough technology to seduce us into a lazy, likely shorter life of worse health, but not yet enough technology to reliably rescue us from this fate.

Thus despite the impending golden future of medicine, it remains the case that taking basic, time-worn, good care of your health still matters. Willpower, exercise, and eating less than you want to. If you desire good odds of living to benefit from first generation rejuvenation therapies, then stay healthy on the one hand, and do all you can to help speed initiatives such as the SENS research programs on the other. Here is a small selection of recent research that might incentivize you a little on the good health side of the house:

NCI study finds extreme obesity may shorten life expectancy up to 14 years

Adults with extreme obesity have increased risks of dying at a younger age from cancer and many other causes including heart disease, stroke, diabetes, and kidney and liver diseases, according to results of an analysis of data pooled from 20 large studies of people from three countries. These groups form a major part of the NCI Cohort Consortium, which is a large-scale partnership that identifies risk factors for cancer death. After excluding individuals who had ever smoked or had a history of certain diseases, the researchers evaluated the risk of premature death overall and the risk of premature death from specific causes in more than 9,500 individuals who were class III obese and 304,000 others who were classified as normal weight.

The researchers found that the risk of dying overall and from most major health causes rose continuously with increasing BMI within the class III obesity group. Statistical analyses of the pooled data indicated that the excess numbers of deaths in the class III obesity group were mostly due to heart disease, cancer and diabetes. Years of life lost ranged from 6.5 years for participants with a BMI of 40-44.9 to 13.7 years for a BMI of 55-59.9. To provide context, the researchers found that the number of years of life lost for class III obesity was equal or higher than that of current (versus never) cigarette smokers among normal-weight participants in the same study.

Sitting too much, not just lack of exercise, is detrimental to cardiovascular health

Sedentary behavior involves low levels of energy expenditure activities such as sitting, driving, watching television, and reading, among others. The findings suggest that sedentary behavior may be an important determinant of cardiorespiratory fitness, independent of exercise. "Previous studies have reported that sedentary behavior was associated with an increased risk for cardiovascular outcomes; however, the mechanisms through which this occurs are not completely understood. Our data suggest that sedentary behavior may increase risk through an impact on lower fitness levels, and that avoiding sedentary behavior throughout the day may represent an important companion strategy to improve fitness and health, outside of regular exercise activity."

The team of physician-researchers analyzed accelerometer data from men and women between the ages of 12 and 49 with no known history of heart disease, asthma, or stroke, and measured their average daily physical activity and sedentary behavior times. Fitness was estimated using a submaximal treadmill test, and variables were adjusted for gender, age, and body mass index. The findings demonstrate that the negative effect of six hours of sedentary time on fitness levels was similar in magnitude to the benefit of one hour of exercise.

Less Exercise, Not More Calories, Responsible for Expanding Waistlines

Sedentary lifestyle and not caloric intake may be to blame for increased obesity in the US, according to a new analysis of data from the National Health and Nutrition Examination Survey (NHANES). [In] the past 20 years there has been a sharp decrease in physical exercise and an increase in average body mass index (BMI), while caloric intake has remained steady. Investigators theorized that a nationwide drop in leisure-time physical activity, especially among young women, may be responsible for the upward trend in obesity rates.

By analyzing NHANES data from the last 20 years, researchers from Stanford University discovered that the number of US adult women who reported no physical activity jumped from 19.1% in 1994 to 51.7% in 2010. For men, the number increased from 11.4% in 1994 to 43.5% in 2010. During the period, average BMI has increased across the board, with the most dramatic rise found among young women ages 18-39.

The study looked at the escalation of obesity in terms of both exercise and caloric intake. While investigators did not examine what types of foods were consumed, they did observe that total daily calorie, fat, carbohydrate, and protein consumption have not changed significantly over the last 20 years, yet the obesity rate among Americans is continuing to rise.

Researchers also tracked the rise in abdominal obesity, which is an independent indicator of mortality even among people with normal BMIs. Abdominal obesity is defined by waist circumference of 88 cm (34.65 in) or greater for women and 102 cm (40.16 in) or greater for men. Data showed that average waist circumference increased by 0.37% per year for women and 0.27% per year for men.


There are a few hundred different types of cell in the body, a collection of types for each major organ and variety of tissue. Cell populations turn over at various different rates, with new cells supplied by dedicated supporting stem cells, existing cells in the tissue dividing, and old cells removing themselves from the picture through forms of programmed cell death. The cells that line your gut have a very short life of a few days. Blood cells are usually in circulation for months. Many nervous system cells last your entire life. Unfortunately old cells that have divided many times don't always self-destruct, and instead slide into a form of growth arrest known as senescence. There they stay unless destroyed by the immune system, making life difficult for surrounding cells and degrading tissue function. The growing number of senescent cells in all tissues is one of the causes of degenerative aging.

