Fight Aging!

Heterochromatin is the name given to the more tightly packaged structural forms of DNA and proteins found in the cell nucleus. It has been shown to be involved in cellular senescence, and is a part of the way in which genes are turned on or off, but like most things in the nucleus it is also involved in the deep, dark depths of many other mechanisms - down there in the basement clockwork of the tall towers of machinery that run a cell. Modern day research tools are making it ever easier to catalog the cogs, gears, and operations that take place on any one level of one particular machine-tower, but it is still very hard and time-consuming to turn localized, disconnected understandings into realizations about the mechanism as a whole.

So researchers can presently say a great deal about heterochromatin and its localized behavior, but far less about how these descriptions of structure and low-level operations relate to higher level cellular mechanisms, and never mind how that all ties into trajectories of health and longevity for organisms as a whole. Cells are complicated, exceedingly so, and as a consequence the life sciences are at a point of simultaneously drowning in data while being unable to answer even a tiny fraction of all the questions about biology that are presently asked. This won't last, given the pace of progress in computational technologies, but it is rather like the prospect of starving amidst plenty for the near future.

You might recall that - in my opinion - the acid test as to whether a biological mechanism is interesting to those us who follow longevity science is not whether you can use it to shorten life span, but rather whether you can use it to extend health life. Even better is a case in which researchers can demonstrate both of those goals: turn the dial one way and life shortens, turn it the other and it lengthens - these are indications that there might be something worthy of further investigation in that research.

That all said, here is a demonstration that heterochromatin levels in flies can be used to dial lifespan up and down:

To understand the role of heterochromatin in animal aging, and the underlying molecular mechanisms, we altered heterochromatin levels in Drosophila by genetically manipulating Heterochromatin Protein 1 (HP1) levels ... we examined the life spans of flies with reduced or increased levels of HP1. These flies exhibit reduced or increased levels of heterochromatin, respectively, during development, as HP1 is an integral component of heterochromatin and controls heterochromatin levels.

We found that reducing HP1 levels by half [caused] a dramatic shortening of life span compared to isogenic controls. ... Conversely, a moderate overexpression of HP1, caused by basal activity of the hsp70 promoter, significantly extended life span, resulting in a 23% increase in median life span and a 12% increase in maximum life span. Similarly, at non-heat shock conditions (25°C), a second (independent) line of hsp70-HP1 flies also lived significantly longer than their control flies.

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These results suggest that heterochromatin levels significantly influence life span, and moderately higher levels of heterochromatin promote longevity.

Too much boosting of heterochromatin via the methods the researchers used is fatal to flies, unfortunately. The full paper offers some thoughts on the potential mechanisms of increased longevity with increased heterochromatin levels, but there is no definitive line item to point to - at this stage, only plausible hypotheses about cellular integrity, a slower rate of decline in muscle strength, and so forth.

To what degree does the slow, expensive, and over-regulated institution of drug development - Big Pharma - contribute to the gentle upward trend in human life expectancy that has held over the past few decades? "This paper investigates the contribution of pharmaceutical innovation to recent longevity growth in Germany and France. The effect of the vintage of prescription drugs (and other variables) on the life expectancy and age-adjusted mortality rates of residents of Germany is examined, using longitudinal, annual, state-level data during the period 2001-7. The estimates imply that about one-third of the 1.4-year increase in German life expectancy during the period 2001-7 was due to the replacement of older drugs by newer drugs. The effect of the vintage of chemotherapy treatments on age-adjusted cancer mortality rates of residents of France is also investigated, using longitudinal, annual, cancer-site-level data during the period 2002-6. The estimates imply that chemotherapy innovation accounted for at least one-sixth of the decline in French cancer mortality rates, and may have accounted for as much as half of the decline."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22283691

Here is another good reason not to get fat and not to stay fat: "One of the largest studies to investigate lumbar spine disc degeneration found that adults who are overweight or obese were significantly more likely to have disc degeneration than those with a normal body mass index (BMI). Assessments using magnetic resonance imaging (MRI) show elevated BMI is associated with an increased number of levels of degenerated disks and greater severity of disc degeneration, including narrowing of the disc space. ... previous research has linked higher BMI to low back pain, which is often debilitating and can limit function, impact psychological well being, diminish overall quality of life, and is associated with substantial socioeconomic and health-care costs. ... The team recruited 2,599 participants aged 21 and older from Southern China between 2001 and 2009. Participants were from diverse social and economic backgrounds and were recruited regardless of whether they had lower back pain or not. The study group included 1,040 men and 1,559 women who had a mean age of 42 years. Researchers conducted radiographic and clinical assessments, and MRIs of the lumbar spine were obtained for all subjects. Study findings reveal that 73% of participants displayed disc degeneration, with men (76%) having a significantly higher prevalence of degeneration than women (71%). Not surprisingly, increasing age was found to increase the prevalence of disc degeneration. ... The authors suggest that with weight gain, physical loading on the disc and/or a chronic low-grade inflammation from the fat cells may play a role in disc degeneration."

Link: http://www.eurekalert.org/pub_releases/2012-01/w-ldd012512.php

A common theme in past posts is that increased human longevity goes hand in hand with increased wealth: there are many economic benefits to living longer in good health beyond the immediately obvious ones. This has been demonstrated over and again in the past few centuries as, one after another, regions of the world have moved from poor to rich, and populations from shorter-lived to longer-lived. This bears repeating, and frequently, as the very vocal Malthusian and environmentalist camps claim that exactly the opposite will happen in the future - the Malthusian vision is of poverty and collapse brought on by longevity. This is, of course, ridiculous and just as wrong now as it has been at any time since Malthus first put forward his ideas. The world simply doesn't work that way, as human ingenuity driven by the urge to profit continually produces new and greater resources in response to the need for them.

Nonetheless, with little regard for history, Malthusian adherents loudly oppose engineered human longevity - and their influence is grand and pervasive. When the average person on the street claims to be against longer lives and greater health, it is the hair-shirt Malthusian teachings of the environmentalist movement that inform that reaction: too many people, using too many resources, living too long, and not deserving any more of either. Yet the world does not work that way - there is no such thing as overpopulation, no such thing as limits on resources, and the arguments for more human death and suffering (and less striving for better medicine) are nothing less than evil. A banal and diffuse evil, with every person doing a little to build the monstrous whole, but still malign and terrible in its end result. Every day by which the development of rejuvenation biotechnology is slowed will cost at least 100,000 lives, and another day of suffering for tens of millions of people.

Thus the more people willing to take up the right side of this debate, the better. Here's a recent op-ed on economics and longevity:

There is little downside to the wonderful reality that human beings are now living longer than ever before. While many assume that society's economic burden radically increases with greater longevity, the reality is the opposite. Everyone is better off because of longer life expectancies.

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For instance, University of Chicago economists Kevin Murphy and Robert Topel have calculated that, for Americans, "gains in life expectancy over the century were worth over $1.2m per person to the current population." They also found that "from 1970 to 2000, gains in life expectancy added about $3.2 trillion per year to national wealth." These enormous numbers represent a spectacular accomplishment in terms of benefits. But aside from what life is valued at, it is also the case that real income grows with greater longevity.

Harvard economist David Bloom and Queen's University economist David Canning show that if there are "two countries that are identical in all respects, except that one has a 5 year advantage in life expectancy," then the "real income per capita in the healthier country will grow 0.3 - 0.5 per cent per year faster than in its less healthy counterpart." While these percentages might look small, they are actually quite significant, especially when one considers that between the years of 1965 to 1990, countries experienced an average per capita income growth of 2 per cent per year. When countries only have an average growth of 2 per cent, an advantage of 0.5 per cent is quite the boost.

You might note that across much of the past five decades Malthusians have been predicting near-term catastrophe year-in and year-out, a catastrophe that never emerged and could not have emerged in their terms. The present cries and dire predictions are more of the same - simply false, driven by fundamental misunderstandings about the way in human beings collaborate and respond to incentives, and the way in which new technology is developed to serve unmet needs.

Via ScienceDaily: researchers "are seeking to restore complete cardiac function with the help of artificial cardiac tissue. They have succeeded in loading cardiac muscle cells onto a three-dimensional scaffold, created using the silk produced by a tropical silkworm. Of all the body's organs, the human heart is probably the one most primed for performance and efficiency. Decade after decade, it continues to pump blood around our bodies. However, this performance optimisation comes at a high price: over the course of evolution, almost all of the body's own regeneration mechanisms in the heart have become deactivated. ... In their attempt to develop a treatment for the repair of cardiac tissue, scientists are pursuing the aim of growing replacement tissue in the laboratory, which could then be used to produce replacement patches for the repair of damaged cardiac muscle. The reconstruction of a three-dimensional structure poses a challenge here. Experiments have already been carried out with many different materials that could provide a scaffold substance for the loading of cardiac muscle cells. ... Whether natural or artificial in origin, all of the tested fibres had serious disadvantages. They were either too brittle, were attacked by the immune system or did not enable the heart muscle cells to adhere correctly to the fibres. ... the fibre produced by the tasar silkworm displays several advantages over the other substances tested. ... The surface has protein structures that facilitate the adhesion of heart muscle cells. It's also coarser than other silk fibres. ... This is the reason why the muscle cells grow well on it and can form a three-dimensional tissue structure. ... The communication between the cells was intact and they beat synchronously over a period of 20 days, just like real heart muscle."

Link: http://www.sciencedaily.com/releases/2012/01/120127135943.htm

An open access paper: "The amount of fat mass of an organism is emerging as key determinant in longevity. Too little or too much fat is associated with early mortality in rodents and humans, whereas leanness, intermediate with respect to these two extremes is associated with relative longevity, possibly reflecting an optimal amount of fat. ... Calorie restriction results in leanness, which is linked to metabolic conditions that favor longevity. We show here that deficiency of the triglyceride synthesis enzyme acyl CoA:diacylglycerol acyltransferase 1 (DGAT1), which promotes leanness, also extends longevity without limiting food intake. Female DGAT1-deficient mice were protected from age-related increases in body fat, tissue triglycerides, and inflammation in white adipose tissue. This protection was accompanied by increased mean and maximal life spans of ~25% and ~10%, respectively. Middle-aged Dgat1-/- mice exhibited several features associated with longevity, including decreased levels of circulating insulin growth factor 1 (IGF1) and reduced fecundity. Thus, deletion of DGAT1 in mice provides a model of leanness and extended lifespan that is independent of calorie restriction."

Link: http://impactaging.com/papers/v4/n1/full/100424.html

Science recently hosted a live chat event with researchers Aubrey de Grey and S. Jay Olshansky, public figures who have debated their views on longevity science a number of times over the last seven years or so. The logs and viewer comments from the event remain available for those interested in viewing the discussion, but note that it takes a little while for the widget containing them to load.

Live Chat: The Science of Antiaging

Jennifer Couzin-Frankel: And here's a question from Roy: Does the paper titled "Clearance of p16 positive senescent cells delays ageing-associate disorder" published in Nature January, 2011, prove the Strategies for Engineered Negligible Senescence (SENS's) validity, i.e. extend lifespan by remediating damage? If so, are their other examples of experimental validation of SENS in animal models?

Aubrey: Roy: that paper is a great proof of concept for one component of SENS, the benefits of removing "death-resistant" cells. The experiment didn't show life extension, but it wasn't expected to, because to do that you have to fix all the things that limit lifespan, not just one of them. Yes, there are various other examples, such as the elimination of amyloid in mouse models of Alzheimer's and the introduction of stem cells (or the stimulation of their division) in various tissues. We'll see more of this soon, that's for sure.

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Jennifer Couzin-Frankel: An interesting question from Morten: Why do you want to live longer (as I understand it at least de Grey is after living longer)? What can't you accomplish in a life time?

Aubrey: Morten: this is the most insidious misunderstanding of the work that I and other biomedical gerontologists do. We are NOT working to extend life for the sake of extending life. We are working to postpone the ill-health of old age, which will probably have the side-effect of extending life, but it's no more than that, a side-effect. I personally have no idea how long I want to live, [any] more than I have an opinion on what time I want to go to the toilet next Sunday. In both cases I know I'm going to have better information nearer the time, so it's idiotic to even think about it. However, I can tell you that I have at least 1000 years of backlog already (books to read, films to se...) - don't you? If not, why not?

S. Jay Olshansky: Morton. The goal of research in this area in my view is not to extend life. The goal is to extend healthy life. If we live longer, I consider that a bonus. However, I would encourage you to be asking the same question of those now working to combat heart disease, cancer, and stroke, and those who experience these conditions. Why [do] we all want to live longer? I believe what we are talking about here are interventions that enable us to live our lives healthy for as long as possible.

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Comment From Guest: Couldn't you guys be focusing on pain control, quality-of-life and ending poverty and depression in the elderly?

S. Jay Olshansky: [Think] about this for a moment. In 1900 life expectancy at birth was about 45. Now it's about 80 for women and 76 for men. We gained 30 years of life -- most healthy. Wasn't that worth it? It's hard to imagine the goal of extending healthy life as being harmful in any way -- it would enable people to remain working longer if they want, or retire healthier for a longer time period. Health also begets wealth for individuals and populations. Goodness -- why are we working so hard to combat heart disease and cancer then?

There's a lot more there to look through; you should certainly read the whole thing.

From the Independent: "It is one of medicine's mysteries: what has caused Britain's plummeting rate of heart disease over the last decade? Deaths from heart attacks have halved since 2002 and no one is quite sure why. Similar changes have occurred in countries around the world but the death rate in England, especially, has fallen further and faster than almost anywhere. ... The researchers looked at 840,000 men and women in England who had suffered a total of 861,000 heart attacks between 2002 and 2010. Overall, the death rates fell by 50 per cent in men and 53 per cent in women. ... For the last 70 years we have been in the grip of a heart disease epidemic that began in the 1940s, rose to a peak in the 1970s and then began to fall. All Western countries were affected and all followed broadly the same pattern. ... researchers conclude that just under half the decline in heart attack death rates in England over the last decade is due to better hospital treatment; the rest is due to changes in lifestyle and the widespread use of pills to lower cholesterol and blood pressure." One might theorize that - at the high level - increased heart disease across the last seven decades is a consequence of the fat and sedentary lifestyles that tend to accompany increases in wealth across the board, while reductions are largely due to improvements in medical technology.

