The end of the year is closing in, and this is about when I usually make an annual donation to the Methuselah Foundation. I prefer the periodic lump sum donations over monthly contributions as it's a good way to force an occasional check on whether you're still making a good choice. In the years since the Foundation's inception, I've donated to the Mprize fund. The fund predates the option to directly sponsor Strategies for Engineered Negligible Senesence (SENS) research aimed at repairing the damage of aging, but I've continued to put money towards the research prize, as I consider it to be important.

Time for a change, I think. This year's donation will go towards SENS research - but not because I think the Mprize is any less worthy. At this point, it looks like the best plausible growth path for the Methuselah Foundation over the next few years is based on following through with present initiatives to establish and publicize a steady stream of modest SENS research achievements. I've long said that advocacy and tangible results have to go hand in hand for optimal progress; when one gets too far ahead of the other, it tends to slow down.

You get what you pay for in this life - so if we want to see that steady stream of research achievements, we have to fund the research. Other people hang around in the wings waiting for more confirmation and mass of support for these projects, but those of us who better understand the science and potential of SENS are the ones who must pay to start the ball rolling. My contributions aren't large, but then no one person can form a crowd. I would hope that discussing this topic moves those of you yet to donate to make that small effort to help progress towards engineered longevity.

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The Millard Foundation [UPDATE 03/08/2009: their public face on the web is now the LifeStar Institute] has been moving towards earnest funding of longevity science over the past few years: there have been initial donations, conference attendances, meetings with movers and shakers. All the normal activities and preparation by people who take investing very seriously. Much like the Glenn Foundation, which I would consider an analogous force in the philanthropic funding space, the Millard family have donated generously to the Methuselah Foundation. But where Paul Glenn opted to place his first major funding initiatives firmly in the present mainstream - calorie restriction research, understanding metabolism, and attempts to slow aging through metabolic and genetic manipulation - the Millard family is more inclined towards the Strategies for Engineered Negligible Senescence (SENS) viewpoint. This approach is to reverse aging without altering the workings of our metabolism by identifying and repairing damage: the engineering approach.

Long-time readers will know that I consider the debate over the methods used to engineer longevity in humans to be the most important scientific battle of this century. If it goes the right way - towards SENS, presently the minority viewpoint - then I believe significant results in applied longevity science will arrive decades sooner than they might, and will include therapies capable of rejuvenating the elderly. If development of metabolic manipulation therapies to slow aging continues to dominate, progress towards enhanced longevity will be much slower, and the resulting therapies will be of no use to those already aged.

From what I've seen, the Millards have money, influence, and the intelligence to use it well. That is good news for SENS-style research over the next few years. Going by the latest news from the Methuselah Foundation, things are moving forward more rapidly now:

Back in June at Aging '08 I met Barbara Logan of the Millard Foundation having previously met her father William Millard at SENS 2. ... Over the following months she became a resource for me and I introduced her to some efforts with the Alberta Government where I had proposed the development of regenerative medicine programs which are under consideration. It soon became clear that there were some strong synergies and I was invited to participate in the efforts of the Millard Foundation in developing a strategy to serve the mission. Unsurprisingly, Aubrey [de Grey] is a consultant on the project and will play an increasingly important role as we move forward - the ideas of SENS are part of the project's DNA. More than that I'm afraid I can't speak to at this time, but suffice to say, it is one of the most exciting efforts (other than the Methuselah Foundation) that I have been involved with.

Diversification in the growth of the money-bearing and money-raising side of the healthy life extension community, and the wider adoption of the ideas of SENS in that group, is a very encouraging sign. Of all the things I'd want to see in a movement primed for growth in the years ahead, diversity amongst the movers and shakers tops the list. Diversity implies competition, and competition is the way to success.

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Deuterium and engineered longevity are in the popular press again:

[The method] centres on fortifying the body's tissues and cells against attack and decay caused by free radicals, dangerous chemicals produced when food is turned into energy. Such 'attacks' on proteins are particularly damaging and have been linked to cancer, Alzheimer's and Parkinson's.

Dr Shchepinov's theory is based on deuterium, a naturally-occurring isotope, or form of hydrogen, that strengthens the bonds in between and around the body's cells, making them less vulnerable to attack.

He found that water enriched with deuterium, which is twice as heavy as normal hydrogen, extends the lifespan of worms by 10 per cent. And fruitflies fed the 'water of life' lived up to 30 per cent longer.