One of the other problems in this context of tissue maintenance is that the supply of new cells dwindles with age. Stem cells stop doing their jobs and spend more time in dormant states. As a result tissue and organ function begins to falter and eventually fail. The consensus viewpoint in the research community is that this is an evolutionary adaptation that reduces cancer risk. The big important difference between humans and possibly immortal highly regenerative lower animals such as hydra is that we are complex and the continuation of an individual's life depends on maintaining the small-scale accumulated structure of our nervous system - we can't just throw it all out and regenerate it as needed. If you have a brain, or even just a rudimentary central nervous system, that rules out the sort of high-powered always-on stem cell activity that allows a hydra to be (possibly) ageless and renew or regrow any lost part.

One of the manifestations of diminished stem cell activity with aging is that we lose tissue mass in most of the important organs. This may be a straightforward consequence of lack of replenishment, but as the paper linked below notes it starts fairly early in adult life. In this viewpoint, the well-known involution of the thymus at end of childhood is just the most noticeable of a set of similar changes that occur throughout adulthood and into old age. Loss of stem cell activity is something that has to be fixed by any comprehensive rejuvenation toolkit of the near future, or at least it has to be fixed to the extent that it is not just a reaction to forms of tissue damage. It is quite likely that stem cell decline in old age is in fact largely driven by epigenetic changes that in turn arise due to rising levels of - for example - mitochondrial DNA damage, metabolic waste in cells and between cells, accumulated senescent cells, and so forth. If this damage is repaired, then stem cells should return to work.

Greater organ involution in highly proliferative tissues associated with the early onset and acceleration of ageing in humans

We employed published data to estimate representative mean values of cell turnover times for 31 different organs and tissues in adult humans and animals (when data in humans were lacking) as well as functional mass loss for 5 organs, accounting for actual mass loss and tissue conversion to fat, in humans over the adult period, age 25 to 70. Actual and functional organ mass was lost from age 25 to 70 years in all organs studied, except the heart and prostate. We found that greater actual and functional mass loss was significantly associated with the log of shorter cell turnover times. We propose that this is characteristic of stem cell exhaustion and replicative senescence.

We found that, in normal ageing, organ mass loss is associated with high cell turnover. At the Hayflick limit, cells go into a senescent state of persistent cell cycle arrest, or undergo cell death, usually by p53-dependent apoptosis. This increase in apoptotic and senescent cells with ageing represents a loss of actual and functional tissue. We suggest that this mass loss may be characteristic of stem cell exhaustion as seen in muscle and marrow and that "replicative senescence" may play a role in this process. Stem cell pools can diminish with age. For example, the number of satellite cells in human skeletal muscle declines from young to old adults. Furthermore, stem cell exhaustion may be due to cell dysfunction characterised by decreased self-renewal and quiescence, increased doubling time, degraded niches and impaired terminal differentiation.

Our analysis of previously published data indicates that mass loss in major organs generally begins between 21 and 35 years of age for reproductive organs and between 22 and 50 years for non-reproductive organs, although involution of the thymus begins even earlier. Likewise, many physiological functions show a decline from 30 years of age. Similarly some aspects of age-related cognitive decline begin in healthy educated adults when they are in their 20s and 30s. Therefore, our evaluation of organ mass loss, especially in terms of functional tissue reduction, is in parallel with, and likely contributes to, the decline in physiological and cognitive function. Furthermore, these studies also provide substantial, but not universal, evidence for the acceleration of actual and functional mass loss in organs. As the few studies dedicated to these ageing changes indicate that these functional tissue losses may be considerable, this suggests that even measures of body cell mass underestimate the true accelerating loss of functional tissue with ageing. Indeed, accelerated functional mass loss could provide an increased elimination of precancerous cells in the very elderly, perhaps providing an explanation, among others, for the decrease in cancer rates observed after age 75.

The general prevalence of the Hayflick limit in human somatic cells, including stem cells, means this aspect of human ageing is likely an evolutionary adaptation, as antidotes against this shortening, such as telomerase, are not employed at sustaining levels in somatic tissues. However, telomere-maintenance mechanisms are fully operational in human germ cells, most neoplasms (clonal cells) and biologically immortal species such as Hydra vulgaris that reproduce asexually when food is plentiful. The immortality (and lack of reported mass loss) of Hydra is assigned to FoxO stem cell maintenance gene variants, which are also found in human stem cells, albeit at levels insufficient to maintain stem cells. Interestingly, a genetic variant in the FOXO3a gene region is more common in German centenarians compared with younger controls.

Our review supports a strongly significant association between cell proliferation and functional mass loss, the latter being an important indicator of fitness and ageing. We found that two-thirds of the human variability of mass loss can be assigned to the log of tissue turnover times. We suggest that this is likely characteristic of replicative senescence of stem cells, which, as the immortal Hydra demonstrates, is not a biological imperative but an evolutionary adaptation, likely suppressing cancer in humans. The onset of functional mass loss first becomes apparent soon after growth terminates, during the early part of the reproductive period, when selective pressure is still considerable. We make the case that, although the deceleration of cell turnover helps mitigate the erosion of maintenance-deficient telomeres, there is an acceleration of functional mass loss in old age as biological conditions change from those existing in early development, when the selective pressure on genetic trade-offs is most influential.


