Fight Aging! Newsletter, May 20th 2013

May 20th 2013

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

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  • Reviewing the Results of Calorie Restriction Primate Studies
  • Are the Most Influential Futurists Those Who Put in the Work to Make Their Visions Real?
  • SENS Research Foundation is the Watering Hole, Not the Herd
  • Telomere Length: Cause of Aging or Marker of Aging?
  • Be Dubious About Longevity Hotspots
  • Discussion
  • Latest Headlines from Fight Aging!
    • A Possible Biomarker for Senescent Cells
    • Inhibiting ICMT as a Progeria Therapy
    • Excess Body Fat Hardens Arteries
    • Therapeutic Cloning Attained
    • The Immune System Ages More Slowly in Women
    • Considering Anti-Amyloid Immunotherapy
    • Membrane Pacemaker Hypothesis and Ames Dwarf Mice
    • On Methionine Restriction
    • Amphibian Species with a Chemical Defence Live Longer
    • Children of Long-Lived Parents Resistant to Dementia


In the past few years two ongoing studies of long term calorie restriction (CR) in primates have started to publish their results on longevity. Both research programs have been underway for more than 20 years, one run by the National Institute on Aging and the other by the University of Wisconsin-Madison. Researchers have followed small groups of rhesus monkeys to see how the benefits to health and life expectancy resulting from a restricted calorie intake compare with those obtained in mice and other short-lived species. At this point the results are ambiguous, unfortunately: one study shows a modest gain in life expectancy that has been debated, while the other shows no gain in life expectancy, and that result has also been debated.

Calorie restriction does produce considerable benefits in short term measures of health in rhesus monkeys and humans, that much is definitive, but the present consensus in the research community is that it doesn't greatly extend life in longer-lived primates - perhaps a few years at most in humans. Differences and issues in the two primate studies mean that effects of this size on longevity may never be clear from the data generated. Other factors will wash it out, such as differences in the diet fed to the control groups, or the different age at which calorie restriction started. Certainly the results so far support the conjecture that calorie restriction is exceedingly good for health but doesn't have the same impressive effects on longevity as it does in short-lived animals. Why that is the case is a puzzle to be solved - but not one that has a great deal of relevance to the future of human longevity. One would hope that we'll be a long way down the road to rejuvenation therapies by the time another set of better constructed primate studies are nearing completion.

You'll find a long article over at the SENS Research Foundation that examines the NIA and Wisconsin primate studies, their differences, and their results in great detail - but I'm just going to skip ahead and quote some of the conclusions:

CR in Nonhuman Primates: A Muddle for Monkeys, Men, and Mimetics

In this post, I have sketched out in detail two major possible interpretations of the disparate mortality outcomes in the NIA and WNPRC nonhuman primate CR studies. The "Diminishing Returns" hypothesis posits that the health and longevity benefits of "CR" reported in the WNPRC study were merely the unsurprising results of one group of animals being fed a high-sucrose, low-nutrient chow on a literally ad libitum basis, and another group being kept to portions of that diet low enough to avoid the deranged metabolisms flowing from obesity and (possibly) fructose toxicity. In this interpretation, the more severe restrictions of energy intake imposed at the NIA - particularly when the chow to which access was restricted may have been healthier to begin with - led to no further health benefit, because there are none to be gained: the dramatic age-retarding effects of CR observed in laboratory rodents and other species do not translate into longevous species such as primates, and the sole benefit of controlling energy intake is avoidance of overweight and obesity.

The "Dose-Response" hypothesis begins from the same interpretation of the WNPRC study, but posits that far from being excessive (or, at best, superfluous) to that required for good health, the additional energy restriction imposed at NIA were too little, and imposed during too narrow a window, to elicit a clear signal in health and lifespan benefits; this is supported by the evidence that the NIA primates were not especially hungry, and only weakly and inconsistently exhibited improvements in risk factors and endocrine signatures of CR that are seen both in life-extending CR in rodents, and in humans under rigorous CR.

Unfortunately, it seems very unlikely that this question will be resolved. Even the narrow question of whether the age-retarding effects of CR in laboratory rodents translate into nonhuman primates could only be established with confidence after yet another trial in nonhuman primates. [Such] a study is extremely unlikely in light of the enormous expense of the first two trials, disappointment (and possibly embarrassment) with the results, [and] the ill winds for nonhuman primate research. [Even] if such a well-designed and well-executed study were initiated: what then? Supposing that support were maintained for the duration of the experiment [it] would be a further three decades before the earliest point at which survival data could be reported.