Link: http://www.independent.co.uk/life-style/health-and-families/health-news/the-curious-case-of-the-vanishing-killer-6294626.html

Here is an open access PDF format mini-review on what is known of growth hormone and aging - that less of it is generally better: "A recent report of virtually complete protection from diabetes and cancer in a population of people with hereditary dwarfism revived interest in elucidating the relationships between growth, adult body size, age-related disease and longevity. In many species, smaller individuals outlive those that are larger and a similar relationship was shown in studies of various human populations. Adult body size is strongly dependent on the actions of growth hormone (GH) and the absence of GH or GH receptor in mice leads to a remarkable extension of longevity. Many mechanisms that may account for, or contribute to, this association have been identified. It is suggested that modest modifications of the diet at different ages may extend human healthspan and lifespan by reducing levels of hormones that stimulate growth."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22261798

The course of our future lives, our health and longevity, is swayed by a population of timid mice - but malicious mice, ever ready to use state force to punish and hold back anyone they see as being insufficiently timid. These are people who support the ball and chain of centralized regulation of medical research, people who fear all change, people who fear everything they don't understand, and people who rush to prevent anyone else from enjoying the freedom to undertake personal risk in the course of advancing progress. This describes the vocal mainstream of Western culture: risk-averse, ignorant, and enamored of control for its own sake: a dangerous combination for those who pull upon the strings of law and regulation.

As I have often remarked in the past, freedom is absolutely essential to progress in medicine: the freedom for researchers to attempt goals as they see fit; the freedom for anyone to fund the research and clinical development they desire; the freedom for people to take personal risks in the use of medical technology; the freedom for groups to create an unhampered marketplace in medicine, in which technologies are rapidly sifted for those with the greatest benefit. These are all simply parts of economic and personal liberty, something that is in extremely short supply in the medical industry.

So the mice stamp their little feet, and the impersonal engines of government - the unaccountable employees of bureaucratic bodies such as the FDA - move to prevent us all from undertaking rapid development in medicine, on penalty of jail. For our own good, supposedly.

If anti-aging drugs are possible, they will require dangerous - and ethically troubling - clinical trials. ... If anti-aging medicine is to become a reality, then the various theories about how to halt or reverse the aging process will require testing on human subjects. Carrying out such tests will place unprecedented pressure on the rules protecting human participants in clinical trials. I suspect, then, that human guinea pigs for anti-aging trials will come disproportionately from the poor and disempowered. ... The rich and powerful will be looking to do away with rules that they perceive as denying them millennial life spans.

Those would be the rules preventing terminal cancer patients from choosing to up and pay for their own personal trial of a promising therapy-in-development - forcing them to die without any recourse. The rules that make formal clinical trials so lengthy and expensive that many potential therapies are simply never developed or tried by humans, and those that are might be a decade in the slow regulatory grind from readiness to actual availability. The rules that raise the costs of medicine too high for those poor folk that the author seems to be concerned about. Regulation of medicine, which raises costs, disrupts the effective market mechanisms of progress, and prevents people from using potential therapies that are technologically feasible and ready to field-test, is a morally bankrupt affair.

But this is the culture we live in, sad to say: one in which vague and poorly articulated discomfort with potential future inequities are given more consideration than the ongoing massive toll of death and suffering that we should be working day and night, as fast as possible, to prevent. A toll of 100,000 lives every day, and the hundreds of millions who are crippled, diminished, and in pain. Instead we get institutions like the FDA, whose staff toil to prevent new medicine from ever seeing the light of day. The mice would close their eyes and drown the world in blood just to feel a little better in their own vague sense of disquiet: they are the very worst of humanity, not even willing to acknowledge the fearsome costs of their own timidity.

Here is another example of work on creating patient-specific cells to order, one of the necessary building block technologies needed for an industry that constructs organs and other larger masses of tissue in the body: researchers have "discovered a method of generating different types of vascular smooth muscle cells (SMCs) - the cells which make up the walls of blood vessels - using cells from patients' skin. ... Cardiovascular disease is the leading cause of death in the world. These deaths are mainly caused by the hardening and subsequent blockage of blood vessels due to the accumulation of fatty materials, a condition called atherosclerosis. As not all patients are suitable for conventional stenting or bypass treatment, an option in the future may be to grow new blood vessels to bypass their own blocked vessels. The [team] worked with embryonic stem cells and reprogrammed skin cells, collectively known as human pluripotent stem cells (hPSCs), which have the potential to form any cell type in the body. They discovered a method of creating all the major vascular smooth muscle cells in high purity using hPSCs which can also be easily scaled up for production of clinical-grade SMCs. This is the first time that such a system has been developed and will open the door for comparative studies on different subtypes of SMCs to be carried out, which are otherwise extremely difficult to obtain from patients."

Link: http://medicalxpress.com/news/2012-01-cambridge-team-smooth-muscle-cells.html

The principle use of stem cells in the near future is actually research, not therapy - generating diseased cells to order will lower the cost of better understanding the mechanisms of disease and age-related conditions. For example: "scientists have, for the first time, created stem cell-derived, in vitro models of sporadic and hereditary Alzheimer's disease (AD), using induced pluripotent stem cells from patients with the much-dreaded neurodegenerative disorder. ... It's a first step. These aren't perfect models. They're proof of concept. But now we know how to make them. It requires extraordinary care and diligence, really rigorous quality controls to induce consistent behavior, but we can do it. ... We're dealing with the human brain. You can't just do a biopsy on living patients. Instead, researchers have had to work around, mimicking some aspects of the disease in non-neuronal human cells or using limited animal models. Neither approach is really satisfactory. ... With the in vitro Alzheimer's neurons, scientists can more deeply investigate how AD begins and chart the biochemical processes that eventually destroy brain cells associated with elemental cognitive functions like memory. Currently, AD research depends heavily upon studies of post-mortem tissues, long after the damage has been done. ... The differences between a healthy neuron and an Alzheimer's neuron are subtle. It basically comes down to low-level mischief accumulating over a very long time, with catastrophic results. ... The researchers have already produced some surprising findings. ... In this work, we show that one of the early changes in Alzheimer's neurons thought to be an initiating event in the course of the disease turns out not to be that significant."

Link: http://www.sciencedaily.com/releases/2012/01/120125131029.htm

This year's Buck Symposium, an event hosted by the Buck Institute for Research on Aging, will be held on March 1st. The Institute is very much a part of the mainstream of biogerontology, wherein frank talk of extending human life span is rare, and the public relations tends to focus on age-related diseases and length of healthy life within the current human life span:

At the Buck Institute, world-class scientists work in a uniquely collaborative environment to understand how normal aging contributes to the development of conditions specifically associated with getting older such as Alzheimer's and Parkinson's disease, cancer, stroke, heart disease, diabetes, macular degeneration and glaucoma. Our interdisciplinary approach brings scientists from disparate fields together to develop diagnostic tests and treatments to prevent or delay these maladies.

Some of their work has application to more useful research programs, however, those that aim directly to extend human life and reverse aging - such as SENS. That said, the program for the event is attractive, and in the speakers list you'll see a few noted researchers who are in fact public supporters of SENS, such as Irina Conboy.

The 2012 Buck Symposium: Stem Cell Research and Aging provides a stage for key players in the rapidly developing areas of stem cell research and the basic biology of aging to share their research, findings and thoughts. Some of the world's most influential and respected investigators from diverse background, in fields such as development, diseases, stem cell biology and model systems will be sharing their ideas, sparking new dialog, new alliances and promising collaborations.

From the New York Times: "A treatment for eye diseases that is derived from human embryonic stem cells might have improved the vision of two patients. The report, published online in the medical journal The Lancet, is the first to describe the effect on patients of a therapy involving human embryonic stem cells. ... The results [come] from the second clinical trial involving the stem cells, using a therapy developed by Advanced Cell Technology to treat macular degeneration, a leading cause of blindness. ... Both patients, who were legally blind, said in interviews that they had gains in eyesight that were meaningful for them. One said she could see colors better and was able to thread a needle and sew on a button for the first time in years. The other said she was able to navigate a shopping mall by herself. ... esearchers at Advanced Cell Technology turned embryonic stem cells into retinal pigment epithelial cells. Deterioration of these retinal cells can lead to damage to the macula, the central part of the retina, and to loss of the straight-ahead vision necessary to recognize faces, watch television or read. Some 50,000 of the cells were implanted last July under the retinas in one eye of each woman in operations that took about 30 minutes. ... Before the treatment, the woman with Stargardt's was able to see the motion of a hand being waved in front of her but could not read any letters on an eye chart. Twelve weeks after the treatment, she was able to read five of the biggest letters on the eye chart with the treated eye, corresponding to 20/800 vision, according to the paper."

Link: http://www.nytimes.com/2012/01/24/business/stem-cell-study-may-show-advance.html

An interview with a researcher: "Advances in the study of stem cells have fueled hopes that someday, via regenerative medicine, doctors could restore aging people's hearts, livers, brains and other organs and tissues to a more youthful state. A key to reaching this goal - to be able to provide stem cells that will differentiate into other types of cells a patient needs - appears to lie in understanding 'epigenetics,' which involves chemical marks stapled onto DNA and its surrounding protein husk by specialized enzyme complexes inside a cell's nucleus. These markings produce long-lasting changes in genes' activity levels within the cell - locking genes into an 'on' or 'off' position. Epigenetic processes enable cells to remain true to type (a neuron, for instance, never suddenly morphs into a fat cell) even though all our cells, regardless of type, share the same genetic code. But epigenetic processes also appear to play a critical role in reducing cells' vitality as they age. ... Aging seems to involve a gradual deterioration of function as cells and tissues are exposed to stresses either from outside the body, such as chemicals we ingest or irradiation from the sun, or from inside the body, such as free radicals, produced every moment when cells are making energy. These myriad insults can, among other things, alter a cell's epigenetic settings, resulting in changed patterns of gene activity that diminish the cell's overall ability to function. ... Although some aspects of cellular aging - DNA mutations, for instance - would be difficult to 'reset,' we and others have done experiments suggesting that many of the characteristics of old cells and tissues can indeed be reversed, restoring them to a more youthful state. Much of our work has focused on stem cells, and in particular on the changes that occur with age and that reduce stem cells' ability to maintain or repair tissues. Our findings fit nicely with the idea that some of the causes of aging are epigenetic in character, as opposed to actual damage to genes. Most importantly, our data suggest that cells and tissues can be rejuvenated without losing their specific characteristics - old muscle stem cells, when rejuvenated, remain muscle stem cells rather than become some more generic, undifferentiated cell."

Link: http://med.stanford.edu/ism/2012/january/5q-rando-0123.html

Exercise extends healthy life in laboratory animals, but not maximum life span as is the case for calorie restriction. In longer lived species such as our own, that difference may be slight: present evidence suggests exercise and calorie restriction to have broadly similar - though very different in detail - effects on life expectancy. The end results are probably in the same ballpark, and quite possibly achieved through an overlapping set of mechanisms. That said, while exercise is certainly good for you, I've yet to see a study on exercise that reproduces similar eye-opening changes in underlying biomarkers of health to those found in human calorie restriction practitioners. Exercise is "merely" great for health, as opposed to amazingly superb for health.

So, obviously, the sensible thing to do is both exercise regularly and practice calorie restriction. Based on the weight of evidence, this is the 80/20 of what can be done today to optimize health for the long term in a basically healthy individual. The complement to this approach is doing your part to ensure that medical technology produces methods of rejuvenation in time to help you in later age when good health practices are no longer enough to stave off significant degeneration and risk of death.

There is a school of thought that places the processes of autophagy front and center when it comes to natural methods of adjusting metabolism for length of health and life. Autophagy is the process by which cells break down damaged components, the first step in recycling and replacement: fewer damaged components at any given time is a good thing, and so more autophagy should also be a good thing. You might recall a demonstration that autophagy is essential to the life span and health benefits of calorie restriction, for example.

I notice that scientists are suggesting that autophagy is similarly important to the health and life span benefits produced by regular exercise:

Dr Levine and her team were testing a theory that exercise works its magic, at least in part, by promoting autophagy. This process, whose name is derived from the Greek for "self-eating", is a mechanism by which surplus, worn-out or malformed proteins and other cellular components are broken up for scrap and recycled.

To carry out the test, Dr Levine turned to those stalwarts of medical research, genetically modified mice. Her first batch of rodents were tweaked so that their autophagosomes - structures that form around components which have been marked for recycling - glowed green. After these mice had spent half an hour on a treadmill, she found that the number of autophagosomes in their muscles had increased, and it went on increasing until they had been running for 80 minutes.

To find out what, if anything, this exercise-boosted autophagy was doing for mice, the team engineered a second strain that was unable to respond this way. Exercise, in other words, failed to stimulate their recycling mechanism. When this second group of modified mice were tested alongside ordinary ones, they showed less endurance and had less ability to take up sugar from their bloodstreams.

There were longer-term effects, too. In mice, as in people, regular exercise helps prevent diabetes. But when the team fed their second group of modified mice a diet designed to induce diabetes, they found that exercise gave no protection at all.

Autophagy is one of a number of potential mechanisms by which exercise improves long term health. You might look back at a post from the archives for more:

Physical inactivity is increasingly recognized as modifiable behavioral risk factor for cardiovascular diseases. A partial list of proposed mechanisms for exercise-induced cardioprotection include induction of heat shock proteins, increase in cardiac antioxidant capacity, expression of endoplasmic reticulum stress proteins, anatomical and physiological changes in the coronary arteries, changes in nitric oxide production, adaptational changes in cardiac mitochondria, increased autophagy, and improved function of sarcolemmal and/or mitochondrial ATP-sensitive potassium channels. It is currently unclear which of these protective mechanisms are essential for exercise-induced cardioprotection. ... A better understanding of the molecular basis of exercise-induced cardioprotection will help to develop better therapeutic strategies.