As the years pass ever more of your cells fall into a state of senescence. This is a response to the age of the cell itself, its internal damage, surrounding levels of metabolic waste, the presence of cell-damaging toxins, or other signals that indicate a potentially raised risk of cancer. Senescent cells do not divide or do much else to support the tissue they are a part of, but rather emit a range of potentially harmful chemical signals that encourage other nearby cells to also enter a senescent state. Senescent cells sometimes self-destruct, or they can be removed by the immune system, but the immune system has its own process of age-related decline and this activity falters. Cellular senescence can indeed reduce the risk of cancer, but by the time there are significant numbers of senescent cells gathered in the body their presence causes all sorts of harm: they degrade tissue function, increase levels of chronic inflammation, and can even eventually raise the risk of cancer due to their generally bad behavior.

Cellular senescence is one of the more exciting areas of the biochemistry of aging, because the research community is very close to being able to produce treatments for the targeted, safe removal of senescent cells. Early animal studies have provided initial evidence that doing so does produce improvements in health and longevity, as expected. Further studies in rodents presently in progress should firmly demonstrate that healthy, normal animals benefit from the removal of senescent cells. After that, it is a matter of pulling together the targeted cell killing techniques pioneered by the cancer research community with one of the new prospective methods for accurately distinguishing senescent cells from their healthy peers. If not for the generally slow, expensive pace of medical regulation this is something that could probably be done within the next five years, or much sooner for technology demonstrations in laboratory animals.

Targeted destruction of senescent cells is an excellent candidate for a treatment that, like early stem cell therapies, could be offered outside the US for years prior to the more formal and straitjacketed medical development community coming to the point of trials. All the prototype parts of the toolkit are nearly ready, and a successful treatment to remove unwanted senescent cells would be an unalloyed benefit for any healthy older adult. Sadly, as is the case for near all of the most important areas of longevity science, there is little interest or funding for this work in comparison to its potential benefits to health. Things are moving more rapidly than for many other important areas of aging research, but funding is still at disappointingly low levels. We can hope that this will change at the point at which it becomes viable to offer prototype clinical treatments via medical tourism, in much the same way as matters proceeded for the development of the first stem cell therapies.

Here is the latest in a series of essays on the details of the SENS vision for rejuvenation therapies penned by philanthropist Jason Hope. Hope is one of the more noteworthy donors to the SENS Research Foundation, and clearly believes in the goals he supports:

Death Resistant Cells

There are two main approaches to the problems associated with senescent cells: develop a drug that is toxic to abnormal cells but harmless to healthy ones, or stimulate an immune response that targets and selectively kills unhealthy cells.

Molecules lining the surface of cells help those cells interact with their surroundings; these molecules are to varying degrees distinctive to their fate. Because each type of cell has different surface molecules, these molecules can serve as markers, or identification for that cell. Liver cells have a different group of molecules on their surface than blood cells, for example.

Abnormal cells have abnormal surface molecules, making these cells easy to target for therapy. Oncologists already use this type of approach when treating some types of cancer with the intent of shutting down the cancer cells' growth with drugs or by stimulating the immune system to do the job. In some cases, killing abnormal cells deters, treats, or prevents illnesses by making room for new, healthy cells.

Using SENS Research Foundation funding, scientists from University of Arizona are investigating ways to restore a healthy immune system in aging mice by purging unhealthy immune cells known as "anergic T-cells" to free up space for new and healthy killer T-cells. The researchers also hope to bolster the immune system by increasing the body's ability to produce new killer T-cells.

With funding from SENS Research Foundation and working in Dr. Judith Campisi's laboratory at the Buck Institute for Research on Aging, PhD candidate Kevin Perrott is investigating how molecules affect one type of senescent skin cell to understand its role in inflammation and the immune system. These scientists also hope to discover how to kill these senescent cells before they can cause a problem. Additionally, these researchers are testing a library of compounds to identify any that are capable of selectively targeting senescent cells.

SENS Research Foundation funding also supports research performed by Nick Schaum in the Campisi lab, which has shed light on the link between the two hallmarks of cell senescence, identifying a key driver of inflammation and halted cell division.

The goal of these research projects is to understand how cell programming can cause illness and to develop ways to control cell senescence, either through therapeutic drugs or by stimulating the immune system so that it destroys only abnormal cells while leaving healthy cells intact. Success will lead to new rejuvenation biotechnologies to prevent, treat, and even reverse the course of the disease and disability caused by these abnormal cells.


As I've noted in the past, attention and investment given to research tends to come in waves. Longevity science has been building from the 1970s in a series of growing waves, each lasting ten to fifteen years. That is long enough for new ideas to arise, a few organizations to be founded, networks established, research accomplished, and the groundwork laid for the next cycle to begin. The faces are generally different each time around: new entrepreneurs and researchers pick up the torch with each decade, putting their own spin on things and building their own flavor of progress. Insofar as longevity science goes the wave starting in the 1970s was financially insignificant, and didn't do much more than seed the ideas for what is taking place now. It wasn't until ten years ago that the current wave grew large enough to raise millions of dollars for serious work on the basis for rejuvenation treatments, or for there to be significant - albeit still modest - public interest in aging research. I think that this present wave is ending now and the next beginning, a change in the funding environment characterized by the ability to raise tens of millions of dollars for ventures related to aging and longevity. Human Longevity, Inc. (HLI) and the California Life Company (Calico) are early indicators of what lies ahead.

