A Rejuvenation Research paper: "As mammals age, the rate of neurogenesis in the brain declines with a concomitant reduction in cognitive ability. Recent data suggest that plasma-borne factors are responsible for inhibition of neurogenesis. When the circulatory systems of old and young mice are connected, the old mice experience increased neurogenesis and the young mice exhibit less neurogenesis, suggesting the importance of systemic circulating factors. Chemokine CCL11/eotaxin has been identified as a factor that increases with aging. Injections of CCL11 inhibit neurogenesis in young mice, an effect likely mediated by CCR3 receptors on neural stem cells. Identification of a specific factor that plays a causative role in stem cell dysfunction in aging is consistent with data showing that transforming growth factor-? (TGF-?) inhibits satellite cell-mediated repair. Together, these data suggest that the systemic milieu plays a critical role in the aging of adult stem cells. Because adult stem cells help maintain homeostasis by providing the possibility of replacing metabolically damaged differentiated cells, aging of the systemic milieu and stem cell niches may drive functional decline during aging. The identification of a specific systemic change suggests that aging is more amenable to therapeutic modulation than work on global metabolism-derived damage and cellular senescence implies."

Link: http://dx.doi.org/10.1089/rej.2011.1301

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

An example of the sort of screening work presently taking place, in China in this case: "Damaged heart tissue is not known for having much inherent capacity for repair. But now, scientists are closing in on signals that may be able to coax the heart into producing replacement cardiac muscle cells. Using a zebrafish model system, researchers have identified a family of molecules that can stimulate stem cells to develop into beating heart muscle cells. ... Despite advances in modern medicine, management of myocardial infarction and heart failure remains a major challenge. There is intense interest in developing agents that can influence stem cells to differentiate into cardiac cells as well as enhance the inherent regenerative capacities of the heart. Developing therapies that can stimulate heart muscle regeneration in areas of infarction would have enormous medical impact. ... The zebrafish is an excellent model organism to study heart growth and development because there are established genetic approaches that permit visualization of fluorescent beating hearts within transparent embryos. After screening nearly 4,000 compounds, the researchers discovered three structurally related molecules that could selectively enlarge the size of the embryonic heart. The compounds, cardionogen-1, -2, and -3, could promote or inhibit heart formation, depending on when they were administered during development. ... Cardionogen opposes Wnt signaling to induce cardiac muscle cell formation. Importantly, the interaction of cardionogen with Wnt seemed to be restricted to specific cell types. ... Evaluating the potential of cardionogen on human adult and embryonic stem cells is the next logical step. This may ultimately aid in design of therapeutic approaches to enhance repopulation of damaged heart muscle and restore function in diseased hearts."

Link: http://www.eurekalert.org/pub_releases/2011-12/cp-hdy121611.php

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

From the New Atlantis, a tour of some of the disturbing views of those who are opposed to enhanced longevity, and in favor of government force used to set limits to life: "Age-retardation technologies are the 'killer app' (so to speak) of enhancements - so deeply and self-evidently appealing that they would seem to sell the whole project of enhancement on their own. Nonetheless, there are those who oppose them. For example, Leon Kass, the former chairman of the President's Council on Bioethics (PCBE) under President Bush, has asserted, 'the finitude of human life is a blessing for every individual, whether he knows it or not.' And Daniel Callahan, co-founder of the Hastings Center, has declared, 'There is no known social good coming from the conquest of death.' Callahan added, 'The worst possible way to resolve [the question of life extension] is to leave it up to individual choice.' When asked if the government has a right to tell its citizens that they have to die, Johns Hopkins University political scientist Francis Fukuyama answered, 'Absolutely.' ... In addition to these concerns, Schaub suggests that 'a nation of ageless individuals could well produce a sclerotic society, petrified in its ways and views.' Daniel Callahan makes a similar argument in a debate with life-extension advocate Gregory Stock, in which he claims, 'I doubt that if you give most people longer lives, even in better health, they are going to find new opportunities and make new initiatives.' Stock goes so far as to help his interlocutor with the hoary example of brain-dead old professors blocking the progress of vibrant young researchers by holding onto tenure. But that seems more of a problem for medieval institutional holdovers like universities than for modern social institutions like corporations. ... In fact, the available evidence cuts against concerns about 'a hardening of the vital social pathways.' Social and technological innovation has been most rapid in those societies with the highest average life expectancies. Yale economist William D. Nordhaus estimates that increases in longevity in the West account for 40 percent of the growth in gross national product for the period 1975-1995. Why? Not only do people work longer, but they work smarter - long lives allow for the accumulation of human capital. ... We do not know what immortality would be like. But should that happy choice become available, we can still decide whether or not we want to enjoy it. Besides, even if the ultimate goal of this technological quest is immortality, what will be immediately available is only longevity. The experience of longer lives will give the human race an opportunity to see how it works out. If immortality is a problem, it is a correctable one. Death always remains an option. Let us turn on its head the notorious argument by Leon Kass that our initial repugnance to biotechnological advances should make us wary of them. Put the other way around, the near-universal human yearning for longer, healthier lives should serve as a preliminary warrant for pursuing age-retardation as a moral good."