Heavy water is toxic to mammals at very high concentrations, and as I mentioned in response to a paper from Rejuvenation Research in 2007:

Shchepinov argues that isotopes would only be incorporated in the sites that need to be protected from oxidation. 'Ideally, they will slow down the oxidation reaction so much that they will never be released to take part in other reactions. If some of them do break free, they will only occur in small concentrations,' he said.

As for the other folk quoted in [a science press article at the time], I'm dubious - it seems to me that the level of technology required to target the isotopes reliably (and keep them targeted) would enable far more effective methdologies of repairing rather than preventing oxidative damage.

I suspect that the main benefit to come out of this research will be an increased understanding of free radical biochemistry and its interaction with degenerative aging.

UPDATE 11/27/2008: You'll find a much better article on this research at the New Scientist.

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The message to take away from much of the research into obesity is "don't let it happen to you." Fortunately for most of us, that is well within our power: obesity is almost always a choice.

While smoking reduces life by an average of ten years, the research says being seriously overweight can cut life expectancy by as much as 13 years.

As for any complicated survey of human health, you'll find dissenting studies, or studies that show widely different results for different studied groups. Here's one that shows no real difference to life expectancy for obese versus non-obese old people:

Total, active, and disabled life expectancy in Americans aged >/=70 is estimated, with and without obesity and arthritis. Results indicate that neither obesity nor arthritis is related to the length of life for older men and women, alone or in combination. However, both conditions are significantly individually associated with increased length of disabled life in older men (1.4 years attributable to obesity; 1.2 years to arthritis at age 70) and women (1.7 years attributable to obesity; 2.1 years to arthritis at age 70). In addition, the combination of the two is significantly related to decreased active life, with nearly 50 and 60% of remaining life for 70-year-old men and women lived with disability, respectively.

I suspect there's some survivorship bias in studying people who are sufficiently inured to obesity by luck of genes or more active lifestyle to make it past 70 - despite the nasty effects that all that visceral fat has on your metabolism. Even if this you're not losing years, it certainly takes its toll in other ways. Disability and age-related disease of any sort is an unpleasant, very expensive experience, yet many people ensure they will suffering more of it by way of the lifestyle they lead and the calories they consume.

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Damaged mitochondria accumulate in your cells with advancing age, and their malfunctions cause all sorts of further harm to your biochemistry. All in all they are a bad thing, and a strong candidate for the most important cause of degenerative aging. So it is with interest I notice that researchers working on Parkinson's disease are uncovering more of the cellular mechanisms that - when working properly - cull damaged mitochondria so that they can be replaced:

Parkin, the product of the Parkinson's disease-related gene Park2, prompts neuronal survival by clearing the cell of its damaged mitochondria.

...

Several lines of evidence suggest that Parkin loss is associated with mitochondrial dysfunction, but exactly how was unknown. To learn more about Parkin's role in cells, Narendra et al. examined the protein's subcellular location. They found that Parkin was present in the cytoplasm of most cells, but translocated to mitochondria in cells that had undergone mitochondrial damage such as membrane depolarization.

Damaged mitochondria can trigger cell death pathways; indeed, dysregulation of mitochondrial health was already thought to be a possible cause of the neuronal cell death associated with Parkinson's disease. The relocation of Parkin to damaged mitochondria, the team showed, sends these defunct organelles to autophagosomes for degradation. Parkin may thus prevent the damaged mitochondria from triggering cell death. Because neurons are not readily replicable, disposing of damaged mitochondria may be especially important in the adult brain.

I'm not so interested in the association with Parkinson's, since the cell death mechanisms for the dopamine-producing neurons that die off in Parkinson's appear to be further downstream in the chain of cause and effect than accumulation of alpha-synuclin. I am, however, very interested any mechanism that shows potential for enhancement to clear out more damaged mitochondria.

If you look back at the details of how damaged mitochondria eventually replace undamaged mitochondria in a cell, however, it isn't clear whether Parkin is involved in such a mechanism. The crucial point is whether Parkin is only involved in responding to damage to mitochondrial membranes, as the type of internal mitochondrial damage that contributes to aging leaves the membranes intact. The devil, as always, is in the details - and biochemistry has no shortage of details.

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Chris Patil of Ouroboros set down some notes earlier this week on the annual meeting of the Larry L. Hillblom Foundation, one of a number of non-profit organizations to fund research into the biochemistry of aging.

