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CONTENT

• 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

REVIEWING THE RESULTS OF CALORIE RESTRICTION PRIMATE STUDIES
http://www.fightaging.org/archives/2013/05/reviewing-the-results-of-calorie-restriction-primate-studies.php

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.

ARE THE MOST INFLUENTIAL FUTURISTS THOSE WHO PUT IN THE WORK TO MAKE THEIR VISIONS REAL?
http://www.fightaging.org/archives/2013/05/are-the-most-influential-futurists-those-who-put-in-the-work-to-make-their-visions-real.php

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.

SENS RESEARCH FOUNDATION IS THE WATERING HOLE, NOT THE HERD
http://www.fightaging.org/archives/2013/05/sens-research-foundation-is-the-watering-hole-not-the-herd.php

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.

TELOMERE LENGTH: CAUSE OF AGING OR MARKER OF AGING?
http://www.fightaging.org/archives/2013/05/telomere-length-cause-of-aging-or-marker-of-aging.php

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."

BE DUBIOUS ABOUT LONGEVITY HOTSPOTS
http://www.fightaging.org/archives/2013/05/be-dubious-about-longevity-hotspots.php

"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.

DISCUSSION

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!

LATEST HEADLINES FROM FIGHT AGING!

A POSSIBLE BIOMARKER FOR SENESCENT CELLS
Friday, May 17, 2013
http://www.fightaging.org/archives/2013/05/a-possible-biomarker-for-senescent-cells.php

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.

INHIBITING ICMT AS A PROGERIA THERAPY
Friday, May 17, 2013
http://www.fightaging.org/archives/2013/05/inhibiting-icmt-as-a-progeria-therapy.php

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.

EXCESS BODY FAT HARDENS ARTERIES
Thursday, May 16, 2013
http://www.fightaging.org/archives/2013/05/excess-body-fat-hardens-arteries.php

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."

THERAPEUTIC CLONING ATTAINED
Thursday, May 16, 2013
http://www.fightaging.org/archives/2013/05/therapeutic-cloning-attained.php

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.

THE IMMUNE SYSTEM AGES MORE SLOWLY IN WOMEN
Wednesday, May 15, 2013
http://www.fightaging.org/archives/2013/05/the-immune-system-ages-more-slowly-in-women.php

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."

CONSIDERING ANTI-AMYLOID IMMUNOTHERAPY
Wednesday, May 15, 2013
http://www.fightaging.org/archives/2013/05/considering-anti-amyloid-immunotherapy.php

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.

MEMBRANE PACEMAKER HYPOTHESIS AND AMES DWARF MICE
Tuesday, May 14, 2013
http://www.fightaging.org/archives/2013/05/membrane-pacemaker-hypothesis-and-ames-dwarf-mice.php

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.

ON METHIONINE RESTRICTION
Tuesday, May 14, 2013
http://www.fightaging.org/archives/2013/05/on-methionine-restriction-1.php

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.

AMPHIBIAN SPECIES WITH A CHEMICAL DEFENCE LIVE LONGER
Monday, May 13, 2013
http://www.fightaging.org/archives/2013/05/amphibian-species-with-a-chemical-defence-live-longer.php

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.

CHILDREN OF LONG-LIVED PARENTS RESISTANT TO DEMENTIA
Monday, May 13, 2013
http://www.fightaging.org/archives/2013/05/children-of-long-lived-parents-resistant-to-dementia.php

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."

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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CONTENT

• Comments on Rapamycin and Metformin
• Parabiosis Points to GDF-11 as a Means to Reverse Age-Related Cardiac Hypertrophy
• Transgenic Mice Expressing Human MTH1 Live Longer
• Forthcoming Book: the Ageless Generation
• Boosted Mitophagy Extends Life in Flies By 25%
• Discussion
• Latest Headlines from Fight Aging!
  • The Present State of Artificial Retinas
  • The State of Electromechanical and Bioartifical Organs
  • Insights into Inflammaging
  • The Complement System and Rheumatoid Arthritis
  • More on Life Extension and Entitlements
  • UV Light, Nitric Oxide, and Blood Pressure
  • Aging, and the Cure of the Diseases of Aging
  • Towards a Patch for Damaged Hearts
  • Evidence Against an Influence of Mitochondrial DNA Haplotypes on Human Longevity
  • Reversing Hair Grayness By Suppressing Oxidative Stress

COMMENTS ON RAPAMYCIN AND METFORMIN
http://www.fightaging.org/archives/2013/05/comments-on-rapamycin-and-metformin.php

Three of the better known efforts to create a drug that modestly slows the rate of aging are centered on the following items:

• Resveratrol analogs that target sirtuins
• Rapamycin analogs that target mTOR
• Metformin

Of these, ways to manipulate the activity of sirtuins have received the greatest attention over the past decade, but there is little to show for all that money and time beyond a modest gain in the understanding of metabolism. There are no replicated, solid results of life extension in mice via sirtuin-influencing drugs, and I'd go so far as to say that the field is under something of a cloud at present. Metformin is in a similar position: while a large body of work relates to its use as a treatment for type 2 diabetes, the evidence for its ability to extend life in laboratory animals is mixed at best. Rapamycin is the only one of the three that can boast solid, replicated evidence of life extension in mice. It is a drug that has been in use as an immunosuppressant for more than a decade, but its ability to extend life is a more recent finding.

For today I thought I'd point out a couple of open access items containing recent findings on the use of rapamycin and metformin in the context of aging. While I don't believe that this branch of research is particularly relevant to extending human life by any meaningful amount in the near term, it is interesting to watch and may help to shed more light on the relative importance of various aspects of our biology in aging. The metformin paper in particular is an educational attempt to tie in the senescent cell aspect of aging to study results:

Metformin, aging and cancer

Metformin, a widely used antidiabetic drug, has been linked to a reduced cancer incidence in some retrospective, hypothesis-generating studies. What is the mechanism by which aging may increase cancer incidence? Although many molecular changes correlate with aging, the presence of senescent cells capable of secreting inflammatory cytokines may be involved. This senescence associated secretory phenotype (SASP) consists of multiple cytokines, chemokines, growth factors and extracellular matrix degrading enzymes that can potentially affect normal tissue structure.

The SASP probably evolved as a gene expression program to assist the senescent tumor suppression response and tissue repair after damage and should be viewed as an initial adaptive response. However, [chronic] SASP [like chronic inflammation] may cause a microenvironment in old tissues that facilitates tumor initiation and then stimulates cancer cell growth.

This unfortunate interaction between senescent cells and cancer cells has been reproduced in experimental mouse models where senescent fibroblasts stimulated tumor progression. [During] experiments to study the potential cancer prevention activity of metformin, we found serendipitously that the drug prevented the expression of many proteases, cytokines and chemokines in senescent cells. We thus propose that metformin prevents cancer by modulating the SASP in tissues where senescent cells were not naturally cleared.

Prolonged Rapamycin treatment led to beneficial metabolic switch

In the first robust demonstration of pharmacologically-induced life extension in a mammal, rapamycin increased longevity of mice via either feeding or injection. However, rapamycin treatment also showed the detrimental metabolic effects, including hyperinsulinemia, hyperlipidemia, glucose intolerance and insulin resistance. Those observations present a paradox of improved survival despite metabolic impairments. How rapamycin extended lifespan with such paradoxical metabolic effects remains to be elucidated.

In the various studies of rapamycin treatment, length of rapamycin treatment varied from two weeks to two years. With short-term rapamycin treatment, mice showed the detrimental metabolic effects, while a much longer length (up to 1.5 to 2 years) of rapamycin treatment led to increased longevity. Duration of rapamycin treatment may be one of the key factors that determine outcomes of the treatment. Longer-term rapamycin treatment may cause beneficial metabolic "switch" that is associated with enhanced insulin signaling and extended longevity.

We [recently] reported that duration of rapamycin treatment indeed has differential effects on metabolism. In our study, rapamycin was given to mice for two, six or 20 weeks. Consistently with the previous reports, mice with two weeks of rapamycin treatment had characteristics of metabolic syndrome. Mice with six weeks of rapamycin treatment were in the metabolic transition status. When rapamycin treatment continued for 20 weeks, the detrimental metabolic effects were reversed or diminished.

It's worth taking some time to look over the state of research for these front-runners in the old-school drug discovery approach to extending life. I find it serves well as a way to inoculate yourself against unfounded optimism and unreasonable expectations, both now and the next time that both the "anti-aging" marketplace and biotech startups tout something that you can buy to supposedly influence metabolism and aging. If you have an enthusiasm for living longer, better to channel it into exercise, calorie restriction, and fundraising for the SENS Research Foundation.

PARABIOSIS POINTS TO GDF-11 AS A MEANS TO REVERSE AGE-RELATED CARDIAC HYPERTROPHY
http://www.fightaging.org/archives/2013/05/parabiosis-points-to-gdf-11-as-a-means-to-reverse-age-related-cardiac-hypertrophy.php

Parabiosis involves joining the circulatory systems of two animals. This is of interest for a number of studies in which old mice and young mice are linked together, known as heterochronic parabiosis. The young mice acquire a little of the metabolic, cellular, and gene expression changes characteristic of old mice, while in the the old mice some of these measures reverse towards more youthful levels. In stem cell activity in particular, the environment of signals present in the blood seems to dictate age-related decline as much as does any inherent damage to stem cells or their niches. This reinforces the view of stem cell aging as an evolved reaction to the cellular damage of aging that acts to extend life by reducing cancer risk, but at the cost of a slow decline into death due to ever more poorly maintained tissues and organs.

Heterochronic parabiosis studies in mice have been taking place for some years now, and researchers are beginning to link differences in gene expression and protein levels in old tissues versus young tissues to specific age-related conditions. The next logical step is to see if age-related dysfunction can be reversed by changing these protein levels in old animals:

Young blood reverses heart decline in old mice

Pumping young blood around old bodies - at least in mice - can reverse cardiac hypertrophy - the thickening and swelling of the heart muscle that comes with age and is a major cause of heart failure. After just four weeks, the older mouse's heart had reverted to almost the same size as that of its younger counterpart. The hearts of the young mice were unaffected, even though they were pumping some blood from the older mice.

After ruling out the effect of reduced blood pressure on the older mice, the team identified a potential candidate: a protein called GDF11, which was present in much higher quantities in the blood of the young mice. To test the effect of GDF11, the researchers gave old mice with cardiac hypertrophy daily injections of it for 30 days. At the end of the treatment, their hearts were significantly smaller than those in a second group of mice of the same age and with the same condition, but that had been injected with saline.

Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy

The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify the biological mechanisms that drive cardiac hypertrophy in aging, we tested the influence of circulating factors using heterochronic parabiosis, a surgical technique in which joining of animals of different ages leads to a shared circulation.

Using modified aptamer-based proteomics, we identified the TGF-β superfamily member GDF11 as a circulating factor in young mice that declines with age. Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging.

Overriding declines in stem cell activity and forms of tissue degeneration by changing the levels of protein signals present in aged tissues is clearly going to be an important field of medicine in the near future. It may ultimately even take over from stem cell transplants as the principle mode of treatment for many age-related conditions. Some of those transplant therapies are most likely working through the same mechanisms, after all. Regeneration happens because the introduced stem cells are altering the signaling environment and waking up native stem cells, not because they are building new cells and patching up tissue structures.

However, one caveat is that this sort of work doesn't address any of the cellular and molecular damage that initiated the evolved response to reduce stem cell activity. That damage is still there: mitochondrial DNA mutations, high levels of oxidative damage, harmful build up of various forms of metabolic byproducts in and around cells, and so on. At the very least one would expect a growing risk of cancer to accompany a resurgence in stem call activity in an old person - which may be an entirely acceptable risk as cancer therapies improve past chemotherapy and towards targeted cell killers with no side effects.

Even if short term benefits can be obtained via altered signaling protein levels in old tissue, it is still the case that the underlying damage of aging must be repaired. Boosting stem cell activity so far appears to be a better class of potential treatment for many conditions than the best of what can be found in the clinic today, but it is still a form of patching over the underlying causes rather than fixing them.

TRANSGENIC MICE EXPRESSING HUMAN MTH1 LIVE LONGER
http://www.fightaging.org/archives/2013/05/transgenic-mice-expressing-human-mth1-live-longer.php

New ways to extend mouse life span arrive at a steady pace these days. It's all largely genetic engineering to alter the operation of metabolism in various ways, and the results help to shed light on the roles of specific genes and on the way in which metabolism and environment together determine the pace of aging. These examples of life extension are not rejuvenation, however, and nor do they lie on any road that leads to rejuvenation. Thus they have little to no bearing on whether or not you and I will lead extended healthy lives: the only way that will happen is for research programs like SENS to make significant progress. SENS-like research aims to repair the underlying causes of aging in a deliberate, targeted fashion and thus reverse aging. It is a completely different approach to research and the development of therapies than that of trying genetic alternations in search of those that can modestly slow down aging.