The timescales involved in resolving these questions cannot be reconciled with the immediate imperatives that drive us to pose them. With the scale of the humanitarian, economic, and social crisis that looms in the coming decades due to global demographic aging and associated ill-health, the near-term need for effective interventions against the aging process could not be greater. Whether CR can retard aging in nonhuman primates or not; whether it can retard aging in humans or not; whether even effective CR mimetics can somehow be shepherded through clinical trials - even the most optimistic projection for retarding aging through such approaches is inadequate to the needs and suffering of aging world.

The point made in the article is the same one that should be made for all means of slowing the pace of aging by altering metabolism, whether by the use of drugs to replicate some of the changes caused by calorie restriction or via other mechanisms. These are very difficult and challenging projects, certainly very expensive in time and funds, and which will produce poor and uncertain end results even if successful. Ways to modestly slow aging do nothing for people who are already old, and we will grow old waiting for success in the development of drugs that can safely tinker our metabolisms into a state of slower aging.

The better approach is that outlined by the SENS Research Foundation: targeted therapies to repair the known forms of cellular and molecular damage that cause aging. This path is cheaper, more certain, and the resulting therapies will be capable of rejuvenation - of reversing degenerative aging, not just slowing it down a little. They will be greatly beneficial for the old, and extend the length of life lived in health and vigor. This is why I say that calorie restriction studies are irrelevant to the future of our health and longevity: the only thing that really matters is whether or not the SENS vision or similar repair therapies are prioritized, funded, and developed.


We'll take a short excursion into ranking futurists for today, prompted by a recent article that offers a (transhumanism-slanted) opinion on the identity of the most important futurists of the past few decades.

The Most Significant Futurists of the Past 50 Years

Our visions of the future tend to be forged in the pages of science fiction. But for the past half-century, a number of prominent thinkers, activists, and scientists have made significant contributions to our understanding of what the future could look like. Here are 10 recent futurists you absolutely need to know about. Needless to say, there were dozens upon dozens of amazing futurists who could have been included in this article, so it wasn't easy to pare down this list. But given the width and breadth of futurist discourse, we decided to select thinkers whose contributions should be considered seminal and highly influential to their field of study.

Those selected include Robert Ettinger, one of the founders of modern cryonics, and Aubrey de Grey, who presently works to make his SENS roadmap to human rejuvenation a reality. Ray Kurzweil is notably absent from the list.

It isn't mentioned as a selection criteria in the article, but I think that ranking the importance of futurists by how effectively they help to create the future that they envisage isn't all that bad of an idea. Advocates and popularists play a needed role in moving from vision to reality, but progress also needs people to perform and orchestrate the actual work of research and development. Kurzweil, for example, is a popularist and an advocate with respect to his futurism: beyond the books and films and persuasion his day job as an inventor and entrepreneur is so far largely irrelevant to the future he envisages. I don't think anyone can argue that he isn't important in the arena of ideas regarding machine intelligence, accelerating change, and how this will all play out in the decades ahead. But how much more important would Kurzweil be if, for example, he had decided a decade or two back to create a company like Zyvex as a long term play to advance molecular manufacturing, or something equivalent in AI work?

In contrast Ettinger and de Grey both founded successful organizations devoted to realizing their particular visions: the Cryonics Institute and the SENS Research Foundation. Both were instrumental in creating the groundwork and the early community of supporters to enable a new industry and branch of research in applied medicine. That seems like the best approach to futurism to me: not just persuasion, but also working to create the change you want to see in the world.


If you visit Fight Aging! on a regular basis you'll know that I strongly favor the SENS Research Foundation and the approach taken by its founders, advisors, and staff to speed the development of human rejuvenation. I think we could do with another ten or twenty similar organizations, and certainly a hundredfold increase in the funding for rejuvenation research, but right now we have just the one. So send the Foundation a donation if you're feeling flush today, because there's no-one else out there at the moment who can do as much for your future longevity with that money.

Or rather I should say that there are dozens and possibly hundreds of people out there who can do as much for your future longevity with those funds - it's just that you don't know who they are. Would you know enough to chase down William Bains in the UK and ask him to work on AGE-breaker drugs for glucosepane, for example? Or pick the group at the Buck Institute best placed work on ways to selectively destroy senescent cells by interfering in their characteristic biology? Or have Janko Nikolich-Žugich in Arizona work on restoring the aged immune system by removing unwanted T cells? Of course not. But there is a whole world of researchers out there with useful specialist knowledge and who are these days quite willing to work on the foundation technologies needed for human rejuvenation - provided that the funding can be found.

Organizations like the SENS Research Foundation are the interface between you and the research community: the Foundation staff provide domain knowledge and relationships needed in order to direct funds effectively. Without their work it would be impossible for folk like you or I to help make this field of science move faster - we wouldn't know where to start or who to talk to, never mind where to send funds, and finding out would be so costly in comparison to what we could donate as to make the whole exercise pointless.