Link: http://www.thenewatlantis.com/publications/the-case-for-enhancing-people

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Here is an interesting application of guided tissue growth, that focuses on blood vessels. A wide range of work is under way on blood vessel engineering and control of growth, as the ability to incorporate blood vessels into tissue in specific ways is essential to realizing the most important goals of tissue engineering: "A team of engineers has created a bandage that in just one week not only encourages new blood vessel growth but helps guide that growth as well. ... The ability to pattern functional blood vessels at this scale in living tissue has not been demonstrated before. ... The team [calls] the bandage a 'microvascular stamp.' Unlike similar bandages developed to help spur blood vessel growth, the stamp contains living cells that encourage damaged tissue to grow according to the stamp's pattern. At nearly a centimeter across, the stamp is made of porous material that enables small molecules to sneak through in addition to the larger growth factors. The team tested it on a chicken embryo; when they removed it from the surface a week later, a network of new blood vessels appeared in the pattern of the stamp's channels. Future applications could include not only healing wounds, but also redirecting blood vessels to grow around blocked arteries, and even improving the delivery of cancer drugs by repairing blood vessels that feed cancerous cells."

Link: http://news.cnet.com/8301-27083_3-57346717-247/high-tech-bandage-spurs-blood-vessel-growth/

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

The latest Rejuvenation Research journal issue is available online. Down a way in the contents list, there's one page commentary on gender that can be read in its entirety provided you're fine with small print:

Life span [will be] limited even in biologically immortal individuals. Death can still occur from causes other than aging such as accident, extrinsic disease, murder, suicide, etc. Due to these factors, the statistical probability of extending life by eliminating aging has been estimated to range from as little as 700 years to a few thousand. Because women tend to take fewer risks than men, estimates for their survival are double those for men. Some authors speculate that because of future developments in medicine and technology, the risk for death can be even more significantly reduced, making it possible to extend human life for as much as 50,000 years. This estimate is obviously the extreme, but for argument's sake let's say it may be possible for cautious, biologically immortal individuals living conservative lifestyles to survive for 10,000 years or so before succumbing to a deadly contagion or catastrophic accident.

Which initially suggests that a world of ageless individuals would be largely a world of women - though by the time agelessness is a going concern, I'd imagine that ad hoc gender transformation and selection will also be practical going concerns. Which is not to mention options beyond the traditional male or female duality, or elective alteration of mental traits such as appetite for risk, decoupling the mind from its biological influences. It's entertaining to take narrow slices of the future and ask how things would change is that one slice stood alone, but the future is a monolith - we'll get the potential for all of these outcomes of biotechnology at once, not one at a time.

From where I stand, the technology needed to reduce risk for a standard issue human far enough to enable 50,000 years of life free from fatal occurrences would have to be some fairly advanced stuff - or at least that is so if the individuals in question intend to live free-range and interesting lives. Safety devices and autonomous watchdogs guided by strong artificial intelligences with millisecond reaction times and long planning horizons spring to mind. That sort of thing will be emerging within a hundred years at the present rate of development, but alongside will come the opportunity to stop being a standard issue human - a fragile package of tissue. The most robust way to reduce risk with the foreseeable high technology of the century ahead seems to be, to me at least, to transform the body rather than strive to protect it.

Your risk of fatality for any given activity is a function of your human physiology. Once the research and development community has achieved the goal of practical biotechnologies for the repair and reversal of aging, that will give us all a few hundred years of life in comparative statistical safety. Technological progress will continue across that long period of time, and I can't imagine that much of the toolkit needed for the next step in long-term risk reduction will remain beyond the human civilizations of the 2200s. Your own personal preferences for that next step will no doubt vary, but I would get my neurons replaced - slowly, one at a time over time, to ensure continuity of the self - with some form of much more robust, easily maintained nanoscale machinery.

...