But still, I post on the topic of genetically engineered mouse longevity for the same reasons I post on topics like the evolution of aging - because it is interesting, not because it will necessarily have any meaningful application in the near term. Below is a recent example in which the human gene for MTH1 / NUDT1 causes enhanced longevity when expressed in mice. The enzyme produced from this genetic blueprint cuts down on oxidative damage to both nuclear and mitochondrial DNA, and the gain in mouse life span is thus an expected outcome under any of the free radical theories of aging.

Prolonged Lifespan with Enhanced Exploratory Behavior in Mice Overexpressing the Oxidized Nucleoside Triphosphatase hMTH1

In this study we used the hMTH1-Tg mouse model to investigate how oxidative damage to nucleic acids affects aging. hMTH1-Tg mice express high levels of the hMTH1 hydrolase that degrades 8-oxodGTP and 8-oxoGTP and excludes 8-oxoguanine from both DNA and RNA. Compared to wild-type animals, hMTH1-overexpressing mice have significantly lower steady-state levels of 8-oxoguanine in both nuclear and mitochondrial DNA of several organs, including the brain. hMTH1 overexpression prevents the age-dependent accumulation of DNA 8-oxoguanine that occurs in wild-type mice.

These lower levels of oxidized guanines are associated with increased longevity and hMTH1-Tg animals live significantly longer than their wild-type littermates. Neither lipid oxidation nor overall antioxidant status are significantly affected by hMTH1 overexpression. The significantly lower levels of oxidized DNA/RNA in transgenic animals are associated with behavioral changes. These mice show reduced anxiety and enhanced investigation of environmental and social cues.

There some muddying of the water here, of course. Nothing is ever simple in biology. The first item to consider is that it's possible that differences in activity levels in the mice could account for some of the longevity differences shown in the research. This is hard to control for, harder than calorie restriction, which is the other thing you have to keep track of in any mouse study. If your mice happen to eat less because your treatment makes them nauseous, or they eat less because they're spending more time running around, then they'll live somewhat longer.

The more interesting line item, however, is the difference between reducing oxidative damage to nuclear DNA versus reducing oxidative damage to mitochondrial DNA. There is some debate over whether nuclear DNA damage contributes meaningfully to aging (as opposed to its contribution to cancer risk), whereas there is a far greater consensus on the importance of mitochondrial DNA damage in degenerative aging. More of it is bad, less of it is good.

I would be very interested to see the results of a similar study in which researchers figure out how to keep the protective enzymes localized to either the nucleus or the mitochondria. My expectation would be that you'd only see increased life span for the mitochondrial localization, which would make sense when considering the extended life that result from studies in which levels of natural antioxidants like catalase are enhanced in mouse mitochondria.

FORTHCOMING BOOK: THE AGELESS GENERATION
http://www.fightaging.org/archives/2013/05/forthcoming-book-the-ageless-generation.php

Alex Zhavoronkov of the Biogerontology Research Foundation and the International Aging Research Portfolio (IARP) has written a popular science book that will be coming out next month. The topic is the defeat of aging, but the focus is on potential economic transformations, particularly those relating to unsustainable entitlements such as pensions, medicare, social security, and the like. These entitlements threaten the destruction of entire economies and societies by virtue of the fact that they cannot be continued indefinitely, and yet no group in society seems willing to do what needs to be done in order to avoid that result.

The Ageless Generation: How Advances in Biomedicine Will Transform the Global Economy

Historically, a continued failure to address national overspending has led to dire results: hyperinflation, extreme unemployment, civil unrest, and ironically, as economies collapse, a loss of funding for the same senior entitlement programs that created the crisis in the first place. Poor financial management was one of the main contributing factors behind the advent of Nazi Germany as well as the collapse of the USSR that put millions of its senior citizens into poverty. As Aldous Huxley warned, "That men do not learn very much from the lessons of history is the most important of all the lessons that history has to teach."

Will we learn from history? Fortunately, we may be bailed out by technology, which has advanced so rapidly in the past decade that a medical solution to these economic problems is now tantalizingly close. Through scientific means, we can dramatically enhance the health and youthfulness of the aging population over the next couple of decades.

This would redefine our current conception of 65 as the standard age of retirement. If tomorrow's 65-year-olds were as healthy as 55-year-olds today, seniors could work an extra ten years if they chose to do so. If millions of seniors continued to pay into the system while postponing their entrance into these senior entitlement programs by a decade or more, the problems of Social Security and Medicare could be pushed decades into the future. And the cycle would continue, as medical researchers would have more time to extend even further the health and vitality of seniors virtually eliminating the retirement age. As you will soon learn, the longevity breakthroughs we could see in the next 20 years could change the entire landscape of aging, including its social and economic implications.

Will we learn from history? The evidence to hand suggests that the answer is "no." The short term incentives for (a) those receiving entitlements and (b) the political elite who do well for themselves on the graft and corruption enabled by centralization of power combine to lead us all off the cliff in the end. The two sides even collaborate after a fashion in the system of voting for more entitlements. This, combined with an enormous military expenditure, is how all empires end - and the American empire-in-all-but-name will be no different.

I am skeptical that technological advances in medicine will do more than patch a small part of the overall problem. The problem is centralized, unaccountable power in the hands of those who make up the state. If it isn't social security that brings down the system in the end, at the point at which the elite run out of other people's money to steal, waste, and transfer to their allies, then it will be some other form of entitlement or abuse of the financial system.

The defeat of aging will of course be very welcome, and is a goal that should be pursued for what it can do to save lives and ameliorate suffering, not for its ability to let the corrupt upper crust continue being corrupt and in charge for a little longer. I am given to think that the technological advances that will do the most to help with the issues of power, entitlements, and economic destruction, are those involving space flight and cheap, reliable orbital access, however. Historically the only thing that has kept the depredations and corruptions of established states at least somewhat in check is the existence of an accessible frontier, a place to which large sections of the population can emigrate in order to escape a controlled, taxed, doomed economy. So very much of the malaise of the modern world is due, I think, to the lack of an effective frontier.

BOOSTED MITOPHAGY EXTENDS LIFE IN FLIES BY 25%
http://www.fightaging.org/archives/2013/05/boosted-mitophagy-extends-life-in-flies-by-25.php

One of the side-effects of research into Parkinson's disease is that scientists are making more rapid progress in understanding the mechanisms of mitophagy than would otherwise be the case. Mitophagy is a set of quality control mechanisms that recycle mitochondria, the bacteria-like powerplants in our cells, and like the more general quality control mechanisms of autophagy it is important in aging and longevity. Boosted autophagy or mitophagy shows up in many of the genetic and metabolic alterations shown to extend life in laboratory animals, and has been shown to be required for some of them - no autophagy means no additional longevity.

This is all thought to be a matter of housekeeping: if cells and cellular components are more damaged or cluttered with waste products, then the life span of the organism is shorter as a result. If damage is reduced and more rapidly repaired when it does occur, life span lengthens. Mitochondrial damage in particular is thought to be connected to the pace of aging, by virtue of the fact that cells with damaged mitochondria can fall into malfunctioning states that export damaging reactive compounds to the surrounding tissues.

The focus on mitophagy in Parkinson's research has come about because some forms of Parkinson's are genetic in origin: the patients have a mutation in one of the proteins that form the machinery of mitophagy, making the process function less effectively. This translates to more damaged mitochondria, more cellular and mitochondrial dysfunction, and at the end of the day more dead dopamine-generating neurons. That last item, the loss of a specialized population of neurons, is the proximate cause of the symptoms of Parkinson's disease - but a range of low level biological process contribute to how exactly it happens.

I mention all of this because the research I wanted to point out today involves the protein called parkin: its association with Parkinson's disease was discovered prior to present theorizing on its involvement in mitophagy, hence the name. Researchers have now shown that more parkin means more mitophagy and longer-lived flies:

Single Gene May Extend Lifespan by 25 Percent

Scientists at UCLA have found a single gene that, when stimulated to be overexpressed, extends the healthy life span of fruit flies by more than 25 percent. The gene, called parkin, plays an important role in disposing of damaged proteins within a cell. Previous studies have suggested that protein build up within cells may play an important role in aging. In fruit flies, and potentially in humans, parkin "marks" damaged proteins and instructs the cell to dispose of them.

By stimulating parkin expression, thereby boosting the power of the "cellular garbage disposal," David Walker, lead author of the study, was able to keep a group of fruit flies alive much longer than normal. "In the control group, the flies are all dead by day 50. In the group with parkin overexpressed, almost half of the population is still alive after 50 days. We have manipulated only one of their roughly 15,000 genes, and yet the consequences for the organism are profound."

Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan

Aberrant protein aggregation and mitochondrial dysfunction have each been linked to aging and a number of age-onset neurodegenerative disorders, including Parkinson disease. Loss-of-function mutations in parkin, an E3 ubiquitin ligase that functions to promote the ubiquitin-proteasome system of protein degradation and also in mitochondrial quality control, have been implicated in heritable forms of Parkinson disease. The question of whether parkin can modulate aging or positively impact longevity, however, has not been addressed.

Here, we show that ubiquitous or neuron-specific up-regulation of Parkin, in adult Drosophila melanogaster, increases both mean and maximum lifespan without reducing reproductive output, physical activity, or food intake. Long-lived Parkin-overexpressing flies display an increase in K48-linked polyubiquitin and reduced levels of protein aggregation during aging. Recent evidence suggests that Parkin interacts with the mitochondrial fission/fusion machinery to mediate the turnover of dysfunctional mitochondria. However, the relationships between parkin gene activity, mitochondrial dynamics, and aging have not been explored.

We show that the mitochondrial fusion-promoting factor Drosophila Mitofusin, a Parkin substrate, increases in abundance during aging. Parkin overexpression results in reduced Drosophila Mitofusin levels in aging flies, with concomitant changes in mitochondrial morphology and an increase in mitochondrial activity. Together, these findings reveal roles for Parkin in modulating organismal aging and provide insight into the molecular mechanisms linking aging to neurodegeneration.

The theory at least is that the resulting life extension in flies is due to boosted mitophagy, and thus a greater pace of recycling of damaged mitochondria. The current understanding of the machinery involved is that parkin interacts with mitofusin to label mitochondria for destruction. Equally at this stage in the research, it might also turn out to be the case that a related but different process is adjusted by overexpressing parkin - there's still room for uncertainty, but time will tell one way or another.

DISCUSSION

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!

LATEST HEADLINES FROM FIGHT AGING!

THE PRESENT STATE OF ARTIFICIAL RETINAS
Friday, May 10, 2013
http://www.fightaging.org/archives/2013/05/the-present-state-of-artificial-retinas.php

Retinal implants that can provide a crude substitute for vision in some forms of blindness are a work in progress at this time, but the path ahead seems fairly clear:

Some people with artificial retinas can read large letters, see slow-moving cars, or identify tableware. Other patients experience no benefit. The variation can be ascribed in some cases to the exact placement of the neuron-stimulating array in the tissue-paper-thin retina as well as the state of the remaining neurons and pathways in each individual's eye. How well people can learn to use the device and retrain their brain is also important. At its best, the current level of vision is very pixelated. What's seen are bursts of light called phosphenes. "It's not restoring vision like you and I think of, it's restoring mobility. They provide contrast so that someone can see a difference in light and dark to the point where they can tell how to walk through a doorway. This is very much the beginning. Retina prostheses are at the stage cochlear implants were 30 years ago. That technology went from being an aid for lip reading to the point now where children with a cochlear implant can go through normal school and even use mobile phones. With retinal implants, we now know it has clinical benefit to patients, and I think we are going to see this technology develop very rapidly over the next decade."

Thousands of pixels [in comparison to the present 60 or so] will likely be required for facial recognition and other detailed visual tasks, and many artificial retina technologies will have trouble getting to such large numbers of pixels because they depend on wires. Wires are used to connect a power supply to electrodes, which requires a surgical procedure to lay the connection through the eyeball. To avoid this limitation, [researchers] are developing a wireless system that transmits image data captured by a video camera to a photovoltaic chip in the eye. Instead of transmitting visible light to the chip, his system uses near-infrared light that is beamed to flexible arrays of small pixels in the retina. The team has tested the system in blind rats and is now working with a company to test the device in patients. But even thousands of pixels are a long way from one million, "which is roughly what we have in the natural eye. And even at that, there is a lot of processing that the retina does that we are going to be skipping with an artificial retina."

THE STATE OF ELECTROMECHANICAL AND BIOARTIFICAL ORGANS
Friday, May 10, 2013
http://www.fightaging.org/archives/2013/05/the-state-of-electromechanical-and-bioartifical-organs.php

An article on the development of prosthetic organs, a field that continues to provide competition for regenerative medicine:

Proponents of biological organ replacements have recently been encouraged by the development of 3D tissue printing, which offers the tantalising possibility that we might build organs mechanically, layer by layer - a much faster process than growing them in the lab. But printing complex internal organs like the liver or heart is still some way off, and the technology will face similar issues to traditional tissue engineering when it comes to implanting. In the meantime, some scientists are pursuing a different approach, combining biological tissue with synthetic materials and/or mechanical and electronic components to create what could be called hybrid or even cyborg organs (cyborgans, if you will), which are more easily manufactured, longer lasting and more successful once implanted into the body.