Morning session 1A:

Bob Hughes, Pankaj Kapahi, Simon Melov and Gordon Lithgow (Buck Institute) gave a group talk under the umbrella topic “Chemical biology of aging” (we heard a bit about this at last year’s meeting). Bob introduced a screen for small molecules that extend lifespan in simple model system; the goal is to screen 100,000 compounds, identify drugs that increase longevity in both yeast and worms, and then test these molecules in mice.

Morning session 1B:

Glabe’s group [has] been developing anti-amyloid antibodies, some of which [recognize] common features of amyloid aggregates formed by many different types of protein (e.g., [amyloid-beta] but also alpha-synuclein, IAPP, and other peptides involved in aggregation-based diseases [such as Alzheimer's, Parkinson's, and so forth]). These reagents will be useful in research but also potentially as therapies against multiple age-related illnesses.

Morning session 2:

Ken Nakamura (UCSF) is studying Parkinson’s disease in a refreshingly original way: he has developed ways to monitor alpha-synuclein [in] live cells, using fusion with fluorescent proteins. The pathological protein aggregates end up associating with membranes, including mitochondria - which then fragment, potentially contributing to [cell damage and death].

As you might guess from the above items, many age-related conditions are marked by a build-up of errant, damaging proteins - such as alpha-synuclein for Parkinson's and amyloid for Alzheimers. This protein aggregation may or may not be sufficiently close to the root cause of an age-related disease for removal of the protein to be a viable treatment, but we're going to find out during the next few years. The development of therapies aimed at soaking up the most common aggregates - or turning the immune system to destroy them - is advancing rapidly.

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Aging researchers are looking into ant biochemistry for much the same reasons as they look into bee biochemistry: these insects produce individuals with vastly different life spans. By comparing long-lived and short-lived specialized members of the same species, researchers may gain greater insight into the biochemical mechanisms of aging:

What can ants, not typically known for long life, tell us about human aging? Potentially much, says Liebig. Ants in a colony are genetically closely related, yet these sisters' body types, behavior and purpose can become specialized and vastly different. Queens typically arise as the single reproductive female in an ant colony, living for as long as 30 years in some species. As head of the colony they stay in the nest dedicated to perform one major task, egg-laying, for their whole life. Workers on the other hand perform brood care, colony maintenance, and complex foraging tasks. Among the workers additional behavioral and morphological differences may exist. Some individuals are larger and more robust with a focus on colony defense, which earned them the name soldiers. How can such big differences arise in each of these ant types' longevity and behavior without some real differences in their DNA?

According to Liebig and his collaborators, the answer can be found in the rising field of epigenetics - the study of inherited changes in the activity of genes - for example, when they turned on or off; changes not caused by alterations in the DNA sequence.

It is an interesting field of study, but I wouldn't hold your breath waiting for applications to human longevity. That might be decades away - by which time I would hope that more direct approaches to engineering greater human longevity are already well advanced.

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Over at Sentient Developments, George Dvorksy has a couple of posts up on the Convergence 08 unconference recently held in Silicon Valley.

Convergence08 examines the world-changing possibilities of nanotech and the life-changing promises of biotech.

A number of well known names from the healthy life extension community were there to present and exchange views.

Tanya Jones discusses Alcor, present and future:

Whole body vitrification: largely depends on the fluid which is a cryopreservant that prevents the formation of ice crystals in the body. Works particularly well for organs, which was its intended application. Automated systems are being built that are dramatically improving the perfusing process. Large animal tests are planned before it's used on a patient, giving unprecedented control over the perfusion process. It's build on bypass operations used in hospitals.

Day 2 closing panel on longevity

Gregory Benford: Benford talks about his research and its implications -- working to augment their genes in the defense of aging. Diabetes is a predictor of Alzheimer's; we share 75% of our genome with fruit flies. Fruit flies get diabetes and Alzheimer's.

Aubrey de Grey: Describes himself as being the most ambitious of the group. But he qualifies that by saying it's because he's the most pessimistic. We need a new approach that's more preventative than the geriatric approach. This has led Aubrey to the belief that we need to apply regenerative medicine to the problem of aging. He said that Terry Grossman and Ray Kurzweil recapitulated many of his views in their book."

Day 2 opening panel on synthetic biology

Benford sees benefits in the medical sciences and talks about advances in Alzheimer's and diabates -- in those fields that are somewhat stuck and not thinking about evolutionary biology in their research and development.

Benford says the European version of the precautionary principle is nothing more than, "never do anything for the first time." But if we're to make any progress about longevity, argues Benford, we need to exploit the entire suite of biology and what it has to offer.

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An article on a successful transplant of a recellularized organ is doing the rounds in the mainstream press:

First a section of trachea was taken from a donor and stripped of cells that could cause an immune reaction, leaving a grey trunk of connective tissue. Stem cells were then taken from Ms Castillo’s bone marrow and grown in Professor Birchall’s laboratory. Stem cells can develop into different kinds of tissue, given the right chemical instructions, enabling researchers to cultivate cartilage and epithelial cells to cover the 7cm graft. It was then “seeded” with the new cells using a process developed in Milan. Finally the trachea, covered in cartilage and lined with epithelial cells, was cut to shape and fitted.

Professor Macchiarini said: “The probability that this lady will have rejection is almost zero. She is enjoying a normal life, which for us clinicians is the most beautiful gift.”

You might recall other news from past months on this technique for converting a donor organ into an organ built with the patient's own cells. In essence this is a clever way around the present inability to construct nanoscale scaffolds that have both the right structure and can provide the right biochemical signals to guide cell growth. The extracellular matrix left behind after the old cells are removed becomes that scaffold:

• A Recellularization Update
• A Look at More Recellularization Work

As you might guess from those two posts, much of the published recellularization work to date has focused on building new heart valves - or even complete hearts. It seems that any comparatively simple tissue structures are well within reach of present day tissue engineering, however. A decade from now, this sort of replacement for damaged organs will be commonplace.

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A recent review paper on calorie restriction (CR) research makes the case that using smaller, short-lived animals has made it hard to see the detailed picture of CR biochemistry. Only now that larger animals - such as humans and other primates - are in longer-term CR studies is the biochemistry becoming clear.

Endocrine alterations in response to calorie restriction in humans

Prolonged CR has been shown to extend both the median and maximal lifespan in a variety of lower species such as yeast, worms, fish, rats and mice. The biological mechanisms of this lifespan extension via CR are not fully elucidated, but possibly involve significant alterations in energy metabolism, oxidative damage, insulin sensitivity and functional changes in both neuroendocrine and sympathetic nervous systems.

Most of the difficulty in characterizing the systemic endocrine and neuroendocrine changes with aging and CR is due to the limited capability to collect large and multiple blood samples from small animals, which are usually shorter lived, and hence the most studied.

Ongoing studies of prolonged CR in humans are now making it possible to analyze changes in the "biomarkers of aging" to unravel some of the mechanisms of its anti-aging phenomenon. With the incremental expansion of research endeavors in the area of energy restriction, data on the effects of CR in non-human primates and human subjects are becoming more accessible. Detailed analyses from controlled human trials involving long-term CR will allow investigators to link observed alterations from body composition and endocrine systems down to changes in molecular pathways and gene expression, with their possible effects on aging.

It is interesting to consider that some degree of advances in CR knowledge stem from increasing the size of laboratory animals (and slowing down the pace of data collection) rather than the rapid advances in the tools of biotechnology taking place across the past decade.

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If you had to pick the absolute hardest, most challenging goal possible in biomedical science, I think it might be to alter the genes of adult humans so as to safely extend healthy life. Yet this is pretty much the course of the mainstream aging research community - and so I believe they are setting themselves up for maximal expense and minimal progress:

It is their belief that this is the only practical way ahead: a laborious slog towards complete understanding of aging and metabolism, followed by an even more complex navigation through re-engineering that metabolism to age more slowly. The sheer scale and difficulty of that task is why many scientists feel that meaningful engineered longevity - more healthy years through science - is a long way away indeed.

Here's a paper restating that point:

Studies performed on various experimental model systems indicate that genetic interventions can increase longevity, even if in a highly protected laboratory condition. Generally, such interventions required partial or complete switching off of the gene and inhibiting the activity of its gene products, which normally have other well-defined roles in metabolic processes. Overexpression of some genes, such as stress response and antioxidant genes, in some model systems also extends their longevity.

Such genetic interventions may not be easily applicable to humans without knowing their effects on human growth, development, maturation, reproduction and other characteristics. Studies on the association of single nucleotide polymorphisms and multiple polymorphisms (haplotype) in genes with human longevity have identified several genes whose frequencies increase or decrease with age.

Whether genetic redesigning can be achieved in the wake of numerous and complex epigenetic factors that effectively determine the life course and the life span of an individual still appears to be a 'mission impossible'.

Not impossible, just far, far harder than the alternative - which is to avoid changing human genes and metabolism, rather aiming to repair the damage of aging in the biochemistry we have today, thus reversing the effects of aging. That goal allows us to skip over a great many things we don't understand about human biochemistry and avoid many challenging endeavors - and it will produce more valuable and effective therapies into the bargain.

Why take the hard path to extend longevity a little by slowing aging when there is an easier and more direct path towards reversing aging? The debate over the approach to aging research in the next few decades is vitally important to progress in engineered longevity: the presently dominant strategy is an inefficient path forward, and it will eventually produce therapies that do little to help those of us who have grown old waiting for them. That has to change.

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From In Search of Enlightenment:

The inborn aging process is now the major risk factor for disease and death after around age 28 in the developed countries

...

Aging is not immutable. The lifespan of organisms such as worms, flies, and mice can be extended by restricting food intake.

...

Despite the fact that the vast majority of the world's 6.5+ population will die from age-related causes, aging research is underfunded.

...

Even a modest deceleration in human aging could be this century’s most important medical intervention. Furthermore, there is a sound scientific basis for believing this could be achieved. We are closer to this goal than we are to eliminating cancer or heart disease. Furthermore, age retardation could yield health dividends far greater than those that would be achieved by the elimination of any specific disease of aging.

Despite the fact that progress is very visible in advocacy for longevity science, members of the healthy life extension community can't go far wrong in continuing to hit on the basic concepts - like those expressed above.

• Aging isn't written in stone: it can be addressed by future medical science
• Living longer means living in good health for longer, not being older for longer
• Longevity science is plausible and underway, but very underfunded
• We could live much longer in good health, but we have to work to make that goal a reality

It is still the case that comparatively few people think this way, or realize the potential of the next few decades for engineered human longevity. Much more public support, fundraising, and applied medical research will be required to realize this potential - which all starts with a large number of people saying "I want to see this come to pass."

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A post at Reddit on predictions for (and arguments against) engineered longevity has been the subject of a long discussion over the past couple of days - a long time for any Reddit post to remain far high enough in the lists to be actively discussed. I think you'll find it an interesting exercise to wander through the hundreds of comments, some of which are reproduced below. The ratio of positive to negative in these sorts of online discussions is growing, I think:

How about this: those who are for living longer, can do so, and those against, can ignore the treatments?

...

Obviously entirely new systems would come into play. We can't see what they will be now, but they will be self-evident once they evolve. To extrapolate current systems into extremely long lives, where people could keep their health and strength and work at what they want far longer than they do now, is bootless. Maybe with a greater time span of non-age-ossified brains people would have time to emotionally mature more than they do now, and make better decisions. Certainly there would be time to use the power of compounding interest to far greater advantage than is possible now. With youth and vigor extended, the expansion of life-possibilities would be immense, and would extend into spaces we can't even see.

...

I think that once we defeat aging, we can work on those other problems which are an order of magnitude less bad.

...

Other definitions that would change are old person and young person. The idea is to lengthen that period of life where you both can and wish to do things, not extend fogeyhood into forever. So if someone looks thirty but is far older, what does that do to our current paradigm of the stages of life? We'll make up a new one, gradually and fitfully. Probably it won't be comfortable, but change seldom is.

...

Who cares about advantage to our species? I only care about advantage to actual, living people. If there were no more humans, ever, but everyone alive today had a better life, I would consider that a net positive.

...

Leon Kass, the former head of Bush's Council on Bioethics, insists that 'the finitude of human life is a blessing for every human individual' ... He's just confused. Obviously, the finitude of his life is a blessing for all of us, but that's not true for everyone.

...

I, for one, would like to live as long as I want. For those of you who would insist I die, what's wrong with you? You actually want people to die? You want to lose the people you love? Really?

...

I saw a comment somewhere that said that it is new generations that bring change, and that people need to die. WRONG. Just think about living more than ten times longer than your current expectancy. One person can learn for much longer, work for longer, and continue to better him or herself. A thousand [years]. You could get alot done, and teach alot of other people, without leaving the next generation to pick up where you left off every 50-80 years.

The tide of educated opinion on engineered longevity has come a long way in the seven years I've been writing on this topic. A great deal of work remains to be accomplished in laying the foundations for truly massive research and development fundraising for longevity science, but the signs of progress exist - matters are further ahead than they were.

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Autoimmune conditions such as rheumatoid arthritis result from errant cellular behavior in the immune system - immune cells are instructed to attack healthy tissue rather than performing beneficial tasks such as hunting down cancerous or senescent cells. As researchers become better at controlling cellular behavior, reprogramming cells for desired tasks by sending the right chemical signals, this type of disease will become a treatable nuisance rather than a life-destroying condition. Here is an example of the sort of work presently taking place:

Normally, immune cells develop to recognise foreign material - antigens; including bacteria - so that they can activate a response against them. Immune cells that would respond to 'self' and therefore attack the body's own cells are usually destroyed during development. If any persist, they are held in check by special regulatory cells that provide a sort of autoimmune checkpoint. A key player in these regulatory cells is a molecule called Foxp3.

...

Dr. Alexander Betz, Group Leader at the MRC laboratory, explains: "We have generated a modified form of Foxp3 which can be introduced into immune cells using genetic engineering techniques and then activated by a simple injection. When administered to and activated in animal models of arthritis, the modified cells inhibit or even reverse the disease process."

Further work is now aimed at elucidating the detailed molecular mechanisms involved in Foxp3 function, and transferring the experimental approach to human cells.

It's a road of a decade or more in the present over-regulated environment to move from a promising therapy in mice to human therapy in late clinical trials. But many groups are working on the reprogramming of immune cells: it is a broad field of endeavor, and advances in the state of the art made by any one group benefit all the others.

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Under at least some circumstances, the practice of calorie restriction appears to increase regenerative capacity - in addition to the range of other benefits it brings to health and longevity. It makes you wonder just how many other ways we harm and hinder ourselves by eating more than is necessary. From a recent paper (for which the full PDF version is freely available):

Caloric restriction (CR) can extend longevity and modulate the features of obesity-related metabolic and vascular diseases. However, the functional roles of CR in regulation of [regrowth of blood vessels] in response to ischemia have not been examined. Here, we investigated whether CR modulates vascular response.

By examining varying strains of mice, the researchers demonstrated that calorie restriction greatly improves regrowth of blood vessels - and also identified components of the biomechanisms which drive this improvement. The enzyme AMPK - already known to increase with CR and to be important in the benefits provided by exercise - is one of the biochemicals involved in this increased regenerative capacity.

Based on that evidence, calorie restriction mimetic drugs might turn out to have many more diverse applications in medicine than first suspected.

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You might recall the links drawn between the protein alpha-synuclein and development of Parkinson's disease:

Patients with Parkinson's disease (PD) have elevated levels of the protein called alpha-synuclein in their brains. As the protein clumps, or aggregates, the resulting toxicity causes the death of neurons that produce the brain chemical dopamine. Consequently, nerves and muscles that control movement and coordination are destroyed.

It looks possible that the reason behind all this clumping synuclein is chronic inflammation - that catch-all bugbear that appears to contribute to all the major diseases and degenerations of aging. As we get older, our immune system slips into faulty states that lead to rising levels of inflammation, damaging our biochemistry in many different ways such that we degrade that much faster. This might be one of those ways:

Aging enhances the neuroinflammatory response and alpha-synuclein nitration in rats:

The Lewy body is a pathological hallmark of Parkinson's disease. It has been revealed that the Lewy body contains nitrated alpha-synuclein which is prone to [forming aggregates]. We tested the hypothesis that aging may enhance nitration of alpha-synuclein due to an exaggerated neuroinflammatory reaction ... greater nitration of proteins like alpha-synuclein occurs in the substantia nigra of 16-month-old rats versus 3-month-old rats ... These results imply that an exaggerated neuroinflammatory response that occurs with aging might be involved in the increase in prevalence of neurodegenerative diseases like Parkinson's disease.

Whether or not this particular linkage is established beyond doubt, there is more than enough evidence demonstrating chronic inflammation to be bad for your health and longevity. Making sensible life choices to minimize inflammation as best you can is a sensible response to the research findings amassed to date.

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Another modest advance in stem cell science is noted in a Japanese paper, one of many on the way to developing a comprehensive repair kit for the aging human body:

Researchers have created cerebral tissue from human embryonic stem [ES] cells, an achievement thought likely to lead to a breakthrough in tackling Alzheimer's disease as well as pave the way for new regenerative treatments and other drugs, The Yomiuri Shimbun has learned.