Physical distribution of the self across many disparate locations is in fact the key point when it comes to considering risk over the long term. Locations have much the same issues with time, probability and bad events as people do. Meteorites happen, as do landslides, earthquakes, war, and volcanoes. The way to reduce your location-based risk dramatically is to spread out. You might imagine a wireless brain, using whatever the most robust communications technology of the time happens to be, scattered in a thousand separate machine bodies or vehicles across a continent, or even the whole planet.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

A study here shows that calorie restriction reduces levels of mitochondrial damage that accumulates with age - that damage being thought of as a contributing cause of aging - but in different levels in different tissues and different species: "The hypothesis that life-span extension by caloric restriction (CR) is contingent upon the attenuation of macromolecular oxidative damage was tested in two different strains of mice: the C57BL/6, whose life span is extended by CR, and the DBA/2, in which CR has relatively minor or no impact on longevity. Mice were fed ad libitum (AL) or restricted to 40% lesser food, starting at 4 months of age. Protein damage was measured as protein-linked adducts of 4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA) in skeletal muscle mitochondria at 6 and 23 months of age. Protein-HNE and -MDA content increased with age in C57BL/6 mice and CR significantly attenuated these augmentations. ... DBA/2 mice exhibited little effect of age or CR on protein HNE/MDA content in skeletal muscle mitochondria. In contrast, protein-HNE levels in liver mitochondria showed a significant increase with age in AL-fed mice of both strains, and CR caused significant attenuation of this damage. Overall, results indicated that the age-related increase in protein oxidative damage and its abatement by CR are genotype- and tissue-specific, and not a universal phenomenon."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22182424

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

It is a truism that, in general, people who look ahead to the future both greatly overestimate predicted progress in the near term of twenty years or less and greatly underestimate predicted progress across longer timeframes. One might argue that this is due in part to most memorable predictions being made about industries and technologies in the early stages of an exponential curve - not much happens for many years as people experiment, persuade, bootstrap support and funding, and then a lot happens in a comparatively short period of time after someone hits the big time, gets it right, and the mainstream wakes up to the latest new new thing. But that's an oversimplification; there are many factors at work here, such as the many variants of hopeful but ultimately self-deluding optimism in the advocacy and technology development communities.

So it is a useful exercise to temper our own predictions of what lies ahead with a look back at earlier well-thought-out and detailed predictions of past progress, to see where they fell down. Here's an example via New Cryonet, written in 1987, and making a set of predictions that, in many cases, have yet to come to pass despite being fairly reasonable - we are not as far along as we'd like to be:

Fairly predictive tests for Alzheimer's disease, schizophrenia, depression, some malignancies, heart disease, and most of the rest of the major killers and disablers will probably be in place by 2000 to 2010. Many if not most of these ailments will be assessable in terms of a very sophisticated genetic risk profile which it will be possible to generate in infancy or childhood (or in utero).

...

Tissue rejection will be amenable to treatment in almost all cases by highly selective destruction or inhibition of certain parts of the immune system without the negative consequences of today's immunosuppressive drugs. Monoclonal and synthetic antibodies carrying toxins or regulatory molecules will be used to turn off or destroy the fraction of immune cells which initially respond and proliferate when a transplant is carried out. More widespread transplantation of tissues will be undertaken, including transplantation of limbs and scalp. Xenografts will be used increasingly in the mid to late 1990's and it will not be uncommon for people to have pancreatic tissue from bovine or porcine sources and perhaps hearts, lungs, and livers from other animals. Expect the first workable transplants to be from great apes (chimps, gorillas, orangutans), with porcine and bovine grafts coming later.

...

By the early decades of 2000, significant rejuvenation and geroprophylaxis of skin, bone, immune, and other "high turn- over" tissues will be possible as the natural regulatory molecules which control these systems are understood and applied. Expect several significant synthetic compounds to be discovered with these kinds of properties as well. There will be the possibility of profound improvement in personal appearance and general health as these agents enter the marketplace. By the early years of the 21st century the first generation of compounds effective at "rejuvenating" (i.e., restoring some degree of normal maintenance and repair to existing brain cells) the central nervous system will be available. These drugs will work by turning on protein synthesis and stimulating natural repair mechanisms.

Many of the specific predictions in the article were in fact demonstrated in the laboratory to some degree, and were technically feasible to develop as commercial products by the year 2000, and in some cases earlier but at much greater expense. Certainly there are partial hits for many of the predictions by 2010, in the sense of it being possible, somewhat demonstrated, or in the early stages of being shown to be a practical goal. Yet the regulatory environment in much of the developed world essentially rules out any form of adventurous, rapid, highly competitive development in clinical medicine - such as exists in the electrical engineering, computing, and other worlds. We are cursed therefore with the passage of many years between a new medical technology being demonstrated possible and then attempted in the marketplace ... if it ever makes it to the marketplace at all. This must change if we are to see significant progress.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