On one level this means incorporating some biological material into a largely man-made device. French firm Carmat [has] begun animal trials on one of the world's most advanced designs for an artificial heart, which includes some biological elements.The two chambers inside the Carmat heart are each divided by a biomembrane that separates blood on side from hydraulic fluid on the other. Tiny motors controlled by an electronic sensor system pump the hydraulic fluid in and out of the chambers, in turn causing the membrane to pump the blood. To increase haemocompatiblity, the membrane is made from animal tissue that helps move the blood without damaging cells. Microporous biological and synthetic biomaterials also cover every other surface that comes in contact with the blood, in order to prevent material from sticking to them.

But scientists are also combining biological and synthetic materials in a more fundamental way, creating permanent artificial structures or scaffolds and then growing living cells around them. [Researchers are] already preparing to clinically trial blood vessels and tracheae (windpipes) made in this way, and [are] also developing urethrae, bladders and cardiac patches for healing hearts.

INSIGHTS INTO INFLAMMAGING
Thursday, May 9, 2013
http://www.fightaging.org/archives/2013/05/insights-into-inflammaging.php

In later years the immune system falls into a malfunctioning state of overactivation and ineffectiveness, generating damaging chronic inflammation while at the same time failing to defend against pathogens and destroy damaged cells.

It is recognized that the immune system, comprising both innate (nonspecific) and acquired (specific) components, is an intricate defence system that is highly conserved across vertebrate species, and has, from an evolutionary perspective, undergone strong pressures to maximize survival to allow procreation. The significant improvements in human survival and lifespan to well beyond childbearing ages have been totally "unpredicted" by evolution. As a consequence, human immune systems are exposed to considerable additional antigenic exposure outside the forces of natural selection. It is in this situation that immunity begins to exert negative effects on human ageing (antagonistic pleiotropy), leading to gradual systemic failures.

Research into age-related changes of the immune system is gathering pace as its importance within the context of multiple pathologies in ageing populations is realized. As part of this advance, [researchers] described the phenomenon of "inflammaging" at the turn of the millennium as part of the spectrum of immunosenescence. Inflammaging denotes an upregulation of the inflammatory response that occurs with age, resulting in a low-grade chronic systemic proinflammatory state.

Inflammaging is believed to be a consequence of a cumulative lifetime exposure to antigenic load caused by both clinical and subclinical infections as well as exposure to noninfective antigens. The consequent inflammatory response, tissue damage and production of reactive oxygen species that cause oxidative damage also elicits the release of additional cytokines, principally from cells of the innate immune system but also from the acquired immune response. This results in a vicious cycle, driving immune system remodelling and favouring a chronic proinflammatory state where pathophysiological changes, tissue injury and healing proceed simultaneously. Irreversible cellular and molecular damage that is not clinically evident slowly accumulates over decades.

THE COMPLEMENT SYSTEM AND RHEUMATOID ARTHRITIS
Thursday, May 9, 2013
http://www.fightaging.org/archives/2013/05/the-complement-system-and-rheumatoid-arthritis.php

Autoimmune diseases like rheumatoid arthritis are one of the few remaining classes of condition where little can be done for many sufferers at this time, and where researchers still know comparatively little about specific causative mechanisms. The most effective treatments are based on suppressing the immune system rather than addressing root causes, and even those are hit and miss.

Meanwhile here is one of the signs that this may all be changing in the years ahead, as modern tools allow a greater understanding and ability to manipulate facets of the immune system:

"We found that fat in the knee joints secretes a protein called pro-factor D which gives rise to another protein known as factor D that is linked to arthritis. Without factor D, mice cannot get rheumatoid arthritis." [With] the discovery of pro-factor D in mice with rheumatoid arthritis, [researchers are] working on gene therapies to eliminate the protein in localized areas. However, these findings still need to be extended to humans. "We are looking at vaccines, drugs or inhibitors to stop the local secretion of pro-factor D in the mouse. Our goal would be to stop the disease before it progresses and leads to joint destruction."

Factor D is part of the complement system, a complex array of over 40 proteins that help the body fight off bacteria and other pathogens. In studies with arthritic mice, [researchers] previously found that the complement pathway involving factor D made the mice susceptible to inflammatory arthritis. [Removing] factor D, rather than the entire complement system, achieves the same result without compromising other parts of the system that can fight infection.

While it's theoretically possible to destroy the entire complement system in humans to prevent arthritis, it eventually returns along with a renewed risk of contracting the disease. In the meantime, patients can get infections and other complications because they lack this critical part of the immune system. "The complement system is both friend and foe. We believe we can shut down one part of the complement system that triggers disease without shutting down the rest. If so, we will be making a major stride toward treating and perhaps even curing rheumatoid arthritis."

MORE ON LIFE EXTENSION AND ENTITLEMENTS
Wednesday, May 8, 2013
http://www.fightaging.org/archives/2013/05/more-on-life-extension-and-entitlements.php

To go along with yesterday's post on the economic disaster of entitlements, here's another piece from someone who sees this as a defining issue in which longevity is important. Yet even if life spans were not increasing and even without the prospect of radical life extension in the near future, states would still be on a path to eventual collapse through growth in entitlements, forced transfers of wealth, and the accompanying corruption that arises with the centralization of power. This is the historical outcome resulting from the growth of a state in its late stages, even in periods of history without ongoing increases in life expectancy.

Truly historic discoveries and therapies are coming online right now that will radically decrease the threat and cost of autoimmune disorders, cancers, cardiovascular disease, Alzheimer's, arthritis, obesity and diabetes, as well as dangerous influenzas, HIV and other virus-borne diseases. [Clearly], this is good news both for humanity in general and investors specifically. However, these changes will be, by definition, enormously disruptive. As is always the case when big changes create new winners and dethrone the old ones. How big will these changes be?

Consider the fact that already, life extension is our No. 1 public-policy challenge. It is, in fact, the root cause of our current mortgage and debt fiascos - both only symptoms of successful life-extending technologies. The technologies that have precipitated these crises, however, will soon be overshadowed by the wave of revolutionary biotech innovation. Even those who have no personal interest in life-extension strategies, beyond those supplied by conventional medical networks, will have to deal with the social and economic problems they cause. Our lives will be profoundly affected by emerging biotechnologies that will push maximum healthy life spans up much faster and further than ever before.

Typically, when I say that life extension brings problems, the default assumption is that I'm referring to traditional fears of resource depletion and overpopulation. I'm not. [To] be clear, there is nothing about longer lives that is inherently adverse. Personally, I'm completely in favor of much longer health spans. Rather, the problem has been the failure to recognize and adjust to accelerating increases in life expectancies. This failure has led to ballooning expenditures and unsustainable debt. I should clarify and restate this thesis: Obsolete actuarial tables and expectations about the length and cost of retirement, especially on the medical cost front, are the proximate causes of the international fiscal meltdown.

Though many people portray the crisis as ideological, especially if their proposed solution is raising taxes, it's actually about math. And it's pretty simple math at that. The working young, who have always paid a disproportionate portion of the retirement and medical costs of the older and generally wealthier population, cannot bear that load in a demographically transforming world.

I would be one of those who see this as ideological. Present economic crises are caused by the ideologies that say its fine to force people to create a communal pool of funds under the control of elites, to suppress free markets in insurance and medicine, to force people to use fiat currencies that allow enormous levels of debt spending by elites, and so on and so forth. All these things trace back to the existence of a coercive state, its inexorable growth, and its inevitable corruption.

UV LIGHT, NITRIC OXIDE, AND BLOOD PRESSURE
Wednesday, May 8, 2013
http://www.fightaging.org/archives/2013/05/uv-light-nitric-oxide-and-blood-pressure.php

Nitric oxide levels show up in a range of mechanisms linked to aging and general health, in particular those to do with blood vessel function. Here is an interesting study that may or may not be examining an example of hormesis, a beneficial response to very minor levels of damage caused by UV light, such as that in sunlight:

Researchers have shown that when our skin is exposed to the sun's rays, a compound is released in our blood vessels that helps lower blood pressure. The findings suggest that exposure to sunlight improves health overall, because the benefits of reducing blood pressure far outweigh the risk of developing skin cancer.

Production of this pressure-reducing compound - called nitric oxide - is separate from the body's manufacture of vitamin D, which rises after exposure to sunshine. Until now it had been thought to solely explain the sun's benefit to human health. [Researchers] studied the blood pressure of 24 volunteers who sat beneath tanning lamps for two sessions of 20 minutes each. In one session, the volunteers were exposed to both the UV rays and the heat of the lamps. In the other, the UV rays were blocked so that only the heat of the lamps affected the skin. The results showed that blood pressure dropped significantly for one hour following exposure to UV rays, but not after the heat-only sessions. Scientists say that this shows that it is the sun's UV rays that lead to health benefits. The volunteers' vitamin D levels remained unaffected in both sessions.

"We suspect that the benefits to heart health of sunlight will outweigh the risk of skin cancer. The work we have done provides a mechanism that might account for this, and also explains why dietary vitamin D supplements alone will not be able to compensate for lack of sunlight. We now plan to look at the relative risks of heart disease and skin cancer in people who have received different amounts of sun exposure. If this confirms that sunlight reduces the death rate from all causes, we will need to reconsider our advice on sun exposure."

AGING, AND THE CURE OF THE DISEASES OF AGING
Tuesday, May 7, 2013
http://www.fightaging.org/archives/2013/05/aging-and-the-cure-of-the-diseases-of-aging.php

An essay on the causes of aging and what we might do to prevent them can be found at the SENS Research Foundation outreach blog:

The diseases of old age. Age-related disease. The diseases of aging. We've all heard this language used by medical experts. But what do we mean by them? What is the mysterious connection between aging and the diseases of aging? And how is SENS Research Foundation targeting that connection to keep people healthy and prevent and cure the suffering of old age's diseases and disabilities?

While we sometimes prefer not to think about it, we all know that people lose their health as they age. Angina, Alzheimer's, breast and prostate cancers, chronic kidney disease ... With rare exceptions caused by birth defects, severe congenital mutations, or traumatic injury, these diseases are never present in young adults. Their first subtle hints crop up in the years between our forties and our seventies, accompanied by the weakening of our muscles (even in athletes), loss of cushioning in our joints, failing of the eyesight, and a generalized decay of the body's resilience and health. Over time, the minor aches and vague malaise of middle age devolve more or less rapidly into clinical diagnoses, leaving us with a rising burden of disease, disability, and dependence.

But why does this happen? What is it about these diseases that causes them to slowly creep into our bodies after decades of relatively healthy life, each joining and building on the others, as if they were so many poorly-coordinated orchestra musicians, playing at different speeds, starting at different times, and raising a cacophony that gets louder and louder until it reveals itself as a terrible, secret symphony? And what can the answers to those questions tell us about what to do about them?

TOWARDS A PATCH FOR DAMAGED HEARTS
Tuesday, May 7, 2013
http://www.fightaging.org/archives/2013/05/towards-a-patch-for-damaged-hearts.php

Progress is noted in the techniques needed to build functional heart tissue:

Biomedical engineers have grown three-dimensional human heart muscle that acts just like natural tissue. This advancement could be important in treating heart attack patients or in serving as a platform for testing new heart disease medicines. The "heart patch" grown in the laboratory from human cells overcomes two major obstacles facing cell-based therapies - the patch conducts electricity at about the same speed as natural heart cells and it "squeezes" appropriately. Earlier attempts to create functional heart patches have largely been unable to overcome those obstacles. The source cells used by [the] researchers were human embryonic stem cells. These cells are pluripotent, which means that when given the right chemical and physical signals, they can be coaxed by scientists to become any kind of cell - in this case heart muscle cells, known as cardiomyocytes.

"The structural and functional properties of these 3-D tissue patches surpass all previous reports for engineered human heart muscle. This is the closest man-made approximation of native human heart tissue to date. In past studies, human stem cell-derived cardiomyocytes were not able to both rapidly conduct electrical activity and strongly contract as well as normal cardiomyocytes. Through optimization of a three-dimensional environment for cell growth, we were able to 'push' cardiomyocytes to reach unprecedented levels of electrical and mechanical maturation."

"Currently, it would take us about five to six weeks starting from pluripotent stem cells to grow a highly functional heart patch. When someone has a heart attack, a portion of the heart muscle dies. Our goal would be to implant a patch of new and functional heart tissue at the site of the injury as rapidly after heart attack as possible. Using a patient's own cells to generate pluripotent stem cells would add further advantage in that there would likely be no immune system reaction, since the cells in the patch would be recognized by the body as self."

EVIDENCE AGAINST AN INFLUENCE OF MITOCHONDRIAL DNA HAPLOTYPES ON HUMAN LONGEVITY
Monday, May 6, 2013
http://www.fightaging.org/archives/2013/05/evidence-against-an-influence-of-mitochondrial-dna-haplotypes-on-human-longevity.php

A range of studies suggest that variations in mitochondrial DNA influence human longevity, which is what we'd expect given the mass of evidence for the importance of mitochondria DNA damage in aging, and the role of mitochondrial function in many age-related diseases. Here, however, is a study showing no statistically identifiable effects resulting from different mitochondrial DNA haplotypes in the old:

Inherited genetic variation of mitochondrial DNA (mtDNA) could account for the missing heritability of human longevity and healthy aging. Here, we show no robust association between common genetic variants of mtDNA and frailty (an "unhealthy aging" phenotype) or mortality in 700, more than 85-year-old, participants of the Newcastle 85+ study. Conflicting data from different populations underscore our conclusion that there is currently no compelling link between inherited mtDNA variants and aging.