NPR interviews Paolo Macchiarini, who leads the group working on transplanted tissue engineered tracheas: "How was the scaffold for the synthetic trachea built? Well, basically, by the same fibers that everybody of us has, nanofibers; very, very small fibers that are composed and native to the human trachea. So when we wanted to transplant this organ, we thought what is best. And the best would be to just replicate what human nature has done. And this is the reason why we use these very thin fibers. ... So I imagine you could try to do this with other organs in the body, other things. ... Well, we are starting to learn what happens with this still experimental therapy. So I'm not so pessimistic to try to do the same with other tissues or organs. And since I'm a thoracic surgeon, I deal with organs of the chest. So I would think of the esophagus at the chest wall, at the liver - at the lung, and eventually at the heart. Yes. ... depending on the degree of difficulty of the three dimensional aspect of the tissue, you can produce a trachea, for instance, just the tube, in two days. And a bifurcated trachea in 10 days. So now - then you need two days for getting the cells, reseeding the grafts, or in two weeks you have an entire trachea. ... And perhaps you might extend your work further, because you deal in this and possibly into the lungs. ... Well, ideally, yes. But to me my dream would be another one. It would be rather than replacing the lung or replacing the heart, you use cell therapy to treat these organs before they ultimately do not work anymore. so rather than doing a transplantation, just when we have the first signs of insufficiency, whether to treat these organs with the patient's stem cells, probably targeting the defect that they have, so prolonging and extending their life." This last point is the likely future of tissue engineering - not to build outside the body and require major surgery, but rather regenerate in situ by issuing commands to existing stem cell populations, or repair those stem cells where they are deficient.

Link: http://www.npr.org/2012/01/20/145525008/synthetic-windpipe-transplant-boost-for-tissue-engineering

The ape inside is troubled when it learns that someone else has more than you do - which is something that you should strive to ignore if you like living in a peaceful society. The lesson to take away from this article and research is that the generally better choices made by the wealthy when it comes to health are equally available to near everyone - the effects of diet and exercise outweigh most other factors in the wealthier nations, assuming that you didn't suffer rare bad luck in your genetic legacy. "Wealthy people possess more than just spending power. They also have more time to live than poor people do, a new study has found. The wealthiest people in the United Kingdom live longer than the poor, according to a new study from the U.K.-based Longevity Science Advisory Panel. Male higher managers and professionals in the U.K. have a life expectancy of 83.8 years, and female higher managers and professionals can expect to live 86.7 years, in contrast to workers with routine tasks who die about three years earlier. The study found that the longevity gap has widened between the rich and poor over time. While male lower management and higher management had virtually the same life expectancy in the early 1980s, now their longevity gap has widened to almost a year, according to the study. Similarly, while male workers with routine tasks died two years earlier than male higher managers in the early 1980s, now male workers with routine tasks die 3.5 years earlier than male higher managers on average, according to the study. The study said that poorer people die earlier because they tended to lead less healthy lifestyles. The study pointed to less access to health services, alcohol consumption, smoking, and obesity as leading to lower life expectancy."

Link: http://www.huffingtonpost.com/2012/01/23/rich-people-live-longer_n_1223505.html

The trachea is certainly having its fifteen minutes of fame these days. Tissue engineered tracheas are one of the better present examples of the near term possibilites of regenerative medicine, and there is a sense of justifiable pleasure in the concrete evidence of progress. So naturally there was a presentation on this brach of clinical research at last year's SENS5 conference.

The ramifications of stem cell research and therapy are enormous. We provided evidence that stem cells can be successfully applied to laryngo-tracheal and windpipe transplants for adults and children but why not imagine to use stem cell therapy in patients with otherwise untreatable end stage diseases of the respiratory system?

Why not, indeed.

The Science for Life Extension Foundation produces very attractive materials to both explain the science of aging and advocate for larger research programs aimed at the extending healthy human life span. Most of these documents and posters start out in Russian, but a fair number are translated over time. Here, Maria Konovalenko shows off an English-language poster describing what is known of the relationships between telomeres, telomerase, and aging. Telomeres are caps of repeated DNA sequences attached to the ends of chromosomes, shortening with cell divisions, and lengthened by the actions of telomerase. They are a central part of evolved feedback loops involving cell aging and replication, and are influenced by health, stress, and many other factors not yet fully understood. Telomeres generally become shorter on average with increased age and ill health, but the roots of that process are complicated: it is unclear as to whether changes in telomere length maintenance are a contributing cause or a resulting consequence of age-related degeneration and accumulated cell-level damage."

Link: http://mariakonovalenko.wordpress.com/2012/01/14/telomeres-and-aging-chart/

An interesting result, albeit with no immediate application - it is perhaps surprising that this wasn't discovered long ago, given the common uses of ethanol in the laboratory: "Minuscule amounts of ethanol, the type of alcohol found in alcoholic beverages, can more than double the life span of a tiny worm known as Caenorhabditis elegans, which is used frequently as a model in aging studies. ... The worms normally live for about 15 days and can survive with nothing to eat for roughly 10 to 12 days. ... Our finding is that tiny amounts of ethanol can make them survive 20 to 40 days. ... Initially, [researchers] intended to test the effect of cholesterol on the worms ... The scientists fed the worms cholesterol, and the worms lived longer, apparently due to the cholesterol. They had dissolved the cholesterol in ethanol, often used as a solvent, which they diluted 1,000-fold. ... It's just a solvent, but it turns out the solvent was having the longevity effect. The cholesterol did nothing. We found that not only does ethanol work at a 1-to-1,000 dilution, it works at a 1-to-20,000 dilution. That tiny bit shouldn't have made any difference, but it turns out it can be so beneficial. ... It's possible there is a trivial explanation, but I don't think that's the case. We know that if we increase the ethanol concentration, they do not live longer. This extremely low level is the maximum that is beneficial for them. ... What is even more interesting is the fact that the worms are in a stressed developmental stage. At high magnifications under the microscope, it was amazing to see how the worms given a little ethanol looked significantly more robust than worms not given ethanol."

Link: http://www.sciencedaily.com/releases/2012/01/120120184540.htm

Last week I posted on what seems to be the strikingly different nature of aging at very advanced ages. For example, there is what is known as the mortality plateau in very late life, a period in which mortality rates stop increasing. This has been studied in flies, and there is a small amount of evidence that suggests it might also exist in humans. But I thought I'd point you in the opposite direction today. The research partnership of Leonid Gavrilov and Natalia Gavrilova published a study on mortality at advanced ages not so very long ago, and their data suggests that there is no mortality plateau for humans. The link below is a PDF version of the paper:

Mortality measurement at advanced ages: A study of the Social Security Administration Death Master File

Accurate estimates of mortality at advanced ages are essential to improving forecasts of mortality and the population size of the oldest old age group. However, estimation of hazard rates at extremely old ages poses serious challenges to researchers: (1) The observed mortality deceleration may be at least partially an artifact of mixing different birth cohorts with different mortality (heterogeneity effect); (2) standard assumptions of hazard rate estimates may be invalid when risk of death is extremely high at old ages and (3) ages of very old people may be exaggerated.

One way of obtaining estimates of mortality at extreme ages is to pool together international records of persons surviving to extreme ages with subsequent efforts of strict age validation. This approach helps researchers to resolve the third of the above-mentioned problems but does not resolve the first two problems because of inevitable data heterogeneity when data for people belonging to different birth cohorts and countries are pooled together. In this paper we propose an alternative approach, which gives an opportunity to resolve the first two problems by compiling data for more homogeneous single-year birth cohorts with hazard rates measured at narrow (monthly) age intervals.

...

Study of several single-year extinct birth cohorts shows that mortality trajectory at advanced ages follows the Gompertz law up to the ages 102-105 years without a noticeable deceleration. Earlier reports of mortality deceleration (deviation of mortality from the Gompertz law) at ages below 100 appear to be artifacts of mixing together several birth cohorts with different mortality levels and using cross-sectional instead of cohort data. Age exaggeration and crude assumptions applied to mortality estimates at advanced ages may also contribute to mortality underestimation at very advanced ages.

All the more reason to work harder on the development of rejuvenation biotechnology, capable of repairing the damage of aging. Time waits for no one.

A bold set of claims from this group working on the genetics of natural variation in longevity for humans: "Like most complex phenotypes, exceptional longevity is thought to reflect a combined influence of environmental (e.g., lifestyle choices, where we live) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity in 801 centenarians (median age at death 104 years) and 914 genetically matched healthy controls. Using these data, we built a genetic model that includes 281 single nucleotide polymorphisms (SNPs) ... Consistent with the hypothesis that the genetic contribution is largest with the oldest ages, the sensitivity of the model increased in the independent cohort with older and older ages ... Further [analysis] suggests that 90% of centenarians can be grouped into clusters characterized by different 'genetic signatures' of varying predictive values for exceptional longevity. ... The different signatures may help dissect this complex phenotype into sub-phenotypes of exceptional longevity." The researchers are claiming some moderately common sets of SNPs found in centenarians (but not so common in the general population) can predict exceptional longevity with odds of 70% or higher, with the much more predictive combinations of SNPs - some at 95% odds of exceptional longevity - being correspondingly very rare. The caveat here is that this is heavily statistical work, and we've already seen one paper from this group withdrawn last year for issues with the statistics.

Link: http://dx.doi.org/10.1371/journal.pone.0029848

An example of the world moving forward, even though the really flashy biotechnology is still in the laboratory rather than the clinic: "Age-related macular degeneration (AMD) is the most frequent cause of blindness in the Western World. A [report] shows the number of new cases of blindness and severe visual loss in Denmark has been halved during the last ten years. ... [Researchers] examined the records of 11,848 new cases of legal blindness. The rate of blindness from AMD fell from 522 cases per million inhabitants aged 50 years or older in 2000, to 257 cases per million in 2010, a reduction by over 50 per cent. The bulk of the decrease occurred after 2006, following the introduction of new effective treatment for wet AMD, which is characterised by leaking blood vessels having formed under the fovea. The treatment consists of repeated injections into the eye of a medication that inhibits the signalling molecule vascular endothelial growth factor (VEGF). ... The observations from Denmark were published together with a corroborating report from Israel that found comparable changes in the incidence of legal blindness in that country. ... The massive implementation of modern wet AMD therapy has been a challenge. It is therefore very important that we can now show an impact on public health and it is wonderful to see a reduction in severe visual loss."

Link: http://news.ku.dk/all_news/2012/2012.1/danish-report-shows-risk-of-blindness-halved/

There are a lot of genes wherein alterations correlate with longevity - either mutations, removal of the gene, or epigenetic variations. Some of these are similar between many species, some restricted to a few small branches of the evolutionary tree. As the costs of investigating the genome and the proteome fall rapidly, ever more data is accumulated on the detailed relationships between biology and longevity at the level of molecular mechanisms.

There really is too much new work emerging to point out every study - it has become unremarkable to discover new correlations in the genetics of longevity. Also, when it comes down to it, little of this research will be of any real relevance to the most direct and important work on rejuvenation biotechnology. The research community knows more than enough to enable work on repairing the damage that causes aging.

In any case, here is a recent and representative selection from the ongoing flood of new results on genetics and longevity:

Reduction of Mitoferrin Results in Abnormal Development and Extended Lifespan in Caenorhabditis elegans

Iron is essential for organisms. It is mainly utilized in mitochondria for biosynthesis of iron-sulfur clusters, hemes and other cofactors. Mitoferrin 1 and mitoferrin 2, two homologues proteins belonging to the mitochondrial solute carrier family, are required for iron delivery into mitochondria. ... In this study we found that reduced mitoferrin levels in C. elegans by RNAi treatment causes pleiotropic phenotypes such as small body size, reduced fecundity, slow movement and increased sensitivity to paraquat. Despite these abnormities, lifespan was increased by 50% to 80% in N2 wild type strain, and in further studies using the RNAi sensitive strain eri-1, more than doubled lifespan was observed. The pathways or mechanisms responsible for the lifespan extension and other phenotypes of mitoferrin RNAi worms are worth further study, which may contribute to our understanding of aging mechanisms and the pathogenesis of iron disorder related diseases.

Activity of mannose-binding lectin (MBL) in centenarians

We analyzed MBL2 gene variants in two cohorts of centenarians, octo- and nonagenarians and in the general population, one from Sardinia island (Italy), recruited in the frame of the AKea study, and another from Campania (southern Italy), to search for haplotypes related to longevity. ...The frequency of high and null activity haplotypes was significantly lower and the frequency of intermediate activity haplotype significantly higher in centenarians and in subjects between 80 and 99 years from both the cohorts as compared each to the general population from the same geographic area.

MICS-1 interacts with mitochondrial ATAD-3 and modulates lifespan in C. elegans

Here, we provide evidence that MICS-1 is an interacting partner of the mitochondrial protein ATAD-3 (homologue of human ATAD3), which is essential for C. elegans development. We demonstrate that [RNA interference of mics-1 causes] enhanced longevity with an increased mean lifespan of up to 54% compared to control animals. Of note, also [RNA interference of atad-3] promoted longevity, although to a lesser extend (29% compared to controls).

Linkage of Cardiac Gene Expression Profiles and ETS2 with Lifespan Variability in Rats

Longevity variability is a common feature of aging in mammals, but the mechanisms responsible for this remain largely unknown. Using microarray datasets [we] identified a set of 252 cardiac transcripts predictive of relative lifespan in [rats]. ... four transcription factors (Max, Ets2, Erg, and Msx2) present in heart displayed longevity-dependent, strain-independent changes in abundance, but only ETS2 had an expression profile that directly correlated with the relative lifespan gene set. ... We conclude that variations in ETS2 abundance in hearts of adult rodents and the associated loss of CMs, contribute at least partially, to the longevity variability observed during normal aging of rats through activation of programmed necrosis.