An open access paper that suggests that producing therapies for the characteristic loss of muscle mass and strength with age - known as sarcopenia - may be more challenging than we'd like it to be: "Several age-related changes occur in skeletal muscle including a decrease in myofiber size and number and a diminished ability of satellite cells to activate and proliferate upon injury leading to impaired muscle remodeling. Although the molecular mechanisms underlying sarcopenia are unknown, it is tempting to hypothesize that interplay between biological and environmental factors cooperate in a positive feedback cycle contributing to the progression of sarcopenia. Indeed many essential biological mechanisms such as apoptosis and autophagy and critical signaling pathways involved in skeletal muscle homeostasis are altered during aging and have been linked to loss of muscle mass. Moreover, the environmental effects of the sedentary lifestyle of older people further promote and contribute the loss of muscle mass. There are currently no widely accepted therapeutic strategies to halt or reverse the progression of sarcopenia. Caloric restriction has been shown to be beneficial as a sarcopenia and aging antagonist. Such results have made the search for caloric restriction mimetics (CRM) a priority. However given the mechanisms of action, some of the currently investigated CRMs may not combat sarcopenia. Thus, sarcopenia may represent a unique phenotypic feature of aging that requires specific and individually tailored therapeutic strategies."

Link: http://impactaging.com/papers/v3/n12/full/100409.html

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Aging is an inevitability, or so we have to assume: the processes of evolution blindly but efficiently explore the space of possible living creatures, and have been doing so for a very, very long time. Surely a very long-lived or ageless species would have a great advantage in evolutionary competition, its individual members able to produce descendants for far longer than their competitors in a short-lived species that ages. Yet virtually all species - with only a very few exceptions - age in easily measured ways. The species that age are also the species that have won in evolutionary terms, and therefore prospered and spread. Why is this?

A recent open access paper (in PDF format) explores one of the approaches used to answer this question, and does so in a very readable fashion:

Living organisms shouldn't age, at least if that could be helped (many of use would certainly like that, but our wishes are not a valid argument). Evolution works in a way that any species whose representatives have any distinct disadvantage will be driven to extinction. It makes sense then to assume that, if aging could be avoided, species that showed senescence as the individuals grow older should be replaced by others where aging does not happen (or happens at a much slower rate). Senescence increases mortality and an individual who dies of old age will leave, in average, a smaller number of descendants than another individual that does not age and manages to live and reproduce for a longer time. And yet many known living organisms show senescence. The time it takes for an individual to show signs of old age varies greatly among species, but aging seems so natural that many people fail to realize there is an apparent contradiction between senescence and evolution.

...

Understanding why we age is a long-lived open problem in evolutionary biology. Aging is prejudicial to the individual and evolutionary forces should prevent it, but many species show signs of senescence as individuals age. Here, I will propose a model for aging based on assumptions that are compatible with evolutionary theory: i) competition is between individuals; ii) there is some degree of locality, so quite often competition will between parents and their progeny; iii) optimal conditions are not stationary, mutation helps each species to keep competitive.

When conditions change, a senescent species can drive immortal competitors to extinction. This counter-intuitive result arises from the pruning caused by the death of elder individuals. When there is change and mutation, each generation is slightly better adapted to the new conditions, but some older individuals survive by random chance. Senescence can eliminate those from the genetic pool. Even though individual selection forces always win over group selection ones, it is not exactly the individual that is selected, but its lineage. While senescence damages the individuals and has an evolutionary cost, it has a benefit of its own. It allows each lineage to adapt faster to changing conditions.

We age because the world changes.

And there is illustrated one of the present competing viewpoints on the origins of aging.

A recent review: "The function of adult tissue-specific stem cells declines with age, which may contribute to the physiological decline in tissue homeostasis and the increased risk of neoplasm during aging. Old stem cells can be 'rejuvenated' by environmental stimuli in some cases, raising the possibility that a subset of age-dependent stem cell changes is regulated by reversible mechanisms. Epigenetic regulators are good candidates for such mechanisms, as they provide a versatile checkpoint to mediate plastic changes in gene expression and have recently been found to control organismal longevity. Here, we review the importance of chromatin regulation in adult stem cell compartments. We particularly focus on the roles of chromatin-modifying complexes and transcription factors that directly impact chromatin in aging stem cells. Understanding the regulation of chromatin states in adult stem cells is likely to have important implications for identifying avenues to maintain the homeostatic balance between sustained function and neoplastic transformation of aging."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21441951

A Newsweek article runs through some of the standard foolish objections to greater human longevity. There is no change so beneficial that people will refrain from protesting it - it is the human nature to be vehemently against a new idea before being grudgingly for it: "When we consider the problem of aging, and imagine that we might be able to cure it, that alternating current we feel consists of longings and dread. We are afraid of what we wish for; and most of our fears, like our hopes, have always cycled in us. Dreams of immortality have led to terrible nightmares of boredom ever since people began writing down their thoughts. ... What happens when we have real antiaging pills that pass the tests of clinical trials? As bioethicists have begun to note, this is a problem that would make all our bioethical debates to date look small. What are the bioethical problems that have exercised us in the last 10 or 20 years? Stem cells. Cloning. Gene therapy. The privacy of genetic information. Steroids. All these problems matter in themselves, but all of them would be subsumed in the transformations of society and human nature that would be wreaked by a significant success with the human life span. And then will come the option of changing the genome itself. We will add or subtract genes to lengthen our lives, until there is no going back, because no human beings alive (however long they may live) will ever be human in the same way again. If we are going to survive to enjoy a good portion of the future, our health and happiness depend on a great deal of luck. The trouble with immortality is endless." There is no objection to longevity that comes close to touching the present horror of aging - the more than 100,000 people who die each and every day.