REVERSING HAIR GRAYNESS BY SUPPRESSING OXIDATIVE STRESS
Monday, May 6, 2013
http://www.fightaging.org/archives/2013/05/reversing-hair-grayness-by-suppressing-oxidative-stress.php

The graying of hair with increasing age is an early sign of increased oxidative stress in skin tissues around hair follicles. Researchers here demonstrate that it can be locally reversed by an antioxidant-based strategy. This shouldn't be taken to indicate that antioxidants are of general utility: the researchers are carefully augmenting the role of a specific natural antioxidant enzyme in an intricate chemical process, not just picking any random antioxidant and throwing it into the mix.

People who are going gray develop massive oxidative stress via accumulation of hydrogen peroxide in the hair follicle, which causes our hair to bleach itself from the inside out. The build up of hydrogen peroxide was caused by a reduction of an enzyme that breaks up hydrogen peroxide into water and oxygen (catalase). Hair follicles could not repair the damage caused by the hydrogen peroxide because of low levels of enzymes that normally serve this function (MSR A and B). Further complicating matters, the high levels of hydrogen peroxide and low levels of MSR A and B, disrupt the formation of an enzyme (tyrosinase) that leads to the production of melanin in hair follicles. Melanin is the pigment responsible for hair color, skin color, and eye color.

The report shows that this massive accumulation of hydrogen peroxide can be remedied with a proprietary treatment developed by the researchers described as a topical, UVB-activated compound called PC-KUS (a modified pseudocatalase). What's more, the study also shows that the same treatment works for the skin condition, vitiligo.

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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CONTENT

• SENS Research Foundation Annual Report for 2012
• A Different Take on NF-κB and the Hypothalamus
• Adjusting Mouse Longevity via the Hypothalamus
• Video: Aubrey de Grey at TEDxDanubia 2013
• Discussion
• Latest Headlines from Fight Aging!
  • T-Regulatory Cells More Numerous in the Aged Immune System
  • HMGA1 as a Potential Common Mechanism in Cancer
  • A Skeptical View of Mitochondrial DNA Damage and Aging
  • Protecting Cryonics Patients
  • A Review of Adenylyl Cyclase Type 5 and Longevity in Mice
  • On Extending Mouse Longevity
  • Growth Hormone and IGF-1 in Aging
  • IGF1R Levels in the Brain Correlate With Species Life Span
  • Calorie Restriction and Calorie Restriction Mimetics
  • The Burrill and Buck Aging Meeting, May 20th 2013

SENS RESEARCH FOUNDATION ANNUAL REPORT FOR 2012
http://www.fightaging.org/archives/2013/04/sens-research-foundation-annual-report-for-2012.php

The SENS Research Foundation is one of the few organizations presently focused on developing medical technologies that will produce rejuvenation in the old. The Foundation researchers and staff undertake targeted research programs in areas that are not getting enough attention from the mainstream life science community, and engage in advocacy to convince more of the research community to work on the goal of reversing degenerative aging, thus preventing age-related disease, frailty, and disability, and extending healthy life.

A newsletter from the Foundation arrived today, with a link to the Foundation's 2012 annual report (PDF). Good news on the budgetary side of things is the order of the day, and the Foundation is continuing to grow its research efforts. The total budget in 2012 was $3 million, in comparison to the $1 million only a couple of years earlier:

We are pleased to report that, in 2012, SENS Research Foundation was able to support expenses that were double those from the previous year. This was made possible through not only the continued support of our generous donors, but the first in a series of annual disbursements from the de Grey family trust, which together caused SRF's income to increase by about $2 million.

As a research-based outreach organization, the scientific work that we fund plays a critical role in our mission. For this reason, we have focused our growth on our extramural research program, tripling its size by adding more than $750,000 of funding. This aggressive expansion has led to the addition of nine new projects, including two at the Wake Forest Institute for Regenerative Medicine, bringing our total funded to seventeen. Meanwhile, we were able to add $300,000 to our intramural research budget, bringing a third major project, more staff, and new equipment to our Research Center in Mountain View, California.

Simultaneously, we built SRF Education into a larger and more robust educational program, creating our first online course and a successful summer internship program that involved both our Research Center and the Buck Institute for Research on Aging. This has set the stage for further growth in 2013, which will include the development of more coursework and the addition of new internship campuses.

Overall, our expenses in 2013 should increase by an amount equal to 2012's increase. Given our secure base of funding sources, we expect to sustain this higher level of operation indefinitely. We are deeply appreciative of the individuals and foundations that enable us to pursue our mission through their support. We would like to thank Peter Thiel, Jason Hope, the de Grey family trust, the Methuselah Foundation, and the many other donors who make all of our efforts possible.

If you read through the report, you'll find good overviews of the present research programs supported by the Foundation, as well as news of recent progress.

Lysosomal Aggregates

Researchers funded by the Foundation are searching for bacterial enzymes that can be safely introduced into the body to break down harmful metabolic byproducts that build up in the lysosomes within cells, degrading their ability to keep up with cellular housekeeping, and contributing to a range of age-related conditions. There are many different types of chemical gunk that building up in the lysosome, so researchers have so far focused on those best known to the research community.

At the SENS Research Foundation Research Center (SRFRC), our Lysosomal Aggregates team is working to efficiently deliver promising A2E-degrading enzymes identified in our earlier research into the lysosome of cells. One in particular (SENS20) has demonstrated tremendous efficacy in degrading A2E not only in vitro but in A2E-loaded retinal pigment epithelium cells.

In 2013, the team will put a recombinant form of SENS20 to the test, assessing its ability to degrade A2E in vitro and in retinal pigment epithelium cells, and verifying that it is not toxic to the cell

It has to be said that it is very pleasing to see the Foundation at the stage of giving the characteristic drug/therapy candidate names (SENS20 in this case) to the results of their work.

Mitochondrial Mutations

Our mitochondria become damaged with age, causing a range of catastrophic consequences to our cells and tissues. The SENS approach to fixing this is to put backup copies of vulnerable mitochondrial genetic material into the cell nucleus. The challenge here was never getting the genes into the nucleus, as that's just straightforward gene therapy, but rather getting the proteins from those genetic blueprints back into the mitochondria where they are needed. This was slow going until fairly recently, when a potential game-changing advance emerged from the broader research community.

It sounds like the SENS Research Foundation folk are working to integrate this new approach into their efforts, as it could in theory allow all the necessary genes to be moved into the nucleus via the same basic method - so get it working once and you're done.

SRF-RC scientists are now working to master and refine a superior method for accomplishing this goal. Our team has taken four cell lines from patients suffering from severe diseases caused by inherited mitochondrial mutations, and made stable lines that express their improved mitochondrial gene constructs. They have begun collecting data confirming the targeting of gene transcripts and proteins to their mitochondrial locations, and the functional activity of the mitochondrial energy system, in such re-engineered cells.

I am very impatient to see a demonstration of mitochondrial repair or DNA replacement running in a mouse life span trial - it is my belief, based on the range of research I've seen over the years, that mitochondrial damage is the dominant cause of degenerative aging, and I'm looking forward to seeing just how right or wrong that hypothesis might be. It's not unrealistic at this point to think that ten years from now we'll have that data in hand.

Extracellular Matrix Stiffening

Crosslinks such as advanced glycation end-products form relentlessly in our tissues, gumming up protein machinery and causing a fair portion of the visible symptoms of skin aging - and worse, the loss of flexibility in blood vessels and other important tissue structures. Old skin I could live with, but you can't live with old blood vessels; they'll kill you in the course of time. The short history of attempts to develop therapies to break down AGEs has been a short history of frustration, with only very limited success to date. Fortunately, we are now past a critical point of discovery regarding AGEs, which is that in human tissue they overwhelmingly consist of a single compound called glucosepane. Unfortunately, beyond the SENS Research Foundation next to nobody cares to do anything about this aspect of aging.

Late in 2012, we announced the establishment of our new SENS Research Foundation Laboratory in partnership with the University of Cambridge Institute of Biotechnology. In collaboration with Dr. Spiegel's lab, the SRF Cambridge center will initiate work on new agents to cleave apart crosslinked proteins, restoring youthful elasticity and buffering capacity to arteries. The specific molecular target will be glucosepane, the main crosslink that accumulates in aging human arteries and other tissues.

Dr. Spiegel has already developed a way to synthesize glucosepane in the lab; this artificially-produced glucosepane can now be used to develop reagents that can rapidly and specifically detect proteins that have been crosslinked by it.

The Cambridge group has been working on methods of extracting crosslinked proteins intact from the tissues of dogs and marmoset monkeys, and to measure glucosepane cleavage in the test tube and in animal and human tissues. It is clear from this research that none of the commercially available monoclonal antibodies against related crosslink molecules are able to cleave glucosepane to any significant degree, and many are useless. All of these findings further emphasize the importance of this project in developing novel crosslink-breaking therapies.

Other Research Programs

A range of other current research programs are given just as much attention in the annual report. I hope that the notes above encourage you to look them over. This is what the future of longevity science looks like: deliberately and carefully working to reverse specific forms of damage that occur in old tissue but not in young tissue. It is a world away from the old school drug discovery process in the Big Pharma mainstream that aims only at modestly slowing down aging - the sirtuins, and resveratrol, and rapamycin, and all the other potential and so far largely disappointing age-retarding drugs. SENS is the only path forward that is likely to produce significant rejuvenation in the old when its therapies are ready for clinical use.

For you and I to have a good shot at living far longer than our ancestors, the SENS approach must come to dominate the mainstream of aging research, displacing less effective and more expensive approaches. Fast progress requires large budgets and hundreds of researchers. The sooner that this happens, the more likely it is that we will still be alive and in good health when rejuvenation therapies arrive.

ADJUSTING MOUSE LONGEVITY VIA THE HYPOTHALAMUS
http://www.fightaging.org/archives/2013/05/adjusting-mouse-longevity-via-the-hypothalamus.php

NF-κB shows up in a number of places in longevity research, and it's associated with mechanisms known to mediate the relationship between metabolism and the pace of aging. In particular it is associated with the processes of inflammation, which regular readers will know are significant in the aging process. The immune system falls into a malfunctioning state of worsening chronic inflammation in later life, and this contributes to further degenerative aging to some degree.

Selective inhibition of NF-κB has been shown to extend life span in flies, as well as revert some aspects of skin and blood vessel aging in mice. This might have something to do with diminished inflammation, or it may work through other mechanisms, such as alterations to insulin signaling - which is a whole other collection of genes and biochemistry that often appears in aging research.

Nothing happens in isolation in biology. Many of these longevity-associated genes are involved in low-level processes like transcription that influence all of our biochemistry in some way or another, or take part in so many different mechanisms that it's hard to pin down their effects to some simple, clear, single outcome.

In any case, my attention was directed today to a new study in which researchers manipulate NF-κB in the brain to modestly extend life in mice. Interestingly, this also adds to the short list of interventions that can be used to move life span in either direction. Less NF-κB activity means a longer life, and more of it shortens life. In addition, the authors claim that NF-κB inhibition has a positive influence on neurogenesis in the brain, not just on the state of the immune system. The paper isn't open access, unfortunately, so you might start with this article from the science press by way of an overview:

The researchers said they have speeded up and slowed down the rate of ageing in laboratory mice by manipulating chemical messengers that affect the hypothalamus, which is known to play a fundamental role in growth, development, reproduction and metabolism. The [study] focused on a molecule known to be central to the many biochemical reactions involved in the process of inflammation, which is important in many age-related conditions. "As people age, you can detect inflammatory changes in various tissues. Inflammation is also involved in various age-related diseases, such as metabolic syndrome, cardiovascular disease, neurological disease and many types of cancer."

By manipulating the levels of the molecule, known as NF-κB, within the hypothalamus, the researchers were able to slow down the rate of ageing and increase longevity of mice by up to 20 per cent. The team also found that they could slow the rate of cognitive decline by up to 50 per cent, which they could measure by how easy the mice remember how to find their way out of a maze.

A DIFFERENT TAKE ON NF-κB AND THE HYPOTHALAMUS
http://www.fightaging.org/archives/2013/05/a-different-take-on-nf-b-and-the-hypothalamus.php

As reported a couple of days ago, researchers have again demonstrated a link between aging and NF-κB, altering its levels in the hypothalamus it to both modestly lengthen and shorten life in mice. This may be completely a matter of dialing down chronic inflammation in later life, or it may also touch on other common ground in the overlap between metabolism and aging such as insulin signaling.

In the course of their work, the researchers followed some of the connections in this biological jigsaw puzzle to study other proteins and genes involved in generating extended life in mice via inhibition of NF-κB in the hypothalamus. One of these is gonadotropin-releasing hormone (GnRH), and the researchers found that enhancing its levels in the hypothalamus has much the same effect as inhibition of NF-κB. This side of the research gained the attention of the fellow who runs Extreme Longevity:

[The scientists] showed that regular GnRH administration to middle aged mice increased the number of brain cells and reduced signs of aging in the animals. To wit they specially said "GnRH treatment (peripheral) reduced the magnitude of ageing histology in control mice," and "GnRH led to an amelioration of ageing-related cognitive decline."

But of course the holy grail question here is simply can regular peripheral administration of GnRH increase lifespan? I contacted lead author Dongshen Cai MD-PhD and asked if the group had any lifespan data on regular GnRH treatment.

"We don't have lifespan data regarding GnRH treatment," he replied.

Too bad. Imagine if simply a weekly or so injection of GnRH from early middle age onwards could lead to decades more good health and reduction of disease? [Clearly] this is an experiment that should be tried in animals right away. Fortunately Dr. Cai agrees, "it is in our plan," he says.

It has to be said that I generally don't think of this sort of study in these terms. I'm not looking to see whether there's a treatment that can be pulled out, because in most cases a 20% life extension in mice by some form of metabolic manipulation (gene therapy, altering levels of proteins, and so forth) isn't going to be all that relevant to the future of human longevity. For one, it's not rejuvenation, it's only slowing aging. Secondly, mice have very plastic life spans, as is the case for most shorter-lived species. All sorts of things that are either known to do very little to nothing for human life span or are expected to do very little to nothing for human life span can nonetheless extend life by 10%-30% in mice.

So what I see here in the NF-κB / GnRH work is the potential for a therapy that might be applied to modestly reduce inflammation or improve the metabolic profile of older people. Something comparable to rapamycin, in other words, a marginal gain. Perhaps it's a little better than today's best therapies that produce similar effects, and perhaps it's not. I'll wager that it's not going to be as good as regular exercise and calorie restriction. So overall it's not something that I'd give a lot of time and interest to. As a general rule if a research result isn't producing actual rejuvenation then it's not going to have the potential to be a part of greatly extending lives in humans. We have a medical industry presently near-entirely focused on picking mechanisms like this and then using them to produce palliative, marginally effective patches to slap over some of the end stage consequences of aging. The dominant paradigm is to try to alter metabolism late in the game for a small benefit, and without attempting repairing the underlying damage that caused all the harm in the first place. This is a paradigm doomed to poor results, high costs, and ultimate failure.

We have to move on past this methodology of medicine and clinical application of research. The future is SENS and similar projects that aim to repair the causes of aging rather than putting patches on the consequences. It seems fairly clear to me from the performance of the medical establishment to date that only repair can be reliably expected to grant us additional decades of healthy life.

VIDEO: AUBREY DE GREY AT TEDXDANUBIA 2013
http://www.fightaging.org/archives/2013/04/video-aubrey-de-grey-at-tedxdanubia-2013.php

Aubrey de Grey is a tireless advocate for the development of rejuvenation biotechnology, the means to repair and reverse the root causes of aging, and he is the more visible face of the SENS Research Foundation - which is not to diminish the hard work of the many other folk, staff and volunteers, who have helped to make the Foundation the growing success it is today. Without their efforts the path towards human rejuvenation would be far longer. If you've been following along these past years, you'll know that de Grey travels widely to give a great many presentations to the public, and here is one example from a recent TEDx event in Hungary.

DISCUSSION

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!

LATEST HEADLINES FROM FIGHT AGING!

T-REGULATORY CELLS MORE NUMEROUS IN THE AGED IMMUNE SYSTEM
Friday, May 3, 2013
http://www.fightaging.org/archives/2013/05/t-regulatory-cells-more-numerous-in-the-aged-immune-system.php

The immune system malfunctions with age, producing harmful chronic inflammation while failing to adequately respond to pathogens and failing to destroy potentially cancerous and senescent cells. Characteristic changes in immune cell populations accompany these changes, and in past years researchers have shown that adjusting these populations by destroying some of the unwanted immune cells can reverse at least some immune system declines.

Here is an open access paper that focuses on changes in the population of regulatory T cells with aging. These are cells involved in suppressing the immune response, for example so as to prevent the immune system from attacking healthy tissues:

Over the course of the human life, age-related diseases develop because of the failure of genetic traits to remain beneficial, as they were in younger years when they aided in successful reproduction. Longevity is correlated with optimal natural immunity. Immunosenescence (aging of the immune system) is continuously influenced by chronic antigenic stimulation, such as infections. This explains why the probability of a long lifespan is improved in an environment of reduced pathogen burden. In the presence of low pathogen burden one can expect a balanced state of immune responses and alter the chances of having advanced inflammatory responses

Older persons have higher autoimmunity but a lower prevalence of autoimmune diseases. A possible explanation for this is the expansion of many protective regulatory mechanisms highly characteristic in the elderly. Of note is the higher production of peripheral T-regulatory cells.

The frequent development of autoimmunity in the elderly was suggested to take place in part due to the selection of T cells with increased affinity to self-antigens or to latent viruses. These cells were shown to have a greater ability to be pro-inflammatory, thereby amplifying autoimmunity. During aging, thymic T-regulatory cell output decreases in association with the loss of thymic capacity to generate new T cells. However, to balance the above mentioned autoimmunity and prevent the development of autoimmune diseases, there is an age-related increase in [peripheral T-regulatory cells]. It remains unclear whether this is an age-related immune dysfunction or a defense response. Whatever the reason, the expansion of T-regulatory cells requires payment in terms of an increased incidence of cancer and higher susceptibility to infections.

HMGA1 AS A POTENTIAL COMMON MECHANISM IN CANCER
Friday, May 3, 2013
http://www.fightaging.org/archives/2013/05/hmga1-as-a-potential-common-mechanism-in-cancer.php

Any mechanism that appears common to all cancers, or even just a wide range of cancers, is worth examination to see if it might serve as the basis for a therapy. Here is an example of speculative research of this nature:

[Researchers] have identified a gene that, when repressed in tumor cells, puts a halt to cell growth and a range of processes needed for tumors to enlarge and spread to distant sites. The researchers hope that this so-called "master regulator" gene may be the key to developing a new treatment for tumors resistant to current drugs. "This master regulator is normally turned off in adult cells, but it is very active during embryonic development and in all highly aggressive tumors studied to date. Our work shows for the first time that switching this gene off in aggressive cancer cells dramatically changes their appearance and behavior."

Genes in the master regulator's family, known as high mobility group or HMG genes, [are] essential for giving stem cells their special powers, and that's no coincidence. [Many] investigators consider cancer cells to be the evil twin of stem cells, because like stem cells, cancer cells must acquire special properties to enable the tumor to grow and metastasize or spread to different sites.

[Researchers applied techniques to block the HMGA1 gene] to several strains of human breast cancer cells in the laboratory, including the so-called triple negative cells - those that lack hormone receptors or HER2 gene amplification. Triple-negative breast cancer cells tend to behave aggressively and do not respond to many of our most effective breast cancer therapies. The team [found] that the cells with suppressed HMGA1 grow very slowly and fail to migrate or invade new territory like their HMGA1-expressing cousins. The team next implanted tumor cells into mice to see how the cells would behave. The tumors with HMGA1 grew and spread to other areas, such as the lungs, while those with blocked HMGA1 did not grow well in the breast tissue or spread to distant sites.

A SKEPTICAL VIEW OF MITOCHONDRIAL DNA DAMAGE AND AGING
Thursday, May 2, 2013
http://www.fightaging.org/archives/2013/05/a-skeptical-view-of-mitochondrial-dna-damage-and-aging.php

Not all researchers are presently convinced that enough evidence exists to place mitochondrial DNA damage front and center as an important cause of aging. I would agree that the tools and measurements discussed below leave some room for argument over what they mean, but at this time the research community is very close to being able to repair mitochondrial DNA, not just talk about it. Thus I think that the best approach for the next few years is to actually go ahead and repair the damage in laboratory animals, and see what happens - that should settle the debate one way or another.

Protection from reactive oxygen species (ROS) and from mitochondrial oxidative damage is well known to be necessary to longevity. The relevance of mitochondrial DNA (mtDNA) to aging is suggested by the fact that the two most commonly measured forms of mtDNA damage, deletions and the oxidatively induced lesion 8-oxo-dG, increase with age. The rate of increase is species-specific and correlates with maximum lifespan.

It is less clear that failure or inadequacies in the protection from reactive oxygen species (ROS) and from mitochondrial oxidative damage are sufficient to explain senescence. DNA containing 8-oxo-dG is repaired by mitochondria, and the high ratio of mitochondrial to nuclear levels of 8-oxo-dG previously reported are now suspected to be due to methodological difficulties. Furthermore, [mice lacking the MnSOD natural antioxidant] incur higher than wild type levels of oxidative damage, but do not display an aging phenotype. Together, these findings suggest that oxidative damage to mitochondria is lower than previously thought, and that higher levels can be tolerated without physiological consequence.

A great deal of work remains before it will be known whether mitochondrial oxidative damage is a "clock" which controls the rate of aging. The increased level of 8-oxo-dG seen with age in isolated mitochondria needs explanation. It could be that a subset of cells lose the ability to protect or repair mitochondria, resulting in their incurring disproportionate levels of damage. Such an uneven distribution could exceed the reserve capacity of these cells and have serious physiological consequences. Measurements of damage need to focus more on distribution, both within tissues and within cells. In addition, study must be given to the incidence and repair of other DNA lesions, and to the possibility that repair varies from species to species, tissue to tissue, and young to old.

In this context, you might also look at the membrane pacemaker theory regarding oxidative damage to mitochondria and longevity differences between species. It places an emphasis on resistance to damage and the consequences of damage over the actual levels of damage.

PROTECTING CRYONICS PATIENTS
Thursday, May 2, 2013
http://www.fightaging.org/archives/2013/05/protecting-cryonics-patients.php

A short article on the need to remember that cryopreserved people are not gone in the same way that the dead are gone, and their interests are served by the maintenance of some form of continued connection to society:

Anyone who has ever reflected on the fragility of human life and the seemingly inevitable rise and fall of complex societies cannot fail to be concerned about the fate of patients in cryopreservation. Cryonics organizations have learned from the early days and abandoned the practice of accepting patients without complete prepayment - a practice that almost invariably guarantees a tragic loss of life when family members or the cryonics organization can no longer afford to care for them. Alcor has given a lot of thought to the financial and legal requirements of keeping patients in cryopreservation but it is understandable that people question the prospect of cryonics patients making it to the time where a suitable treatment of their disease will be available.

This challenge is further exacerbated by the fact that cryonics patients do not have the legal standing that ordinary human beings (or patients) enjoy. [The] first step to protect cryonics patients is to strengthen your cryonics organization and the legal and logistical structures that have been erected to keep them in cryopreservation. But almost just as important is to give people who have not made cryonics arrangements themselves reasons to protect them. In the case of surviving family members that is usually not a challenge but time may eventually pass the direct descendants of those people by as well.

One important practice that can be strengthened is to give these people a face. Cryopreserved persons are not just a homogenous group of anonymous people (unless they chose to be so!) but are our friends, family members, and patients who would like their story to be told. Fortunately, in the age of the internet this has become a lot easier. Social networking websites like Facebook retain the profiles of deceased and cryopreserved persons unless the family requests removal. Cryonics organizations themselves can offer opportunities for members, friends, and family members to maintain their presence online.

A REVIEW OF ADENYLYL CYCLASE TYPE 5 AND LONGEVITY IN MICE
Wednesday, May 1, 2013
http://www.fightaging.org/archives/2013/05/a-review-of-adenylyl-cyclase-type-5-and-longevity-in-mice.php

Gene therapy to remove adenylyl cyclase type 5 (AC5) was shown to increase mouse longevity a few years back, and researchers have since been working to better understand the mechanisms involved. Like many longevity mutations, this gene is involved in many crucial low-level cellular processes, and researchers are interested in producing drugs to mimic some of the effects of a full gene therapy:

G-protein coupled receptor/adenylyl cyclase (AC)/cAMP signaling is crucial for all cellular responses to physiological and pathophysiological stimuli. There are 9 isoforms of membrane-bound AC, with type 5 being one of the two major isoforms in the heart. Since the role of AC in the heart in regulating cAMP and acute changes in inotropic and chronotropic state are well known, this review will address our current understanding of the distinct regulatory role of the AC5 isoform in response to chronic stress.

Transgenic overexpression of AC5 in cardiomyocytes of the heart (AC5-Tg) improves baseline cardiac function, but impairs the ability of the heart to withstand stress. For example, chronic catecholamine stimulation induces cardiomyopathy, which is more severe in AC5-Tg mice, mediated through the AC5/SIRT1/FoxO3a pathway.

Conversely, disrupting AC5, i.e., AC5 knockout (KO) protects the heart from chronic catecholamine cardiomyopathy as well as the cardiomyopathies resulting from chronic pressure overload or aging. Moreover, AC5-KO results in a 30% increase in healthy lifespan, resembling the most widely studied model of longevity, i.e., calorie restriction. These two models of longevity share similar gene regulation in the heart, muscle, liver and brain that are both protected against diabetes and obesity. A pharmacological inhibitor of AC5 also provides protection against cardiac stress, diabetes and obesity. Thus, AC5 inhibition has novel, potential therapeutic applicability to several diseases, not only in the heart, but also in aging, diabetes and obesity.

ON EXTENDING MOUSE LONGEVITY
Wednesday, May 1, 2013
http://www.fightaging.org/archives/2013/05/on-extending-mouse-longevity.php

Here is a popular science article on the many ways to extend life in laboratory mice, and the relevance of that research to human health and longevity:

Biologists have successfully extended the life spans of some mice by as much as 70%, leading many to believe that ongoing experimentation on our mammalian cousins will eventually lead to life-extending therapies in humans. But how reliable are these studies? And do they really apply to humans?

Many scientists will tell you that "mice are not people" which is true of course. It is also true that we have cured cancer many times in mice with therapies that do not work in humans, so we must be careful about saying that interventions that work in mice will be directly translatable to humans. But at the same time, functional life extension therapies in mice do hold prospects for human longevity. Extending the lifespan of a mouse that normally lives only three years to five by applying a treatment late in its life could capture the imagination of many. "In this day of the Internet, everyone would be able to view video clips of mice the equivalent of 120 human years in age - healthy, active and being social with their fellows.This would do something, I think, to the human psyche that would enable much more rapid development of interventions for humans, hence the reason for the Methuselah Mouse Prize which is designed to create this result."

Near everything demonstrated to date to extend life in mice has been a form of gene therapy or metabolic manipulation. It changes the pace of aging, but isn't rejuvenation. To create longer lives [than the present best efforts in mice], you need to work on rejuvenation attained by repairing the cell- and tissue-level damage that causes aging, not just finding ways to gently slow aging by slowing down the pace at which that damage accumulates. The future of mouse longevity is SENS (Strategies for Engineered Negligible Senescence), which is a radically different approach to any of the work currently extending life in mice.

GROWTH HORMONE AND IGF-1 IN AGING
Tuesday, April 30, 2013
http://www.fightaging.org/archives/2013/04/growth-hormone-and-igf-1-in-aging.php

The longest lived mice are those that have been altered to remove growth hormone or growth hormone receptors. In humans there is an analogous population of natural mutants, their condition known as Laron syndrome, who, like the mice, seem resistant to cancer and type 2 diabetes. They do not appear to live significantly longer than the rest of us, but that doesn't rule out modest extension of life - the data is lacking to say either way at this time.

Secretion of growth hormone (GH), and consequently that of insulin-like growth factor 1 (IGF-1), declines over time until only low levels can be detected in individuals aged ≥60 years. This phenomenon, which is known as the 'somatopause', has led to recombinant human GH being widely promoted and abused as an antiageing drug, despite lack of evidence of efficacy.

By contrast, several mutations that decrease the tone of the GH/IGF-1 axis are associated with extended longevity in mice. In humans, corresponding or similar mutations have been identified, but whether these mutations alter longevity has yet to be established. The powerful effect of reduced GH activity on lifespan extension in mice has generated the hypothesis that pharmaceutically inhibiting, rather than increasing, GH action might delay ageing. Moreover, mice as well as humans with reduced activity of the GH/IGF-1 axis are protected from cancer and diabetes mellitus, two major ageing-related morbidities.

Here, we review data on mouse strains with alterations in the GH/IGF-1 axis and their effects on lifespan. The outcome of corresponding or similar mutations in humans is described, as well as the potential mechanisms underlying increased longevity and the therapeutic benefits and risks of medical disruption of the GH/IGF-1 axis in humans.

IGF1R LEVELS IN THE BRAIN CORRELATE WITH SPECIES LIFE SPAN
Tuesday, April 30, 2013
http://www.fightaging.org/archives/2013/04/igf1r-levels-in-the-brain-correlate-with-species-life-span.php

The mechanisms of insulin signaling are one of the better studied metabolic determinants of longevity, though as for all such things it is a very complex system, not yet fully understood, and there a lot of debate and uncertainty in the resulting science. New data continues to roll in, however, here looking at variations of levels of the receptor for insulin-like growth factor 1 (IGF1R) in various different rodent species:

The insulin/insulin-like growth factor signaling (IIS) pathway is a major conserved regulator of aging. Nematode, fruit fly and mouse mutants with reduced IIS signaling exhibit extended lifespan. These mutants are often dwarfs leading to the idea that small body mass correlates with longevity within species. However, when different species are compared, larger animals are typically longer-lived. Hence, the role of IIS in the evolution of life history traits remains unresolved.

Here we used comparative approach to test whether IGF1R signaling changes in response to selection on lifespan or body mass and whether specific tissues are involved. The IGF1R levels in the heart, lungs, kidneys, and brains of sixteen rodent species with highly diverse lifespans and body masses were measured. [We] report that IGF1R levels display strong negative correlation with maximum lifespan only in brain tissue and no significant correlations with body mass for any organ. The brain-IGF1R and lifespan correlation holds when phylogenetic non-independence of data-points is taken into account. These results suggest that modulation of IGF1R signaling in nervous tissue, but not in the peripheral tissues, is an important factor in the evolution of longevity in mammals.

CALORIE RESTRICTION AND CALORIE RESTRICTION MIMETICS
Monday, April 29, 2013
http://www.fightaging.org/archives/2013/04/calorie-restriction-and-calorie-restriction-mimetics.php

Today I noticed this very readable open access paper that reviews calorie restriction research and ongoing efforts to produce drugs that can mimic some of the beneficial effects of calorie restriction on health and longevity. It can be downloaded in PDF format from the journal website:

Everyone desires a long and healthy life, and many researchers have investigated methods to overcome and to retard the aging process. The most well defined intervention of retarding aging is caloric restriction. Caloric restriction, also known as dietary restriction, is the reduction of food intake without malnutrition. Experimentally, caloric restriction means a reduction in calorie intake by 10-30% when compared to an ad libitum diet. Lifespan extension in response to caloric restriction is thought to be caused by a decreased rate of increase in age-specific mortality. It is widely believed that caloric restriction delays the onset of age-related decline in many species, as well as the incidence of age-related diseases such as cancer, diabetes, atherosclerosis, cardiovascular disease, and neurodegenerative diseases. Caloric restriction affects the behavior, animal physiology, and metabolic activities such as modulation of hyperglycemia and hyperinsulinemia, as well as increases insulin sensitivity.

Reductions of protein source in the diet without any changes in calorie level have been shown to have similar effects as caloric restriction. Furthermore, restriction of individual amino acids has been shown to induce lifespan extension in some species, especially methionine restriction. Moreover, the restriction of tryptophan is believed to have a positive effect on longevity. Thus, several researchers have stated that this phenomenon occurs as a result of dietary restriction, not caloric restriction. However, other studies have indicated that protein and/or methionine restriction is not involved in the caloric restriction-induced lifespan extension.

THE BURRILL AND BUCK AGING MEETING, MAY 20TH 2013
Monday, April 29, 2013
http://www.fightaging.org/archives/2013/04/the-burrill-and-buck-aging-meeting-may-20th-2013.php

Here is a pointer to the website for a forthcoming conference to be held at the Buck Institute for Research on Aging in California. It is one of the many signs indicating that large, conservative financial entities like Burrill & Company are becoming more interested in longevity science:

Around the world, lifespans are increasing and populations are aging. This demographic shift presents opportunities for drug and device developers, as well as significant challenges for healthcare systems and payers. Diseases of aging are among the costliest and most intractable diseases we face. These include heart disease, stroke, cancer, neurological disease, pulmonary disease, and diabetes. While policy makers across the globe have taken steps to look for ways to restrict spending, others are turning to innovative approaches that can keep people healthy and allow them to live independently longer. Please join us at this inaugural Burrill & Buck Aging Meeting as we explore the consequences of aging, how therapeutics in development seek to address chronic diseases related to aging, and how innovative approaches from regenerative medicine to digital health stand to change our notion of what it means to grow old.

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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CONTENT

- Three and a Half Ways to Cure Cancer
- More Data on Granulocyte Transplant Cancer Therapies
- US Medicine: Death by Command and Control Regulation
- Recent Calorie Restriction Research
- Discussion
- Latest Headlines from Fight Aging!
    - Joining the Dots in Genetic Parkinson's Disease
    - Considering the Electron Transport Chain in Aging
    - Measures of Mitochondrial DNA Damage Lower in Long-Lived Mice
    - Small Amounts of Bioprinted Liver Tissue from Organovo
    - Regenerating Articular Cartilage in Rabbits
    - Targeting Cancer With Radioactive Bacteria
    - Some Preliminary Findings From CALERIE
    - 2013 CR Society Conference, June 5th in California
    - Size and Aging From a Programmed Perspective
    - Study Suggests Dementia Risk Declining

THREE AND A HALF WAYS TO CURE CANCER
http://www.fightaging.org/archives/2013/04/three-and-a-half-ways-to-cure-cancer.php

Today's topic is the cure for cancer, something a grail in medicine. It will be challenging to produce, but I think that the difficulty is presently overestimated by much of the public and those in the mainstream of the research community. The reasons for this are understandable: the past half century of cancer research is a story of continually discovered ever greater complexity in cancer biology. It is the sheer exuberant variation in cancer - between types, between tissues, between individuals, and even between tumors in an individual - that makes it such a daunting foe. Every cancer is an evolving mess of broken cells with its own character and biochemical quirks.

We stand now in the early stages of a revolution in biotechnology, however, and the rapidly expanding capabilities that brings to the research community are beginning to reveal that, for all their variety, cancers do have at least some shared characteristics and shared vulnerabilities. It is the commonalities in cancer, things that are emerging now and would have been exceedingly expensive to discover and exploit even a mere twenty years past, that will act as a foundation for the coming generation of effective cancer therapies. In that spirit, I offer you three and a half ways to cure cancer, outlined very briefly below:

1) WILT, whole-body interdiction of lengthening of telomeres

WILT is my least favorite cure for cancer, but it is nonetheless hard to argue that it isn't in fact the ultimate cure for cancer. Cancers absolutely depend upon ways to lengthen telomeres, the protective caps at the end of chromosomes that shorten with each cell division, putting a limit on the life span of ordinary cells. A cell with little left of its telomeres stops dividing, destroys itself, or becomes senescent - and thus not much use as a cancer cell. Telomeres are lengthened by the activities of the telomerase enzyme and the mechanisms imaginatively known as alternative lengthening of telomeres (ALT), both of which are abused by all cancers in order to create unfettered growth.

Disable telomerase and the genes for ALT in a human, and the result will most likely be a human who cannot suffer cancer. There is a reason this is my least favorite approach however, and that is that your stem cell populations require the ability to lengthen telomeres in order to continue to maintain your tissues over the long term. A person who underwent a hypothetical WILT treatment would need stem cell transplants or a similar way to refresh all of the different stem cell populations of the body - and there are many - every decade at least. WILT means exchanging the threat of cancer for an arguably greater dependency on medical technology.

Research into WILT is currently funded to a modest degree by the SENS Research Foundation under the OncoSENS program, with a focus on establishing a a sufficient understanding of ALT to determine the best and most comprehensive way to disrupt its mechanisms.

2) LIFT/GIFT, leukocyte/granulocyte transfusions

Somewhere out there, someone possesses immune cells (the white blood cells called leukocytes or granulocytes) that can kill your cancer. You might consider this approach to immune therapy as being analogous to first generation stem cell therapies that are presently available in many parts of the world: take someone else's immune cells, grow them in culture, and then transplant large numbers of them into your body, where they work to destroy cancer. This methodology has been shown to produce exceedingly impressive results in mice, such as entire lineages of cancer-resistance mice, but it isn't known why exactly it works so well - which makes it hard to proceed to clinical applications in the US, where a full scientific understanding of the mechanisms involved is generally required.

A couple of startups are presently working in this area, such as ImmunePath (probably) and Munogenics, with little funding and slow progress, so far as I'm aware. There is also a small ongoing clinical trial in Florida that looks like it'll wrap up later this year.

This is exactly the sort of application of cell therapies that should do well in the medical tourism arena, and indeed is appearing as an option in some overseas clinics. It is easy enough to implement that any group that can presently carry out stem cell transplants should also be able to manage immune cell transplants. More publicity, signs of progress in obtaining human results, and greater funding for trials would go a long way towards speeding the spread of this therapy and this determining whether the results in mice continue to translate well into humans.

3) Targeted cell killing technology, plus the search for commonalities in cancer

Modular targeted cell killing technology platforms with a slot for a sensing system are well in hand in the lab, and are a big part of why the next generation of cancer therapies will be far more effective and far less traumatic than chemotherapy. A great variety of such systems are presently under development: nanoparticles such as gold rods that can be heated by radiation; nanoparticles such as dendrimers that carry motes of chemotherapy drugs; nanoparticles that carry an RNA interference payload; engineered viruses; engineered bacteria; trained immune cells; and so forth.