The SENS Research Foundation is the watering hole, not the herd. It is the gateway, not the city. It is the door to a network of researchers who are interested in human rejuvenation, but that network is a greater and broader thing than the Foundation. I bring up this point because many people look no further than the gateway: they see the SENS Research Foundation and think of an enclosed group, off to one side of the scientific community, doing its own thing in isolation, and therefore easy to dismiss. For all that this point of view is absolutely incorrect, it is not uncommon. You'll see it liberally applied to biotechnology companies, noted laboratories, and other organizations that are also gateways to broader scientific networks. People look at an organization, see its staff performing some research work in its own domain, but fail to see beyond that to take in the great tree of relationships and connections behind the name plate.

The greatest achievement of the folk behind the SENS Research Foundation (and the Methuselah Foundation before it) is their construction of a lasting and growing network of supporters of rejuvenation research within the life sciences. This was quite the task over the past decade and involved a lot of persuasion, changing the culture of the research community to become more receptive towards longevity science, building relationships, holding conferences, and tireless advocacy. It is that web of relationships, and not the existence of the Foundation per se, that enables growth in funding and progress towards the goal of ending aging. As for all areas of human endeavor, it is relationships and networking that make the world turn: the Foundation is a mailbox, a guidebook, and a banner for a larger community, an outgrowth of that community even, and it is the community that gets things done.

This is worth bearing in mind, because it's all to easy to focus on organizations rather than people and thus miss the whole point of the exercise.


Telomeres are repeating sequences of nucleic acids that cap the ends of chromosomes in the cell nucleus and stop actual gene-coding DNA from being chopped off when a cell divides. The mechanisms of DNA replication require extra leg room at the ends of the strand, a trailing sequence that is not copied over to the new strand under assembly - and the primary role of telomeres is to be the part that is dropped on the floor. A little of their length is thus lost with every cell division. This shortening acts as a clock to count cell divisions, and cells with very short telomeres stop replicating - they either enter cellular senescence (which ideally then causes the immune system to destroy them) or destroy themselves directly via programmed cell death mechanisms.

Telomere length is more dynamic than this simple picture, however. In some cell populations, such as the various types of stem cell that maintain tissues and produce new cells to replace those lost or damaged, an enzyme called telomerase continually lengthens telomeres so as to allow a cell lineage to continue dividing indefinitely.

Ordinary, non-stem cell populations exhibit a range of telomere lengths, some short, some long. You might imagine that a population of cells replenished more frequently or recently by stem cells will have longer telomeres on average. A population that is receiving less support might have shorter telomeres. Researchers have shown that a higher proportion of short telomeres in white blood cells correlates well with ill health or stress, and somewhat correlates with age. Some more complex measures of telomere length, a step above just taking the average, have been shown to correlate well with age, however, and other techniques do a fair job of predicting future life expectancy in laboratory animals.

A few years back a brace of startup biotech companies were aiming to address aspects of aging by lengthening telomeres through the use of telomerase. None of that went anywhere, unfortunately, but it's possible that they were just too early - it is frequently the case that all of the first batch of companies in a new area of biotechnology fail. It's a tough business to be in. I was a skeptic at the time regarding their potential for success based on my expectation that telomere length will prove not to be a root cause of aging.

Nonetheless, researchers are demonstrating extension of life in mice through telomerase these days, but it is as yet unknown as to exactly why this works. Perhaps it makes stem cells work harder to maintain tissues, perhaps there is just one critically limiting type of stem cell or tissue that benefits from more telomerase, or perhaps it involves other effects causes by increased levels of telomerase that have nothing to do with telomere length. It is worth bearing in mind that there are considerable differences in natural levels of telomerase and the resulting telomere dynamics between mice and people, however. Telomerase therapy is probably not something you'd want to just up and try without the research community first obtaining a much greater understanding of why it works to extend life in mice.

Why? Well, the risk of telomere lengthening in humans is cancer. Any mechanism that globally, or possibly even narrowly, extends telomere length in people will raise the risk of suffering cancer. The whole system of telomere dynamics and cellular senescence is intimately tied to the processes of cancer suppression, while all cancers evolve ways of lengthening their telomeres to allow unlimited cell division. Boosting your telomerase levels looks a lot more risky to me than, say, undergoing first generation stem cell transplants.

There continues to be a lot of activity in telomere research and development. The present brace of telomere-related biotech startups are commercializing ways to measure telomere length rather than extend it. The products are tests that will at first add another measure to inform patients on the state of their health, then possibly act as an effective biomarker of biological age, and perhaps later prove useful in further research if it turns out that telomerase-based therapies can be beneficial in humans.

How Long Will You Live?