View the Article Under Discussion: http://services.newsweek.com/id/238720/output/print

Read More Longevity Meme Commentary: http://www.longevitymeme.org/news/

A promising open access study: "Transplanting autologous renal progenitor cells (RPCs), (kidney stem cells derived from self-donors), into rat models with kidney damage from pyelonephritis - a type of urinary infection that has reached the kidney - has been found to improve kidney structure and function. ... Advancements in stem cell therapies and tissue engineering hold great promise for regenerative nephrology. Our RPC transplant study demonstrated benefits for pyelonephritis, a disease characterized by severe inflammation, renal function impairment and eventual scarring, and which remains a major cause of end-stage-renal disease worldwide. ... The researchers divided 27 rats into three groups, two of which were modeled with an induced pyelonephritis in their right kidneys, while the third group did not have induced disease. RPCs were obtained from the diseased animals' left kidneys and injected into the right kidney six weeks later. Two weeks after injection, tubular atrophy was reduced. After four weeks, fibrosis was reduced and after sixty days, right renal tissue integrity was 'significantly improved.' ... We propose that kidney augmentation was mainly due to functional tissue regeneration following cellular transplantation. Kidney-specific stem/progenitor cells might be the most appropriate candidates for transplantation because of their inherent organ-specific differentiation and their capacity to modulate tissue remodeling in chronic nephropathies. ... The researchers concluded that because renal fibrosis is a common and ultimate pathway leading to end-stage renal disease, amelioration of fibrosis might be of major clinical relevance."

Link: http://www.eurekalert.org/pub_releases/2011-02/ctco-sct021411.php

T-cell vaccines are a comparatively new approach to steering the immune system to perform tasks normally left undone, such as clearing out persistent herpesviruses. It is a reminder that the heading of immune therapy covers a very wide range of possible technologies, not all of which are even on the drawing board yet, and it will be an important part of the longevity science toolkit in the years to come.

An introduction to T-cell vaccine research can be found at the Technology Review:

All existing vaccines rouse the body into creating antibodies that attach to the surface of infecting microbes and flag them for destruction. But pathogens that live inside our cells, such as the viruses, bacteria, and other microbes that cause AIDS, malaria, herpes, and chlamydia, can evade this surveillance. ... In order to deal with those types of pathogens, oftentimes we have to stimulate what we call cellular immunity. Unlike antibody immunity, which recognizes pathogens directly, cellular immunity has to recognize the infected cell and get rid of your own infected cells.

But activating cellular immunity - and the family of infection-fighting cells known as T cells that drive it - is challenging. The trial-and-error method used to develop antibody-based vaccines has not worked for T-cell vaccines. Despite years of academic and industry work, and even clinical trials, there are no T-cell vaccines for infectious disease on the market.

...

A Cambridge, Massachusetts, biotech company called Genocea thinks its high-throughput method could change that. The company will begin its first clinical trial later this year, when its experimental herpes vaccine will be the first test of its claims.

The first and most straightforward way in which a working T-cell vaccine platform might be used to extend life expectancy is as a therapy to clear out the common herpesvirus known as cytomegalovirus (CMV). Most of the population carries strains of CMV by the time they reach old age, and it is thought that CMV plays a role in progressive immune system disarray:

Most people are exposed to this mild persistent herpesvirus over the course of their life; it causes few obvious symptoms, but over time more and more of your immune system resources become uselessly specialized to fight it. An immune cell dedicated to remembering the signature of CMV is unavailable for other uses - and eventually you run out of cells to protect you from new threats, destroy cancers, and clear out senescent cells. This process is one part of the frailty and increased risk of death and disease that comes with old age.

But there are other many other potential uses as well. A more mature T-cell vaccine platform could lead to an array of targeted cell destruction therapies. Destroying cells is, after all, one of the tasks that immune cells have evolved to carry out. A way of rapidly generating new, reliable, and selective methods to destroy very specific cell populations will be helpful in a very wide range of therapies designed to hold back the depredations of aging. For example, such a therapy might be used to cull the unwanted cells that clog up the immune system and degrade its effectiveness - including the memory cells uselessly devoted to persistent CMV strains.