Advanced glycation end-products (AGEs) are implicated in aging - one of the forms of chemical gunk that accumulates in the body over time, harming the operation of intricate biomolecular machinery (in this case probably by triggering cells to respond in an undesirable way). AGEs are a part of our dietary intake as well as being generated in the body, and there is a debate over the degree to which dietary intake of AGEs is important in the pace of buildup over a lifetime - and the role of gut bacteria for that matter, given that they can independently produce AGEs as well. Here is a review paper on the subject: "Advanced glycation end products (AGEs) are a heterogeneous, complex group of compounds that are formed when reducing sugar reacts in a non-enzymatic way with amino acids in proteins and other macromolecules. This occurs both exogenously (in food) and endogenously (in humans) with greater concentrations found in older adults. While higher AGEs occur in both healthy older adults and those with chronic diseases, research is progressing to both quantify AGEs in food and in people, and to identify mechanisms that would explain why some human tissues are damaged, and others are not. In the last twenty years, there has been increased evidence that AGEs could be implicated in the development of chronic degenerative diseases of aging, such as cardiovascular disease, Alzheimer's disease and with complications of diabetes mellitus. Results of several studies in animal models and humans show that the restriction of dietary AGEs has positive effects on wound healing, insulin resistance and cardiovascular diseases. Recently, the effect of restriction in AGEs intake has been reported to increase the lifespan in animal models. This paper will summarize the work that has been published for both food AGEs and in vivo AGEs and their relation with aging, as well as provide suggestions for future research."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22254007

A brief overview of one of the lines of work advocated by the Science for Life Extension Foundation: "Aging biomarkers are parameters that always, and in all people, change during aging. It is possible to evaluate and improve therapies that are aimed at slowing down aging, using the biomarkers of aging. The value and changing dynamics of aging markers provides information about the intensity of aging processes in the cells of the patient. Aging biomarker monitoring allows us not only to diagnose various diseases, but also to prevent their development. Aging can be slowed down. At the moment, there are already several scientific approaches that could lead to slowing down aging, and extending life. Scientists have been able to significantly extend the lifespans of model animals. Now, it is time to apply the biogerontology knowledge in clinical practice. To understand if a given therapy is effective or not, first of all we compile data via conventional clinical tests to create the 'electronic health passport.' After that, we can perform measurements of the aging biomarkers listed in the table. The indicators will inform us if the therapy is working. Soon we will be able to look at thousands of parameters, obtained using genome and transcriptome sequencing, epigenome mapping and analysis of proteome and metabolome. The additional data will make the anti-aging therapies more precise. ... view our entire booklet that lists twenty (20) aging bio-markers."

Link: http://ieet.org/index.php/IEET/more/konovalenko20120118

I'm not a big fan of the optimization mindset when it comes to long term health and longevity. Like all forms of optimization, it makes for a great hobby - with the potential to turn into a massive sink of time and money if you head on all the way down the rabbit hole. Importantly, however, and unlike optimization hobbies that involve cars, games, and other easily measured items, you will never really know how well you are doing when it comes to your own life expectancy. It's extremely easy to get the 80/20 result: practice calorie restriction and exercise regularly. But beyond that, there's no real way to tell whether any of your more esoteric practices are helping, hindering, or doing more or less nothing. There is no meaningful scorecard for future remaining life expectancy that you can measure and check your optimization efforts against.

This may well change over the next ten years, but for now it is what it is. By all means make health your hobby - it beats some of the other options in terms of general utility - but don't for one moment imagine that you actually know how well you're doing past the 80/20 point. And if you're not practicing calorie restriction, then it doesn't much matter what else you're doing because you haven't even captured all of the easy 80%.

Anyway, that all said, here is an interesting article that looks at measuring risk and life expectancy at the small scale - which is often a prelude to optimization, given human nature.

Many risks we take don't kill you straight away: think of all the lifestyle frailties we get warned about, such as smoking, drinking, eating badly, not exercising and so on. The microlife aims to make all these chronic risks comparable by showing how much life we lose on average when we're exposed to them: a microlife is 30 minutes off your life expectancy

Life expectancy for a man aged 22 in the UK is currently about 79 years, which is an extra 57 years, or 20,800 days, or 500,000 hours, or 1 million half hours. So, a young man of 22 typically has 1,000,000 half-hours (57 years) ahead of him, the same as a 26 year-old woman. We define a microlife as a chronic risk that shortens life on average by just one of the million half hours that they have left.

Here are some things that would, on average, cost a 30-year-old man 1 microlife:

Smoking 2 cigarettes

Drinking 7 units of alcohol (eg 2 pints of strong beer)

Each day of being 5 Kg overweight

A chest X-ray will set a middle-aged person back around 2 microlives, while a whole body CT-scan would weigh in at around 180 microlives.

This falls under the general heading of "fun with population-wide statistical measures of mortality," but you should find it food for thought, even if not of immediate application. On that note, an interesting speculative calculation to run, or at least build a framework for, would be a guesstimation of the benefit in microlives gained per dollar donated to the SENS Foundation.

An interview with Aubrey de Grey of the SENS Foundation: "I'm interested in making sure that none of [the forms of biological damage that cause aging] are left behind. ... the main reason why we prioritize certain things over others is simply if they are not being prioritized by the rest of the world. At the moment, [in] our Research Center in Mountain View, we are working on LysoSENS, as you said, but we are also working on MitoSENS, the elimination of mitochondrial mutations in aging, and ways to make those mitochondrial mutations harmless essentially by putting copies of the mitochondrial genome into the nuclear genome. And in projects that we are funding in university labs around the country, we are doing a number of other things relating to other aspects of SENS. So yes, we are interested in focusing on all of these things in parallel. ... So at the moment, there are just a few areas within SENS that we are de-prioritizing because they are being funded quite well elsewhere. One of them is the elimination of amyloids [that] occurs in Alzheimer's disease. And even there, it's only sort of that one subset of that one deadly thing that we are not working on. So we are working on something very similar, the accumulation of a similar type of garbage outside cells that occurs predominantly in the heart. It just turns out that even though Alzheimer's work is well-funded and well respected and everything, nevertheless during the same sort of approach for other types of amyloids, other types of extracellular garbage, it is not being particularly enthusiastically pursued by other people, so we are doing our bit. Similarly, in the case of lost cells where cells die and they are not automatically replaced by other cells or by the division of other cells - that is what stem cells are for. Stem cell therapy is very real - people are working in lots of areas in that field, so of course we are not trying to duplicate that effort. But even there, we are doing one of two things. For example, we're interested in a particular type of cell loss which is the shrinkage of an organ called the thymus, which is responsible for the creation of certain types of immune cells. It turns out that restoration of the thymus to its useful size is something that not many people work on. The approaches that have been tried have not been very successful. We are looking at some more ambitious but we think more promising approaches that have not been looked at by other people."

Link: http://hplusmagazine.com/2012/01/17/progress-in-therapies-for-rejuvenation-and-their-delivery/

Another telomere length correlation, adding data to a relationship known for some years: "A process linked to natural cell aging has now also been associated with knee osteoarthritis, researchers say. Telomeres - lengths of DNA on the ends of chromosomes, sometimes described as being like the plastic cap on a shoelace tip - naturally shorten with age, but can also shorten due to sudden cell damage. Abnormally short telomeres have been found in some types of cancer and preliminary research has suggested that the average telomere length is also shortened in osteoarthritis. In this new study, Danish researchers used new technology to closely examine the telomeres of cells taken from the knees of osteoarthritis patients who had joint replacement surgery. The cells had abnormally shorted telomeres and the percentage of cells with ultra-short telomeres increased with proximity to the damaged area in the knee joint ... The telomere story shows us that there are, in theory, two processes going on in osteoarthritis. Age-related shortening of telomeres, which leads to the inability of cells to continue dividing and so to cell senescence [deterioration], and ultra-short telomeres, probably caused by compression stress during use, which lead to senescence and failure of the joint to repair itself. We believe the second situation to be the most important in osteoarthritis. The damaged cartilage could add to the mechanical stress within the joint and so cause a feedback cycle driving the progression of the disease."

Link: http://health.usnews.com/health-news/family-health/pain/articles/2012/01/17/knee-arthritis-may-speed-up-process-linked-to-cell-aging

One of the more important parts of any future comprehensive toolkit of rejuvenation biotechnologies, capable of repairing the biological damage that causes aging, is the means to repair the brain in situ. The brain is in a class of its own: in theory everything other than the brain could be tissue engineered from scratch and replaced. This, in fact, will quite likely be the case for anyone who is cryopreserved and later restored to life in the flesh - easier to grow a new body than to restore the old one. But we can't replace the brain: its fine structure encodes our minds, and throwing out the old brain to replace it with even a perfect copy is just a very expensive form of suicide.

So it is encouraging to see that stem cell research is heading in the direction of ways and means to convince the brain to repair itself. This is just one thread of many needed lines of research - there is a lot more to the repair of aging than just ensuring a steady supply of new cells and refreshed stem cells that perform upkeep of tissue. But progress is progress; it all has to be done if we are to enjoy longer lives than our ancestors.

The cerebrum, as the substrate for our consciousness, memories, personality, and self-identity, presents unique challenges for regenerative medicine. Regenerative approaches must not only maintain general cerebral function, but also preserve as much as possible the details of the wiring and firing parameters that define each individual. A combination of molecular repair and gradual cellular replacement appears most likely to succeed. Toward this end, we are establishing paradigms in mice for replacing glutamatergic projection neurons in the neocortex, seat of our highest cognitive functions.

Any strategy for using transplanted cells for neocortical cell replacement is currently hampered by the inability to get cells to disperse into the existing neural tissue. To overcome this issue, we will transplant at the edge of the neocortex highly migratory embryonic GABAergic precursor cells that are engineered with lentiviruses to transdifferentiate to a glutamatergic fate once they have dispersed throughout the neocortex.

A great deal of what takes place in the laboratory these days is science fiction by the standards of the 1970s: cells transformed back and forth to order. Time moves on, and biotechnology advances.

A possibly interesting position is put forth in this blog post, an attempt to merge a package of right to end of life decisions and acceptance of death with the urge to extend healthy life through biotechnology - an argument that the present cultural debate that places these two things in opposition is misguided: "People who try to fend off death are being selfish, are in denial, and are pouring money down the drain for cockamamy schemes to preserve their frozen heads for some fingers-crossed future, which will never arrive. At the same time, we shouldn't let people die, particularly (and ironically) if they really want to. Choosing death is untenable. It's against nature. No, death is good only when death decides it's ready for you. Or so go the arguments of many who oppose anti-aging technology. But just because we accept death as good and necessary, that doesn't necessarily mean we have to say the same about aging. Can we argue for anti-aging technology, for 2,000-year lifespans of perpetual youth, and admit death can be good at the same time? Not only can we; we must. We can accept death yet also seek to live vastly longer, healthier, and happier. Death is good, but so too is a long, long, long life. We can attain long lives of quality by rejecting extreme 'life-saving measures,' embracing euthanasia, and accepting that there are just some things we cannot cure. Death has got to be our closest kept enemy if we want to be ageless. Baffling as it may seem, wanting to live to be a thousand years old is inextricably connected to the ability to decide when it's time to give up the ghost." I can't say as I agree with the rush to incorporate acceptance of death, but I'm certainly very much on the side of the right to choose when and how you die. One of the many great and horrible cruelties in our present culture is the sadistic enforcement of prohibition against the choice of euthanasia - not least because it is the source of most of the challenges and costs that attend the organization of a successful cryopreservation.

Link: http://blogs.discovermagazine.com/crux/2012/01/06/aging-is-our-enemy-death-is-our-ally/

The pace has picked up for discovery of longevity-correlated genetic and epigenetic variations in humans; there are too many for each and every new publication to be noted individually here - and we should expect there to be, ultimately, a very great many minor correlations between genes and natural variations in longevity. Here is an example: "The Leiden Longevity Study consists of families that express extended survival across generations, decreased morbidity in middle-age, and beneficial metabolic profiles. To identify which pathways drive this complex phenotype of familial longevity and healthy aging, we performed a genome-wide gene expression study within this cohort to screen for mRNAs whose expression changes with age and associates with longevity. ... The expression of 360 probes was found to change differentially with age in members of the long-lived families [and] we confirmed a nonagenarian specific expression profile for 21 genes out of 25 tested. Since only some of the offspring will have inherited the beneficial longevity profile from their long-lived parents, the contrast between offspring and controls is expected to be weak. Despite this dilution of the longevity effects, reduced expression levels of two genes, ASF1A and IL7R, involved in maintenance of chromatin structure and the immune system, associated with familial longevity already in middle-age. The size of this association increased when controls were compared to a subfraction of the offspring that had the highest probability to age healthily and become long-lived according to beneficial metabolic parameters."

Link: http://dx.doi.org/10.1371/journal.pone.0027759

I note that a Life Extension Conference organized by Christine Peterson of the Foresight Insititute is coming up in a few months. In general I see this as a prime example of the disappointing direction sometimes taken by people who are nonetheless very much supporters of the best long term visions for engineered longevity. They step off the train and start focusing on what's right in front of our nose today, things that are shiny but generally useless - the syndrome of looking under the lamp-post for the lost keys because that's where the light is. So this conference is very much an "anti-aging" event, only a single step removed from those held by the American Academy of Anti-Aging Medicine (A4M).

If we want to continue developing and guiding nanotech and other advanced technologies in the decades to come, we need to apply our high-tech knowledge and judgment to keeping our own bodies and brains functioning optimally. Should we be eating and exercising differently, taking supplements, getting our DNA read and telomeres measured, using sleep-monitoring or stress-reduction devices? These are challenging questions with new information arriving continually - let's pool our efforts to come up with good answers.

The trouble with this sort of statement is that there's already one good answer with a massive weight of science behind it. That answer is that you should be practicing calorie restriction and exercising moderately on a daily basis, and everything else that people are trying to sell you as a way to meaningfully extend health and life now is a waste of time and money. No technology or technique that is presently available or in any danger of becoming presently available within the next decade can even begin to approach the demonstrated benefits of calorie restriction and regular exercise for a basically healthy individual of any age. The only practical way to do far better than this is to support and help speed research and development of the SENS program for rejuvenation biotechnology - or related repair-based technologies aimed at reversing the causes of aging. The future isn't here yet when it comes to engineered longevity, and if we want that future to happen then we have to help make it happen.

Making it happen means accepting that there are no silver bullets now and that we'll have to work hard to create those silver bullets in time to be used by our older, future selves. But that truth doesn't sell products and services here and now, so you're not likely to hear it said by too many of those involved in a conference whose purpose is to sell you on presently available products and services.

Should I be appreciative that someone is making a serious effort to produce conferences attractive to the "anti-aging" industry that are one step up from the garbage that populates A4M and similar conferences? Possibly. But as I've said a number of times in the past, if gaining the attention of the anti-aging industry actually worked as a method to advance the cause of real rejuvenation biotechnology, such as SENS, then it would have worked already - and long ago, given that the Life Extension Foundation, A4M, and others have been hoeing that row for longer than many of us have been alive. But it doesn't work: the billions of dollars that flow through the "anti-aging" marketplace do not lead to any meaningful level of support, understanding, education, or funding for real longevity science - beyond the funding for research offered by the LEF, all you'll hear is crickets. Interactions with that industry are a dead end until that fact changes.

From the Globe and Mail: "Brian Delaney, the president of the North Carolina-based Calorie Restriction Society International, is 48 years old, but he may as well be 25. Mr. Delaney, co-author of the book The Longevity Diet, began practising calorie restriction nearly two decades ago. He attributes his remarkably youthful condition to his active lifestyle and diet of less than 2,000 calories a day, compared with his prerestriction diet of about 3,000 calories a day. (Three thousand calories a day is on par with Health Canada's estimated energy requirements for active 19- to 30-year-old men.) As a participant in a calorie restriction study at the Washington University in St. Louis, he's had a variety of biomarkers measured, such as blood pressure levels, fasting glucose levels, cholesterol, DNA damage and arterial elasticity, and the results are typical of someone at least 20 years younger. ... 'I don't look 25. ... I look a little bit younger than I am,' he acknowledges, but those test results, he says, provide validation for limiting what he eats. In recent years, as calorie restriction has gained legitimacy, Mr. Delaney's society, which he helped create in 1994, has recorded a surge in membership. It now numbers roughly 2,500 members, including at least a few dozen based in Canada. 'We've seen a huge amount of growth in the last three or four years,' he says, 'and that's primarily because ... there have been a lot of new [human] studies coming out that confirm what most of us believed, based on past studies with laboratory animals.' ... It's impossible, however, for researchers to say whether calorie restriction can really lead to longevity in humans. That would require an unrealistically long study. But when it comes to 'secondary aging,' which is all the diseases associated with age and obesity, such as diabetes, cardiovascular disease, hypertension and some forms of cancers, [there's] no question that you would delay the occurrence of these diseases by calorie restriction."

Link: http://www.theglobeandmail.com/life/health/new-health/health-nutrition/nutrition-features/can-fewer-calories-longer-life/article2302056/singlepage/

Limited forms of Lamarkian inheritance, such as in the operation of metabolism, seem to be a reality, passed down through generations by epigenetic modifications. Here is a popular science article on the topic: researchers "described a series of experiments that caused nematodes raised under the same environmental conditions to experience dramatically different lifespans. Some individuals were exceptionally long-lived, and their descendants, through three generations, also enjoyed long lives. Clearly, the longevity advantage was inherited. And yet, the worms, both short- and long-lived, were genetically identical. This type of finding - an inherited difference that cannot be explained by variations in genes themselves - has become increasingly common, in part because scientists now know that genes are not the only authors of inheritance. There are ghostwriters, too. At first glance, these scribes seem quite ordinary - methyl, acetyl, and phosphoryl groups, clinging to proteins associated with DNA, or sometimes even to DNA itself. ... There is increasing evidence that epigenetic modifications are transgenerational (inherited through multiple generations) in a variety of species. Examples include coat color in mammals, eye color in Drosophila, symmetry in flowers, and now longevity in C. elegans. ... There seems to be a renewed acceptance for the Lamarckian concept (in limited cases). This could change our understanding of inheritance in that it would add another component, probably minor, but present, in addition to Mendelian genetics."

Link: http://blogs.scientificamerican.com/guest-blog/2012/01/16/epigenetics-a-turning-point-in-our-understanding-of-heredity/

We can understand aging as being an accumulation of damage - of various types - to the biological machinery in and between our cells. This proceeds in an accelerating fashion as it passes various thresholds, and prompts evolved systems and feedback loops in our biology to flail, try to compensate, or fail in cascades. But in the very late stages of aging, for the oldest old, things stop being quite so easy to frame, and relationships between functional components - that hold throughout the rest of life - change dramatically. We see some of this change of phase in aging at work in the mortality plateau of flies; the risk of death per unit time in very old flies simply stops increasing, which poses interesting questions given that they are still alive and therefore presumably still accumulating biological damage. There are some signs that this late-life plateau of mortality rate might also exist in humans - but by no means enough data to be confident in that.

Here are a couple of papers from the Rejuvenation Research advance publication queue that also point towards the interesting nature of the late stages of aging. The first one is eye-opening, given everything we know about the effects of exercise at all other stages of life.

Physical Activity and Cardiac Function in the Oldest Old

The relationship of physical activity (PA) and cardiac function in the oldest old remains unclear. The objective of this study was to evaluate the relationship between PA and cardiac structure and function, in the oldest old. Subjects were recruited from the Jerusalem Longitudinal Cohort Study that was initiated in 1990 and has followed an age homogeneous cohort of Jerusalem residents born in 1920-1921. ... After adjusting for sex, education, diabetes, ischemic heart disease, hypertension, dependence in activities of daily living, and body mass index (BMI), no significant associations were found between systolic or diastolic function, or left ventricular structure and PA. Gender-specific analyses yielded similar findings. Our study of the oldest old did not demonstrate an association between PA and cardiac structure or function.

Paradoxical Physiological Transitions from Aging to Late Life in Drosophila

In a variety of organisms, adulthood is divided into aging and late life, where aging is a period of exponentially increasing mortality rates and late life is a period of roughly plateaued mortality rates. In this study we used 57,600 Drosophila melanogaster from six replicate populations to examine the physiological transitions from aging to late life in four functional characters that decline during aging: desiccation resistance, starvation resistance, time spent in motion, and negative geotaxis. Time spent in motion and desiccation resistance declined less quickly in late life compared to their patterns of decline during aging. Negative geotaxis declined at a faster rate in late life compared to its rate of decline during aging.

These results yield two key findings: (1) Late-life physiology is distinct from the physiology of aging, in that there is not simply a continuation of the physiological trends which characterize aging; and (2) late life physiology is complex, in that physiological characters vary with respect to their stabilization, deceleration, or acceleration in the transition from aging to late life. These findings imply that a correct understanding of adulthood requires identifying and appropriately characterizing physiology during properly delimited late-life periods as well as aging periods.

I would like to see the advent of a world in which this sort of knowledge is a mere curio, as no-one ever experiences the final stages of degenerative aging, nor indeed does anyone even become what we'd now call old, aged, over the hill. Long lives, but no decline in vigor or health. That is a world in which the SENS research program has succeeded, and everyone has the opportunity to undergo periodic repair of metabolism, mitochondria, stem cells, and removal of harmful aggregates - no more remarkable than flu shots today.

Researchers are examining cellular biochemistry in people who belong to long-lived families: "The offspring of nonagenarian siblings suffer less from age related conditions and have a lower risk of mortality compared to their partners. Fibroblast strains derived from such offspring in middle age show different in vitro responses to stress, more stress-induced apoptosis and less senescence when compared to strains of their partners. Aiming to find differences in cellular metabolism in vitro between these fibroblast strains, [cells were] analysed using (1)H nuclear magnetic resonance (NMR)-based metabolic footprinting. ... Strains from offspring and their partners were compared ... The ala-gln and glucose consumption were higher for fibroblast strains derived from offspring when compared to strains of their partners. Also, production of glutamine, alanine, lactate and pyroglutamic acid was found to be higher for fibroblast strains derived from offspring. In conclusion, differences in NMR-based metabolic profiles of human cells in vitro reflect the propensity for human longevity of the subjects from whom these were derived."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22218423

Via EurekAlert!: "For years, researchers seeking new therapies for traumatic brain injury have been tantalized by the results of animal experiments with stem cells. In numerous studies, stem cell implantation has substantially improved brain function in experimental animals with brain trauma. But just how these improvements occur has remained a mystery. Now, an important part of this puzzle has been pieced together by researchers ... In experiments with both laboratory rats and an apparatus that enabled them to simulate the impact of trauma on human neurons, they identified key molecular mechanisms by which implanted human neural stem cells - stem cells that are in the process of developing into neurons but have not yet taken their final form - aid recovery from traumatic axonal injury. A significant component of traumatic brain injury, traumatic axonal injury involves damage to axons and dendrites, the filaments that extend out from the bodies of the neurons. The damage continues after the initial trauma, since the axons and dendrites respond to injury by withdrawing back to the bodies of the neurons. ... Axons and dendrites are the basis of neuron-to-neuron communication, and when they are lost, neuron function is lost. In this study, we found that our stem cell transplantation both prevents further axonal injury and promotes axonal regrowth, through a number of previously unknown molecular mechanisms. ... We identified about 400 proteins that respond differently after injury and after grafting with neural stem cells. ... a group of cytoskeleton proteins was being changed, and in particular one called alpha-smooth muscle actin, which had never been reported in the neurons before.""

Link: http://www.eurekalert.org/pub_releases/2012-01/uotm-slh011212.php

One of the world's more active tissue engineering research and development groups works on building replacement tracheas from a scaffold and the patient's own cells. They have carried a number of successful transplants in recent years, and seem on a par with Tengion's work on bladders, or the folk producing heart valves for children in terms of outcomes and technological sophistication.

Here's an update on a transplant carried out late last year:

Surgeons in Sweden have replaced the cancerous windpipe of a Maryland man with one made in a laboratory and seeded with the man's cells.

...

"What we did is surgically remove his malignant tumor," Dr. Macchiarini said. "Then we replaced the trachea with this tissue-engineered scaffold." The Y-shaped scaffold, fashioned from nano-size fibers of a type of plastic called PET that is commonly used in soda bottles, was seeded with stem cells from Mr. Lyles's bone marrow. It was then placed in a bioreactor - a shoebox-size container holding the stem cells in solution - and rotated like a rotisserie chicken to allow the cells to soak in.

After two of days, it was installed in Mr. Lyles during an elaborate operation in which it was sutured to his throat and lungs. All told, the treatment cost about $450,000, Mr. Lyles said.

...

Dr. Macchiarini has performed a dozen trachea transplants since 2008, but the first 10 used organs from cadavers in which all the living cells were removed, leaving behind a natural scaffold of cartilage. Donated tracheas are rare, however, and are never a perfect fit. In Mr. Lyle's case, and in the case of an Eritrean man who received a similar transplant last June and is doing well, the synthetic scaffold is made using CT scans of the existing trachea to ensure it matches precisely.

The cost of the first tissue engineered parts will fall dramatically once the procedures become more widespread and the underlying technologies more robust and commoditized. But costs will not fall as far is they would in an actual free market in medicine, and there will be long and unnecessary years of delay - and vast expense for the sponsoring companies - before regulators in wealthy Western countries will approve these new applications of cell science for broad use.

Another cell population thought to be static throughout life turns out to be capable of regeneration and renewal, given the right cues: "Damage to podocytes - a specialized type of epithelial cell in the kidney - occurs in more than 90 percent of all chronic kidney disease. Now researchers [have] uncovered an unexpected pathway that reveals for the first time how these cells may regenerate and renew themselves during normal kidney function. ... Podocytes are found only in the kidney and are an integral structural component of its blood-filtering system. They stand shoulder-to-shoulder in a part of the organ called the glomerulus and wrap their long 'feet' around the semi-permeable capillaries through which blood flows. Narrow slits between the feet allow small molecules, such as water and salts, to pass while blocking large proteins. This filtering process is the first step to forming urine, and it is critically important - even one missing cell can leave a gap that would allow unwanted molecules through the barrier. ... It used to be thought that you were born with podocytes, and you died with the same podocytes - you don't make any more during your lifetime. ... The problem was, such a scenario doesn't make a lot of evolutionary sense - particularly when other epithelial cells routinely regenerate themselves. ... Podocytes may utilize recognized pathways of regeneration to renew themselves throughout life, [and] people suffering from chronic kidney disease may simply have worn out or outpaced their podocytes' capacity for renewal ... Now that the researchers know podocytes have the ability to regenerate in response to common cellular signals, their next step is to learn whether this regeneration occurs in healthy animals and people. ... If we can harness this regeneration, we may one day be able to treat people with chronic kidney disease."

Link: http://www.sciencedaily.com/releases/2011/12/111205102706.htm

Here is an open access paper from a researcher who focuses on mTOR and sees aging as almost entirely programmed, not the consequence of stochastic damage. His view as outlined in the paper is analogous to the view of nuclear DNA damage as not being significant over the present human life span. I think he has a very large hill of evidence for the damage-based view of aging to overcome in order to make a convincing point, however, and this should serve as a reminder that there are a great many diverse (but not necessarily well supported) views in the scientific community when it comes to the nuts and bolts of aging: "Aging is defined as a decline caused by accumulation of all sorts of damage, in particular, molecular damage. This statement seemed so obvious that it was not questioned. Yet several lines of evidence rule out molecular damage as a cause of aging. Yes, of course, molecular damage accumulates over time. But this accumulation is not sufficient to cause organismal death. Eventually it would. But the organism does not live long enough, because another cause terminates life first. This cause is aging, a continuation of developmental growth. Definitely, developmental growth is not driven by accumulation of molecular damage, although molecular damage accumulates. Similarly, aging is not driven by damage. Growth is stimulated in part by mitogen- and nutrient-sensing (and other) signaling pathways such as mTOR. Aging, 'an aimless continuation of developmental program', is driven by the same signaling pathways including mTOR. Aging in turn causes damage: not molecular damage but non-random organ damage (stroke, infarction, renal failure and so on) and death. Seemingly, one objection to this concept is that cancer is caused by molecular damage. And cancer is often a cause of death in mammals. So how may one claim that damage does not drive aging, if it is involved in cancer. Let us discuss this."

Link: http://impactaging.com/papers/v3/n12/full/100422.html

It isn't only rodent species that have a wide enough range of longevity to intrigue researchers. Amongst the rodents, naked mole rats can live nine times longer than shorter-lived and similarly sized cousin species, but amongst birds it is the case that parrots on average live more than five times as long as quail. The hope is that by comparing in detail the biochemistry of similar species with very different life spans, the research community will gain important new knowledge of aging - such as which of the mechanisms known to be associated with aging are more important determinants of life span. That understanding could help to steer research priorities in rejuvenation biotechnology by knowing which issues in the aging body will lead to greater benefits if repaired.

But back to the parrots and the quails: here is an example of the sort of research taking place in which researchers compare two species with different life spans. The context you should consider leading into the article is that there is some basis for thinking that levels of naturally produced antioxidants should partially determine life span in a species: oxidative damage can be tied to aging via a number of theories and their supporting evidence, and there are points in the biology of the cell where targeted antioxidants appear to be beneficial. So it is an interesting puzzle that this really doesn't seem to be the case in a direct and straightforward manner when comparing species. Mole-rats, for example, have high indicators of levels of oxidative compounds while being perfectly healthy and long-lived.

The oxidative damage hypothesis of ageing posits that the accumulation of oxidative damage is a determinant of an animal species' maximum lifespan potential (MLSP). Recent findings in extremely long-living mammal species such as naked mole-rats challenge this proposition. Among birds, parrots are exceptionally long-living with an average MLSP of 25 years, and with some species living more than 70 years. By contrast, quail are among the shortest living bird species, averaging about 5-fold lower MLSP than parrots.

To test if parrots have correspondingly (i) superior antioxidant protection and (ii) lower levels of oxidative damage compared to similar-sized quail, we measured [total antioxidant capacity and indicators of oxidative damage] in three species of long-living parrots and compared these results to corresponding measures in two species of short-living quails (average MLSP = 5.5 years). All birds were fed the same diet to exclude differences in dietary antioxidant levels.

...

Only glutathione peroxidase was consistently higher in tissues of the long-living parrots and suggests higher protection against the harmful effects of hydroperoxides, which might be important for parrot longevity. The levels of oxidative damage were mostly statistically indistinguishable between parrots and quails. ... Despite indications of higher protection against some aspects of oxidative stress in the parrots, the pronounced longevity of parrots appears to be independent of their antioxidant mechanisms and their accumulation of oxidative damage.

This is largely a null result - a lot of science is that way, as much a matter of eliminating leads or adding to a pile of data that may later, as a whole, contribute to a full understanding. For more on oxidative damage, birds, and mammals, you might look back into the archives:

• Of Rats, Pigeons, and Cell Membranes
• Why Avian Longevity?
• Bats and Birds: High Metabolic Rates, Great Longevity

The latest in a series of articles on immunotherapies aimed at clearing out the build up of cellular aggregates involved in Alzheimer's disease: "Immunotherapy targeting the age-related accumulation of extracellular aggregates, in the form of ß-amyloid, is the first rejuvenation biotechnology to reach Phase III human clinical trials. The promise of this therapy for the treatment and prevention of Alzheimer's disease (and ultimately, of so-called 'normal' brain aging) has sparked an interest in utilizing the same approach for other forms of aging damage, including the clearance of aggregated intracellular proteinaceous aging damage. Notably recent years have seen the appearance of a rising number preclinical studies of therapeutic vaccines targeting pathological tau species accumulating in the brains and spinal cords of transgenic rodent models of tauopathic neurodegeneration. These studies have reported -- somewhat surprisingly -- the antibody-mediated clearance of these primarily intracellular aging lesions, accompanied by functional improvements in treated animals. These two forms of structural damage are major contributors to the age-related degeneration of the brain, whether it leads to frank dementia or to the diagnostic euphemism of 'normal' age-related cognitive decline, and novel therapeutics to effect the removal of both from aging neurons will be key elements of a comprehensive panel of rejuvenation biotechnologies."

Link: http://sens.org/node/2577

Via the IEET: "Suppose you had a chance to question an ancient Greek or Roman - or any of our distant ancestors, for that matter. Let's say you asked them to list the qualities of a deity. It's a pretty good bet that many of the 'god-like' traits he or she described might seem trivial nowadays. After all, we think little of flying through the air. We fill pitch-dark areas with sudden lavish light, by exerting a mere twitch of a finger. Average folks routinely send messages or observe events taking place far across the globe. Copious and detailed information about the universe is readily available through crystal tubes many of us keep on our desks and command like genies. Some modern citizens can even hurl lightning, if we choose to annoy our neighbors and the electric company. Few of us deem these powers to be miraculous, because they've been acquired by nearly everyone in prosperous nations. After all, nobody respects a gift if everybody has it. And yet, these are some of the very traits that earlier generations associated with divine beings. Even so, we remain mortal. Our obsession with that fate is as intense as it was in the time of Gilgamesh. Perhaps more, since we overcame so many other obstacles that thwarted our ancestors. Will our descendants conquer the last barriers standing between humanity and Olympian glory? Or may we encounter hurdles too daunting even for our brilliant, arrogant, ingenious and ever-persevering species? ... Here's the safest prediction for the next 100 years - that mortality will be a major theme. Assuming we don't blow up the world, or fall into some other catastrophic failure mode, human beings will inevitably focus on using advanced technology to cheat death."

Link: http://ieet.org/index.php/IEET/more/5068

Telomeres are the protective caps of repeated DNA sequences stuck onto the end of chromosomes, cut short with each cell division, but maintained by an enzyme called telomerase whose job, amongst others, is to extend telomeres by adding extra repeats. As you can imagine, this lays the groundwork for complex feedback loops, influenced by many genes, and different in different species and cell types. Telomere biology is associated with aging, and telomeres tend to shorten in some species and some tissues with both advancing age and ill health - but it's still an open field for the development of a full explanation as to exactly how and why that is the case. Of great interest is whether the erosion of telomeres is one of the few primary causes of aging, or whether it is only a secondary consequence - for example, do telomeres erode because of mitochondrial damage?

At the moment, the best possible outcome would be that telomeres turn out to be a primary cause of aging and the various groups working on telomerase-based therapies wind up producing a useful tool for the rejuvenation toolkit. A more plausible outcome would be that telomeres are a useful biomarker of health and remaining life expectancy but don't actually require any specific medical intervention - other forms of rejuvenation biotechnology will address the primary causes of aging, and telomeres will lengthen as a result. But we shall see where it all ends up.

There has been a fair amount of back and forth as to just how well telomere length can serve as a biomarker: lots of different outcomes in different studies. To some degree this was expected due to the differing behavior of telomerase in different tissues, but even so there is much to debate given the results to date. Here, a study in birds provides further food for thought by showing that telomere length varies in usefulness as a measure at different periods in life:

The birds with the longest telomeres - the protective caps at the ends of chromosomes - live the longest, according to a new study. "It is the first time this has been shown for any species," ... The scientists measured telomere length in red blood cells of 99 captive zebra finches (Taeniopygia guttata). The birds resemble long-lived animals in that there is little restoration of telomeres in body cells as they age. The first measurement was taken at 25 days; the researchers then followed the birds over their natural life span, ranging from less than a year to nearly 9 years, and measured telomeres again at various time points. They found a highly significant correlation between telomere length at 25 days and life span; birds with longer telomeres lived longer. Length measured at 1 year also predicted life span, but the relationship was weaker, whereas at later time points (after 3, 4, 6, and 7 years) there was no correlation ... This might explain why previous results in humans and animals have not been consistent. "So far studies just looked at individuals that were already quite old," Monaghan says. "But if you look at telomeres in old age, then those individuals with the shortest telomeres will have already died."

And birds, by the way, are not necessarily the best model for thinking about telomeres in mammals - they are quite different, possibly as a result of the metabolic demands of flight given that bats exhibit many of the same tropes. It has to be said that the general theme in biology is that the situation inside a living organism is always more complex than was thought a few years ago, and definitely more complex than we'd like. The foundations of medical technology would be easier if we were simpler.

The decline of the brain is all the more reason to work harder on rejuvenation biotechnology and make better lifestyle choices: "researchers found a 3.6% decline in mental reasoning in women and men aged 45-49. They assessed the memory, vocabulary and comprehension skills of 7,000 men and women aged 45 to 70 over 10 years. ... Previous research had suggested that cognitive decline does not begin much before the age of 60. But the results of this study show that it could in fact begin in middle age. This is important, the researchers say, because dementia treatments are more likely to work at the time when individuals start to experience mental impairment. The results of the tests show that cognitive scores declined in all categories except vocabulary - and there was a faster decline in older people. The study found a 9.6% decline in mental reasoning in men aged 65-70 and a 7.4% decline for women of the same age. ... We now need to look at who experiences cognitive decline more than the average and how we stop the decline. Some level of prevention is definitely possible. Rates of dementia are going to soar and health behaviours like smoking and physical activity are linked to levels of cognitive function. It's important to identify the risk factors early. If the disease has started in an individual's 50s but we only start looking at risk in their 60s, then how do you start separating cause and effect? ... Previous research suggests that our health in mid-life affects our risk of dementia as we age, and these findings give us all an extra reason to stick to our New Year's resolutions. Although we don't yet have a sure-fire way to prevent dementia, we do know that simple lifestyle changes - such as eating a healthy diet, not smoking, and keeping blood pressure and cholesterol in check - can all reduce the risk of dementia."

Link: http://www.bbc.co.uk/news/health-16425522

The important portion of a targeted therapy for killing cells - cancer cells in this case - is not the part that destroys the cell itself. Any old chemotherapy drug can be used to that end. The point of the targeting mechanism is that the drug can be delivered in tiny, precise doses to minimize side-effects and any harm to surrounding tissues. These technologies are well worth watching because they will have far broader applications than just cancer. There are many areas in the aging body where targeted cell destruction will do a great deal of good, such as senescent cells and portions of the immune system. Here is an example from the cancer research community: "The process involved is akin to building and equipping a car with the finest features, adding a passenger (in this case the cancer drug), and sending it off to its destination (in this case the cancer cell). To design the 'vehicle,' researchers used a selection strategy developed by Farokhzad's team that allowed them to essentially select for ligands (molecules that bind to the cell surface) that could specifically target prostate cancer cells. The researchers then attached nanoparticles containing chemotherapy, in this case docetaxel, to these hand-picked ligands. To understand Farokhzad's selection strategy, one must understand ligand behavior. While most ligands mainly have the ability to bind to cells, the strategy of Farokhzad and his colleagues allowed them to select specific ligands that were not only able to bind to prostate cancer cells, but also possessed two other important features: 1) they were smart enough to distinguish between cancer and non-cancer cells and 2) they were designed to be swallowed by cancer cells. ... Most ligands are engulfed by cells, but not efficiently. We designed one that is intended to be engulfed."

Link: http://www.brighamandwomens.org/about_bwh/publicaffairs/news/pressreleases/PressRelease.aspx?PageID=1036

One of the numerous modestly-sized projects running under the auspices of the SENS Foundation is their Academic Initiative: helping to bring more life science undergraduate and postgraduate students into contact with the Strategies for Engineered Negligible Senescence, encourage them to become biogerontologists and build a career on the defeat of aging, and get them working on one of the many needed research projects that form the foundation of rejuvenation biotechnology. Science at the cutting edge takes place at many levels, from projects that can be funded with less than ten thousand dollars and three months of student time all the way up to the big hundred million dollar lab proposals. As biotechnology becomes ever cheaper and more capable, the number of significant projects and project components that can be funded at low cost and carried out successfully by graduate students grows larger by the month.

The future of life science is many more smaller projects: a huge number of tasks to be accomplished, and technologies that make each individual task small in comparison to the labor that would have been required in previous decades. Advanced life science students should be out there making connections and accomplishing meaningful tasks - helping to advance the state of knowledge and biotechnology, not just learning and recapitulating. It's well within their capabilities, and, thanks to progress in technology, it's now also well within the appropriate budget. Programs like the SENS Foundation Academic Initiative will grow in number and become more important across the board in the life sciences.

The Academic Initiative launched a new website recently:

Welcome to the SENS Foundation Academic Initiative's new website. In addition to containing more comprehensive information about the Initiative and what it does, this site offers a number of new features, including a listing outreach projects and a searchable database of member profiles. The site leaves plenty of room for the Initiative to grow into, thanks to its new committee pages, its new media section, and its more streamlined navigation.

The single greatest feature of this new website -- an extension and enhancement of an overlooked, underused feature of our previous site -- is its ability to offer our members their own spaces. Each research project, outreach project, and volunteer committee has its own updatable page, so that people who are part of any given project or committee can edit and care for their own corner of our site.

If you wander over to the projects section, you'll see lists of available projects and ongoing projects. If this sort of thing interests you, it's worth remembering that the SENS Foundation makes modest grants in connection with the Academic Initiative:

The SENS Foundation Academic Initiative is pleased to announce that it will be awarding up to $30,000 in materials grants in 2012. These grants are available to undergraduate, graduate, and medical students, and may be used to cover the cost of laboratory materials for aging- and rejuvenation-related research projects. A typical grant will range from $500-$2000, but grants of up to $5000 may be awarded for group projects. These grants are meant to provide students with valuable experience in research and leadership, and to help set recipients on the course to a career in SENS-related research.

The processes that keep cells clear of debris and otherwise well maintained are important in aging - what we know of autophagy should make that clear. Here, researchers are taking a brute force approach to enumerating the controlling mechanisms of cellular homeostasis: "To do its job properly within the cell, a protein first must fold itself into the proper shape. If it doesn't, trouble can result. More than 300 diseases have at their root proteins that misfold, aggregate and eventually cause cellular dysfunction and death. [The] research identifies new genes and pathways that prevent protein misfolding and toxic aggregation, keeping cells healthy, and also identifies small molecules with therapeutic potential that restore health to damaged cells, providing new targets for drug development. ... These discoveries are exciting because we have identified genes that keep us healthy and small molecules that keep us healthy. Future research should explain how these two important areas interact. ... [Researchers] tested all of the approximately 19,000 genes in C. elegans. They reduced expression of each gene one at a time and looked to see if the gene suppressed protein aggregation in the cell. Did the gene increase aggregation or lessen it or have no effect at all? The researchers found 150 genes that did have an effect. They then conducted a series of tests and zeroed in on nine genes that made all proteins in the cell healthier. ... These nine genes define a core homeostastis network that protects the animal's proteome (the entire set of proteins expressed by the organism) from protein damage. ... These are the most important genes. Figuring out how nine genes - as opposed to 150 - work is a manageable task."

Link: http://www.eurekalert.org/pub_releases/2012-01/nu-twp010612.php

Via EurekAlert!: researchers "have found that the age-related impairment of the body's ability to replace protective myelin sheaths, which normally surround nerve fibers and allow them to send signals properly, may be reversible, offering new hope that therapeutic strategies aimed at restoring efficient regeneration can be effective in the central nervous system throughout life. ... Using a surgical technique, the researchers introduced an experimental demyelinating injury in the spinal cord of an old mouse, creating small areas of myelin loss, and then exposed those areas to cells found the blood of a young mouse. By doing so, they found that the influx of certain immune cells, called macrophages, from the young mouse helped resident stem cells restore effective remyelination in the old mouse's spinal cord. This 'rejuvenating' effect of young immune cells was mediated in part by the greater efficiency of the young cells in clearing away myelin debris created by the demyelinating injury. Prior studies have shown that this debris impedes the regeneration of myelin. ... Aging impairs regenerative potential in the central nervous system. This impairment can be reversed, however, suggesting that the eventual development of cell-based or drug-based interventions that mimic the rejuvenation signals found in our study could be used therapeutically."

Link: http://www.eurekalert.org/pub_releases/2012-01/jdc-sfa010512.php

Uncoupling proteins (UCPs) govern the process of mitochondrial uncoupling, which changes the operation of the mitochondria in our cells to generate more heat and less of the cellular fuel chemical ATP. It's one of the mechanisms by which mammals regulate their body temperature. As for many processes that alter the behavior of mitochondria, uncoupling has an effect on life span, with more uncoupling usually leading to longer life spans:

Mitochondria are the power plants of your cells: they toil to turn food into ATP, used as fuel by the cell. In recent years, the eye of the research community has turned towards the process of mitochondrial uncoupling, whereby the processing of food is uncoupled from the generation of ATP. The result is less ATP and more energy in the form of heat - this is a part of the temperature regulation process in mammals, for example. It also appears to be important in calorie restriction, and therefore possibly important to longevity and aging.

The mitochondria are clearly very important in any consideration of aging, given that there are so very many ways to manipulate them to either shorten or lengthen life in laboratory animals. This is one of the reasons that any serious program of rejuvenation biotechnology has to include efforts to repair accumulated, age-related mitochondrial damage: there is an enormous weight of evidence telling us that mitochondria are a lynchpin in aging.

But back to uncoupling: there are compounds that promote uncoupling in mammals, such as DNP, but you can't just load up on an uncoupler and wait for the benefits to roll in. If your mitochondria produce too much heat for too long, you will simply roll over and die from something that looks a lot like heat stroke. Metabolism is a finely balanced machine, and taking it beyond its limits is easy to do once you bring this sort of process manipulation into the picture.

There exists a sizable amount of published work on uncoupling and longevity, and this field is, I think, helped by the fact that it borders on the study of calorie restriction, which is a heated area of research these days. A group that has published previously on human uncoupling protein variations and longevity in the past recently put out an open access paper on their research, which goes into more detail as to the findings.

Further Support to the Uncoupling-to-Survive Theory: The Genetic Variation of Human UCP Genes Is Associated with Longevity:

In humans Uncoupling Proteins (UCPs) are a group of five mitochondrial inner membrane transporters with variable tissue expression, which seem to function as regulators of energy homeostasis and antioxidants. In particular, these proteins uncouple respiration from ATP production, allowing stored energy to be released as heat. Data from experimental models have previously suggested that UCPs may play an important role on aging rate and lifespan. We analyzed the genetic variability of human UCPs in cohorts of subjects ranging between 64 and 105 years of age (for a total of 598 subjects), to determine whether specific UCP variability affects human longevity. Indeed, we found that the genetic variability of UCP2, UCP3 and UCP4 do affect the individual's chances of surviving up to a very old age.

...

Substantial evidence suggests that the ability of UCPs to reduce ROS and regulate energy utilization underpins the ability of UCPs to promote lifespan in various experimental models. In the present study we found that variants in UCP2, UCP3, and UCP4 significantly affect an individual's chances of becoming ultra-nonagenarians. The different localization of the proteins we found associated with longevity allows us to predict the areas where the uncoupling process may play an important role in survival at very old age.

From CTV News: "Researchers say they have discovered a new source of stem cells at the back of the eye, which they hope may one day provide a way to repair the damage from age-related macular degeneration, or AMD. ... [Researchers] identified the central nervous system stem cells in a single layer called the retinal pigment epithelium, or RPE, which lies behind the retina. ... The researchers salvaged the stem cells from the RPE layer in the eyes of more than 100 deceased donors, who ranged in age from 22 to 99. But the cells can also be isolated from the fluid surrounding the retina at the back of the eye, meaning they're also accessible in living people. ... You can literally go in and poke a needle in the eye and get these cells from the sub-retinal space. It sounds awful, but retinal surgeons do it every day. ... In culture dishes in the lab, the researchers were able to coax about 10 per cent of the RPE-derived stem cells to grow in the lab. Further prodding caused the cells to differentiate into, or give rise to, a variety of cell types - those that make bone, fat or cartilage. [The researchers] also generated a progenitor cell that carries some characteristics of one type of nervous system cell, although it was not fully differentiated. ... But the fact that we could make these cells that were part-way, that were immature, indicates to us that if we keep on manipulating them, going forward in the future, we should be able to find ways to create other types of central nervous system cells."

Link: http://www.ctv.ca/CTVNews/Health/20120106/macular-degeneration-stemcells-120106/

One of the predictions of reliability theory as applied to aging is that we are all born with an existing level of damage. One of the ways in which that damage might occur - and "damage" here is a very broad term, which might include suboptimal epigenetic changes - stems from maternal influence while in the womb. For example, researchers "have shown one way in which poor nutrition in the womb can put a person at greater risk of developing type 2 diabetes and other age-related diseases in later life. This finding could lead to new ways of identifying people who are at a higher risk of developing these diseases and might open up targets for treatment. ... The research shows that, in both rats and humans, individuals who experience a poor diet in the womb are less able to store fats correctly in later life. Storing fats in the right areas of the body is important because otherwise they can accumulate in places like the liver and muscle where they are more likely to lead to disease. ... One of the ways that our bodies cope with a rich modern western diet is by storing excess calories in fat cells. When these cells aren't able to absorb the excess then fats get deposited in other places, like the liver, where they are much more dangerous and can lead to type 2 diabetes. ... The team found that this process is controlled by a molecule called miR-483-3p. They found that miR-483-3p was produced at higher levels in individuals who had experienced a poor diet in their mother's wombs than those who were better nourished."

Link: http://www.eurekalert.org/pub_releases/2012-01/babs-hpm010512.php

If research and development in medicine is to move at anywhere near the pace it is capable of, given the rapid progress in all forms of underlying biotechnology, it must find a way to extend beyond the most heavily regulated regions. The most capable and largest research communities, like that based in the US, are also those with the least ability to locally develop their advances into medical products, thanks to the straitjacket of regulation from government bodies like the FDA.

For much of clinical development, this means that the expense imposed by the FDA makes progress either very slow indeed - and lacking in the competitive vigor that characterizes less regulated industries - or simply non-existent where the costs make a business of medicine unprofitable. Much of this weighing down of development is invisible to the casual observer: you cannot see lost opportunities, or count the medical technologies that might already exist if not for decades of the ball and chain of the FDA.

For some potential clinical applications it's worse than that: they are simply forbidden outright, with no path towards becoming permitted. Treatment of aging, development of rejuvenation biotechnology, is one such field in the US. The FDA doesn't recognize aging as a medical condition, and so will not approve treatments aimed to intervene in aging. Given that, raising funds for development of potential longevity science is very hard - there is next to no for-profit funding, and where that funding does exist, the regulatory path to approval steers development away from potentially useful treatments for aging into the sidelines of diabetes therapy or late-stage treatment of other age-related conditions. This effectively prevents any effective path towards longevity-enhancing therapies for healthy people from being followed within the US.

The way out of this mess, short of a revolution or collapse of government, is a systemic extension of the industry of clinical application of longevity science to include regions outside the US. The logical end result of the growing medical tourism industry is better defined roadway of connections and multinational organizations that will usher scientific developments from regions like the US into other parts of the world where they can be offered as clinical treatments. What has happened for stem cell therapies and medical tourism in the past decade is just a tiny beginning, a few first steps towards what must become a much more systematic, high-bandwidth, highly visible, reliable transfer of knowledge and funds - such that the US government can't just shut it down with a few threats of prosecution, such that every life scientist in the US knows how to monetize their research outside the US by shopping around for deals with offshore developers, and such that a large enough and competitive enough marketplace exists to make that shopping around a viable process.

This is a topic I have strong opinions on. So it's pleasing to see other people touching on these themes as well. Here's a post from the IEET blog on the intersection of visions for seasteading and visions for offshore medical tourism and clinical development:

What is the likelihood of seeing research vessels devoted to scientific research outside the bounds of national jurisdiction? The idea of relocating for the sake of circumventing law, in particular the notion of establishing new nations in international waters, is an idea typically initiated with liberty in mind. ... For instance, the idea of ships offering in vitro fertilization, flying Denmark flags, has been proposed to provide UK residents with a service, locally illegal. In the U.S., major delays in safe and effective regenerative medical services are likely. Regenerex, a company offering regenerative stem cell therapies, faces a potential halt in operation by the FDA. The company has been in dispute with the FDA over whether or not stem cell therapies should be considered 'drug' therapies. If the FDA succeeds in this dispute, Regenerex would then be required, by law, to discontinue treatments until appropriate certification is in place, which could be 'staggeringly expensive' and take several years.

Biotech companies researching longevity also inconveniently face roadblocks from the FDA, which only approves drugs aimed at treating diseases in a specific, defined manner. Aging is not currently considered a disease by the FDA, which makes the delay of essential treatment virtually inevitable. The need for extensive reform in policy is a reality of a good deal of near and future medical services, and both businesses and patrons are incentivized by the unique opportunity of circumventing regulatory systems.

I don't think that the sea is the answer on the scale of development industry needed to break loose the FDA's ball and chain - the goal seems to me to more a case of linking existing (land-based) infrastructure and development institutions, creating the roadway of knowledge, deals, and contractual ties, and the community that sustains that roadway.

Type 2 diabetes (T2D) is a lifestyle disease for the vast majority of people - you avoid it by refraining from overeating, becoming fat, and giving up exercise to turn sedentary. But some folk are more likely to succumb than others, given the same lifestyle choices, and different people descend into metabolic syndrome and then type 2 diabetes at different rates. It won't be too many more years before clinics will be able to tell you exactly where you stand on the downward spiral, and what your risks are: research "has provided the first proof of molecular risk factors leading to type 2 diabetes, providing an 'early warning' sign that could lead to new approaches to treating this and other human disease conditions. ... Taking an innovative research direction, [the] research team decided to map DNA methylation variations rather than DNA sequence variations, as was traditionally done. The team undertook a proof-of-concept study among 1,169 type 2 diabetes patients and non-diabetic controls. The results demonstrated the unique abilities of this novel research approach by revealing a clear-cut, disease-predisposing DNA methylation signature. This is a first report in the scientific literature of epigenetic risk factor for T2D. DNA methylation is a naturally occurring mechanism used to regulate genes and protect DNA from some types of cleavage. It is one of the regulatory processes that are referred to as epigenetic, in which an alteration in gene expression occurs without a change in the nucleotide sequence of the DNA. Defects in this process cause several types of disease that afflict humans. ... telltale methylation signature marks were also shown to appear on the DNA of young individuals who latter developed impaired glucose metabolism, even before the appearance of clinical diabetic manifestations."

Link: http://www.sciencedaily.com/releases/2011/12/111228134841.htm

The onset of Alzheimer's is not a sudden thing, which reinforces the view of it as a lifestyle disease: "The first changes in the brain of a person with Alzheimer's disease can be observed as much as ten years in advance - ten years before the person in question has become so ill that he or she can be diagnosed with the disease. [Researchers] are studying biomarkers - substances present in spinal fluid and linked to Alzheimer's disease. The group has studied close to 140 people with mild memory impairment, showing that a certain combination of markers (low levels of the substance beta-amyloid and high levels of the substance tau) indicate a high risk of developing Alzheimer's disease in the future. As many as 91 per cent of the patients with mild memory impairment who had these risk markers went on to develop Alzheimer's within a ten-year period. In contrast, those who had memory impairment but normal values for the markers did not run a higher risk of getting Alzheimer's than healthy individuals. ... This is a very important finding with regard to the development of new therapies against the disease. All prospective therapies have so far shown to be ineffective in stopping the disease, and many people are concerned that the pharmaceutical companies will give up their efforts in this field. But these failures may depend on the fact that the new therapies were initiated too late. When a patient receives a diagnosis today, the damage has already gone too far." I'm not sold on this last comment, given the evidence suggesting that Alzheimer's symptoms are reversible.

Link: http://www.lunduniversity.lu.se/o.o.i.s?id=24890&news_item=5773

Exercise mimetics are drugs that can replicate some fraction of the beneficial effects of exercise; their development is in the early stages. I don't think it's too far-fetched to suggest that the next ten years of exercise mimetic development will look a lot like the last ten years of calorie restriction mimetic development. In other words there will be a couple of well-funded, well-hyped lines of research that fizzle out with nothing to show for it, some solid advances towards identifying mimetics that, for one reason or another, aren't terribly practical for clinical development, and all of that against a backdrop of across-the-board progress in understanding metabolic processes that relate to exercise and its long-term effects. But, you'll note, no actual products that are legally available for use by healthy people.

Absent the straitjacket regulation it would be a whole other story when it came to products and product development, of course, but we live in a world of centralized control and socialism for medicine for those regions that also boast the most active and capable research communities. It's unfortunate, and it needs to change.

In any case, here is an example of the sort of early stage work that will lead to exercise mimetic development. If you cast your mind back ten years or so, you'll see it looks just like the sort of research taking place into the mechanisms of calorie restriction back then.

We take it for granted, but the fact that our muscles grow when we work them makes them rather unique. Now, researchers have identified a key ingredient needed for that bulking up to take place. A factor produced in working muscle fibers apparently tells surrounding muscle stem cell "higher ups" that it's time to multiply and join in. ... In other words, that so-called serum response factor (Srf) translates the mechanical signal of work into a chemical one.

"This signal from the muscle fiber controls stem cell behavior and participation in muscle growth," says Athanassia Sotiropoulos of Inserm in France. "It is unexpected and quite interesting." It might also lead to new ways to combat muscle atrophy. ... Srf works through a network of genes, including one known as Cox2. That raises the intriguing possibility that commonly used Cox2 inhibitors - think ibuprofen - might work against muscle growth or recovery, Sotiropoulos notes. ... "It may be difficult to find a beneficial amount of Srf," she says. "Its targets, interleukins and prostaglandins, may be easier to manipulate."

And so this will lead to a tree of research spanning the next few years, in parallel to a web of other, similar spreading investigations of proteins and genes and their effects on exercise.

From Big Think: "The loss of a human limb is a tragedy. We know that once they're gone, mammalian arms and legs can't ever be restored. But if you cut off a salamander's leg - or tail - it will reappear in just a few weeks. ... Now, a new generation of longevity-seekers hopes to apply the power of amphibians like the salamander, the axlotl, and the worm to human medicine. ... In the future, if we had the ability to grow a brand new heart or parts of hearts with that person's very own adult stem cells, then when we know that they have heart disease, we could just replace the heart. All of those [costly] visits to the hospital, all of the drugs, won't be required. ... Better tools will enable us to repair people rather than just sort of patching them up for a little while until they get sicker and sicker. ... Over the past few decades, scientists have begun to understand exactly how the regeneration process works in nature. When a salamander is injured, a clump of cells called a blastomea forms at the site of the wound. Like embryonic stem cells, the blastomea are especially plastic. These cells are then triggered to de-differentiate and re-initiate growth. ... Debate remains over whether they're fully pluripotent, meaning that they have the ability to form any type of tissue, or whether the cellular dynamics merely have to be reprogrammed. ... The trick, of course, is applying this knowledge to human anatomy."

Link: http://bigthink.com/ideas/41794

Two supercentenarian genomes have been sequenced, and suggest that - as always - the roots of variations in human longevity are more complex than we'd like them to be: "Supercentenarians (age 110+ years old) generally delay or escape age-related diseases and disability well beyond the age of 100 and this exceptional survival is likely to be influenced by a genetic predisposition that includes both common and rare genetic variants. In this report, we describe the complete genomic sequences of male and female supercentenarians, both age >114 years old. We show that: (1) the sequence variant spectrum of these two individuals' DNA sequences is largely comparable to existing non-supercentenarian genomes; (2) the two individuals do not appear to carry most of the well-established human longevity enabling variants already reported in the literature; (3) they have a comparable number of known disease-associated variants relative to most human genomes sequenced to-date; (4) approximately 1% of the variants these individuals possess are novel and may point to new genes involved in exceptional longevity; and (5) both individuals are enriched for coding variants near longevity-associated variants that we discovered through a large genome-wide association study. These analyses suggest that there are both common and rare longevity-associated variants that may counter the effects of disease-predisposing variants and extend lifespan. The continued analysis of the genomes of these and other rare individuals who have survived to extremely old ages should provide insight into the processes that contribute to the maintenance of health during extreme aging."

Link: http://dx.doi.org/10.3389/fgene.2011.00090

The popular press will give just as much attention to an advance that extends life in healthy laboratory animals as they will to a technology demonstration that even partially reverses an artificially induced shortness of life. This is a problem, because the former is worthy of our attention, while it is almost always the case that the latter is not. Here is another example of the type from today's news:

Researchers at the University of Pittsburgh Medical Center genetically altered mice to make them age faster, making them old and weak in a span of 17 days. The scientists then injected the mice with stem cell-like cells taken from the muscle of young, healthy mice. The result was they reversed the aging process. The rapidly aging mice lived up to three times longer, dying after 66 days, rather than 28 days. The cell injection also appeared to make the animals healthier, improving their muscle strength and brain blood flow.

No, they did not reverse the aging process. What these researchers achieved was to partially (very partially) ameliorate the unnatural form of accelerated aging that they themselves created in these mice - which could be due to any number of mechanisms that have no application whatsoever to the treatment of normal aging.

You might recall that this same talking point came up a little over a year ago in connection with research into telomerase and accelerated aging:

It's interesting stuff, but unfortunately this present research is being headlined as "scientists reverse aging in mice" - which is absolutely not what was accomplished. Reversing an artificially created accelerating aging condition by removing its cause is not the same thing as intervening in normal aging, and it will rarely have any relevance to normal aging. ... The bottom line is that it is really only worth getting excited over a study that shows extension of life rather than an un-shortening of life. It's all too easy to create short-lived mice and then make them less short-lived - hundreds of studies have achieved this result in one way or another.

But this seems a little too subtle for much of the media - or, more cynically, perhaps it's more a matter that the employees of those press institutions don't really care all that much about accuracy or background for so long as the page views keep rolling in.

The proteasome is a cellular repair system that seems to be important in the evolution of longevity; here researchers show that impairing it causes accelerating aging. This is expected - aging is damage. Even if it fits with the established view, however, we should be wary of putting too much weight on studies that show shortened life span. There are all too many ways to reduce life span that have no application to extending life span, and the true proof of an interesting mechanism is to demonstrate increased maximum life span in mammals. Still, this is interesting work when held up against the broader context of what is known about the proteasome and the role of low level biochemical damage in aging: "The proteasome is a multicatalytic enzyme complex responsible for the degradation of both normal and damaged proteins. An age-related decline in proteasomal activity has been implicated in various age-related pathologies, including obesity and hepatic steatosis. The relevance of decreased proteasomal activity to aging and age-related diseases remains unclear, however, because suitable animal models are not available. In the present study, we established a transgenic (Tg) mouse model with decreased proteasomal chymotrypsin-like activity. Tg mice exhibited a shortened life span and developed age-related phenotypes. In Tg mice, polyubiquitinated and oxidized proteins accumulated. ... Our results provide the first in vivo evidence that decreased proteasomal chymotrypsin-like activity affects longevity and aggravates age-related metabolic disorders, such as obesity and hepatic steatosis."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22210478

Researchers are applying the most modern tools of biotechnology in efforts to better understand the evolution of longevity: "The genetic basis of the large species differences in longevity and aging remains a mystery. Thanks to recent large-scale genome sequencing efforts, the genomes of multiple species have been sequenced and can be used for cross-species comparisons to study species divergence in longevity. By analyzing proteins under accelerated evolution in several mammalian lineages where maximum lifespan increased, we identified genes and processes that are candidate targets of selection when longevity evolves. We identified several proteins with longevity-specific selection patterns, including COL3A1 that has previously been related to aging and proteins related to DNA damage repair and response such as DDB1 and CAPNS1. Moreover, we found that processes such as lipid metabolism and cholesterol catabolism show such patterns of selection and suggest a link between the evolution of lipid metabolism, cholesterol catabolism, and the evolution of longevity. Lastly, we found evidence that the proteasome-ubiquitin system is under selection specific to lineages where longevity increased and suggest that its selection had a role in the evolution of longevity. These results provide evidence that natural selection acts on species when longevity evolves, give insights into adaptive genetic changes associated with the evolution of longevity in mammals, and provide evidence that at least some repair systems are selected for when longevity increases."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22205409

Video of presentations from last year's SENS5 conference on rejuvenation biotechnology and longevity science continue to be posted to YouTube as SENS Foundation volunteers complete the processing. This latest presentation is one of the more interesting ones - an example of actual rejuvenation demonstrated for one narrow aspect of the immune system.

Aging is associated with a decline in B-lymphopoiesis in the bone marrow and accumulation of long-lived B-cells in the periphery. These changes decrease the body's ability to mount protective antibody responses. The mechanisms underlining these alterations are poorly understood. We found that the age-related alterations in the B-lineage reflect homeostatic pressures that are imposed by the accumulating long-lived B cells. Thus, a continuous demand for peripheral B cells renders the [bone marrow] devoid of senescence, and depletion of B cells in old mice revives B cell production in the bone marrow and rejuvenates the peripheral B cell compartment. Collectively, our studies suggest that immunosenescence in the B-lineage can be reversed to enhance immune responsiveness in aging.

You might recall that this approach and its foundations have been mentioned here at Fight Aging! a number of times. At the moment, the evidence suggests that this general approach of selectively destroying immune cells will work to restore a more youthful capacity to other components of the immune system as well. If you look back in the archives, you'll find a great many references to more reading material on this subject. For example:

• Reversing B Cell Aging
• An Addendum to the Destructive Rejuvenation of B Cell Immune Function
• More Support for Destroying Immune Cells to Improve Function
• Immune System Rejuvenation Achieved Through Targeted Cell Destruction

One of the needed shifts in our culture is to move away from the dominant themes of apologism and acceptance of aging - this is a necessary precursor for widespread support of longevity science, to the level needed to raise up rejuvenation biotechnology research to match cancer research or regenerative medicine in funding and enthusiasm. So more of this sort of thing is welcome: "In 1981, five days before cancer killed him, the life-loving writer William Saroyan told the Associated Press: 'Everybody has to die, but I always believed an exception would be made in my case. Now what?' There it is: 'Now what?' That is the great question growing all the greater for being asked by the biggest, most self-conscious and possibly most self-deluded generation in American history, the baby boomers. The youngest of them are middle-aged now, taking a hard-headed look at old age and asking: Now what? Some are also taking a soft-headed look, as if they were already demented beyond grappling with reality. Some of them like to think of old age as 'elderhood,' which is thinking of old age as just another stage of life, like childhood or adulthood. But then what? Surely not deathhood. Or afterhood, or oblivionhood. No, a lot of people are making a lot of money promising immortality. But I digress. Then again, digression is the essence of William Ian Miller's book about old age. It answers the question of 'Now what?' with its title: 'Losing It.' ... The point, if I may dare to sum up: Old age is an annoying, ridiculous and pathetic decline toward the state of a turnip softening in a compost heap, if death is not kind enough to intervene first. But why write a book about it? ... Mr. Miller wants to express his contempt for the positivity crowd that echoes 'grow old along with me, the best is yet to be,' in the words of Robert Browning, one of the softer turnips of 19th-century English poetry."

Link: http://online.wsj.com/article/SB10001424052970204226204576601162391437564.html

An example of the sort of research work undertaken by cryonics provider Alcor: "During the month of November the research and development team made a field trip to a local medical CAT scanning service, taking with them two recent neuro patients. Due to circumstances surrounding their death, one patient was cryoprotected and the other was not. ... Having safely returned from our trip and taking care of returning the patients to the patient care bay, Steve Graber opened up the first of the patient scan files in our 3-D visualization software. This is where the team could really see some interesting things. ... looking into the brain cavity we could make out the sensor wires which were previously placed into the brain cavity during surgery. Through the slice we can see variations in brain density ... When one compares these identically composed, sectioned and displayed images of a cryoprotected brain [vs] non-cryoprotected brain it is clear that there is a big difference in overall density between these two brains. A-1546 displays a significantly greater electron density than A-1088 throughout the majority of the brain. Overall the A-1546 brain is much more electron dense and we believe this to be evidence that perfusion [of cryoprotectant] did occur, at least in certain areas. ... A future test of a variety of substances under the CAT scanner [is] expected to help to identify electron density specifics of cryoprotectants, which in turn will make our analysis that much more complete. We also expect to test a locally pronounced patient vs an out of state pronounced patient to determine the quality differences in cryoprotection caused by the time-lag to cryoprotection between these two scenarios.... We also expect to test a locally pronounced patient vs an out of state pronounced patient to determine the quality differences in cryoprotection caused by the time-lag to cryoprotection between these two scenarios."

Link: http://www.alcor.org/blog/?p=2396