A growing number of researchers say telomere length is a critically important indicator of how old we really are, and of how many healthy years we may have in front of us. A new industry is sprouting up around the science of longevity, offering telomere testing to the public - and Nobel laureate Elizabeth Blackburn is a notable part of it. Her company, Telome Health, is set to launch a telomere test later this year, joining a handful of others that already do. Like a cholesterol or blood-pressure test, telomere testing could one day become standard in doctors' offices.

And maybe in the future, we'll be able to slow or reverse the effects of aging -the vision of researchers searching for ways to boost telomerase, a goal already achieved in lab mice. Some are already marketing so-called "telomerase activators" to a public hungry for ways to stop the clock, although no such drugs have been approved. With so many companies rushing to come on board, "there's a lot of weird stuff going on out there," cautions Jerry W. Shay of the University of Texas Southwestern Medical Center, an expert on cell biology and telomere length.

Certainly you should be looking askance at any group that's selling herbal "telomerase activators" - it's the standard garbage from the supplement marketplace, and sadly that's the place that formerly funded companies doing original research often end up. It's hard to make money doing something useful in medical research, but depressingly easy to make money doing something useless in the supplement business. The traditional model here is to grab a little research that's somewhat relevant, scare up a bunch of Chinese herb extracts, and then hope that if you market the thing hard enough it'll overcome the obvious ineffectiveness and pointlessness. If you can buy out the shell of a company formerly doing research to try to profit from its one-time reputation, then all the better. Caveat emptor is the watchword, as ever.

So where do telomeres fit in the taxonomy of cause versus secondary effect in aging? Because of the dynamic nature of telomere length I'm given to think that it's a secondary effect: get sick and average telomere length in white blood cells shortens; get well and it lengthens again. This sounds very much like a system responding to circumstances, and those circumstances most likely include the general level of cellular damage, inflammation, and metabolic waste products - all of which grow with age. As for so many other similar questions about aging, the fastest and cheapest way to answer this question about telomere length is to implement the Strategies for Engineered Negligible Senescence (SENS): build the biotechnologies to repair these forms of damage and then see what happens to telomere length once its done. That is a good deal easier at this point than obtaining a full understanding of the aging of human biology.

None of the above precludes short telomeres from causing further damage or changes of their own, of course. Aging proceeds as a cascade of harmful effects as damage causes further damage and flailing biological systems cope badly with the new circumstances they find themselves in. Here is a recent article on how telomere length can impact gene expression and thus the operation of metabolism in a previously unsuspected way, for example:

Telomeres Affect Gene Expression

DUX4, a gene responsible for the genetic disease facioscapulohumeral muscular dystrophy (FSHD), is normally silenced because it sits next to a telomere - a protective DNA sequence that caps the ends of chromosomes, according to [a recent study]. But as telomeres shorten, as they do with age, DUX4 expression climbs, which may explain the late onset of FSHD. Another gene, called FRG2, which sits 100 kilobases away from the telomere, is also affected by telomere length.

"This was completely unexpected. We think that DUX4 and FRG2 are the tip of an iceberg." Due to shrinking telomeres, many genes might gradually become more active as we get older, which may be important for several diseases of old age. "This represents a very significant general advance in our understanding of how telomere shortening may affect human biology."


"Cui bono?", "to whose benefit?", is a question that should never be far from mind. It is rarely the case that the loudest threads in our grand, connected cultural conversation represent the best, the most useful, or the most virtuous of what is possible. That is just as true in any subculture as it is in the mainstream: follow the money and much becomes clear.

Longevity hotspots might not be a term familiar to you, but Blue Zones might be thanks to a fair degree of publicity for that latter term. They mean the same thing, but the latter is a brand rather than a description. A small industry associated with this brand is devoted to promoting the idea that some parts of the world exhibit pockets of exceptional human longevity. It is convenient for various businesspeople to act as though this is proven beyond a doubt and that the root causes involve aspects of local culture, diet, and lifestyle that can be packaged up and sold. So the world goes on: this sort of thing is a textbook example of how small science projects on minor aspects of human longevity can spawn commercial monstrosities set on muddying the waters, promoting myths, and profiting from the credulous.

It is by no means certain that longevity hotspots exist in actuality, or at least not in the sense that Blue Zone business ventures would like you to think, but those most interested in carrying on a dialog on this topic - i.e. marketing folk involved in tourism, diet, lifestyle coaching, and so forth - don't really care to hear that message. Nonetheless:

Designating longevity hotspots: cautions concerning the instability of per capita centenarian estimates

Estimates of per capita centenarians in a Utah population varied between one per 12,864 and one per 4,675, depending on the data that were used, the population assumptions that were made, and the boundary limits that were employed. In general, caution is warranted in claims about the existence of longevity hotspots.

Performing any sort of statistical study on human populations in a given geographical area, even on something as apparently simple as age, is enormously complex. People move and data is ever incomplete or outright false. Some locations attract the wealthy in large numbers, a demographic already well correlated with greater life expectancy. When a region in the US with good demographic data can produce a threefold range of results for a simple population question, one has to wonder about the accuracy of other studies - and the smaller the group the less helpful that statistical procedures become.

This is not to say that there is nothing to be learned by comparing different populations with different lifestyles, but I would be extremely surprised to see the end results be anything other than additional support for the value of exercise and calorie restriction (and derived measures such as body mass index). These line items strongly correlate with health in large statistical studies.

Neither exercise nor calorie restriction will let you reliably live to see 100, however. The only thing that can achieve that goal is significant progress in new medical science. Longevity hotspots are, like so much of what is discussed in relation to aging these days, nothing but a sideshow - something that occupies time and energy and attention, and all to no good end. That the data is most likely flawed and what little science there was is now largely buried beneath an industry that strives to make money by promoting magical thinking and ignorance just makes the joke a little more black.


The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!


Friday, May 17, 2013

There are any number of techniques under development that allow individual cells to be destroyed provided that you can distinguish them from their neighbors: the challenge is in finding characteristic differences in the cells you want destroyed, such as cancer cells or senescent cells. Most of the efforts aimed at producing targeted cell destruction therapies are taking place in the cancer research community, but senescent cells accumulate with age and contribute to degenerative aging - they must also be destroyed. Unfortunately good ways to target senescent cells are somewhat lacking. Candidate mechanisms are emerging, however, and here is another of them:

Due to its role in aging and antitumor defense, cellular senescence has recently attracted increasing interest. However, [the] detection of senescent cells remains difficult due to the lack of specific biomarkers. ndeed, most determinants of cellular senescence, such as the upregulation of p53, p16Ink4a, p21WAF/CIP1 or SASP-associated cytokines, are not exclusively observed in senescence, but can also occur in other types of stress responses. In addition, alterations like SAHF or DNA-SCARS formation are frequently observed, but not necessarily a mandatory feature or exclusive to senescent cells.

The current gold standard for the detection of senescence is the so-called senescence-associated β-galactosidase (SA-β-Gal) activity. Although SA-β-Gal has been first suggested as a distinct enzyme, its activity is derived from lysosomal β-Gal encoded by the GLB1 gene. β-Gal is an accepted marker of senescence, but its reliability and specificity have been questioned, as a positive β-Gal reaction has also been detected in human cancer cells that were chemically induced to differentiate, or upon contact inhibition. Moreover, several cell types, such as epithelial cells and murine fibroblasts generally show a weak β-Gal staining.

In the present study, we investigated several lysosomal hydrolases for their suitability as senescence markers and identified α-fucosidase, a lysosomal glycosidase involved in the breakdown of glycoproteins, oligosaccharides and glycolipids, as a novel biomarker for senescence. We demonstrate that α-fucosidase is upregulated [in] all canonical types of cellular senescence, including replicative, DNA damage- and oncogene-induced senescence. Our results suggest that detection of α-fucosidase might be a highly valuable biomarker for senescence in general and in particular in those cases where SA-β-Gal activity fails to properly discriminate between senescent- and non-senescent cells.

Friday, May 17, 2013

Progress towards a therapy for the rare accelerated aging condition progeria continues. It remains unclear as to whether the mechanisms responsible for progeria exist in normal aging to a level that is in any way significant. Progeria is caused by malformed prelamin A, and tiny amounts of broken prelamin A can be found in old tissues - but it would really require a therapy for progeria that addressed the issues with prelamin A to easily find out whether this has any meaningful contribution to normal aging.

The classical form of progeria, called Hutchinson-Gilford Progeria Syndrome (HGPS), is caused by a spontaneous mutation, which means that it is not inherited from the parents. Children with HGPS usually die in their teenage years from myocardial infarction and stroke.

The progeria mutation occurs in the protein prelamin A and causes it to accumulate in an inappropriate form in the membrane surrounding the nucleus. The target enzyme, called ICMT, attaches a small chemical group to one end of prelamin A. Blocking ICMT, therefore, prevents the attachment of the chemical group to prelamin A and significantly reduced the ability of the mutant protein to induce progeria. "We are collaborating with a group in Singapore that has developed candidate ICMT inhibitor drugs and we will now test them on mice with progeria. Because the drugs have not yet been tested in humans, it will be a few years before we know whether these drugs will be appropriate for the treatment of progeria."

"The resemblance between progeria patients and normally-aged individuals is striking and it is tempting to speculate that progeria is a window into our normal aging process. The children develop osteoporosis, myocardial infarction, stroke, and muscle weakness. They display poor growth and lose their hair, but interestingly, they do not develop dementia or cancer." [The researchers are] also studying the impact of inhibiting ICMT on the normal aging process in mice.