The commonality here is that all of these systems are designed to destroy specific cells with minimal damage to surrounding cells - all that is needed are mechanisms to ensure that these cell-killers only target cancer cells. This largely means discovering suitable markers on a cell surface: specific proteins that differentiate cancer cells by the degree to which they are present, and which are sufficiently general to appear in a sizable population of patients or many types of cancer.

The big uncertainty here is whether or not researchers will find targets shared by many cancers that are sufficiently discriminating to allow enough preferential targeting of cancer cells. It's possible to layer multiple poorly discriminating targets to get a highly discriminating system, however, and there are promising signs of late on this front. You might look at trials involving therapies targeting CD47, for example, which appears on most cancers per the latest research.

If there are enough markers like CD47 out there, then it should be possible to build a comparatively small suite of general cancer therapies that will kill 80% of cancers at any stage, metastatic or not, with minimal side effects. At this point in the development of medicine even twenty different loads for the same basic system to effectively tackle 80% of all cancers looks like a very good thing - and very plausible too, if the process of discovering cancer commonalities keeps going the way it is. All that is needed is one kill mechanism and a delivery platform modular enough to accept the different sensor mechanisms while still being manufacturable at low cost, such as through the use of dendrimers or viruses.

3.5) The mechanisms used by naked or blind mole rats

Naked mole rats don't get cancer, and it appears the same is true of blind mole rats, but for different reasons. Present understanding of the evolved mechanisms by which these animals manage to stay cancer-free for the several decades of their life spans, even while living in an environment that produces a tremendous amount of cellular damage, is advanced enough to have a sensible discussion on how to recreate it in humans.

This really only counts as half a potential cancer cure, however. It does seem to grant cancer immunity, or as near to it as counts, but it is a big question mark as to how hard it will be to safely have our cells start to behave in the same way as those of a mole-rat - even only temporarily. In the case of naked mole rats, the mechanism in question involves the genes p16 and p27, which suggests that it's something that could be accomplished via gene therapy, but much remains to be done in order to find out how much work there is here.

So this is certainly as intrusive a proposal as WILT, i.e. we're talking about altering human metabolism and genetic programming, but far less is known regarding how best to move forward with this strategy. Still, it is probably the case that more researchers are working on it than are in the case of WILT - the cancer community is large and well funded, and the study of mole rats is well recognized these days.

MORE DATA ON GRANULOCYTE TRANSPLANT CANCER THERAPIES
http://www.fightaging.org/archives/2013/04/more-data-on-granulocyte-transplant-cancer-therapies.php

I mentioned GIFT/LIFT, the immune cell transplant approach to cancer therapy in a short list of research that might lead to cancer cures. This line of research derives from the fortuitous discovery of a cancer-immune lineage of laboratory mice, followed by the finding that this immunity is transferable via transplant of granulocyte or other forms of leukocyte immune cells.

This discovery raises the possibility that effective cancer treatments can be established by finding donors with appropriately equipped immune cells and then transplanting those cells into patients, even in advance of a complete understanding of how this all works. That complete understanding might enable an effective cure for cancer therapy based on altering a patient's own immune cells, or a much more reliable way to determine useful donors, but it'll take much longer to get to that point, possibly decades. Thus there is considerable incentive to take the shortcut if there's one to be had, in the same way as first generation stem cell transplant therapies continue to be established usefully far in advance of the complete understanding of how they work.

You can look back in the archives for posts that cover this topic, though I should mention that the younger organizations mentioned as being involved in work on this are mostly defunct or going nowhere, it seems. Finding funding is an issue, though the Florida clinical trial partially funded by the Life Extension Foundation is apparently still ongoing. Good for them.

A reader pointed me to recently published research on the cancer-immune mice that reinforces the previous work by Zheng Cui and others, demonstrating once more a transfer of cancer immunity between mice, but the authors note that the approach isn't as general as hoped - meaning that there are other factors at work that will make it much more of a hard slog to either (a) find a donor with immune cells that will work on your cancer, or (b) figure out how what's going on under the hood here. Why does it work for some cancers and not for others? So it's the same old story: biology is always considerable more complicated than we'd like it to be. Granulocyte transplants are very effective when they do work, however, not just causing remission of cancer, but also granting immunity. This means that research will continue, though as usual never as rapidly nor with as much funding as we'd like.

US MEDICINE: DEATH BY COMMAND AND CONTROL REGULATION
http://www.fightaging.org/archives/2013/04/us-medicine-death-by-command-and-control-regulation.php

When I discuss the corrosive effects of regulation on progress in medicine, such as the enormous and entirely unnecessary costs and barriers put in place by the US Food and Drug Administration (FDA), I usually focus on the research and development side of the coin: the process of creating new therapies. That is greatly impacted, not least because as the system presently stands it is actually impossible to gain approval for any treatment for degenerative aging - no medicine is permitted into the clinical trial system if its purpose is to treat old people to reverse some of their symptoms. The FDA doesn't recognize aging as a named medical condition that can be be treated, and there is no path short of complete revolution in the regulatory system in the US to make this any different.

The costs and prohibited actions due to the FDA propagate back down the fundraising chain. You can't raise venture capital if there's prospect for selling the resulting therapy. It's harder to raise funds for basic research when there's no connection to later commercial activity. There are thus far fewer research groups working on potentially important ways to address aging than there might be, and less press and public understand of what might happen if the FDA were not standing in the way, a hideous roadblock, a ball and chain that stops the research community from improving the human condition. The invisible costs, the therapies that might have existed but do not because of regulation, are always the hardest to make people understand.

But that's just one side of the coin. The other side is the provision of medical services: once therapies exist, how are they delivered, priced, and bought and sold? Here the institutions of regulation have just as horrific and corrosive an effect, raising costs and reducing availability to no good end - a system has come into being that benefits no-one, as every individual would be better off under a free market for medical services, and yet this system seems destined to become even worse in the future. Perverse short term incentives steer us all in the wrong direction. You might click through to this Fight Aging! post for pointers to an article giving a very clear example of all that's going wrong with medicine today.

If provision of medicine stultifies, then so does much of the impetus for research. In the field of aging and human longevity that matters greatly - we're on a timer, all aging to death one day at a time, and cannot afford to suffer through decades of collapse and slow progress in research, development, and provision of medical services. To my eyes the present system is doomed; the only way through is for it to fail utterly in one way or another. The most plausible collapse is the one the US regulatory monolith continues to exist, a drain on the declining US, but where near everyone travels to Asia-Pacific countries or other less regulated destinations for any meaningful medical services - in other words much like the UK, or other European countries. The only hope for the future is competition through medical tourism, which requires that other advanced regions of the world maintain far less onerous regulations for medicine.

RECENT CALORIE RESTRICTION RESEARCH
http://www.fightaging.org/archives/2013/04/recent-calorie-restriction-research.php

Human calorie restriction studies continue onward at the normal sedate pace of all human research, as noted in a recent post on the CALERIE program. It remains the case that the vast majority of work on calorie restriction and its beneficial effects involves mice, flies, worms, and other laboratory animals. Most such species exhibit increased longevity and improved measures of long term health when on a calorie restricted diet, provided that they still receive suitable levels of nutrition. That this is so universal is one of the reasons to suggest calorie restriction with optimal nutrition as a lifestyle choice in humans.

Other reasons include the results from human studies to date; if there was a pill you could take that provided half the benefits that calorie restriction has been shown to produce in humans, then everyone would be falling over themselves to take it. It's somewhat harder to convince people to eat less in this day and age, however, no matter how beneficial the results might be. The paper quoted below is illustrative of results from human studies, in that the measures taken tend to line up with what is seen in short-lived animals like mice and rats:

"Here we report that long-term CR in humans inhibits the IGF-1/insulin pathway in skeletal muscle, a key metabolic tissue. We also demonstrate that CR-induced dramatic changes of the skeletal muscle transcriptional profile that resemble those of younger individuals. Finally, in both rats and humans CR evoked similar responses in the transcriptional profiles of skeletal muscle. This common signature consisted of three key pathways typically associated with longevity: IGF-1/insulin signaling, mitochondrial biogenesis and inflammation."

The fact that more easily gathered measures of metabolism like those noted above are similar for rat and human calorie restriction makes CR look like a good option - where these measures match up, the hope is that the long term rewards do so as well. Studies in rats can achieve what studies in humans cannot, which is to follow large numbers of rats for their entire lives and catalog the impressive long term health benefits, as well as the characteristic increase in life expectancy, that accompanies CR in rodent species.

DISCUSSION

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!

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LATEST HEADLINES FROM FIGHT AGING!

JOINING THE DOTS IN GENETIC PARKINSON'S DISEASE
Friday, April 26, 2013
http://www.fightaging.org/archives/2013/04/joining-the-dots-in-genetic-parkinsons-disease.php
Some people are more predisposed to suffer Parkinson's disease than others, a fraction of those due to mutations in genes involved in mitochondrial quality control. The state of mitochondrial function shows up as an important component of many different conditions and indeed in aging itself. In Parkinson's disease it is thought that mitochondrial dysfunction contributes to the conditions in which the population of dopamine-producing neurons in the brain die off, producing the characteristic symptoms of the disease. It may be that more of Parkinson's disease is genetic than was previously thought, and the odds of that being the case increase as the chain of molecular machinery involved in mitochondrial quality control is followed and new components identified. This sort of work also helps clarify the mechanisms associated with mitochondrial dysfunction in aging: "Mitofusin 2 (Mfn2) is known for its role in fusing mitochondria together, so they might exchange mitochondrial DNA in a primitive form of sexual reproduction. "Mitofusins look like little Velcro loops. They help fuse together the outer membranes of mitochondria. Mitofusins 1 and 2 do pretty much the same thing in terms of mitochondrial fusion. What we have done is describe an entirely new function for Mfn2." Mitochondria work to import a molecule called PINK. Then they work to destroy it. When mitochondria get sick, they can't destroy PINK and its levels begin to rise. Once PINK levels get high enough, they make a chemical change to Mfn2, which sits on the surface of mitochondria. This chemical change is called phosphorylation. Phosphorylated Mfn2 on the surface of the mitochondria can then bind with a molecule called Parkin that floats around in the surrounding cell. Once Parkin binds to Mfn2 on sick mitochondria, Parkin labels the mitochondria for destruction. The labels then attract special compartments in the cell that "eat" and destroy the sick mitochondria. As long as all links in the quality-control system work properly, the cells' damaged power plants are removed, clearing the way for healthy ones. "But if you have a mutation in PINK, you get Parkinson's disease. And if you have a mutation in Parkin, you get Parkinson's disease. About 10 percent of Parkinson's disease is attributed to these or other mutations that have been identified." The discovery of Mfn2's relationship to PINK and Parkin opens the doors to a new genetic form of Parkinson's disease."

CONSIDERING THE ELECTRON TRANSPORT CHAIN IN AGING
Friday, April 26, 2013
http://www.fightaging.org/archives/2013/04/considering-the-electron-transport-chain-in-aging.php
The electron transport chain is the core piece of biological machinery inside mitochondria, the cell's power plants. It occupies a central place in the various free radical theories of aging as well. A good number of longevity-related mutations in laboratory animals appear to alter electron transport chain function as their primary mode of operation, and a good case is made for a large portion of degenerative aging to rest atop damage to the mitochondrial genes that encode proteins essential to proper electron transport chain function. "Most biogerontologists agree that oxygen (and nitrogen) free radicals play a major role in the process of aging. The evidence strongly suggests that the electron transport chain, located in the inner mitochondrial membrane, is the major source of reactive oxygen species in animal cells. It has been reported that there exists an inverse correlation between the rate of superoxide/hydrogen peroxide production by mitochondria and the maximum longevity of mammalian species. However, no correlation or most frequently an inverse correlation exists between the amount of antioxidant enzymes and maximum longevity. Although overexpression of the antioxidant enzymes SOD1 and CAT (as well as SOD1 alone) have been successful at extending maximum lifespan in Drosophila, this has not been the case in mice. Several labs have overexpressed SOD1 and failed to see a positive effect on longevity. [Although overexpression of CAT has been shown to extend life in mice by some groups]. An explanation for this failure is that there is some level of superoxide damage that is not preventable by SOD, such as that initiated by the hydroperoxyl radical inside the lipid bilayer, and that accumulation of this damage is responsible for aging. I therefore suggest an alternative approach to testing the free radical theory of aging in mammals. Instead of trying to increase the amount of antioxidant enzymes, I suggest using molecular biology/transgenics to decrease the rate of superoxide production, which in the context of the free radical theory of aging would be expected to increase longevity." Personally I think the better approach to testing theory here is to implement mitochondrial repair or replacement, both of which are very feasible, and see what effect that has on older animals. It will both extend life and produce some degree of rejuvenation if the mitochondrial free radical theory of aging is correct.