So what of the SENS Research Foundation in all of this? To my eyes, and I'm far from alone in this, the work done by the Foundation and its allies is presently the best hope for real progress towards rejuvenation therapies in our lifetimes. At this time the Foundation is emerging from the end of the wave that saw its creation with a runway of roughly $5 million per year for the next four to five years. This is largely assured by co-founder Aubrey de Grey's donation of $13 million to research, but without replenishment the vault is empty after that. Four to five years is a long time for a for-profit startup business, but not very long at all in medical research. In the sciences this is a decent amount of time to chase an idea from "this looks plausible" to "now we should start trying it out in animal studies." The goal of the Foundation's staff will be to use this runway to gain access to funding sources of the next wave, and ideally to grow tenfold over the next ten to fifteen years if HLI and Calico are representative of the interest that lies ahead. At this level of funding that would require a foundation similar to the Glenn Foundation to be persuaded to make SENS its cause, or for a billionaire philanthropist with interests in medicine such as Paul Allen to step into the space, or for a similarly sized source of public funding to be established.

The very real prospect of attaining this high road goal is why we folk in the grassroots make the effort to raise a few tens of thousands of dollars here and a few tens of thousands of dollars there. If you want to raise millions from big donors and establishment funding, then you have to be able to demonstrate a continuing ability to attract the support and funding of thousands and then tens of thousands of everyday individuals. Large scale funding follows public interest, and we are the trailblazers lighting the way. It would be nice to believe that bolt from the blue multi-million dollar funding just happens for deserving new technologies and research initiatives, but the reality is it doesn't. Massive philanthropic and investments turn up very late in the game, and only when everyone has heard of the cause they are supporting: they are only just nowadays arriving for stem cell research, for example. The only way to get to that point is to build step by step with the grassroots leading the way.

Simply growing funding to take the research programs to the next level is far from the only thing that the SENS Research Foundation can plan for in the new five years. I recognize that the community here is impatient for results: research is slow, and SENS research has been funded to a level of a few million a year for five years or so now. Supporters always want to see more tangible signs of progress than high profile scientific publications or incremental advances in steps seven through twelve of a twenty step process. The unfortunate truth of the matter is that many parts of SENS are not going to be realized anytime soon at the present rate of funding, and even given a tenfold increase are still a decade or more away. But some parts of SENS are much closer, within just a couple of years of technology demonstrations in mice. I think that the best candidates here are firstly elimination of senescent cells and secondly removal of glucosepane cross-links. In the case of senescent cell removal there is already momentum in the research community towards creating and assembling the necessary tools, and furthermore these tools are nearly ready. For glucosepane removal there is no momentum beyond projects funded by the SENS Research Foundation, but it is really just a matter of developing one way to break down one compound, a far, far simpler goal than any other part of the rejuvenation toolkit.

If either of these items is brought usefully close to fruition within the SENS Research Foundation's present runway, then one possible path for the future of SENS is that the Foundation itself becomes rather irrelevant in comparison to a community of overseas developers who begin to offer prototype treatments via medical tourism. Both removal of senescence cells and glucosepane cross-links should be meaningfully beneficial to all older people. This is exactly the same playbook as for the past fifteen years in stem cell research, and should produce the same outcome: a great influx of funding and attention, and real progress. In this scenario it doesn't really matter all that much what becomes of the Foundation, and whether it succeeds in growing or not. It is just one part of a much larger process at that point, and everyone who was directly involved will no doubt do well for themselves as a result of their earlier activities.

So in the sense that people are impatient for progress because they believe that tangible progress in any one aspect of SENS will unlock doors to growth: I agree with this. The thing that keeps me awake at night, and I'm sure others too, is the prospect of failure, and by that I mean that the SENS Research Foundation reaches the end of its runway without achieving either of the two goals above, nor attracting even a sustaining level of donations. It is perfectly possible to fire up the scientific community, change minds, and then be left sitting on empty coffers while the revolution you inspired arrives only decades later. That has happened numerous times in the history of technological development, so we shouldn't be overconfident. Failure in this sense wouldn't destroy SENS, it would just slow things down and relegate it to obscurity for some period of time - but that is a disaster when every year counts.

What is the best way for us to help ensure that this doesn't happen? That would be the grassroots fundraising and all that goes with it: the networking, the publicity, the spread of knowledge. This is why I undertake these tasks, to do my part to help shift the odds for organizations like the SENS Research Foundation to succeed one way or another. Generating the growth in research and development we want to see in the years ahead is a community effort of many moving parts. The next decade is going to be a fairly wild ride, but only if we all work on making it turn out well.


Monday, July 7, 2014

Telomeres are lengths of repeated DNA at the end of chromosomes that in part serve as a sort of clock to limit the life span of some cell types. Telomeres shorten with each cell division, but can be lengthened in longer-lived cells (such as stem cells) by the activity of telomerase. Average telomere length tends to shorten in white blood cells with ill health and aging, but this is somewhat dynamic: go out and exercise more and your average telomere length will increase, for example. Looking at the average length is a smeared-out measure of numerous low-level processes in our biology, such as telomerase activity, the pace at which stem cells are generating new cells with long telomeres, rate of cell division, and so on and so forth.