Yoshiki Sasai, a group director of the RIKEN Center for Developmental Biology, said the tissue also can be created using induced pluripotent stem (iPS) cells. ... Sasai's group solidified about 3,000 human ES cells into balls 0.2 millimeter in diameter, added material that helped them develop into nerve cells, and cultured them for 50 days. The balls grew into mushroomlike objects one millimeter to two millimeters in diameter. Four types of nerve cells arranged in layers, which appeared very similar to those found in the cerebral cortex of a fetus, were observed inside each of the mushroom-shaped objects. The nerves also sent out electrical signals and showed other functional capacity.

Sasai said brain tissue can be created in the same way using human iPS cells. He said he planned to attempt to create six-layered tissue, far closer in structure to adult brain tissue. "This achievement will enable us to forge ahead with research into the adverse reactions caused by drugs as well as develop new vaccines," Sasai said. "It will lead to treatment capable of regenerating cerebral nerves."

There is much that could be done to lengthen life with the fully developed technology to generate new, undamaged tissue as needed. For all that, it is far from the be-all and end-all of longevity science - just one necessary technology of many - but it is encouraging to see the pace of development accelerating in the tissue engineering field in recent years.

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An interview with one of the pillars of that nebulous and hard to define thing, the transhumanist community:

I'd make a distinction between the "Transhumanist movement" and a larger group of people - many of whom probably read io9 (and Boing Boing, Slashdot, Wired, and on and on). There are lots of people out there who are fully cognizant of transhumanist views, and who are interested in - and possibly supportive of, or ambiguously curious about - say, cyborg body enhancements, or memory enhancement, or ending aging. And in fact, my friend Ramez Naam argues that anybody who wears glasses or takes birth control pills is a transhumanist and so he refuses the label as sort of banal.

If you look around at the serious efforts to make progress in longevity science or other means of postponing permanent death, you'll find members of the transhumanist community involved and amongst the most vocal supporters: the Methuselah Foundation; Alcor and the Cryonics Institute; the Immortality Institute. Similarly in the fields of strong artificial intelligence and advanced nanotechnology - organizations like the Singularity Institute, the Future of Humanity Institute and the Center for Responsible Nanotechnology are outgrowths of the transhumanist community of the 80s and 90s. Collectively these organizations and others have raised tens of millions of dollars over the years.

The transhumanist community that was - once upon a time - clearly defined at the edges, and largely in the business of talking rather than doing, actually attained its immediate goals. This is to say its members and the general progress of technology brought the transhumanist view to a much broader audience. Ideas once strange and unthinkable became accepted as plausible extrapolations of present trends; which was always the case, but some people can see farther ahead than others. During this process, the transhumanist community became diffuse at the edges and no longer ahead of its time; most of the core ideas and goals spread into the mainstream, changing along the way. That's the best end possible for any subculture, a victory in the sense that all of these ideals - bioengineering, the defeat of aging, enormously lengthened healthy life spans, artificial beings, molecular manufacturing, and much more - will come to pass. Too many people are thinking about these goals now for any but the impossible to vanish from the horizon.

It's just a question of when it all comes to pass - which is a very big question when it comes to the development of medical technologies that can rescue us from aging to death. Soon enough, or too late? What are you doing to help things along?

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In recent years researchers have been sketching a convincing picture of causal links between shortened telomeres, damaged mitochondria, rising oxidative stress, and the degenerations of aging. This is important because researchers are on the verge of being able to both manipulate telomere length and repair or replace damaged mitochondria. Here are some introductory posts from the archives:

• Linking Telomere Shortening and Mitochondrial Damage?
• More On Telomere Shortening and Mitochondrial Dysfunction
• Filling in the Gaps Between Telomeres and Mitochondria in Aging

Following on from that, a paper that adds a little more to the pile of evidence by demonstrating a correlation between different forms of genes associated with oxidative stress, shortened telomeres, and measurable symptoms of aging:

Oxidative stress, telomere length and biomarkers of physical aging in a cohort aged 79 years from the 1932 Scottish Mental Survey

Telomere shortening is a biomarker of cellular senescence and is associated with a wide range of age-related disease. Oxidative stress is also associated with physiological aging and several age-related diseases. Non-human studies suggest that variants in oxidative stress genes may contribute to both telomere shortening and biological aging. We sought to test whether oxidative stress-related gene polymorphisms contribute to variance in both telomere length and physical biomarkers of aging in humans.

Telomere lengths were calculated for 190 (82 men, 108 women) participants aged 79 years and associations with 384 SNPs, from 141 oxidative stress genes, identified 9 significant SNPS, of which those from 5 genes [had] robust associations with physical aging biomarkers, respiratory function or grip strength. Replication of associations in a sample of 318 (120 males, 198 females) participants aged 50 years confirmed significant associations for two of the five SNPs on telomere length.