Equally there are cancer cells, senescent cells (if researchers can figure out a better way of reliably identifying them from their surface chemistry), and all sorts of other cells we'd be better off without. Destroying them will repair some of the harms of aging caused by their presence. The most cost-effective way to get rid of them all is via some form of versatile technology that can be quickly adapted to new targets - and it's a fair bet that the first forms of that technology will involve learning how to manipulate the immune system to get the job done. Why reinvent the wheel when you can use what already exists?

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Rapamycin extends life in mice through mechanisms similar to those of calorie restriction, but has serious side-effects - though researchers are working to separate the positive mechanisms from the undesirable negative mechanisms. Metformin is also thought to be a calorie restriction mimetic drug, but the evidence for it to extend life in mice is mixed. Here, researchers suggest trying both drugs at the same time in the hopes that metformin blunts some of the side-effects of rapamycin: "Treatment with rapamycin, an inhibitor of mammalian target of rapamycin complex 1 (mTORC1) can increase mammalian life span. However, extended treatment with rapamycin results in increased hepatic gluconeogenesis concomitant with glucose and insulin insensitivity through inhibition of mTOR complex 2 (C2). Genetic studies show that increased life span associated with mTORC1 inhibition can be at least partially decoupled from increased gluconeogenesis associated with mTORC2 inhibition. Adenosine monophosphate kinase (AMPK) agonists such as metformin, which inhibits gluconeogenesis, [might] be expected to block the glucose dysmetabolism mediated by rapamycin."

Link: http://dx.doi.org/10.1089/rej.2012.1347

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

I would take this as an indicator that simple, ongoing maintenance of fitness and avoidance of a sedentary lifestyle pays off: "Simple tests such as walking speed and hand grip strength may help doctors determine how likely it is a middle-aged person will develop dementia or stroke. ... More than 2,400 men and women with an average age of 62 underwent tests for walking speed, hand grip strength and cognitive function. Brain scans were also performed. During the follow-up period of up to 11 years, 34 people developed dementia and 70 people had a stroke. The study found people with a slower walking speed in middle age were one-and-a-half times more likely to develop dementia compared to people with faster walking speed. Stronger hand grip strength was associated with a 42 percent lower risk of stroke or transient ischemic attack (TIA) in people over age 65 compared to those with weaker hand grip strength. This was not the case, however, for people in the study under age 65. ... Researchers also found that slower walking speed was associated with lower total cerebral brain volume and poorer performance on memory, language and decision-making tests. Stronger hand grip strength was associated with larger total cerebral brain volume as well as better performance on cognitive tests asking people to identify similarities among objects." We might theorize that this is related to exercise and blood flow in the brain, and related effects on the heath of blood vessels in the brain.

Link: http://www.sciencedaily.com/releases/2012/02/120215185850.htm

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

A number of research groups have spent the past few years aggressively mining the population of ongoing human longevity studies, taking advantage of the falling cost of biochemical and genetic assays in order to conduct as many tests as they can: the more data the better. This has resulted in a steady stream of papers that report an increasing number of correlations between specific biological markers and longevity in human populations - though as noted in past posts here, these rarely hold up in different study groups, indicating a large number of tiny contributions to longevity, most of which vary greatly in their effects between human lineages. Metabolism is ferociously complex, and the metabolic aspects that determine natural human longevity no less so.

At this point, there is more pouring of data into the hopper and sorting it all into buckets than there is real progress in understanding - that comes later. Here are two recent examples of this sort of research publication:

Cortisol serum levels in familial longevity and perceived age: The Leiden Longevity Study

Cortisol levels are strongly associated with a person's health. Familial longevity and age assessment of facial photographs (perceived age) are both associated with morbidity and mortality. The present study aimed to investigate morning cortisol levels in familial longevity and the association of these levels with perceived age. ... Perceived age and serum morning cortisol levels were measured for 138 offspring from long-lived families and 138 partners from the Leiden Longevity Study. ... This study demonstrates that high levels of cortisol are associated with a higher perceived age. This association was attenuated in offspring from long-lived families compared to their partners, suggesting enhanced stress resistance in these subjects. Future research will be aimed at elucidating potential mechanisms underlying the observations in this study.

Family History of Exceptional Longevity Is Associated with Lower Serum Uric Acid Levels in Ashkenazi Jews

OBJECTIVES: To test whether lower serum uric acid (UA) levels are associated with longevity independent of renal function.

PARTICIPANTS: Long-lived individuals (LLI) of Ashkenazi Jewish ethnicity, their offspring and controls (without family history of longevity).

RESULTS: Offspring were less likely to have hyperuricemia and had lower UA levels than controls. ... Furthermore, significant association between UA levels in LLI and their offspring has been observed.