For some years now there has been a contingent of researchers focused on telomeres: producing better ways to measure them, or more ambitiously trying to construct therapies that lengthen telomeres using telomerase. It seems to me that most research indicates shortening telomere length to be a secondary marker of aging, and thus not a helpful target to either slow or reverse aging, but there exist studies in which mouse life span was extended by upregulating the activity of telomerase. This may, however, be one of those areas of biology in which mice are in fact significantly different from people, or it may be the case that telomerase has other effects independent of lengthening telomeres, such as acting to reduce levels of mitochondrial damage.

Why is that telomere lengths are such good predictors of longevity, but too much telomerase can be bad for you? The answer is probably that telomere lengths measured in the white blood cells reflect a broad range of factors, such as our genetic makeup but also the history of a cell. Some of us may be lucky because we are genetically endowed with a slightly higher telomerase activity or longer telomeres, but the environment also plays a major role in regulating telomeres. If our cells are exposed to a lot of stress and injury - even at a young age - then they are forced to divide more often and shorten their telomeres. The telomere length measurements which predict health and longevity are snapshots taken at a certain point in time and cannot distinguish between inherited traits which confer the gift of longer telomeres to some and the lack of environmental stressors which may have allowed cells to maintain long telomeres.

What are the stressors which can affect cellular aging and shortening of telomeres? Oxidative stress, the excess production of reactive oxygen species oxidizes proteins, disrupting their structure and function to the extent that oxidized proteins become either useless or even harmful. Inflammatory stress refers to excessive inflammation which transcends the normal inflammatory response of cells from which they can recover. Prolonged inflammation, for example, can cause cells to activate a cell-death program. Recent studies in mice have shown that activation of inflammation pathways in the brain can suppress cognitive function, muscle strength and overall longevity. Stressors are often interconnected. Prolonged elevation of stress hormones or prolonged inflammation can increase oxidative stress. The higher the level of these stressors, the more prematurely cells will age. This means that the body of a person in their 30s or 40s exposed to high levels of inflammation or oxidative stress may already numerous cells showing signs of aging.

How do these stressors lead to premature aging? Shortening of telomeres could be one answer. If cells are chronically inflamed due to autoimmune diseases or inflammation-associated diseases such as obesity and atherosclerosis then they have to be continuously replaced by cell division which shortens telomeres. However, telomere shortening is not the only route to cell aging. Aging research groups have uncovered multiple additional pathways which can accelerate the premature aging of cells without necessarily requiring the shortening of telomeres. Inflammation or oxidative stress can activate certain aging pathways such as the aging regulator p16INK4a. An inflammatory cytokine can convert highly regenerative blood vessel progenitor cells into aged cells which no longer replicate by activating p16INK4a, and that this occurs without affecting telomere length. Researchers have uncovered an important vicious cycle: Once cells begin aging, they themselves release inflammatory proteins which in turn can activate aging in neighboring cells, thus setting a self-reinforcing cascade of aging in motion.

Where does this interaction of telomere-dependent and telomere-independent aging pathways as well as the influence of known (and many unknown) stressors leave us? The molecular understanding of cellular aging is progressing steadily, but the complexity of cellular aging and the even more complex question of how organs such as the brain and heart age requires a lot more work. There will be no single molecular switch which can reverse or halt aging and triple our lifespan, but most aging researchers do not have this as their goal. Understanding specific aging pathways, as well as the genes and stressors which activate them, will allow us to prevent and treat age-related diseases as well as one day be able to provide personalized advice to individuals on how to maximize their "healthspan".

Monday, July 7, 2014

Near all of the discussion on human aging and longevity that takes place even nowadays, in this age of revolutionary progress in biotechnology, is characterized by a profound lack of ambition. People think about aging and wisely nod their heads and say things like "we should focus on our lifestyle choices" so as to marginally alter the outcome of disability and death. This is disappointing on many levels. It seems that the majority gravitate to tinkering with what is, to doing easy things simply because they are easy, rather than trying in earnest to change matters for the better. The best lifestyle choices in the world will still lead to a 75% mortality rate by age 90: the only way to do better is the creation of new medical technologies, such as the SENS vision of periodic repair of the known forms of cellular and molecular damage that cause aging.

Here is one example of failing to reach far enough: a post on a new longevity blog that glances at the present range of theories of aging, and then concludes that we should focus on lifestyle and environment because that is what we have control over now. It is disappointing to see this sort of response from someone who has actually looked into the science.

By knowing a little about why we age, we can begin to understand the things that we can and can't change about the process. Exerting control in certain areas of our lives, can give us the best chance to lead a longer, healthier, and happier life. There are many theories that offer an explanation of why human beings grow older. It has even been claimed that there are over 300 current hypotheses that attempt to explain aging. Space precludes a full evaluation of all perspectives, but in very general sense the main ideas can be summarized as evolutionary, biological, and wear-and-tear perspectives.

The evolutionary theories of aging suggest that natural selection has optimized the fitness of individuals only until they have conceived and reared children. Beyond middle age, it is theorized that evolution is essentially blind to the fate of individuals as by this time they are likely to have already passed on their genetic material and successfully raised their offspring to the point at which they can fend for themselves. In evolutionary terms, the work of life is done.

The biological theories of aging contend that there are inherent limits within our physiology that constrain individual lifespan. Theorized processes include limits in the number of times that certain cells can divide, the increasing potential for random mutations in the body, and the tendency for bodily systems to become increasingly unreliable over time. These perspectives suppose that we are ruled by the rhythm of a biological clock, which will tick, tick, tick until the main spring loses its charge and we expire.

The rate-of-living and wear-and-tear theories of aging are concerned with the accumulation of damage in the human body that results from either normal bodily functions (such as respiration and the conversion of food into energy that produces free radicals and oxidative damage) or the impacts of negative lifestyle behaviors and exposure to certain environmental conditions. Lifestyle factors that can influence aging are many and include exposure to UV radiation, smoking, body composition (proportion of body fat), exposure to chemicals and pollutants, mechanical injury or overuse, and others. It is in the realm of lifestyle and environment that we have the greatest hope of healthy life extension because these tend to be the domains over which we have the greatest control.

Tuesday, July 8, 2014

Certain forms of mitochondrial DNA damage are one of the causes of aging. Your mitochondria, the cell's power plants, are the remnants of ancient symbiotic bacteria. Most of their original DNA is lost or migrated to the cell nucleus, but a small number of genes remain. This DNA is much more vulnerable to damage and has worse repair mechanisms than nuclear DNA, but if important parts are lost then the outcome can be dysfunctional mitochondria that overtake the cell because they are more resistant to being cleared out by quality control mechanisms. That cell will then cause harm to surrounding tissues by exporting damaged proteins and reactive molecules: this is the modern mitochondrial free radical theory of aging in a nutshell.

Since this is likely an important cause of aging we should expect to see that everyone has an appreciable load of stochastic damage to their mitochondrial DNA, and that this damage grows over time. As the cost of DNA sequencing continues to fall and thousands of human genomes are being sequenced, this data is becoming available:

Mutations in one or more copies of mitochondrial DNA, known as heteroplasmies, are likely to be much more common in healthy people than previously anticipated. Approximately 90 percent of healthy participants in the 1000 Genomes Project harbored at least one heteroplasmy, and 20 percent bore mitochondrial genome mutations implicated in diseases. "It's been known for a long time that lesions in mitochondrial DNA become more prevalent with age. This study offers the intriguing possibility that maybe everybody has a little bit of something wrong with their mitochondrial DNA and that might play a role in aging."

Because a single cell can contain hundreds to thousands of mitochondria, it also carries multiple copies - and, sometimes, variants - of these maternally inherited genomes. Pathogenic mutations can co-exist with healthy mitochondrial DNA (mtDNA) within a cell or group of cells; clinical signs of disease only occur when the frequency of mutations crosses a threshold, which typically ranges from 60 to 85 percent of mitochondria. Severe mtDNA mutations can cause certain myopathies, epilepsy, and other diseases, while less pathogenic variants have been implicated in complex conditions such as type 2 diabetes, aging, and cancer.

Although these results suggest pathogenic mtDNA mutations are more prevalent than previously thought, the low frequency at which they occur is unlikely to have a negative impact on health. However, if the mutations increase in frequency in some fraction of cells as they divide, they could provide a likely source of mitochondrial dysfunction. "The problem is that mitochondrial DNA isn't stable, so there's nothing to say that a 1 percent load of mutation won't blossom into a different level later." Even though a low-frequency mutation "isn't pathogenic in and of itself, it's harder to develop a mutation later if you don't have one, compared to when you start with some level of mutation."

Tuesday, July 8, 2014

Researchers have been looking into the biochemistry of TDP43 and failure of autophagy for a few years now in the context of some age-related dementias and amyotrophic lateral sclerosis (ALS). The processes of autophagy are cellular housekeeping mechanisms, acting to recycle damaged components and remove unwanted waste. More autophagy is shown to occur in connection with many of the presently known methods of slowing aging and extending life in laboratory animals. The research community has been slow off the mark to make inroads into the development of treatments based on enhanced autophagy, however - there is nowhere near as much interest and funding for this goal as for, say, the production of calorie restriction mimetic drugs.

Still here is one example of this approach gaining traction, though here the aim is to treat conditions in which autophagy is impaired in a specific way, through the presence of too much TDP43. It is unclear as to whether a treatment to reduce levels of TDP43 would be of any application to boosting autophagy in an undamaged metabolism.

Deep inside the brains of people with dementia and ALS, globs of abnormal protein gum up the inner workings of brain cells - dooming them to an early death. But boosting those cells' natural ability to clean up those clogs might hold the key to better treatment for such conditions. Though the team showed the effect worked in animals and human neurons from stem cells, not patients, their discoveries point the way to find new medicines that boost the protein-clearing cleanup process.

The researchers focused on a crucial cell-cleaning process called autophagy - a hot topic in basic medical research these days, as scientists discover its important role in many conditions. In autophagy, cells bundle unwanted materials up, break them down and push the waste products out. [The team] showed how the self-cleaning capacity of some brain cells gets overwhelmed if the cells make too much of an abnormal protein called TDP43. The found that cells vary greatly in how quickly their autophagy capacity gets swamped.

"Using [a] new visualization technique, we could truly see how the protein was being cleared, and therefore which compounds could enhance the pace of clearance and shorten the half-life of TDP43 inside cells. This allowed us to see that increased autophagy was directly related to improved cell survival." Longer-living, TDP43-clearing brain cells are theoretically what people with ALS and frontotemporal dementia need. But only further research will show for sure.

Wednesday, July 9, 2014

The all volunteer Gerontology Research Group is a online notable hub for the aging research community, thanks to a mailing list and a few highly connected scientists who keep things running along with a shoestring budget. This article takes a look at the offline work of the organization, the challenging process of accumulating reliable data on survival and mortality in extreme old age:

Since 1990, the Gerontology Research Group has assumed the role of record keepers for the world's supercentenarians, or persons older than 110. Previously, research groups, individual countries and private hobbyists tracked supercentenarians for studies or for census purposes, or simply out of personal interest. But that information was not compiled into a central, standardized database, and it was largely closed to public viewing. In addition to satiating curiosity and providing world-record listings, the Gerontology Research Group's database also offers scientific insight into the phenomenon of living an exceedingly long life. Expert volunteers with the organization conduct extensive interviews with the people on the list, taking blood samples for DNA analysis from those who are willing. Ultimately, the group's goal is to use such data to design drugs that will slow down the aging process itself, though such breakthroughs - if even possible - are likely years away.

For every supercentenarian that the Gerontology Research Group confirms, probably at least one more slips through the cracks. Some families simply prefer to protect their privacy, so they do not reach out to the group. In other cases, the researchers might not have the logistic capacity to investigate every lead. Although the group includes about 40 volunteer correspondents based around the world who are in charge of tracking down supercentenarians in their country or region, sometimes claims prove impossible to follow-up on. In other cases, individuals who don't make the cut likely are genuine supercentenarians, but they are unable to provide the documentation to prove it. While Japan has kept scrupulous birth records for more than a century (perhaps partly explaining why that country has so many supercentenarians per capita), other countries have historically been less meticulous about that task.

For now, very few make it to 110. "The probability of getting to be a supercentenarian is about one in seven million," and living beyond that milestone is even more exceptional. A 110-year-old's odds of seeing her 111th birthday is about 50-50, meaning that living to 113, 114 or 115 is like getting three, four or five heads in a row in a coin toss. This, of course, leads to the burning question: how do those who make it to 110 and beyond manage that feat?

The short answer is that we do not know. Supercentenarians come from diverse occupations and social backgrounds. Some drink and smoke, while others abstain from the partying lifestyle; some are religious, others atheists; some have rich networks of family and friends, others are virtually on their own. While centenarians tend to cluster in Sardinia, Italy, and Okinawa, Japan, supercentenarians, on the other hand, have no significant association with any particular geographic area. "I've interviewed more supercentenarians than probably anyone else, trying to find out what they have in common. The answer is almost nothing."

Wednesday, July 9, 2014

The belief that extending life through new medical science will lead to people who spend their additional years becoming ever more decrepit and frail is widespread and hard to shake. Scientists have told the public over and again that this is not going to be the outcome: any successful treatment for the causes of aging will produce patients who are younger than their years. Extending life will inevitably mean extending youthful, healthy life, because aging is just an accumulation of damage. The medical conditions that we call age-related diseases are just late manifestations of very high levels of damage. The only sound way to extend life is through reduction or repair of this damage, and that extends the period of health, pushing back the onset of medical conditions and deterioration.

But it doesn't seem to matter how many times this is repeated by members of the research community. People just aren't listening. The article quoted below is a microcosm of this larger picture: an author who hears what is said about aging, medicine, and healthy life, and cruises right on past to conclude with the same fear of extended years of frailty that he started with:

The idea of defeating old age and even death has been with us for a long time. In Greek mythology, there was a handsome young fellow called Tithonius who was in love with Eos, the Goddess of Dawn. Aware that he was getting older while she remained young and beautiful forever, he asked her to make him immortal. She couldn't do it herself but passed on the request to Zeus, who obligingly granted it. Unfortunately, Tithonius had asked only for immortality, not for eternal youth. So he became a horrible-looking old man, suffering aches and pains and unable to die. Eos took pity on him and turned him into a grasshopper, presumably an immortal one. Motto: be careful of what you ask from the gods.

The possibility of extending life far beyond what is now its usual term is apparently becoming a reality. Of course, thanks to medical advances, this has been happening for some time. Most of us can already expect to live quite a bit beyond the Bible's allotted span of 70 years. But the science is marching quickly. Aubrey de Grey, co-founder of SENS (Strategies for Engineered Negligible Senescence), believes that we can eliminate the symptoms of ageing, and live for as long as 1,000 years. Ninety per cent of us apparently die of what is nothing more than old age - bits wearing out and all that - and this, he says, is unnecessary. A thousand years may seem a touch extravagant, but we are already accustomed to being fitted with spare parts that help to keep us going. Then that great killer, cancer, is usually, though not always, a disease of old age, and, if/when a cure is found, then that will be another cause of death that has been abolished.

Now, most of us are quite in favour of staying alive, so long as our bodies and minds keep functioning with reasonable efficiency. For many the real fear is dementia, and most of the over-70s I know will say that if that happens and the mind crumbles, they hope that somebody will be kind enough to put a pillow over their face and press down hard. Unfortunately, for obvious and respectable reasons, few are ready to oblige. Nevertheless, many will agree with me that it's preferable to go to the grave than to go nuts.

However, assuming that the life-extension scientists can also find ways of fending off dementia, how do we feel, individually and as a society, about the prolongation of life? Are we happy about the prospect of so lop-sided a society? Aubrey de Grey, with the enthusiasm of a pioneer, says he hopes to make it possible for people of 90 to wake up feeling as ready to go as they did when they were 30, and with no greater chance of not waking up the next day as they had 60 years previously. However, he admits that this transformation will require "hi-tech intervention", which is what he says he is working on.

It's quite possible that the life-extended might be as useless and miserable as Swift's Strulbrugs. Why prolong life, some sage once asked, save to prolong pleasure? Why indeed? Can the life-extension zealots assure us of continuing pleasure? I don't know. Nobody knows. But evidently the prospect of life-extension is real. We had better start thinking about it. Will it make for individual happiness and social contentment? If not, shouldn't we oldies get ready to shuffle off the mortal coil? One thing is sure: few of us want to end up like Tithonius, condemned to live in decrepitude and misery. Worse than Tithonius indeed, there being no kindly former lover and goddess on hand to change us into a grasshopper.

Thursday, July 10, 2014

As a companion piece to a recent post on the cost of obesity and lack of exercise, as determined by epidemiological studies, here is another study that looks at the costs and benefits of various lifestyle choices:

Cardiovascular diseases (CVDs), cancer, diabetes and chronic respiratory disorders - the incidence of these non-communicable diseases (NCDs) is constantly rising in industrialised countries. Attention is focusing, amongst other things, on the main risk factors for these diseases which are linked to personal behaviour - i.e. tobacco smoking, an unhealthy diet, physical inactivity and harmful alcohol consumption. For the study the researchers used data from the Swiss National Cohort (SNC). The Zurich public health physicians focussed on CVDs and cancer as they account for the most deaths in Switzerland. The researchers succeeded in correlating data on tobacco consumption, fruit consumption, physical activity and alcohol consumption from 16,721 participants aged between 16 and 90 from 1977 to 1993 with the corresponding deaths up to 2008. The impact of the four forms of behaviour was still visible when biological risk factors like weight and blood pressure were taken into account as well.

Compared with a group of non-smokers, smokers have a 57 percent higher risk of dying prematurely. The impact of an unhealthy diet, not enough sport and alcohol abuse results in an elevated mortality risk of around 15 percent for each factor. An unhealthy lifestyle has above all a long-lasting impact. Whereas high wine consumption, cigarettes, an unhealthy diet and physical inactivity scarcely had any effect on mortality amongst the 45 to 55-year-olds, it does have a visible effect on 65 to 75-year-olds. The probability of a 75-year-old man with none of the four risk factors surviving the next ten years is 67 percent, exactly the same as the risk for a smoker who is ten years younger, doesn't exercise, eats unhealthily and drinks a lot. An individual who smokes, drinks a lot, is physically inactive and has an unhealthy diet has 2.5 fold higher mortality risk in epidemiological terms than an individual who looks after his health. Or to put it positively: "A healthy lifestyle can help you stay ten years' younger."

Thursday, July 10, 2014

Klotho is one of numerous genes demonstrated to influence longevity in several species of laboratory animal. Like all of the other genes it influences many fundamental cellular and metabolic processes, which makes deciphering how and why it all works to affect the pace of aging a real challenge. There are probably a few core (and very complex) arrays of biological machinery that influence aging greatly enough to be easily measurable, established long ago in the deep evolutionary past, and thus shared across many different species. However influencing these mechanisms can be accomplished by altering any one of many varied genes, or changing the level of any one of many varied proteins in tissues, and all of these changes produce other effects as well. Biology likes reuse, and any one gene or protein might play a role in dozens of mechanisms.

Thus the low-level details of the progression of aging are a maze, poorly understood at present, even though the actual results in terms of differences between old tissue and young tissue are very well cataloged and understood. This is one of the reasons why attempting to produce age-slowing drugs that work through targeted metabolic manipulation is the slow, expensive road to marginal results. More than a decade of work and upwards of a billion dollars have been poured into simply trying to recreate some aspects of one well-studied metabolic alteration that increases longevity in laboratory species, the response to calorie restriction. There is little to show for it so far but more knowledge. If that same billion dollars had been put into SENS-like repair strategies, aimed at reverting the known changes in tissues that occur with aging and letting meta


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