MEASURES OF MITOCHONDRIAL DNA DAMAGE LOWER IN LONG-LIVED MICE
Thursday, April 25, 2013
http://www.fightaging.org/archives/2013/04/measures-of-mitochondrial-dna-damage-lower-in-long-lived-mice.php
Damage to mitochondrial DNA accumulates as a side-effect of the operation of mitochondria in your cells, and per the mitochondrial free radical theory of aging proceeds to cause some fraction of degenerative aging though a long chain of ever worsening consequences. Below you'll find recently published research that shows long-lived mice to have less mitochondrial DNA damage, which is what you'd expect to see under this model. This reinforces the need for ways to repair or replace mitochondrial DNA throughout the body in order to remove this contribution to degenerative aging. A wide range of possible approaches exist, but currently little funding is devoted towards realizing them and there is no path to getting treatments to reverse aging through the regulatory process - the standard lament when it comes to rejuvenation biotechnology. "The single gene mutation of Ames dwarf mice increases their maximum longevity by around 40% but the mechanism(s) responsible for this effect remain to be identified. This animal model thus offers a unique possibility of testing the mitochondrial theory of aging. In this investigation, oxidative damage to mitochondrial DNA (mtDNA) was measured for the first time in dwarf and wild type mice of both sexes. In the brain, 8-oxo,7,8-dihydro-2'-deoxyguanosine (8-oxodG) in mtDNA [a measure of oxidative stress] was significantly lower in dwarfs than in their controls both in males (by 32%) and in females (by 36%). The heart of male dwarfs also showed significantly lower mtDNA 8-oxodG levels (30% decrease) than the heart of male wild type mice, whereas no differences were found in the heart of females. The results, taken together, indicate that the single gene mutation of Ames dwarfs lowers oxidative damage to mtDNA especially in the brain, an organ of utmost relevance for aging. Together with the previous evidence for relatively lower level of oxidative damage to mtDNA in both long-lived and caloric restricted animals, these findings suggest that lowering of oxidative damage to mtDNA is a common mechanism of life extension in these three different mammalian models."

SMALL AMOUNTS OF BIOPRINTED LIVER TISSUE FROM ORGANOVO
Thursday, April 25, 2013
http://www.fightaging.org/archives/2013/04/small-amounts-of-bioprinted-liver-tissue-from-organovo.php
Organovo has demonstrated the 3-D printing of small amounts of functional liver tissue, suitable for use in research. The limiting factor for printing larger masses is at this time largely the challenge of creating a suitable blood vessel network - something that researchers are still working on. "For the first time, human liver tissues have been generated that are truly three-dimensional, being up to 500 microns in thickness in the smallest dimension, and consisting of multiple cell types arranged in defined spatial patterns that reproduce key elements of native tissue architecture. The tissues, fabricated using Organovo's [bioprinting] platform, are highly reproducible and exhibit superior performance compared to standard 2D controls. "We have achieved excellent function in a fully cellular 3D human liver tissue. We've combined three key features that set our 3D tissues apart from 2D cell-culture models. First, the tissues are not a monolayer of cells; our tissues are approximately 20 cell layers thick. Second, the multi-cellular tissues closely reproduce the distinct cellular patterns found in native tissue. Finally, our tissues are highly cellular, comprised of cells and the proteins those cells produce, without dependence on biomaterials or scaffold for three-dimensionality. They actually look and feel like living tissues. Not only can these tissues be a first step towards larger 3D liver, laboratory tests with these samples have the potential to be game changing for medical research. We believe these models will prove superior in their ability to provide predictive data for drug discovery and development, better than animal models or current cell models.""

REGENERATING ARTICULAR CARTILAGE IN RABBITS
Wednesday, April 24, 2013
http://www.fightaging.org/archives/2013/04/regenerating-articular-cartilage-in-rabbits.php
Cartilage is one of the more challenging tissues to regenerate - it's comparatively easy to grow something that's more or less like cartilage, but it's proven hard to reproduce the necessary small-scale structure and mechanical properties of the real thing. So work continues in laboratory animals: "[Researchers] have suggested that articular cartilage defects can be repaired by a novel thermo-sensitive injectable hydrogel engineered with gene modified bone marrow mesenchymal stromal cells (BMSCs). The chitosan and polyvinyl alcohol composite hydrogel containing hTGFβ-1 gene modified BMSCs was injected into rabbits with defective articular cartilage. Sixteen weeks later the defected cartilage regenerated. No reliable approach is currently available for complete restoration of damaged articular cartilage. Tissue engineering combined with gene therapy technology has the potential to manage the repair of defective articular cartilage. CS/PVA gel can be applied to the repair of articular cartilage defects as an injectable material in tissue engineering, and the regenerated cartilage can secrete cartilage matrix and perform the functions of hyaline cartilage. Use of this gel for cartilage repair has advantages such as the minor surgical procedure required, tight bonding with the damaged tissue and lack of rejection."

TARGETING CANCER WITH RADIOACTIVE BACTERIA
Wednesday, April 24, 2013
http://www.fightaging.org/archives/2013/04/targeting-cancer-with-radioactive-bacteria.php
Here is one of many examples of different forms of targeted cancer therapies under development. Most use nanoparticles, immune cells, or viruses as the agent that selectively transports a cell-killing mechanism to the cancer cells, but bacteria are also a viable possibility: "[Researchers] have developed a therapy for pancreatic cancer that uses Listeria bacteria to selectively infect tumor cells and deliver radioisotopes into them. The experimental treatment dramatically decreased the number of metastases (cancers that have spread to other parts of the body) in a mouse model of highly aggressive pancreatic cancer without harming healthy tissue. Several years ago, scientists observed that an attenuated (weakened) form of Listeria monocytogenes can infect cancer cells, but not normal cells. [The] tumor microenvironment suppresses the body's immune response, allowing Listeria to survive inside the tumors. By contrast, the weakened bacteria are rapidly eliminated in normal tissues. Scientists later showed that Listeria could be harnessed to carry an anti-cancer drug to tumor cells in laboratory cultures, but this concept was never tested in an animal model. These findings prompted [researchers to couple] a radioactive isotope called rhenium to the weakened Listeria bacteria. "We chose rhenium because it emits beta particles, which are very effective in treating cancer. Also, rhenium has a half-life of 17 hours, so it is cleared from the body relatively quickly, minimizing damage to healthy tissue." Mice with metastatic pancreatic cancer were given intra-abdominal injections of the radioactive Listeria once a day for seven days, followed by a seven-day "rest" period and four additional daily injections of the radioactive bacteria. After 21 days, the scientists counted the number of metastases in the mice. The treatment had reduced the metastases by 90 percent compared with untreated controls. In addition, the radioactive Listeria had concentrated in metastases and to a lesser extent in primary tumors but not in healthy tissues, and the treated mice did not appear to suffer any ill effects."

SOME PRELIMINARY FINDINGS FROM CALERIE
Tuesday, April 23, 2013
http://www.fightaging.org/archives/2013/04/some-preliminary-findings-from-calerie.php
CALERIE is an ongoing series of studies on calorie restriction in humans and its effects on measures of health and metabolism. In this blog post you'll find some notes on results from the latest phase, yet to be published formally, but presented at conferences: "Three speakers described how a select group of 220 healthy volunteers [chose] to shun a quarter of their dietary calories in the hope of improving their long-term health and, potentially, extending lifespan. These participants of the CALERIE phase 2 trial were randomized to 25 percent CR or ad libitum eating. The large NIH-funded, mulitcenter, parallel group, randomized controlled trial was designed to evaluate how a calorie restricted diet affected biomarkers of aging and age-related disease over the long-term. The primary aim of the trial [was] to evaluate whether 25 percent CR resulted in a sustained metabolic adaptation. One of the underlying theories of how CR worked is that attenuates the biological aging process by reducing resting metabolic rate (RMR) leading to reduced cumulative oxidative damage from aerobic respiration. [However] the calorie restriction did not cause a change in body temperature that would be indicative of reduced resting metabolic rate that would show adaptation. These data (which are not published yet) are currently being evaluated for proper interpretation. [The] findings are interesting because they are inconsistent with previous studies in animals and a recently in humans showing a metabolic adaptation through RMR and core body temperature in response to CR. "Basically, these are the primary mechanisms in humans - reduction of metabolic rate and core body temperature - we did not find an adaptation in the resting component, but we did find an adaptation in the non-resting component. If there was a reduction, that is supposed to lend support to the oxidative theory. What exactly this means is still being worked out." The long-term CR had a significant effect on a variety of [cardiovascular disease risk factor] measurements including a reduced metabolic syndrome score, reduced systolic blood pressure, reduced LDL, reduced triglycerides, and increased HDL that were maintained over the study. There were no significant differences on glucose measures or inflammatory markers IL-6 and TNF-a. These results are consistent with previous studies related to reductions in body weight."

2013 CR SOCIETY CONFERENCE, JUNE 5TH IN CALIFORNIA
Tuesday, April 23, 2013
http://www.fightaging.org/archives/2013/04/2013-cr-society-conference-june-5th-in-california.php
The CR Society is a long-standing organization that promotes and provides information about the practice of calorie restriction with optimal nutrition, something shown to extend life and greatly improve measures of health in many species. There are some thousands of members, and the Society mailing lists are quite busy. The Society has done well over the years in encouraging research into the long-term health and potential longevity benefits of calorie restriction in humans, and is an excellent example of what can be achieved by building strong ties between health advocates and the scientific community. The next CR Society conference is coming up in June, so there's still time to register: "The next CR Society conference will be held at the Buck Institute for Research on Aging in Novato California June 5 - 8, 2013. This conference will mark the 10-year anniversary of the founding of the CR Society as a non profit organization. The topics will include CR and Cancer, CR Primate Studies, Biological Clocks and Physical Activity, Stem cell/senescence/rejuvenation. This will be a very special opportunity to interact with CR comrades, and researchers at the Buck Institute, see and tour the Buck Institute - not to be missed!"

SIZE AND AGING FROM A PROGRAMMED PERSPECTIVE
Monday, April 22, 2013
http://www.fightaging.org/archives/2013/04/size-and-aging-from-a-programmed-perspective.php
Within a given species, larger individuals tend to age faster and die younger. Between species, larger species tend to live longer - though there are many exceptions to this rule. Here is an open access article on this phenomenon from a programmed aging perspective, i.e. the author is building on his hyperfunction theory to say that aging is a genetic program of growth that runs awry to cause damage in old age, past the point at which evolutionary selection guides its operation. This is as opposed to aging as straightforward "wear and tear" type damage that accumulates as a result of the normal operation of metabolism over time, becoming meaningfully harmful only past the age at which evolutionary selection favors further adaptations to reduce, avoid, or repair this damage. "It has been known for millennia that large animals live longer, inspiring numerous theories of aging. For example, elephants and humans live longer than mice, which in turn live longer than worms and flies. The correlation is not perfect, with many explainable exceptions, but it is still obvious. In contrast, within each species (e.g., mice and some other mammals) small body size is associated with longevity and slow aging. The concept that aging (and age-related diseases) is an aimless continuation of developmental growth, a hyperfunction driven by the same nutrient-sensing and growth-promoting pathways such as MTOR, may explain this longstanding paradox. Fast versus slow aging may depend on whether the organism "grows fast" or "develops longer": first case should be associated with high MTOR. Exceptions may be numerous. Small size is not always related to the GH/IGF/MTOR pathway but instead may be caused by defects that shorten life span. But understanding of each exception will further illuminate the rules. On a wider scale (from worm to whale), large animals live longer because aging is quasi-programmed. In contrast, "big" mice live shorter because they grow faster than dwarf mice and growth is driven by the same pathways that drive aging. Fast-growing mice are expected to have over-activation of growth-promoting pathways (either by excessive calorie consumption or due to genetic mutations), which drive aging and age-related diseases later. Cellular hyperfunction is the key feature of aging cell, leading to organismal death. Yet, there are also two other crucial aspects of hyperfunction theory: (a) aging as a quasi-program of developmental growth and (b) both processes are driven by the same growth-promoting-signaling pathways including MTOR."

STUDY SUGGESTS DEMENTIA RISK DECLINING
Monday, April 22, 2013
http://www.fightaging.org/archives/2013/04/study-suggests-dementia-risk-declining.php
This study result is contrary to the mainstream view, which is that absent advances in medicine the risk of suffering dementia will continue to rise along with life span. However, it makes sense from a reliability theory point of view; if aging and dysfunction and life span are all consequences of the level of damage suffered in cells and molecular machinery, then reducing that damage should extend life by slowing aging and also reducing dysfunction. "The risk of developing dementia may have declined over the past 20 years, in direct contrast to what many previously assumed. The result is based on data from SNAC-K, an ongoing study on aging and health that started in 1987. "We know that cardiovascular disease is an important risk factor for dementia. The suggested decrease in dementia risk coincides with the general reduction in cardiovascular disease over recent decades. Health check-ups and cardiovascular disease prevention have improved significantly in Sweden, and we now see results of this improvement reflected in the risk of developing dementia." The result shows the prevalence of dementia was stable in both men and women across all age groups after age 75 during the entire study period (1987-1989 and 2001-2004), despite the fact that the survival of persons with dementia increased since the end of the 1980s. This means that the overall risk of developing dementia must have declined during the period, possibly thanks to prevention and better treatment of cardiovascular disease. "The reduction of dementia risk is a positive phenomenon, but it is important to remember that the number of people with dementia will continue to rise along with the increase in life expectancy and absolute numbers of people over age 75.""

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