CONCLUSION: Offspring had lower UA levels than controls despite similar renal function, suggesting that other factors such as UA metabolism or renal tubular transport determine UA levels. The association between UA levels and longevity is particularly intriguing because UA levels are potentially modifiable with diet and drugs.

Interesting as these studies are - when you read through them in connection with the dozens of other correlation studies examining the biochemistry of human longevity - this is really all something of a sideshow. There is no such thing as useless knowledge in the long term, and this all goes towards the final complete understanding of human metabolism that will exist in the future, but it doesn't help us move any faster now towards the goals of engineered longevity. There is an existing, well-defined path towards the production of rejuvenation biotechnology, and that path is where the majority of funding and effort should go if we want to see a real impact on the future trajectory of our own longevity.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

DNA methylation is a part of epigenetics, one of the mechanisms by which protein machinery produced from DNA creates feedback loops to change the production levels of many different proteins. Genes are decorated with a continually altering array of chemical signals, changing with circumstances and environment. The cell nucleus is a factory, DNA the component blueprints, and DNA methylation one portion of the chaotic parts order list: from moment to moment, how much to make of each piece of protein machinery encoded in the genome.

DNA methylation changes with age, location within the body, and type of cell, a fuzzy and very complicated pattern of decorated genes. Some of the myriad changes are sufficiently similar from person to person to be a possible method to determine age quite accurately. Others are known to reflect the degree to which a person becomes frail with age. Many more are not understood at all, or may be largely random.

A great many debates within aging science revolve around the difference between cause and consequence - and so too with DNA methylation. Is it a part of the expected attempts by the body to adapt to increasing levels of cellular damage caused by aging, or is at least some alteration in DNA methylation a form of damage in and of itself? Good arguments can be made either way, but for my money I'd be surprised to see significant levels of epigenetic changes that were anything other than the results of underlying damage and evolutionary adaptations that try (and ultimately fail) to cope with that damage.

This debate is significant, of course, because of how it directs research and development funding. Will scientists try to patch over the root causes of aging by altering its secondary effects - inevitably doomed to be expensive and comparatively ineffective - or will they work to repair the true causes, and thereby remove the secondary effects for free? There's been a great deal too much work on patching over the cracks in the medicine of past decades, and in this age of biotechnology it seems a sin to continue that way when we don't have to.

In any case, here is news of more recent work on DNA methylation that has been doing the rounds:

DNA Switches Discovered to Decline Significantly with Age

An important element of the DNA is what is known as the epigenome. This refers to the pattern of added chemical tags on the DNA called methyl groups. These tags may alter the expression of genes near or on which they reside. Usually they turn off expression of the gene on which they reside.

...

A team of researchers decoded and compared the entire epigenome from blood cells in a neonate, a 26 year old, and a 103 year old. The results were striking. The researchers discovered that as the cells aged, the epigenome changed dramatically. They found 80% of all cysteine residues were methylated in the newborn compared to just 73% of them in the centenarian. A 26 year old subject had 78% of them methylated. They also found almost 18,000 locations in the genome where methylation varied the most. About one third of those regions occurred in genes linked to increase risk of cancer. Mostly aging involved loss of methyl groups.

Why do we age? Genomes of baby and 103-year-old may offer clue

The researchers analyzed the genome of the baby's white blood cells (obtained from cord blood). They found more than 16 million spots where methyl groups had been attached to the baby's DNA. But when they did the same thing with the old man's DNA (obtained from his white blood cells), they found nearly 500,000 fewer sites with methyl groups attached. The sites weren't as densely methylated either.

The scientists got a similar result when they looked in a larger group of 19 Caucasian newborns and 19 Caucasian nonogarians (average age 92.6). And they found an intermediate level of methylation when they examined the white-blood-cell DNA of 19 middle-aged people (average age about 60).

The scientists went on to take a closer look at a few specific genes where they'd spotted changes in methylation in their samples and found that the activity of the genes that had been depleted in methyl groups was, indeed, changed. And they noted that some of the genes - such as two called Sirtuin 5 and Sirtuin 7 - are thought from other studies to be involved in the biology of aging.

As I said above, I don't think epigenetic changes have much to say about why we age, as they are not a fundamental change. They may encode many of the details of how we age, however - ways in which low-level damage translates into characteristic changes in the way that cells, systems, and organs operate. This may be very valuable, but equally it doesn't change the basic goal, which is to repair the fundamental forms of damage that drive aging.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

It has been an interesting year, and I suppose it is traditional at the tail end of December to cast a thoughtful eye back at the highlights. Which I will do, and the following items are in no particular order of importance or chronology.

This was the year that marked the end of the Longevity Meme, launched in 2001 and finally shut down and folded into Fight Aging!