These data indicate that oxidative stress genes may be involved in pathways that lead to both telomere shortening and physiological aging in humans. Oxidative stress may explain, at least in part, associations between telomere shortening and physiological aging.

Which leads nicely into the role of mitochondrial damage in rising levels of oxidative stress with age, thereby reinforcing the evidence for accumulated mitochondrial damage as the important root cause of telomere shortening. All the more reason to support research aimed at repairing that damage.

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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.

Research is still in full swing, however, and the vision of how mitochondrial uncoupling fits into the big picture of metabolism and aging is present incomplete. A number of natural uncoupling proteins (such as UCP1, UCP2, and UCP3) as well as manufactured uncoupling drugs like DNP have been investigated with contradictory results. The following items provide a sampling of the confusion.

Mitochondrial Uncoupling and Tissue Aging:

Mitochondrial uncoupling is much as it sounds; a feedback mechanism in which processing is disconnected from ATP production; energy from food goes elsewhere, as heat for example. Because this affects free radical production, it seems to be important in tissue aging: "Faster aging is predicted in more active tissues and animals because of greater reactive oxygen species generation. Yet age-related cell loss is greater in less active cell types, such as type II muscle fibers. Mitochondrial uncoupling has been proposed as a mechanism that reduces reactive oxygen species production and could account for this paradox between longevity and activity. ... These results reject respiration rate as the sole factor impacting the tempo of cellular aging. Instead, they support mild uncoupling as a mechanism protecting mitochondrial function and contributing to the paradoxical longevity of the most active muscle fibers.

More Building of Better Mice:

We were a little bit disappointed because we had hoped uncoupling in muscle would slow aging, but maximum lifespan didn't increase. However, the odds of reaching that maximum lifespan did improve in the uncoupled mice. ... mice with [increased UCP1] were more likely to live longer, presumably because they were able to avoid age-related diseases. One result appeared in all of the experiments: Decreasing body fat and inflammation in the animals by accelerating muscle metabolism with uncoupling protein delayed death and diseases, including atherosclerosis, diabetes, hypertension and even cancer.

Ouroboros On Mitochondrial Uncouplers:

The DNP treated mice ate the same amount of food as control mice but had lower body mass [and] showed many phenotypes observed in calorie restricted mice. Like CR mice, DNP treated mice had higher rates of respiration with lower production of ROS. ... Most importantly, DNP treated mice showed an extended lifespan. This study suggests that mitochondrial uncouplers are an effective mimic of calorie restriction and might be a realistic therapeutic intervention for delaying aging and extending lifespan.

Uncoupling extends life, except that it doesn't - depending on how you go about it, which suggests that greater complexity is, as always, hidden under the hood. I noticed a paper today that adds weight to the negative side, though in a way that leaves the door open for further ambiguity:

Characterization of survival and phenotype throughout the life span in UCP2/UCP3 genetically altered mice:

In the present investigation we describe the life span characteristics and phenotypic traits of ad libitum-fed mice that overexpress UCP2/3 (Positive-TG), their non-overexpressing littermates (Negative-TG), mice that do not express UCP2 (UCP2KO) or UCP3 (UCP3KO), and wild-type C57BL/6J mice (WT-Control). We also included a group of C57BL/6J mice calorie-restricted to 70% of ad libitum-fed mice in order to test partially the hypothesis that UCPs contribute to the life extension properties of CR.

Mean survival was slightly, but significantly, greater in Positive-TG, than that observed in Negative-TG or WT-Control; mean life span did not significantly differ from that of the UCP3KO mice. Maximal life span did not differ among the ad libitum-fed groups. Genotype did not significantly affect body weight, food intake, or the type of pathology at time of death.

Calorie restriction increased significantly mean and maximal life span, and the expression of UCP2 and UCP3. The lack of difference in maximal life spans among the Positive-TG, Negative-TG, and UCP3KO suggests that UCP3 does not significantly affect longevity in mice.

So, to summarize that last paper: calorie restriction increases UCP2 and 3 - which is one of the reasons that aging researchers become interested in the uncoupling process - but getting rid of UCP2 or UCP3 entirely doesn't seem to do much. There is an agreement that more uncoupling helps resist age-related degeneration to some degree without extending maximum species longevity. Questions remain as to whether uncoupling is important in calorie restriction, and how DNP is extending longevity if uncoupling proteins have no effect in that regard.

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