Thursday, May 16, 2013

There are all sorts of good reasons to avoid becoming fat. Excess fat tissue is linked to an increased risk of all the common diseases of aging, and correlates well with a shorter life expectancy and higher lifetime medical expenditures. Fat tissue creates higher levels of chronic inflammation and alters the signaling environment in the body, causing a wide range of changes. Here is another of them:

Having too much body fat makes arteries become stiff after middle age, a new study has revealed. In young people, blood vessels appear to be able to compensate for the effects of obesity. But after middle age, this adaptability is lost, and arteries become progressively stiffer as body fat rises - potentially increasing the risk of dying from cardiovascular disease. The researchers suggest that the harmful effects of body fat may be related to the total number of years that a person is overweight in adulthood. Further research is needed to find out when the effects of obesity lead to irreversible damage to the heart and arteries, they said.

Researchers [scanned] 200 volunteers to measure the speed of blood flow in the aorta, the biggest artery in the body. Blood travels more quickly in stiff vessels than in healthy elastic vessels, so this allowed them to work out how stiff the walls of the aorta were using an MRI scanner. In young adults, those with more body fat had less stiff arteries. However, after the age of 50 increasing body fat was associated with stiffer arteries in both men and women. Body fat percentage, which can be estimated by passing a small electric current through the body, was more closely linked with artery stiffness than body mass index, which is based just on weight and height.

"We don't know for sure how body fat makes arteries stiffer, but we do know that certain metabolic products in the blood may progressively damage the elastic fibres in our blood vessels. Understanding these processes might help us to prevent the harmful effects of obesity."

Thursday, May 16, 2013

Therapeutic cloning or somatic cell nuclear transfer are names given to a method of producing embryonic stem cells from a patient's own cells. These embryonic stem cells could then be used to generate cells of any type as a basis for regenerative therapies. Making the process work has proven to be challenging, however, both from a technical point of view and thanks to misguided attempts to make it illegal. In recent years the focus shifted towards work on induced pluripotent stem cells instead, but a research group now claims success in the original goal:

Scientists [have] successfully reprogrammed human skin cells to become embryonic stem cells capable of transforming into any other cell type in the body. It is believed that stem cell therapies hold the promise of replacing cells damaged through injury or illness. The technique used [is] a variation of a commonly used method called somatic cell nuclear transfer, or SCNT. It involves transplanting the nucleus of one cell, containing an individual's DNA, into an egg cell that has had its genetic material removed. The unfertilized egg cell then develops and eventually produces stem cells.

Previous unsuccessful attempts by several labs showed that human egg cells appear to be more fragile than eggs from other species. Therefore, known reprogramming methods stalled before stem cells were produced. To solve this problem, the [researchers] studied various alternative approaches first developed in monkey cells and then applied to human cells. Through moving findings between monkey cells and human cells, the researchers were able to develop a successful method. The key to this success was finding a way to prompt egg cells to stay in a state called "metaphase" during the nuclear transfer process. Metaphase is a stage in the cell's natural division process (meiosis) when genetic material aligns in the middle of the cell before the cell divides. The research team found that chemically maintaining metaphase throughout the transfer process prevented the process from stalling and allowed the cells to develop and produce stem cells.

Wednesday, May 15, 2013

Women tend to live longer than men, and there are any number of competing explanations as to why this is the case. They range from risk of mortality relating to lifestyle choices to evolutionary selection operating on the male role in reproduction to various differences in biochemistry that exist between the genders. That the female immune system ages more slowly shouldn't be terribly surprising - but it might be cause or consequence.

Women's immune systems age more slowly than men's, [and] the slower decline in a woman's immune system may contribute to women living longer than men. Researchers looked at the blood of healthy volunteers in Japan, ranging in age between 20 and 90 years old; in both sexes the total number of white blood cells per person decreased with age. The number of neutrophils decreased for both sexes and lymphocytes decreased in men and increased in women. Younger men generally have higher levels of lymphocytes than similarly aged women, so as aging happens, the number of lymphocytes becomes comparable.

Looking in more detail it became apparent that the rate in decline in T cells and B cells was slower for women than men. Both CD4+ T cells and NK cells increased with age, and the rate of increase was higher in women than men. Similarly an age-related decline in IL-6 and IL-10 was worse in men. There was also a age-dependent decrease in red blood cells for men but not women.

"The process of aging is different for men and women for many reasons. Women have more oestrogen than men which seems to protect them from cardiovascular disease until menopause. Sex hormones also affect the immune system, especially certain types of lymphocytes. Because people age at different rates a person's immunological parameters could be used to provide an indication of their true biological age."

Wednesday, May 15, 2013

Amyloids are solid masses that form in tissues as a result of misfolded proteins. The amount of amyloid increases with age, perhaps due to a failure of mechanisms that keep the levels of damaged or misfolded proteins under control, and this is thought to cause harm and contribute to degenerative aging. In most cases researchers are still lacking a full understanding of the mechanisms involved, however. At the very least having solid clumps and fibrils present where they shouldn't exist can disrupt tissue integrity or even cause larger scale issues such as clogging blood vessels.

One approach to removing amyloid involves the use of the immune system. Immune therapies direct immune cells to attack and break down a specific target, and much of the innovation in their use as a therapy to remove amyloid is happening in the Alzheimer's research community. That condition is associated with amyloid beta, but we can hope that any successful therapies will prove adaptable to other forms of amyloid and thus applicable to human rejuvenation.

Alzheimer's disease (AD) is the most common dementia in the industrialized world, with prevalence rates well over 30% in the over 80-years-old population. AD is strongly associated with Amyloid-beta (Abeta) protein aggregation, which results in extracellular plaques in the brain, and according to the amyloid cascade hypothesis appeared to be a promising target for the development of AD therapeutics.

Within the past decade convincing data has arisen positioning the soluble prefibrillar Abeta-aggregates as the prime toxic agents in AD. However, different Abeta aggregate species are described but their remarkable metastability hampers the identification of a target species for immunization. Passive immunotherapy with monoclonal antibodies (mAbs) against Abeta is in late clinical development but recently the two most advanced mAbs, Bapineuzumab and Solanezumab, targeting an N-terminal or central epitope, respectively, failed to meet their target of improving or stabilizing cognition and function.

Preliminary data from off-label treatment of a small cohort for 3 years with intravenous polyclonal immunoglobulins (IVIG) that appear to target different conformational epitopes indicate a cognitive stabilization. Thus, it might be the more promising strategy reducing the whole spectrum of Abeta-aggregates than to focus on a single aggregate species for immunization.

Tuesday, May 14, 2013

Ames dwarf mice lack growth hormone and as a consequence live much longer than their peers. Here the biochemistry of this lineage is considered in light of the membrane pacemaker hypothesis of aging, which suggests that the degree of resistance to oxidative damage in cell membranes is a driving factor in determining longevity. Thus similar species with different proportions of more resistant and less resistant molecules making up their cell membranes have different life spans. Is it possible that this can happen within a species thanks to genetic engineering of the sort that produced the Ames dwarf mouse lineage?

Membrane fatty acid (FA) composition is correlated with longevity in mammals. The "membrane pacemaker hypothesis of ageing" proposes that animals which cellular membranes contain high amounts of polyunsaturated FAs (PUFAs) have shorter life spans because their membranes are more susceptible to peroxidation and further oxidative damage. It remains to be shown, however, that long-lived phenotypes such as the Ames dwarf mouse have membranes containing fewer PUFAs and thus being less prone to peroxidation, as would be predicted from the membrane pacemaker hypothesis of ageing.

Here, we show that across four different tissues, i.e., muscle, heart, liver and brain as well as in liver mitochondria, Ames dwarf mice possess membrane phospholipids containing between 30 and 60 % PUFAs (depending on the tissue), which is similar to PUFA contents of their normal-sized, short-lived siblings. However, we found that that Ames dwarf mice membrane phospholipids were significantly poorer in n-3 PUFAs. While lack of a difference in PUFA contents is contradicting the membrane pacemaker hypothesis, the lower n-3 PUFAs content in the long-lived mice provides some support for the membrane pacemaker hypothesis of ageing, as n-3 PUFAs comprise those FAs being blamed most for causing oxidative damage. By comparing tissue composition between 1-, 2- and 6-month-old mice in both phenotypes, we found that membranes differed both in quantity of PUFAs and in the prevalence of certain PUFAs. In sum, membrane composition in the Ames dwarf mouse supports the concept that tissue FA composition is related to longevity.

At some point a research group will find a way to alter only membrane constituent molecules and no other factors in laboratory mice, which should go some way towards quantifying the effect on aging and longevity. The challenge with using any of the well known long-lived lineages of mice is that many aspects of their metabolism are different - it is difficult to point to any one of those and talk about how important it may or may not be to extended longevity given the presence of the others.

Tuesday, May 14, 2013

Levels of the essential amino acid methionine in the diet appear to be involved in generating the beneficial effects of calorie restriction on health and longevity. Some portion of the resulting changes in the operation of metabolism is based on sensing low levels of methionine. It is thus possible that humans might obtain benefits comparable to those generated by calorie restriction from a sensibly constructed low-methionine diet with a normal calorie intake. The research in support of this supposition is still sparse in comparison to that for calorie restriction, however.

It was first reported in 1993 that rats subjected to a diet restricted in methionine (MR) enjoyed comparable life spans to rats that were on caloric restriction (CR). In the first experiments, methionine was reduced to ⅕ its normal level in the diet, and growth of the rats was severely stunted. We can't live entirely without methionine - the body would not be able to make any proteins at all. Restricting methionine is likely to have impacts on growth, health, and wellbeing that are as yet unstudied in humans. Rats fed a diet without methionine developed steatohepatitis (fatty liver), anemia and lost two thirds of their body weight over 5 weeks. In one experiment where methionine was severely restricted but not eliminated entirely, ⅕ of the mice died, and the other ⅘ went on to live longer than control mice.

Here's a clue about why methionine is special. The instructions for making proteins is coded into DNA, via the genetic code, which specifies words of 3 DNA letters, each corresponding to one of the 20 amino acids. The genetic code also contains "punctuation", instructions to start and stop. The "start codon" is also the word for methionine. Every chain of amino acids that the body constructs begins with methionine. No methionine - no protein synthesis. A shortage of methionine means that the body is inhibited in making every kind of protein. More genes are expressed (more proteins synthesized) as the body grows older. Perhaps methionine restriction is putting a brake on this production of extra proteins that are not produced when we're young, and that contribute to aging.

Methionine restriction in practice involves eating foods that are low in methionine. Though all protein has methionine, some protein sources are much lower in methionine than others. All animal sources (including milk and especially eggs) are high in methionine. So a methionine-restricted diet is a vegan diet, not just any vegan diet, but a subset of vegan protein sources. There appear to be no general rules. For example, almonds are a good source of low-methionine protein, but Brazil nuts are terrible. Even a strict vegan diet would only reduce methionine intake by about 1/2. Extrapolating from the rodent experiments, we may need to reduce by ~ 3/4 before crossing a threshold where benefits kick in.

Monday, May 13, 2013

When it comes to evolutionary influences on longevity, the evidence supports the idea that species with a high mortality rate due to external causes (e.g. being eaten) will tend to be short-lived. There is no evolutionary pressure to develop the biological mechanisms that will lead to longer reproductive lives if near all individuals are killed comparatively early in life. This study is a novel way to add further supporting evidence to this point of view:

Evolutionary hypotheses for ageing generally predict that delayed senescence should evolve in organisms that experience lower extrinsic mortality. Thus, one might expect species that are highly toxic or venomous (i.e. chemically protected) will have longer lifespans than related species that are not likewise protected. This remarkable relationship has been suggested to occur in amphibians and snakes.

First, we show that chemical protection is highly conserved in several lineages of amphibians and snakes. Therefore, accounting for phylogenetic autocorrelation is critical when conservatively testing evolutionary hypotheses because species may possess similar longevities and defensive attributes simply through shared ancestry. Herein, we compare maximum longevity of chemically protected and nonprotected species, controlling for potential nonindependence of traits among species using recently available phylogenies.

Our analyses confirm that longevity is positively correlated with body size in both groups which is consistent with life-history theory. We also show that maximum lifespan was positively associated with chemical protection in amphibian species but not in snakes. Chemical protection is defensive in amphibians, but primarily offensive (involved in prey capture) in snakes. Thus, we find that although chemical defence in amphibians favours long life, there is no evidence that chemical offence in snakes does the same.

Monday, May 13, 2013

Some degree of human longevity is genetic rather than the result of environment and lifestyle choice; researchers have guessed that perhaps 25% of variations are genetic, but this is hardly a firm number. It appears to be the case that survival at extreme old age is more influenced by genetic variations than it is in early old age, for example. Given that some predisposition to longevity is thus inherited, it isn't surprising to find that risk levels for specific conditions of aging also correlate with familial longevity:

Based on comparisons of people in their 90s, their spouses, siblings, children and their children's spouses, researchers found that the offspring of people with exceptional longevity were about 40 percent less likely than peers to be cognitively impaired between ages 65 and 79. "It's not necessarily that these individuals never become cognitively impaired, but what it seems like is that there is a delayed onset of cognitive impairment."

For the new study, the researchers used data on cognitive impairment from 1,870 people who are part of the Long Life Family Study, which includes volunteer participants in New York, Massachusetts, Pennsylvania and Denmark. The study included 1,510 people with a family history of longevity and 360 of their spouses, but for this study, researchers used information on just the volunteers who were 89 years old or older when they were recruited.

Overall, the researchers found that about 6 percent of the volunteers' children were cognitively impaired between ages 65 and 79 years old, compared to 13 percent of their spouses and about 11 percent of their cousins. Among the study's long-lived older generation, participants were just as likely to be cognitively impaired by about age 90 as their siblings or spouses. "These families seem relatively protected, but once they reach extreme old age - say after 90 (years old) - their rates of cognitive impairment become comparable."


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