2011 was also the year that I finally redesigned Fight Aging! - something I'd been threatening to get around to since somewhere in the middle of 2005. Speed of action is not high on the list of things to expect around these parts.

The SENS Foundation issued research reports that showed definite signs of progress - a million dollar budget in the prior year and concrete results starting to emerge from the research program focused on the means to repair the biological damage of aging.

Speaking of SENS, the Strategies for Engineered Negligible Senescence, the fifth SENS conference was held only a few months ago. There have been a range of presentations posted to the Foundation YouTube channel as high quality videos.

An important confirmation of the role of senescent cells in aging was accomplished in mice. Find a way to remove senescent cells and health and longevity benefit - that has been shown in action, and now the research community needs to develop a way to accomplish that goal that is better suited to clinical development of a therapy for humans.

This past year the Methuselah Foundation has refocused their efforts on establishing the New Organ Mprize as a part of the comprehensive strategy to accelerate tissue engineering and organ creation - and with it improve human longevity.

Max More has been working away as CEO of Alcor for the past year, making changes aimed at improving the transparency, community relations, and long term prospects for that part of the cryonics industry.

Some noteworthy progress was made early in 2011 in selectively reversing some of the decline of the immune system with age - this adds weight to the evidence for immune rejuvenation through selective destruction of errant cells.

I launched Open Cures this year, an effort to do something about the ridiculous state of regulation and medical development of longevity science. It is a project that I need to get back to working on more aggressively as soon as possible; change doesn't make itself happen.

An study showing an unexpected five year effect on human longevity - a good half the expected effect of regular exercise, a magnitude highly unusual for an established medical treatment - came and went largely unremarked.

The Russian side of the longevity science community has continued to build connections with the English-speaking world. The Science for Life Extension Foundation puts out very attractive materials, the Russian cryonics company KrioRus continues to grow, and more data is emerging on mitochondrially targeted antioxidants under development by Vladimir Skulachev's group.

Resveratrol and indeed the whole sirtuin endeavor has fallen out of favor in the last year - looking like yet another dead end to add to the annals of overly optimistic pharmaceutical development. I would expect to see much more of this sort of thing until the research community switches more of their focus to working on SENS program goals. Try to fix the damage, not just dig up drugs that alter metabolism a little bit.

Tissue engineering in 2011 has been a matter of leaps and bounds - too many to mention. There has been pancreas regeneration, more engineered trachea transplants, building of urethras, blood vessels, and mouse teeth. Which is not to mention small intestine sections, decellularized lungs, and the construction of a working sphincter. And more; this is what an energetic, well funded field looks like.

The naked mole rat genome was sequenced earlier in the year. This is a big step forward for the contingent of researchers agitating for the genetic comparison of long-lived mammals. Why are they long-lived? What can we learn? The mole rat genome is doing the rounds, and researchers will refine their present investigations of the species' noteworthy longevity and cancer resistance.

Sonia Arrison published 100+, a book that aimed to introduce many of the topics here at Fight Aging!, and garnered a fair amount of attention from the mainstream.

And of course, a hundred other items that I'm omitting. It's been busy out there - we're slowly edging into the early barnstorming age of longevity science, in which novel ways to extend life in mice are arriving every couple of months and new longevity-related genes are cataloged at a much faster rate. We measure progress by the degree to which people like me stop talking about certain topics or reporting on certain forms of research because they have become commonplace. It's an exciting time, certainly, and shows no signs of slowing down yet.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Like many age-related conditions, Alzheimer's disease results from an excess in processes of degeneration that are common to all of us. We all have ?-amyloid building up in our brains, and we are all being damaged by it (or by the underlying causes that lead to it) - just to a lesser extent. A practical therapy for Alzheimer's that works by removing causes of aggregate buildup is something that everyone would benefit from: "Several lines of evidence suggest that pathologic changes underlying Alzheimer disease (AD) begin years prior to the clinical expression of the disease, underscoring the need for studies of cognitively healthy adults to capture these early changes. The overall goal of the current study was to map the cortical distribution of ?-amyloid (A?) in a healthy adult lifespan sample (aged 30-89), and to assess the relationship between elevated amyloid and cognitive performance across multiple domains. ... A? deposition is distributed differentially across the cortex and progresses at varying rates with age across cortical brain regions. A subset of cognitively normal adults aged 60 and over show markedly elevated deposition, and also had a higher rate of APOE ?4 (38%) than nonelevated adults (19%). A? burden was linked to poorer cognitive performance on measures of processing speed, working memory, and reasoning. ... Even in a highly selected lifespan sample of adults, A? deposition is apparent in some adults and is influenced by APOE status. Greater amyloid burden was related to deleterious effects on cognition, suggesting that subtle cognitive changes accrue as amyloid progresses."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22302550

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm