Partaking of the Hope
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If you go through the first half of your life basically healthy, there are actually only a few important differences between your situation and that of your ancestors a century or two ago when it comes to health and medical technology. For all that we live in the opening years of an era of advanced biotechnology, and in an age of far greater wealth, a healthy person benefits only through (a) the reduced burden of infectious disease, and (b) through the insulating effects of wealth against malnutrition, exposure, and other environmental misfortunes. These two points are enough to explain much of the steady rise in life expectancy that occurs with growing wealth and advancing medical technology over the past centuries.

What is the point of mentioning this? It is to remind us that we are not bathed in the golden aura of biological science, and the many ways to extend the healthy lives of mice demonstrated in the laboratory over the past decade have not yet translated into any medical technology we can use. As a healthy person in the US or Europe, the trajectory of your life under present day medicine isn't in fact terribly different from that of a privileged and healthy individual in the late 1800s. The only differences lie in your burden of infectious disease and the ability for even today's poor to enjoy a degree of protection from life's slings and arrows that was once only affordable to the wealthy. The trajectory of your life will only change meaningfully when prospective technologies for reversing the damage of aging are developed and become available in the clinic. Until then, you are only incrementally better off.

From the perspective of the life sciences and medical technology, these are amazing years to be alive, as I'm sure you've already noticed if you're a regular reader at Fight Aging! Yet that means exactly nothing for us until laboratory work is built into clinical applications. Detailed descriptions of technologies that can reverse aging give us hope, but nothing other than hope until the job of turning descriptions into real therapies is complete.

There are all too many people in the world who are happy to partake in the growing hope of engineered longevity and human rejuvenation, but who then sit back and do nothing to help bring about that desired future. And so the world works as it has always done: if everyone drinks hope and air, then hope and air is all that will come into being. Medical technologies do not develop themselves. They only arise in an environment of support, aggressive fundraising, and widespread agitation for their creation - environments in which a lot of people are materially contributing, in other words.

So don't feel as though you are made shielded or special by the fact that biotechnology is in the zeitgeist: you aren't, and you won't be until much more work is accomplished. Give some thought to helping out: after all, your life is as much on the line as everyone else's.

Severe Calorie Restriction in Rats Leads to 50% Life Extension
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Here is a repetition of the sort of research from the last century that initially drew interest to calorie restriction, in which researchers are trying to pin down the point at which beneficial calorie restriction becomes harmful malnutrition: "It has been firmly established that the longevity of 20- to 60 %-calorie-restricted rodents, with malnutrition (essential nutrients deficiency) being avoided, is increased when compared to ad libitum fed rodents. However, the effects on life span of severe dietary restriction (i. e. malnutrition), with limited weight loss, remained unknown. The purpose of this 4-year study was to investigate the effects on longevity of a severe form of dietary restriction, with limited and controlled weight loss. To this end, a group of male Long-Evans rats severely dietary restricted (SDR group), with a weight loss throughout the experiment <= 25 % of their weight before the onset of the experiment at 9 weeks of age, was compared to a control group of rats 30- to 40 %-calorie-restricted (C group). Our results show that a severe dietary restriction, excessive weight loss being prevented, paradoxically increased rat longevity by nearly 50 %. The life span increase observed in our SDR rats is in accordance with some other studies investigating the effects on longevity of partial essential nutrients deficiencies (tryptophan, methionine, and fat, for example)."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21792819

Cryonics in the UK Press
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The recent cryosuspension of Robert Ettinger has led to a flurry of press articles; this is one of the better ones: "British photojournalist Murray Ballard, who has documented every aspect of cryonics there is to see (beyond the currently unachievable final stage, of course). Ballard's project began while he was studying photography at the University of Brighton, when he was inspired by the story of a French couple who had held hopes of being revived after their death; unfortunately the freezer storing their bodies broke down. Intrigued, the photographer's research led him first to a group of enthusiasts based just along the Sussex coast in Peacehaven, and before long he and his camera made their first trip to the three main cryonic storage sites in the US and Russia. There are around 1,000 people around the world like those in Peacehaven who have signed up to be preserved in the hope they can be reanimated in the future - with 459 having signed contracts with Ettinger's non-profit organisation - but Ballard says that most of those he has met understand it is very much an experimental and unproven science. ... During his project he paid two visits to Ettinger's institute, as well as three visits each to the KrioRus plant just outside Moscow, where another 15 'patients' are currently held in cryostasis, and the Alcor Life Extension Foundation in Arizona which holds 104. ... Essentially all you need is the brain. The theory is that the brain is like a hard drive that stores all your memories and your personality. When you are revived at some point in the distant future, a new body will be grown to house your brain, or an entirely new brain may be built for them to somehow upload your personality into it."

Link: http://www.independent.co.uk/life-style/gadgets-and-tech/features/cryonics-the-chilling-facts-2326328.html

A Single Gene Modification that Improves Both Mood and Longevity in Mice
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A number of genetic modifications that enhance longevity in mice are unambiguously positive: the result is quite literally a measurably better breed of mouse, stronger, with greater endurance, or smarter, or more resilient in some other way. Downsides are minimal or non-existent. Researchers are paying more attention to benefits other than longevity that result from these studies nowadays - there are now so many ways of extending mouse life that announcing a new one won't get you much press unless it has some other novel twist to accompany it.

So here we have a novel twist: a single gene manipulation that improves mood and neural function as well as modestly extending life. Take a look at the abstract or open access PDF paper:

The role of α1-adrenergic receptors (α1ARs) in cognition and mood is controversial, likely due to past use of non-selective agents. α1AAR activation was recently shown to increase neurogenesis, which is linked to cognition and mood.

We studied the effects of chronic α1AAR stimulation using transgenic mice engineered to express a constitutively active mutant (CAM). CAM-α1AAR mice showed enhancements in several behavioral models of learning and memory. ... WT mice treated with the α1AAR-selective agonist, cirazoline, also showed enhanced cognitive functions. In addition, CAM-α1AAR mice exhibited antidepressant and less anxious phenotypes in several behavioral tests when compared to WT. Furthermore, the lifespan of CAM-α1AAR mice was 10 percent longer than that of WT mice.

Our results suggest that chronic α1AAR stimulation improves synaptic plasticity, cognitive function, mood, and longevity. This may afford a potential therapeutic target for counteracting the decline in cognitive function and mood associated with aging and neurological disorders.

Some caution is called for however, as is the case for the results of all studies that don't control for calorie intake. Mice are so very sensitive to calorie restriction that any alteration or treatment that incidentally reduces their calorie intake will extend life - and 10 percent life extension is well within the bounds of that happenstance. If you look at the Wikipedia entry for cirazoline, you'll see:

Cirazoline has also been shown to decrease food intake in rats, purportedly through activation of alpha 1-adrenoceptors

So this is a study that should be repeated with calorie controlled mice.

Still, it remains the case that at what is still the dawn of the age of biotechnology, mice can already be tweaked in more than a score of ways to produce a better species. This raises the question of how true this is for other mammals - such as we humans, for example. Nowhere near as much work, testing, and experimentation has been performed on any other mammal species as has been accomplished with varying breeds of rodents. But we all came to have our own specific biological systems through the same general workings of evolution, and if one mammal species can be improved with a few selective genetic modifications, we might well wonder how true is that of the others:

The question for today is whether there exist as yet undiscovered and comparatively simple mutations in humans that will significantly extend healthy and maximum life spans. How likely is this, given what we know to date? Are potential human longevity mutations worth chasing?
The Mechanisms of Reversing Working Memory Decline in Monkeys
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The Technology Review looks at the work of researchers attempting to restore youthful function in brain cells associated with memory: "By delivering a certain chemical to the brain, researchers could make neurons in old monkeys behave like those in young monkeys. Clinical trials of a generic drug that mimics this effect are already underway. The findings support the idea that some of the brain changes that occur with aging are very specific - rather than being caused by a general decay throughout the brain - and can potentially be prevented. [Researchers] recorded electrical activity from neurons in a part of the brain called the prefrontal cortex, a region especially vulnerable to aging in both humans and [other] primates. It is vital for our most high-level cognitive functions, such as working memory and the ability to multitask and inhibit distractions. ... neural circuits in this region are organized to create a sustained level of activity that is crucial for working memory. ... By analyzing activity recorded from young, middle-aged, and old monkeys, the researchers found that the firing rate of the neurons in this area declines with age. They found that other neurons, such as those that respond to cues in the environment, still fired normally even as the monkeys aged. ... The researchers were able to rein in the problem by treating the cells with a drug that blocks the potassium channels. After treatment, brain cells in old monkeys fired more rapidly - just like those in their younger counterparts. The researchers already knew that giving monkeys this drug systemically, rather than delivering it directly into the brain, could reverse age-related deficits in working memory. A clinical trial of the compound, a generic drug called guanfacine, originally used to treat hypertension, is underway."

Link: http://www.technologyreview.com/biomedicine/38158/

Working on Kidney Regeneration
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VIa EurekAlert!: "Approximately 60 million people across the globe have chronic kidney disease, and many will need dialysis or a transplant. [Research] indicates that patients' own kidney cells can be gathered and reprogrammed. Reprogramming patients' kidney cells could mean that in the future, fewer patients with kidney disease would require complicated, expensive procedures that affect their quality of life. In the first study, [researchers] took cells from an individual's kidney and coaxed them to become progenitor cells, allowing the immature cells to form any type in the kidney. Specifically, they inserted several key reprogramming genes into the renal cells that made them capable of forming other cells. In a second study, [researchers] found that kidney cells collected from a patient's urine can also be reprogrammed in this way. Using cells from urine allows a technology easy to implement in a clinic setting. Even better, the urine cells could be frozen and later thawed before they were manipulated. If researchers can expand the reprogrammed cells - called induced pluripotent stem cells (iPSCs) - and return them to the patient, these IPSCs may restore the health and vitality of the kidneys. In addition to providing a potentially curative therapy for patients, the breakthroughs might also help investigators to study the causes of kidney disease and to screen new drugs that could be used to treat them."

Link: http://www.eurekalert.org/pub_releases/2011-07/ason-cpo072711.php

Calorie Restriction Improves Quality of Life
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A mixed calorie restriction and intermittent fasting study focused on measuring quality of life rather than biochemical markers caught my eye today.

Efficacy of fasting calorie restriction on quality of life among aging men:

Calorie restriction (CR) has been promoted to increase longevity. Previous studies have indicated that CR can negatively affect mood and therefore the effect of CR on mood and quality of life (QOL) becomes crucial when considering the feasibility of CR in humans. We conducted a three month clinical trial on CR (reduction of 300 to 500kcal/day) combined with two days/week of Muslim sunnah fasting (FCR) to determine the effectiveness of FCR on QOL among aging men in Klang Valley, Malaysia. A total of 25 healthy Malay men (age 58.8±5.1years), with no chronic diseases and a BMI of 23.0 to 29.9kg/m(2) were randomized to FCR (n=12) and control (n=13) groups.

Body composition measurements and QOL questionnaires were ascertained at baseline, week 6 and week 12. QOL was measured using the Short-Form 36, sleep quality was determined using the Pittsburgh Sleep Quality Index, the Beck Depression Inventory II was used to measure mood and the Perceived Stress Scale was used to measure depression. The FCR group had a significant reduction in body weight, BMI, body fat percentage and depression (P<0.05). The energy component of QOL was significantly increased in FCR group (p<0.05). There were no significant changes in sleep quality and stress level between the groups as a result of the intervention. In conclusion, FCR resulted in body weight and fat loss and alleviated depression with some improvement in the QOL in our study and has the potential to be implemented on a wider scale.

One of the common knee-jerk reactions to calorie restriction as a health practice is for people to think that it will make them unhappy: less food is equated with austerity, privation, misery and so forth. Perhaps this is a part of the unintentional indoctrination we all go through in our youth as a result of fiction and history lessons - for the vast majority of human history obtaining enough food was a continual struggle. Still, to equate calorie restriction with unhappiness is a naive view, held by people in the privileged position of being so wealthy in comparison to their ancestors that they can consistently overeat to the point of harming health and shortening life over the long term.

This bottom line: what has come to pass for normal in the modern diet is in fact caloric overkill and then some, and indulging has measurable consequences in the form of poor health and higher risk of age-related and lifestyle diseases. Eating only what is optimal - considerably less that what is now normal in other words - is beneficial in comparison. It enhances some evolved responses in cellular housekeeping mechanisms, removes some of the harm done by eating too much, and generally improves matters. What's not to like?

Universal Donor Immune Cells in Cancer Immunotherapy
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Via ScienceDaily: "One of the latest attempts to boost the body's defenses against cancer is called adoptive cell transfer, in which patients receive a therapeutic injection of their own immune cells. This therapy, currently tested in early clinical trials for melanoma and neuroblastoma, has its limitations: Removing immune cells from a patient and growing them outside the body for future re-injection is extremely expensive and not always technically feasible. ... scientists have now tested in mice a new form of adoptive cell transfer, which overcomes these limitations while enhancing the tumor-fighting ability of the transferred cells. ... The new approach should be more readily applicable than existing adoptive cell transfer treatments because it relies on a donor pool of immune T cells that can be prepared in advance, rather than on the patient's own cells. Moreover, using a method pioneered [more] than two decades ago, these T cells are outfitted with receptors that specifically seek out and identify the tumor, thereby promoting its destruction. In the study, the scientists first suppressed the immune system of mice with a relatively mild dose of radiation. They then administered a controlled dose of the modified donor T cells. The mild suppression temporarily prevented the donor T cells from being rejected by the recipient, but it didn't prevent the cells themselves from attacking the recipient's body, particularly the tumor. This approach was precisely what rendered the therapy so effective: The delay in the rejection of the donor T cells gave these cells sufficient opportunity to destroy the tumor."

Link: http://www.sciencedaily.com/releases/2011/07/110725091728.htm

Aerobic Fitness Improves the Aging Immune System
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Another reason to exercise: "Senescent T-cells accumulate with age, lowering the naive T-cell repertoire and increasing host infection risk. As this response is likely to be influenced by certain lifestyle factors, we examined the association between aerobic fitness (VO(2max)) and the age-related accumulation of senescent T-cells. Blood lymphocytes from 102 healthy males (18-61yr) were analyzed for [marker] surface expression on CD4+ and CD8+ T-cells ... Advancing age (yr) was positively associated with the proportion (%) of senescent [and] CD8+ T-cells and inversely associated with naive CD4+ and CD8+ T-cells. VO(2max) was inversely associated with senescent CD4+ and CD8+. Strikingly, age was no longer associated with the proportions of senescent or naive T-cells after adjusting for VO(2max), while the association between VO(2max) and these T-cell subsets withstood adjustment for age, BMI and percentage body fat. Ranking participants by age-adjusted VO(2max) revealed that the highest tertile had had 17% more naive CD8+ T-cells and 57% and 37% less senescent CD4+ and CD8+ T-cells, respectively, compared to the lowest tertile. This is the first study to show that aerobic fitness is associated with a lower age-related accumulation of senescent T-cells, highlighting the beneficial effects of maintaining a physically active lifestyle on the aging immune system."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21784146

A Modest Early Step Towards Implantable Artificial Lungs
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Progress in materials science, and in the areas in which that field overlaps with biotechnology, are enabling many different lines of artificial organ development. The resulting machinery will be competitive with tissue engineering in the decades to come: everything from artificial blood through to artificial hearts and artificial kidneys are on the agenda - even artificial brain sections are under development.

Work on replacement electromechanical and bioartificial solutions for other organs are in earlier stages, and these include artificial lungs. Here, the first necessary step towards enabling lung devices as an implantable option is to make them small enough to fit into the chest cavity. Artificial lungs remain large devices in the popular imagination, but in fact have been shrinking just as rapidly as other medical technologies, as noted in a recent popular science article:

Scientists at Case Western Reserve University in Cleveland have designed an artificial lung that uses air instead of pure oxygen as a ventilating gas - an advance that could turn accompanying oxygen cylinders into relics of the past. What's more, the device for use in humans could come in at just 6x6x4 inches, which is roughly the volume of the real human lung, meaning it could conceivably pave the way for implantable artificial lungs. The team first built a miniature-feature mold, layered a liquid silicone rubber over it that hardened into artificial capillaries and alveoli, and then separated the air and blood channels with a gas diffusion membrane. By building a small unit, they were able to maximize the surface-area-to-volume ratio and shrink the distance for gas diffusion to improve efficiency.

This is a prototype technology, tested on blood but yet to be trialed over the long haul in animals. Yet it remains a good indicator of what lies ahead as researchers ever more effectively mimic or integrate biological functions in artificial devices. The mid-term future will feature a competitive race between tissue engineering and prosthetics technology, but in the long term the distinction between biological and non-biological replacement parts will begin to blur. Nanotechnology will lead to artificial cells, artificial immune systems, swarms of tiny machines to replace blood cells, and a range of other foreseeable machinery far better at their jobs than our evolved organs. It's a future worth trying to hang around for, as it will certainly include rejuvenation of one form or another: if you can make it another fifty years, there is a fair chance that you'll have the opportunity to live for centuries - or longer.

The Complexities of p53 in Aging and Longevity
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An open access paper: "p53 plays a critical role in tumor suppression. As a transcription factor, in response to stress signals, p53 regulates its target genes and initiates stress responses, including cell cycle arrest, apoptosis, and/or senescence, to exert its function in tumor suppression. Emerging evidence has suggested that p53 is also an important but complex player in the regulation of aging and longevity in worms, flies, mice, and humans. Whereas p53 accelerates the aging process and shortens life span in some contexts, p53 can also extend life span in some other contexts. Thus, p53 appears to regulate aging and longevity in a context-dependent manner. Here, the authors review some recent advances in the study of the role of p53 in the regulation of aging and longevity in both invertebrate and vertebrate models. Furthermore, they discuss the potential mechanisms by which p53 regulates aging and longevity, including the p53 regulation of insulin/TOR signaling, stem/progenitor cells, and reactive oxygen species." You might recall that p53 was involved in one of the most effective methods of extending healthy and maximum life span in mice discovered to date.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135645/

Vascular Changes and Dementia Go Hand in Hand
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Via ScienceDaily: "The same artery-clogging process (atherosclerosis) that causes heart disease can also result in age-related vascular cognitive impairments (VCI) ... Cognitive impairment, also known as dementia, includes difficulty with thinking, reasoning and memory, and can be caused by vascular disease, Alzheimer's disease, a combination of both and other causes. Atherosclerosis is a build- up of plaque in the arteries associated with elevated blood pressure, cholesterol, smoking and other risk factors. When it restricts or blocks blood flow to the brain, it is called cerebrovascular disease, which can result in vascular cognitive impairment. ... We have learned that cerebrovascular disease and Alzheimer's disease may work together to cause cognitive impairment and the mixed disorder may be the most common type of dementia in older persons ... Treating risk factors for heart disease and stroke with lifestyle changes and medical management may prevent or slow the development of dementia in some people ... Physical activity, healthy diet, healthy body weight, tobacco avoidance as well as blood pressure and cholesterol management could significantly help many people maintain their mental abilities as they age." An unhealthy lifestyle corrodes the body and mind faster than would otherwise be the case. As we approach the era of age-reversing biotechnologies, it's worth thinking about how you might maximize your chance of reaching and benefiting from those years yet to come.

Link: http://www.sciencedaily.com/releases/2011/07/110721163023.htm

We Don't Need to Persuade Everyone
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The point of advocacy and education for the development of rejuvenation biotechnology, such as evangelism for the Strategies for Engineered Negligible Senescence, is not to persuade everyone. It's to persuade enough of the right people: enough to ensure that progress occurs and ways to significantly reverse aging and its diseases are produced within our lifetimes. That doesn't have to be a sizable fraction of the population: the plausible cost of achieving radical life extension in mice is one to two billion dollars over a decade. Most of the really big pharmaceutical companies each spend that much on the development of two or three mainstream drugs, all costs included.

A billion dollars is small change when considered against the economic output of even small segments of the human race. But of course first you have to talk that small segment into seeing things your way. Ideas spread in characteristic ways: there are no new things in advocacy and persuasion. All the strategies are time-worn and well understood; advocates put their shoulder to the wheel and keep on pushing until it moves. This has worked, does work, and will continue to work. On that note, I noticed a recent article on simulational research aiming to quantify how the spread of ideas works:

Scientists at Rensselaer Polytechnic Institute have found that when just 10 percent of the population holds an unshakable belief, their belief will always be adopted by the majority of the society. The scientists, who are members of the Social Cognitive Networks Academic Research Center (SCNARC) at Rensselaer, used computational and analytical methods to discover the tipping point where a minority belief becomes the majority opinion.

...

An important aspect of the finding is that the percent of committed opinion holders required to shift majority opinion does not change significantly regardless of the type of network in which the opinion holders are working. In other words, the percentage of committed opinion holders required to influence a society remains at approximately 10 percent, regardless of how or where that opinion starts and spreads in the society.

Considering this, it doesn't do to become discouraged when you are rejected in an attempt to persuade a friend of the merits of supporting the SENS Foundation, or to give more thought to longevity science. It wouldn't matter if a majority of your friends rejected these ideas. So long as a solid minority of supporters can grow to that one in ten estimate, most of the world will eventually follow along. The research mentioned above may or may not be right in detail, but it's just another way of looking at the well known truths of advocacy: you don't need to get everyone on your side, and you will achieve great things if even a small fraction of the population can be persuaded to give their support.

Attention and White Matter Pathology in Aging
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The mind decays in characteristic ways, and researchers are making inroads in linking the symptoms to the specific physical causes: "Advanced aging is associated with reduced attentional control and less flexible information processing. ... Older adults often perform poorly in situations where multiple goals and response rules must be maintained and coordinated ... Here, we explored age differences in recruitment of brain systems associated with attentional control and their relationship to behavior and markers of neuropathology. ... Examining 2 markers of preclinical pathology in older adults revealed that white matter hyperintensities (WMHs), but not high amyloid burden, were associated with failure to modulate activity in response to changing task demands. In contrast, high amyloid burden was associated with alterations in default network activity. ... These results, in addition to the rarity of co-occurrence between amyloid and white matter pathology among our sample of clinically normal adults, suggest that age-related cognitive failures may arise from multiple distinct pathologies. ... Age-related failures of dynamic allocation of attention may be an early consequence of disrupted neural integrity within prefrontal-parietal networks."

Link: http://cercor.oxfordjournals.org/content/early/2011/07/16/cercor.bhr172.long

Robert Ettinger Cryopreserved
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From the Washington Post: "Robert C. W. Ettinger, a physics teacher and science fiction writer who believed death is only for the unprepared and unimaginative, died July 23 at his home in Clinton Township, Mich. He was 92 and had suffered declining health in recent weeks, said his son David, who could not specify a cause. 'We're obviously sad,' said the younger Ettinger. But 'we were able to freeze him under optimum conditions, so he's got another chance.' Mr. Ettinger is widely considered the father of the cryonics movement, whose adherents believe they can achieve immortality through quick-freezing their bodies at death in anticipation of future resurrection. Mr. Ettinger's frozen body is being stored in a vat of liquid nitrogen at a nondescript building outside Detroit, home to more than 100 fellow immortalists - including his mother and two wives - who are awaiting revival. If all goes as Mr. Ettinger envisioned, he will remain in a period of icy stasis for decades - or perhaps centuries - however long it takes for doctors, armed with technology of the future, to defrost him and restore him to good health. ... Mr. Ettinger was a little-known community college professor in the mid-1960s when he wrote the founding document of cryonics, 'The Prospect of Immortality,' a manifesto that described the practical and moral aspects of deep-freezing the dead. Introducing what he called the Freezer Era, Mr. Ettinger described a world in which people would become nobler and more responsible as they were confronted with the reality of living forever." It is important to note that cryonics nowadays is less about freezing and more about vitrification: ice crystal formation is minimized amd thus so is cellular damage.

Link: http://www.washingtonpost.com/local/obituaries/gIQAupuIXI_print.html

The Economics of the Late Realization of Life's High Value
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When you're young, you expect to have a great deal of time ahead of you. You haven't spent much time yet, and so what remains seems like a fortune in comparison - enough to squander. Think of the way that wealthy children so often turn out despite the best efforts of their parents, their view of the value of money and economic common sense poisoned by having grown up with access to a great deal of money. But before you look down on them or pity them, think of your own situation with respect to the expected time remaining in your life. Your viewpoint on time, life, and the future was poisoned by having what appeared to be a great deal of remaining time, far more than it was easy to compare against what little you had lived to date ... so you valued time poorly.

We are evolved to squander the resources that shower upon us and gather in their piles, while spending a great deal of care, thought, and worry on resources that are scarce. So we care little about air, not so very much more about water, and not at all about time when we are young. But that stock of time diminishes as you grow old, and because there is less of it, it becomes more valuable. This is one reason why people are willing to spend greatly on medical technologies at the end of their lives - and here I am talking only of willingness, not any need to spend more. Aging brings with it degeneration and disease, and the cost of remaining alive and able to enjoy life accelerates with the passing years: the old spend increasingly more than the young because they have to in order to stay in the game. Note that "have to in order to stay in the game" is not the same thing at all as "willing to."

To be old is to live in in the mirror image of youth: time and no money has turned into money and no time. The value of money to an old person is typically less than it is to a young person, and that is nothing more than a measure of how much of the stuff you have: old people are typically much wealthier. The converse is true of remaining time, of which the young have a great deal, whilst the old are time-poor; thus the exchange rate between the time and money is radically different at the opposite ends of life. A young person will give away an hour to gain a small number of dollars, while an old person will spend ten times that sum to gain another hour. A cynic might suggest there is some form of arbitrage to found in this truth of human nature. If you like thinking along these lines, you might look back at past ruminations on the nature of wealth in a past post.

Time is everything. How much have time you spent reading this far? Could you have been doing something more useful, more optimal from your perspective? We make these small evaluations constantly, because time is the most valuable thing we have.

There are always people in the academic world who'd rather spend time looking at factors other than the obvious ones when it comes to aging and economic activity, of course:

Low opportunity cost, weak influence of quality of life in the face of death, the social value of life extension to others, shifting psychological reference points, and hope have been proposed as factors to explain why people apparently perceive marginal life extension at the end of life to have disproportionately greater value than its length. Such value may help to explain why medical spending to extend life at the end of life is as high as it is, and the various factors behind this value might provide normative rationale for that spending.

Upon critical analysis, however, most of these factors turn out to be questionable or incompletely conceived; this includes hope, which is examined here in special detail. These factors help to explain complexity and nuance in the normative issues, but they do not provide adequate justification for spending as high as it often is. In any case, two additional factors must be added to the descriptive explanation of high spending, and they throw its normative justification into further doubt: the "insurance effect" and provider-created demand. Overall, the perception of especially high value of life at the end of life provides some normative justification for high spending, but seldom strong justification, and not for spending as high as it often is.

The trouble begins with a person deciding that an entire clade of people are making systematically incorrect assessments of value despite having access to complete and correct data. Value is subjective, not objective, and it shouldn't be at all surprising that at the end of life there are radical shifts in the value placed by a dying person upon money and time. Note that I don't say "perceived value" - that phrase is just a subtle way of suggesting that the author is correct and the members of the clade are systematically wrong, which is in turn a subtle way of suggesting that value can be objective.

If you have bad or incomplete data, the value you ascribe will probably prove to be unhelpful if you act upon it, but it is still your subjective value: there is no "wrong" or "right" here, just a record of the outcome of a series of actions. People have a way of saying that you valued something wrongly if, by your actions based on that value, you manage to do yourself harm, economic or otherwise. But that really isn't a helpful way to look at subjective value: it is what it is, at any given moment. Either way, I'd argue that when it comes to life, longevity, and medical technology, there's a lot of reliance on bad and incomplete data taking place these days, given the possibilities presented by longevity science and the level of public ignorance of those possibilities. A fraction of people alive today will have the opportunity to live for centuries or longer, but consideration of that possibility is almost entirely absent from their economic calculations.

I suppose I should also mention that this short discussion has nothing much to say in connection with the horrible state of medical economics in the US. Participation in the heavily regulated marketplace for medical technology and services is a pit of horrors for both old and young: everyone suffers from the effects of regulation, lack of accountability for costs incurred, and the general miasma of government-induced systems failure. So arguments based on differential willingness to spend on medicine by age stand apart from that mess.

The neat endpoint to this post, if you want one, is that it can't hurt to think on the value you place on the time remaining in your life expectancy, and to look at whether you are basing both expectation and value on factual data.

Loco and Fly Longevity
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Here is another piece in the exceedingly complicated puzzle of metabolism and longevity, touching on some other pieces that have shown up here before, such as adenylate cyclase: "Despite the various roles of regulator of G protein signaling (RGS) protein in the G protein signaling pathway that have been defined, the function of RGS has not been characterized in longevity signaling pathways. We found that reduced expression of Loco, a Drosophila RGS protein, resulted in a longer lifespan of flies with stronger resistance to stress, higher MnSOD activity and increased fat content. In contrast, overexpression of the loco gene shortened the fly lifespan significantly, lowered stress resistance and reduced fat content, also indicating that the RGS domain containing GTPase-activating protein (GAP) activity is related to the regulation of longevity. Interestingly, expressional changes of yeast RGS2 and rat RGS14, homologs to the fly Loco, also affected oxidative stress resistance and longevity in the respective species. It is known that Loco [reduces] activity of adenylate cyclase (AC) and RGS14 interacts with activated H-Ras and Raf-1 kinases, which subsequently inhibits ERK phosphorylation. We propose that Loco/RGS14 protein may regulate stress resistance and longevity as an activator in AC-cAMP-PKA pathway and/or as a molecular scaffold that sequesters active Ras and Raf from Ras*GTP-Raf-MEK-ERK signaling pathway. Consistently, our data showed that downregulation of Loco [leads to] higher resistance to the oxidative stress."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21776417

Calorie Restriction Slows DNA Methylation in the Hippocampus
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DNA methylation is proposed to be a good biomarker of aging, and here researchers show that calorie restriction slows the progression of DNA methylation in the hippocampus - continuing the expected trend of calorie restriction slowing near every identified biological change that occurs with aging: "Aberrant DNA methylation patterns have been linked to molecular and cellular alterations in the aging brain. Caloric restriction (CR) and upregulation of antioxidants have been proposed as interventions to prevent or delay age-related brain pathology. Previously, we have shown in large cohorts of aging mice, that age-related increases in DNA methyltransferase 3a (Dnmt3a) immunoreactivity in the mouse hippocampus were attenuated by CR, but not by overexpression of superoxide dismutase 1 (SOD1). Here, we investigated age-related alterations of 5-methylcytidine (5-mC), a marker of DNA methylation levels, in a hippocampal subregion-specific manner. Examination of 5-mC immunoreactivity in 12- and 24-month-old wild type (WT) mice on control diet, mice overexpressing SOD1 on control diet, wild type mice on CR, and SOD1 mice on CR, indicated an age-related increase in 5-mC immunoreactivity in the hippocampal dentate gyrus, CA3, and CA1-2 regions, which was prevented by CR but not by SOD1 overexpression. ... These findings suggest a crucial role for DNA methylation in hippocampal aging and in the mediation of the beneficial effects of CR on aging."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21764481

A Little Cryonics History
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To my eyes, Chronosphere is chiefly important as an insider's personal view of the 40-year history of modern cryonics movements. For decades, people have been working on the indefinite low temperature storage of the deceased, aiming to preserve the fine structure of the brain that encodes the mind's data. There is, to my eyes, still far from enough of a recounting of that history, the lessons learned, and efforts made - the more memoirs and personal accounts presented online the better. So here are pointers to a couple of recent Chronosphere posts on what went on, back in the day, when cryonics was a younger initiative, both of which are liberally scattered with photographs:

In Camera Historia: Cryonics Institute Facility, 1978

On 21 March, 1978 the Cryonics Institute (CI) acquired their first facility, a storefront building in the Detroit Metro area. The CI building was the first wholly owned (cash purchase) patient storage facility in the history of cryonics, and remains one of only two in the world today. ... As was the case with all cryonics organizations' initial facilities, the CI facility was small and cramped. It also lacked the ceiling height necessary for upright (open at the top) cryostats and this limitation was an additional impetus for CI to develop the fiberglass-epoxy resin type of cryostat (using perlite and low vacuum insulation) that they currently use to store their patients.

The Armories of the Latter Day Laputas, Part 7

The Alcor Life Extension Foundation, Inc. (Alcor) and its brother for-profit organization, Manrise Corporation (Manrise), were founded in 1972 by Fred and Linda Chamberlain ... The Chamberlains had previously been members of the Cryonics Society of California (CSC) and both had served as officers of CSC. When they became suspicious about the integrity of CSC's financial and cryogenic patient care operations and were unable to obtain answers to their questions, they left CSC and founded Alcor/Manrise. As was the model at the time, Alcor was the 501c3 non-profit organization tasked with accepting cryonics patients under the Uniform Anatomical Gift Act (UAGA) and acting as their custodian and advocate until such time as reanimation might become possible.

If this were a better world then cryonics or a similar industry based on plastination would be large and well known, and a majority of people would be spared the oblivion of the grave. We don't live in that world, evidently, and is a sad statement on vision, priorities, and human nature that cryonics remains a small industry.

An Example of Lifespan Extension Through Induced Hormesis
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Hormesis is the name given to the processes by which a little damage at the cellular level can actually be beneficial, as it spurs repair and maintenance systems to greater efforts - the result is a net gain. Here researchers demonstrate one method of inducing hormesis in nematode worms: "As organisms age, cellular proteins, lipids and nucleic acids sustain damage that can lead to functional deficits in tissues and, ultimately, death. The free radical theory of aging proposes that aging results, at least in part, from damage to cellular components by reactive oxygen species (ROS) ... Indeed, oxidative modification is a major form of damage detected in aging tissues ... Here, we report that hormetic chemicals can be modified to optimize beneficial effects and minimize toxicity in C. elegans, a model for studying aging in whole organisms. C. elegans is well-suited to this problem due to the short lifespan, ease of genetic manipulation and transparent anatomy. First, we examined whether lifespan extension is common among biological toxins with various chemical structures and mechanisms of action. In a small screen of natural phytochemicals, we identified two ROS generating compounds, plumbagin and juglone, which extended lifespan at subtoxic doses. Mean lifespan extension by plumbagin was dependent on SKN-1, a cap'n'collar transcription factor that promotes antioxidant gene expression in response to oxidative stress. We further screened a collection of six plumbagin analogs, identifying three additional naphthoquinones that activated expression of a skn-1 target. One of these could extend lifespan over a larger range of doses than plumbagin, demonstrating the utility of stress hormesis mechanisms as promising prolongevity intervention."

Link: http://dx.doi.org/10.1371/journal.pone.0021922

Snapping out of the Pro-Death Trance
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From TechNewsWorld: "In America, a large part of funding for regenerative medicine comes from the Department of Defense, whose goal is to repair soldiers who come home wounded. That is an effort everyone recognizes as important. Yet, when it comes to repairing older people whose hearts and lungs are failing, society seems at peace accepting their demise because that is all humanity has ever known - a state of mind that some call the 'pro-death trance.' ... A Swedish hospital recently announced that a cancer patient was saved after doctors grew him a new windpipe in the lab using a synthetic structure and the man's own stem cells. That might have sounded like science fiction just a few years ago, but today it is landmark news. Regenerative medicine has the ability to usher in radically longer and healthier lives, yet few are considering the implications. The ability to grow new replacement parts for humans when original organs break down is a game-changer when it comes to extending human 'health spans' - the amount of time one is alive and healthy. A handful of human subjects have already benefited from innovations in this area and dozens of organs have been successfully grown in the lab, including a rat heart. ... The coming changes will be enormous - but on the whole, positive. Why then, is there no sustained dialog about how to get to that point sooner? ... Humans now have the opportunity to live much longer and healthier lives - for the greater benefit of all. It is time to break free from the pro-death trance and work toward speeding the revolution."

Link: http://www.technewsworld.com/story/America-Its-Time-to-Snap-Out-of-the-Pro-Death-Trance-72907.html

A Question and Answer Session with Aubrey de Grey
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Over at h+ Magazine you'll find a question and answer session with Aubrey de Grey that covers some old ground and some new ground. The SENS Foundation, which de Grey cofounded, is presently deploying a modest million-dollar yearly budget to work on the biotechnologies needed to repair the cellular and molecular damage that causes aging. A great deal of that budget presently goes towards the first of the Foundation's programs, an effort focused on using bacterial enzymes to break down harmful waste chemicals that build up in our cells and contribute to a range of age-related diseases and degenerations.

I should mention that SENS Foundation funding is due entirely to philanthropic donations - including those of a few high net worth individuals - and I know that many of the readers here are long-standing supporters dating back to the years when the SENS Foundation's work was a program of the Methuselah Foundation. I find it very gratifying to see that so much has been made of the early efforts, when it was a matter of a few dollars given at time. I would hope that the rest of you feel the same way.

The SENS Foundation will also be hosting the forthcoming SENS5 conference in Cambridge at the end of August - there's a lot going on at the moment. But back to the h+ Magazine piece:

H+: SENS describes a whole battery of medical treatments that could theoretically defeat the aging process. These treatments range from relatively simple ones like injecting people with enzymes that can break down tough wastes inside of cells, to highly advanced ones like genetically altering trillions of somatic cells in full grown adults. Considering the differential technical challenges, what SENS therapies will most likely become available first, and which will be developed last?

AdG: Some of them are already pretty close: probably the closest is in fact not the enzyme therapy you mention, but the use of vaccines to eliminate extracellular aggregates (especially amyloid). But when we consider the others, actually I wouldn't like to make the call, because the hardest ones are the ones that the SENS Foundation and I are prioritizing in terms of the early research. In other words, we're hoping that they will start to catch up with the easier ones. I suspect that the challenge of genetically modifying a high proportion of cells by somatic gene therapy will have been largely solved before we complete the development of all the genes that we want to introduce.

...

H+: Are you worried that a single company or government might obtain the secrets to longevity first and then use its monopoly on the science to hold the human race hostage forever (or even for just a long period of time)?

AdG: There's no chance whatever of this scenario, because the defeat of aging will depend on the simultaneous application of a lot of different interventions, all of which will first have been developed in the laboratory rather than in humans.

There's a lot more in that vein, so read the whole thing. The point on gene therapy in the quote above is an interesting and important one. A great many very promising demonstrations in the laboratory depend upon gene therapy in one form or another - take the method of largely preventing atherosclerosis I pointed out earlier today for example. If we want to see these lines of research become more than simply interesting technology demonstrations then selective, tissue-specific gene therapy for humans must become routine and safe.

Arguing Against a Correlation Between Blood Type and Aging
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Does blood type in any way affect longevity? A resounding "maybe" from what little work exists on the topic, which suggests that if there is any effect then it is small in comparison to other factors. But we'll never know unless the research community looks into the matter, and so here is another batch of evidence to add to the pile: "Centenarians are the best example of extreme human longevity, and they represent a selected population in which the appearance of major age-related diseases, such as cancer, and cardiovascular diseases among others, has been consistently delayed or escaped. The study of the long-lived individual genetic profile has the purpose to possibly identify the genes and the allelic variations influencing extended life expectancy, hence considering them as biomarkers of age-related diseases onset and development. The present study shows no significant differences between allelic variations of ABO blood groups among a group of centenarians from Western Sicily."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21766224

Gene Therapy Versus Atherosclerosis
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Via EurekAlert!, news of a promising study in rabbits: "A one-dose method for delivering gene therapy into an arterial wall effectively protects the artery from developing atherosclerosis despite ongoing high blood cholesterol. ... As applied in our study, the introduced genes can produce proteins that counteract the fundamental processes that drive atherosclerosis, including preventing lipid accumulation inside the artery wall and decreasing recruitment of inflammatory cells. We found both of these effects. ... Gene transfer would move the production of the therapeutic 'drug' (in this case a therapeutic gene) directly to the site of atherosclerosis development: the blood vessel wall. The approach maximizes delivery of the drug to the artery wall and minimizes side effects in the rest of the body. ... The deployed gene produces a protein that is likely responsible for the beneficial effects of high-density lipoprotein, or HDL, commonly known as good cholesterol. This substance is apolipoprotein A-1, or apoA-1. It pumps out harmful cholesterol from the scavenger-type cells that ingest fats and congregate in early atherosclerotic lesions. ApoA-1 appears to remove cholesterol from the lesions and is capable of transporting it to the liver, where it can be excreted from the body. Lack of a suitable vector to transfer apoA-1-manufacturing genes into the cells lining the arterial wall has hampered the progress of this approach. Normally apoA-1 is produced by cells in the liver, stomach and intestine and enters the artery wall only after circulating through the blood. [The] researchers successfully used a helper-dependent adenovirus (HDAd) as the vehicle to transfer a genomic clone of rabbit apo-A1 into the carotid artery. This large blood vessel sends oxygenated blood to the brain. After the vector was infused into the artery, the gene was taken up almost exclusively by the cells in the thin layer that lines the carotid's inner surface and is in contact with circulating blood."

Link: http://www.eurekalert.org/pub_releases/2011-07/uow-gtd071911.php

To Learn How Cryopreservation Works in Practice Start by Reading the Case Summaries
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Cryonics, as I'm sure you're all aware, has for decades been the best and only shot at a long life in the future for people who die before the advent of rejuvenation biotechnologies capable of reversing the damage of aging. That is a massive number of people, possibly including you and I unless we get our act together - and sadly, all too few will choose to be cryopreserved, even though they have the opportunity and the means. Cryonics is, in essence, a form of indefinite low temperature storage of the body and brain immediately following death. It is carried out with the reasonable expectation, based on present scientific knowledge, that it preserves the fine structure of the brain that stores the information of the mind - you might not be running, but all your data is backed up.

We can envisage the technologies needed to restore a preserved person to active life once again, and none of it is prohibited by the laws of physics. It most likely require a far greater understanding of the structure human brain, the ability to build a new body from scratch, the use of a molecular manufacturing technology base and swarms of nanoscale medical robots, capable of manipulating and repairing cellular machinery - and the computational power to support sophisticated use of these medical technologies. But all of these are foreseeable, and presently being worked on by a range of research groups. It isn't pie in the sky to expect there to be a chance of resuscitation for cryopreserved individuals. Their lives are on hold, but not gone - you are only irrevocably gone if you choose the grave.

But how does a cryopreservation work in practice? How does one go from the last weeks of life to being safely stored in liquid nitrogen, awaiting the future? As I've noted in the past, it takes a fair amount of organization to do well, and the regulatory environment surround end of life choices doesn't make a good cryopreservation any easier - you are not allowed to choose when to do it, and in most jurisdictions no-one is allowed to help you plan your death to be at the time of your choosing either. If you want to learn more about how a cryopreservation tends to unfold, then you should note that cryonics provider Alcor publishes case summaries on a regular basis, as patients are preserved. You'll find some referenced back in the Fight Aging! archives, and here are a couple of recent case summaries:

Case Summaries: A-1408 and A-2357:

This past quarter, Alcor cryopreserved two of its members. The first member, A-1408, lived just north of the Tampa, FL area. Alcor team members initiated a standby at the hospital for three days during the time the individual was listed as critical and medical providers anticipated that he might stop breathing. The member stabilized and Alcor ended the standby while continuing to monitor the patient's condition remotely. When his medical condition deteriorated again, Alcor was on the verge of initiating a standby for another member and therefore decided to request Suspended Animation to provide the standby this time.

On the afternoon of the fourth day of the standby (May 26, 2011), the member was pronounced, stabilized and cooled on-site, followed by a field washout. The transport commenced the next morning by commercial airlines and the patient was brought to Alcor with the surgical team at the ready. After the neuro cryopreservation ensued, member A-1408 became Alcor's 105th patient.

Case Report for A-1614 (PDF)

Wesley Du Charme authored a book: Becoming Immortal: Nanotechnology, You and the Demise of Death in 1995, which discussed the opportunity for virtual immortality through combining nanotechnology and cryonics. He lived life fully while always looking to the future; he joined Alcor in hopes of living in the far future.

....

The tests showed that Wesley now had pancreatic cancer with metastases to the liver and duodenum. At this point, the oncologist said that his condition was terminal and nonoperable, and Wesley would not respond to chemo or radiation treatments. When asked how long Wesley had to live, he responded with "...longer than three days, but less than six months."

Given Wesley's greatly weakened condition, the family desired to have him admitted to hospice care in Scottsdale, Arizona, close to Alcor. As Wesley was currently hospitalized, his physician who was supportive of the cryopreservation directives, prescribed TPN (Total Parenteral Nutrition) as a way to increase Wesley's strength and stamina to endure the trip to Arizona. Alcor personnel helped facilitate communication between the hospice facility and the family to finalize the admittance process.

You should read the whole PDF document, and be appreciative of the folk who were thoughtful enough to allow a detailed account of the arrangement of Du Charme's cryopreservation to be published. The end of a life and the terminal breakdown of a body's necessary systems are never pretty, and most people prefer to sweep all of that behind the curtain - and the same goes for the hundred small organizational details that go into managing death and cryopreservation. But if they aren't published, we don't learn.

What is the Limiting Factor on the Lifespans of the Oldest Old?
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Slate here ponders the consistency of the upper limits of the human lifespan: "Last month, a 114-year-old former schoolteacher from Georgia named Besse Cooper became the world's oldest living person. Her predecessor, Brazil's Maria Gomes Valentim, was 114 when she died. So was the oldest living person before her, and the one before her. In fact, eight of the last nine 'world's oldest' titleholders were 114 when they achieved the distinction. Here's the morbid part: All but two were still 114 when they passed it on. Those two? They died at 115. The celebration surrounding Cooper when she assumed the title, then, might as well have been accompanied by condolences. If historical trends hold, she will likely be dead within a year. It's no surprise that it's hard to stay the 'world's oldest' for very long. These people are, after all, really old. What's surprising is just how consistent the numbers have been." Based on the work of the Supercentenarian Research Foundation we might suspect a single class of age-limiting process - something different from the collection of common issues and biological system failures that kill most people across their 70s, 80s, and 90s. Autopsies of supercentenarians revealed that they die from a form of amyloidosis, something that you will only rarely see in younger old people. Fortunately this is very amenable to foreseeable treatments - so as rejuvenation biotechnology advances, we need not worry too greatly about this apparently limiting process.

Link: http://www.slate.com/id/2299256/

On Increasing Your Chances of Avoiding Alzheimer's
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In many ways, Alzheimer's disease looks a lot like type 2 diabetes - it can be argued that there are some biochemical similarities in the underlying mechanisms, Alzheimer's appears to be a lifestyle disease to some degree, and the two conditions have many of the same risk factors, such as obesity and being sedentary. So: "Over half of all Alzheimer's disease cases could potentially be prevented through lifestyle changes and treatment or prevention of chronic medical conditions. ... Analyzing data from studies around the world involving hundreds of thousands of participants, [researchers] concluded that worldwide, the biggest modifiable risk factors for Alzheimer's disease are, in descending order of magnitude, low education, smoking, physical inactivity, depression, mid-life hypertension, diabetes and mid-life obesity. ... In the United States, [researchers] found that the biggest modifiable risk factors are physical inactivity, depression, smoking, mid-life hypertension, mid-life obesity, low education and diabetes. ... What's exciting is that this suggests that some very simple lifestyle changes, such as increasing physical activity and quitting smoking, could have a tremendous impact on preventing Alzheimer's and other dementias in the United States and worldwide." Many lines of research demonstrate the importance of exercise for health in later life.

Link: http://www.eurekalert.org/pub_releases/2011-07/uoc--oho071811.php

There is No Such Thing as a Scientific Breakthrough
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The concept of the scientific breakthrough is firmly embedded in our popular culture: a great leap forward happens in the laboratory, ushered in by the enlightened work of a tiny inner circle of researchers, and bursts upon the world to change everything. I would argue, however, that this doesn't happen, never happens, and there is, really, no such thing as a scientific breakthrough in this sense.

Science is nothing if not a business of incremental advances, each carefully built atop a pyramid of many earlier research results. Science is not the province of lone researchers and microcommunities: progress occurs reliably and steadily only in those fields where a great many people are working away - and among those workers, it is no great secret as to what are most plausible forthcoming items of progress. Someone will join the last pieces of the puzzle together, and to the best team goes the spoils of fame. But for any great discovery or step forward in the world of science, when we look back with the benefit of hindsight we see that if the discoverers didn't exist, any one of several other groups would still have completed the work at around the same time.

The scientific community based around any significant portion of any field of research consists of many groups, all working in the same milieu, at the apex of the same pyramid built from past research. That community generates an ongoing body of work, most of which will never make the news, but for any insider clearly points the way towards what will most likely next be accomplished. To anyone following along, the discoveries clearly don't come from nowhere: each is telegraphed from what came before.

So breakthroughs only look like breakthroughs to people who haven't been paying attention. That largely means the press, as they have the biggest megaphone in this day and age. When the popular scientific press shouts "breakthrough!" what they really mean is "look at what just popped out of nowhere while we weren't paying attention!" But it wasn't out of nowhere. It was, just like every other new brick set upon the pyramid, resting on a solid foundation of recent and directly related research: an incremental advance, and one that most people in the research community knew was coming in some form or another.

The point I want to make with all of this is that longevity science, work that will lead to biotechnologies capable of human rejuvenation, is no different. It is a process of incremental advances, requiring a large research community for any sort of reliable progress, and in which the nature of forthcoming discoveries are telegraphed by the nature of the work today.

If you think that scientific breakthroughs are the way in which the world works, then you might be sitting there expecting significant advances in engineered human longevity to arrive no matter what the state of the present research community. Because some people are working on it, right? And it's just a few scientists and a eureka moment, right? Sadly not. One of the biggest challenges facing us today is that there is no large rejuvenation research community, and if we want to see real progress, that community must come into being - large enough and vigorous enough to match the stem cell research community pace for pace.

So there are two large advocacy initiatives taking place in longevity science: the first to educate and persuade the broader public, and the second to convince researchers to work on the next generation of longevity science. These things go more or less in lockstep, and it is unlikely that either one will get a long way ahead of the other. Large strides in advocacy, fundraising, and persuasion on both sides of the aisle have been made in the last ten years, but a great deal remains to be accomplished.

This is where folk like you and I can help: every additional effort brings us all that little bit closer to where we need to be in order to engineer success in increasing human longevity, one foreseeable and expected incremental advance at a time.

Four Scenarios to Link Progeria to Aging
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In light of recent research demonstrating that the longevity-inducing drug rapamycin may treat the accelerated aging condition progeria, a researcher here offers up a fairly comprehensive commentary on what this might mean for work on "normal" aging. It is educational, but should be read with the caveat that the author has a strong conviction that the TOR gene is central in the aging process: "Here I discuss four potential scenarios, comparing progeria with both normal and accelerated aging. This reveals further indications of rapamycin both for accelerated aging in obese and for progeria. ... Scenario 1. Progerin is detectable in normal cells from normal elderly humans. In normal human fibroblasts, telomere damage during replicative senescence activates progerin production. In theory, progerin can accumulate. In this scenario, normal aging is caused by progerin or at least in some individuals accumulation of progerin is life-limiting. If so, progeria is a truly accelerated aging or at least accelerated component of aging. ... Scenario 2. Normal aging is caused by overactivation of TOR-centric pathways such as mTOR, MAPK and kinases of the DNA damage response (DDR). Progerin can activate DDR. In turn, DDR may activate the mTOR pathway. ... Therefore, by activating DDR pathways, progerin might also promote geroconversion. ... Scenario 3. mTOR inhibits autophagy and insufficient autophagy is involved in normal aging. Rapamycin also causes clearance of aggregation-prone proteins. In progeria, rapamycin activates clearance of progerin thus slowing down the progeric aging. Thus, rapamycin can affect both progeria and normal aging via activation of autophagy of different proteins and structures. ... Scenario 4. Two different mTOR activities are responsible for deceleration of normal and progeric aging. In progeria, this is autophagy. In normal aging, this is suppression of cellular hyper-functions ... Rapamycin would be effective in both conditions but by different reasons."

Link: http://impactaging.com/papers/v3/n7/full/100352.html

Maria Konovalenko Presents at Singularity University
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Longevity science advocate Maria Konovalenko recently presented at Singularity University; you'll find a link to the presentation materials in the post: "Last week I gave a talk at the Singularity University about how we can extend life. Those who have never heard about the Singularity University, should definitely check out what the SU is all about. I talked about the current records in life extension achieved in model animals, overviewed the main scientific approaches to fighting aging and looked at why activation of stress resistance genes may be a very good idea for extending our longevity. I wrapped up by noting the potential profitable business side of life extension, which is creation of geroprotective drugs. You can find the presentation "The Best Strategy for 5,000,000,000 people" here. ... A couple of pictures from the place where great ideas and poeple are mixed together with the common goal of transforming the humanity. Although, it's such a pity that life extension doen't get much attention." It is true the Singularity University crowd are less focused on radical life extension than on other transhumanist topics such as molecular manufacturing and strong AI.

Link: http://mariakonovalenko.wordpress.com/2011/07/15/the-best-strategy-for-5000000000-people/

Three Studies on the Genes and Biochemistry of Human Longevity
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I'll point out three recently published papers today, all of which are the fruits of the ongoing studies of long-lived people. There are a fair number of these efforts at the present time, a combination of decades-long longitudinal studies which now consist of a cohort of exceptionally old survivors, combined with new studies launched over the past decade as academic interest in the genetics of human longevity grew. As it turns out, long-lived human lineages differ from the rest of us in a number of identifiable ways - and given that it's really only been a handful of years that these sorts of study have been underway, I would imagine that many more characteristic genetic differences remain to be identified.

A genome-wide association study confirms APOE as the major gene influencing survival in long-lived individuals

We conducted a case-control genome-wide association study (GWAS) of human longevity, comparing 664,472 autosomal SNPs in 763 long-lived individuals (LLI; mean age: 99.7 years) and 1085 controls (mean age: 60.2 years) from Germany. ... Our GWAS failed to identify any additional autosomal susceptibility genes [beyond the APOE gene]. One explanation for this lack of success in our study would be that GWAS provide only limited statistical power ... A recent GWAS in Dutch LLI independently confirmed the APOE-longevity association, thus strengthening the conclusion that this locus is a very, if not the most, important genetic factor influencing longevity.

Mitochondrial Haplogroup X is associated with successful aging in the Amish

Mitochondrial lineages described by patterns of common genetic variants ("haplogroups") have been associated with increased longevity in different populations. We investigated the influence of mitochondrial haplogroups on [health in later life] in an Amish community sample. ... [Healthier old people] were more likely to carry Haplogroup X (OR = 7.56, p = 0.0015), and less likely to carry Haplogroup J (OR = 0.40, p = 0.0003). Our results [suggest] that variants in the mitochondrial genome may promote maintenance of both physical and cognitive function in older adults.

Relationship between plasma ghrelin, insulin, leptin, interleukin 6, adiponectin, testosterone and longevity in the Baltimore Longitudinal Study of Aging

Caloric restriction (CR) is the most robust and reproducible intervention for slowing aging, and maintaining health and vitality in animals. Previous studies found that CR is associated with changes in specific biomarkers in monkeys that were also associated with reduced risk of mortality in healthy men. In this study we examine the association between other potential biomarkers related to CR and extended lifespan in healthy humans. .... Based on the Baltimore Longitudinal Study of Aging, "long-lived" participants who survived to at least 90 years of age (n=41, cases) were compared with "short-lived" participants who died between 72-76 years of age (n=31, controls) in the nested case control study. Circulating levels of ghrelin, insulin, leptin, interleukin 6, adiponectin and testosterone were measured from samples collected between the ages 58 to 70 years. ... At the time of biomarkers evaluation (58-70 yrs), none of the single biomarker levels was significantly different between the two groups. However, after combining information from multiple biomarkers [the] global score differentiated the long- and short-lived participants.

While interesting, and probably the basis for what will eventually be a massive industry of drug development aimed at gently slowing down the aging process, this sort of work is still something of a sideshow. Understanding the contributions of metabolic differences to the pace of aging and resistance to frailty and degeneration will not lead to a true cure for aging. Repair and reversal of aging, the foreseeable biotechnologies that can make the old young once again, can only come from lines of research like those undertaken by the SENS Foundation.

Continued Investigations of RasGrf1 and Longevity
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RasGrf1 is the gene associated with longevity in engineered mice with two female parents, and a deficiency in the gene achieved through other means boosts life span as well. Here is more theorizing on what it all means: "Interestingly, RasGrf1 is one of parentally imprinted genes transcribed from paternally-derived chromosome. Erasure of its imprinting results in RasGrf1 downregulation and has been demonstrated in a population of pluripotent adult tissues-derived very small embryonic like stem cells (VSELs), stem cells involved in tissue organ rejuvenation. ... downregulation of RasGrf1 in VSELs [protects] from premature depletion from adult tissues. Thus, the studies in RasGrf1-/- mice indicate that some of the imprinted genes may play a role in ontogenetic longevity and suggest that there are sex differences in life span that originate at the genome level. All this in toto supports a concept that the sperm genome may have a detrimental effect on longevity in mammals." So in summary, one of the ways in which RasGrf1 extends life seems to involve improvement in the capacity of stem cells in the older organism, and a significant effect on longevity can emerge from the contributions of one parent through the epigenetic imprinting process.

Link: http://impactaging.com/papers/v3/n7/full/100354.html

A Stem Cell Trial for Macular Degeneration
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From the Technology Review: "In a bid to harness the potential of embryonic stem cells, surgeons in California have implanted lab-grown retinal cells into the eyes of two patients going blind from macular degeneration. ... The two patients, whose names weren't released, are among the first volunteers ever to receive a treatment created using embryonic stem cells. ... We are excited about this treatment, because we think this has the potential to slow the disease progression. This company has had their ups and downs, and I am really happy to see they got into the clinic. We've had our fingers crossed. ... During a recent visit to Advanced Cell's laboratories, a research technician adjusted a microscope to show off the company's lead product: cube-shaped retinal pigment epithelial cells growing in a petri dish. Some were translucent, while others already had the brownish coloring of a mature cell. (The pigment absorbs stray light in the eye, acting as a kind of glare shield.) These retinal cells are the type that are killed off in macular degeneration, eventually leading to the death of photoreceptors, and the gradual loss of central vision. Advanced Cell believes that injecting new, lab-grown cells into the eye may cure the condition. ... It's no accident [that] both early studies of embryonic stem-cell therapies - those of Geron and Advanced Cell - involved cells of the nervous system. The reason is that embryonic stem cells naturally want to make neuroectoderm, a cell lineage in the embryo that forms the nervous system. ... Embryonic stem cells have a mind of their own, and they want to do certain things ... Efforts to produce other cell types, such as liver cells, have proved far more difficult."

Link: http://www.technologyreview.com/biomedicine/38030/

An Open Cures Progress Report
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Open Cures is an initiative aimed at speeding up progress along the best and most logical path for commercial development of demonstrated longevity-enhancing biotechnologies. Which is to say that they should be developed overseas, outside the reach of the FDA, and then accessed via medical tourism - just like all the cutting edge medical technologies that are available only outside the US, thanks to massive regulatory overkill.

Open Cures kicked off in earnest in May 2011, so this is still very much the stage of telling people about the idea and letting the community of potential supporters know that the initiative even exists. One part of that effort is a series of essays, the latest of which was published at h+ Magazine today under the title "Longevity Science Needs Documentation". Open Cures is a phased initiative, and the article is a deeper look at why Phase 1 of Open Cures involves the production of documentation - pulling out the best and most promising of present biotechnologies of longevity buried in research papers, and producing textbook quality how-to documents that are comprehensible to people who are not cutting edge researchers:

One of the challenging attitudes I've encountered of late is the idea that documentation of longevity science in this manner is largely worthless - that time and funds spent trying to make science clear to developers and laypeople should go towards other, more direct activities like further research. This sort of criticism is, I think, symptomatic of a failure to understand the necessary role of documentation in the broader scope of technological progress. This article, then, is an answer of sorts: what is the role of documentation, and why is it important enough to need dedicated organizations that do it well?

Read the whole thing, as the answer to that question isn't easily summarized in a single sentence - and that in and of itself is actually a part of the challenge. Complex ideas are hard to convey, and that fact places constraints on support for new technologies.

On the topic of producing documentation, you can see some of the early work in the Open Cures Wiki, such as a protocol outline for DIYbio participation in LysoSENS, and a similar protocol outline for mitochondrial protofection. For reference, a protocol is the name given to the step by step directions followed by a researcher or technician when carrying out a procedure in the laboratory. Both of these sketch outlines provide only the technical bare bones of their respective protocols, but are presently being expanded into full protocol documents, with the aim of producing textbook-quality publications.

Over the past few weeks, I've been working through oDesk to contract with biologists and biochemists around the world to work on these and other documents. It's an interesting business, and the global competition largely keeps the rates at an appropriate level for a volunteer initiative, even for writing that is fairly technical. My goal for the next few months is to acquire a reliable stable of writers this way, though this and similar services, and produce the first few high-quality protocols documents in full.

This involves a fair degree of learning and working through the pitfalls - but it should settle the questions of price and feasibility. So far it looks like there are a sufficient number of life scientists out there on these global contracting sites, some of whom can write decently well in addition to knowing their field. Also so far it looks like my initial guesses at the cost of producing documentation is not a million miles away from the reality - we'll see if that still holds once I'm into the next stage of finding artists to produce the necessary diagrams where openly available versions cannot be found.

In working with biologists scattered around the world, I've been greatly aided by those Open Cures volunteers willing to review and comment on works in progress. Many hands make light work, and while I've followed biotechnology for a number of years, I'm far from qualified to judge the contents of a protocol as accurate or not. I should also note that along the way, some other folk are also looking into producing informational documents on the state of medical tourism by country, and an early example of that sort of thing can also be found in the wiki.

Once this first stage of the first stage of the way and the Open Cures group has a set of completed protocols and writers ready to go, then it will be time to open things up to run a little faster: make the big list of documentation we'd like to have done in Phase 1, and push it into the sausage-making process of technical writing just as fast as it will go. That's about when I'll probably start soliciting funds and doing the rounds with cap in hand, but we'll see how that turns out.

The ability to use funding in and of itself requires some organization to set up: there's the legal side of the house, management and paperwork, and getting into the process to become a formally registered 501c3 charity. Fortunately some of the folk in the community are willing to help out on that front - it's "just" a matter of more time and energy put in that direction. Postponing it while the first stage of documentation is underway doesn't hurt, and in many ways it's better to put off the legal formalization of an initiative until you're sure that there's something there and that it's working the way you want it to.

So that's where things stand at the moment. Very early days yet, and lot yet to be accomplished.

A Popular Science Article on Centenarian Studies
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At the Wall Street Journal: "At his lab in the Bronx, geneticist Nir Barzilai has spent more than a decade trying to unlock the biology of aging. His secret weapon: some of the New York area's oldest Jews. One of his major studies analyzes the genetic make-up and life habits of the oldest of the old: 500 physically and cognitively healthy individuals living well past the century mark. ... Research that began with some of the oldest New Yorkers is now set to spread throughout the U.S. Barzilai's work is the template for a ambitious national study to create a full sequencing of the genomes of 100 ethnically and geographically diverse centenarians. ... Barzilai's work seeks to improve the quality of life for the elderly. His research has found, to his surprise, that the 100-plus crowd has less than sterling health habits. As a group, they were more obese, more sedentary and exercised less than other, younger cohorts. ... Biologically speaking, what has allowed the centenarians in his study to live so long, even with life habits that often lead to disease and death in others? ... Barzilai and his team at Einstein's Institute for Aging Research have so far discovered three uncommon genotype similarities among the centenarians: one gene that causes HDL, good cholesterol, to be at levels two- to three-fold higher than average; another gene that results in a mildly underactive thyroid, which slows metabolism; and a functional mutation in the human growth hormone axis that may be a safeguard from age-related diseases, like cancer. He suspects there may be additional genotypes that scientists have yet to locate."

Link: http://blogs.wsj.com/metropolis/2011/07/13/in-the-science-of-aging-oldest-new-yorkers-hold-the-key/

An Update on Organovo
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Organovo is the bioprinting startup whose investors include the Methuselah Foundation: "Organovo has been generating enough revenue from a series of new partnerships that [the company] put off an expected Series A venture round. ... the company has raised just over $2 million from private investors to develop 'bio-printing' technology that operates much like an inkjet printer. Instead of laying down ink, however, Organovo's bio-printer lays down a pattern of cultured cells and a jello-like hydrogel that supports the cells in a 3-D structure. In this way, Organovo already has been able to grow bio-engineered blood vessels, and to lay more ambitious plans to create kidneys, livers, and other vital organs in the same way. ... the work is still highly experimental, so getting regulatory approval to graft a bio-engineered blood vessel in a living patient will take years. In the meantime, [Organovo] found a burgeoning market among pharmaceutical companies by [creating] 3-dimensional 'constructs' of diseased or dysfunctional human cells that can be used as models for testing new drugs. Creating a 3-D matrix of cells enables each cell to interact with adjoining cells, so they react to drug compounds much as they would in the body. ... one of the pharmaceutical partnerships is with Pfizer to create 3-D constructs for drug discovery in two therapeutic areas. Organovo also is in talks with several additional partners ... One of the things that's been good about the past six months is that the promise of our technology is holding true. The constructs we're creating robustly build [blood vessels] with collagen, so the blood vessel grows stronger over time. The next challenge is getting to greater and greater vascularization of the construct. The emerging story is going to be, 'Who can make thicker tissues with more blood vessels inside?'"

Link: http://www.xconomy.com/san-diego/2011/07/13/organovos-bio-printing-technology-yields-unanticipated-revenue-from-pharma-partners/?single_page=true

Ways to Accelerate Biological Damage are Not Necessarily Interesting
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If you spend time following life science research, you'll see a fair amount of work in which scientists remove a piece of biological machinery in laboratory animals so as to try to figure out what it does - the changes that occur in the studied animals will hopefully allow researchers to piece together the surrounding biology and place the machinery in the full context of what is already known. In many cases this reduces life span or accelerates the pace of some form of damage that normally increases with aging - but that outcome doesn't necessarily mean that the machinery removed is connected to aging in any significant way, or that it has any relevance to ways to slow aging and extend healthy life.

I'm sure, if you put your mind to it, you could think of a dozen ways to slowly ruin the type of machine you are most familiar with (clog up the spark plugs, remove the oil, pull out the filter head, and so forth), and few of them can be extrapolated the other way into ways to make a perfectly maintained machine last much longer than it normally does.

So it is with the biochemical machinery of life. The only true test of relevance to aging is to demonstrate that you can use the mechanism in question to extend life beyond the normal limits for a healthy individual in that species, or reduce some form of biological damage to levels far below what is normally the case at a given age. If all you are showing is that you can increase damage and shorten life span, then there's no doubt interesting science involved, but it's too soon to be getting excited.

This is why I think that the title and summary of a recent news item is absolutely wrong:

Researchers from the Universities of Bonn and Mainz have discovered a previously unknown function of the cannabinoid-1 receptor (CB1): it can protect against aging processes. Cannabinoids, such as THC (the active agent in Cannabis sativa) and endocannabinoids, and those formed by the body bind to the CB1 receptors. ... The animals in which the CB1 receptor had been switched off genetically [showed] clearly diminished learning and were less successful in their search for the platform. In addition, they showed a clear loss of nerve cells in the hippocampus, the researchers said.

The original paper, which is a matter of increasing damage only, has nothing but inference on how this applies to aging while CB1 is active and normally operational, and it's speculative to say that anything could come from this to move the needle in the opposite direction.

The reason I noticed this work at all is because it's possible that endocannabinoids are involved in calorie restriction in some way, based on work in nematode worms:

Not only have we been able to identify some of these molecules for the first time in the worm, but we have also been able to show they act as a signal of nutrient availability and ultimately influence the worm's lifespan. What makes this important is that the same molecules are present in both humans and C. elegans, so these molecules may play similar roles in both organisms. ... The molecules identified in the new study are N-acylethanolamines (NAEs), a group of signaling molecules derived from lipids that help indicate nutrient availability in the environment and maintain an animal's internal energy balance. [Researchers showed that] NAE abundance in the worm is reduced during periods of dietary restriction, and that NAE deficiency in the presence of abundant food is sufficient to extend the animal's lifespan. ... Importantly, this particular NAE is similar to endocannabinoids in mammals, which regulate many different physiological processes including nutrient intake and energy balance, as well as inflammation and neuronal function.

The CB1 paper above adds nothing much in the way of weight to that conjecture, however, and so I'd say it remains a fairly tenuous connection at this time. You'd need a study that shows extended life in mice through something very similar to NAE deficiency in worms, but engineered using endocannabinoids. So further research is required - and there are a great many more important things that researchers could be doing with their time.

On Theories of Aging
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An introductory open access review paper looks briefly at some of the theories of aging: "Ageing and senescence are related words and are often used interchangeably as both processes are characterized by progressive changes in the tissue of the body, eventually leading to a decline in function and death of the organism. Senescence refers to a post-maturational process that leads to diminished homeostasis and increased vulnerability of the organism to death. Ageing, in contrast, refers to any time-related process and is a continuous process that starts at conception and continues until death. The mechanisms involved in ageing are partially intrinsic to the organism, like genetic and epigenetic factors, and partially to the external origin, such as nutrition, radiation, temperature and stress. ... Various theories have evolved to improve our understanding of the ageing process so as to formulate strategies that enhance extension of life. The theories of ageing are classified based on the level at which the ageing mechanism is targeted: 1. Evolutionary theories, 2. Systemic theories, 3. Molecular and cellular theories ... Evolutionary theories state that ageing results from a decline in the force of natural selection. As evolution acts primarily to maximize reproductive fitness in an individual, longevity is a trait to be selected only if it is beneficial for fitness. Life span is, therefore, the result of selective pressures and may have a large degree of plasticity within an individual species as well as among species. ... In systemic theories, the ageing process is related to the decline of organ systems essential for control and maintenance of other systems within the organism. ... [Molecular and cellular theories] theories attempt to discern the mechanisms of ageing process at the cellular and subcellular levels."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3125059/

Newt Regenerative Capacities Do Not Diminish With Age
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Another good reason for researchers to better understand the biochemical roots of regeneration in lower animals such as newts and salamanders: "Goro Eguchi has shown that a newt's healing powers don't diminish with age. As long as they live, they retain the ability to efficiently regrow their body parts (or at least, the lenses of their eyes), even if they have to do so over and over again. We've known about the abilities of newts and other salamanders for over 200 years, thanks initially to Lazzarro Spallanzini, an Italian biologist and Catholic priest. But the limits of this ability have been unclear. Spallanzani once amputated limbs from a salamander six times over three months, and watched them grow back. ... The salamanders could repeatedly regrow their limbs, but eventually, abnormalities crept in. For example, the animals would occasionally develop missing bone structures. Both Spallanzani and Bonnet (and, indeed, Charles Darwin after them) held that newts regenerate their body parts less efficiently as they get older, especially if they accrue repeated injuries. But Eguchi thinks that these experiments, while historically important, were also flawed. The exposed stumps of the severed legs would have been exposed to the messy environment, which might have scuppered a clean regeneration. To truly test the extent of these animals' powers, Eguchi set up a 16-year-long experiment. In 1994, he collected several Japanese fire-bellied newts (Cynops pyrrhogaster) and successfully kept them in captivity. During that time, Eguchi periodically anaesthetised the animals and carefully removed the lens from their eyes. The surgeries involve a small nick to the cornea that quickly sealed, creating a protected environment where the lens could regenerate without any influence from the outside world. This happened 18 times in total. Eguchi found that the 17th and 18th lenses were exactly the same as the original ones, and those from untouched newts of the same age."

Link: http://blogs.discovermagazine.com/notrocketscience/2011/07/12/newt-healing-factors-unaffected-by-age-and-injury/

Tissue Engineered Mouse Tooth Grown, Implanted, and Functional
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Dental tissue engineering is one of the most advanced areas in the broader field, as illustrated by work on growing teeth from stem cells. Several groups over the past five years have successfully implanted stem cells that led to the growth of replacement teeth in mice, and other forms of procedure such as the reattachment of teeth via engineered ligaments have also been demonstrated in laboratory animals.

In a more recent project, researchers grew mouse teeth outside the body, implanted them, and produced a very satisfactory end result as the teeth grew in and became functional:

In this proof of concept study [a] bioengineered tooth unit comprising mature tooth, periodontal ligament and alveolar bone, was successfully transplanted into a properly-sized bony hole in the alveolar bone ... Partial bone integration was observed at 14 days after transplantation, and full bone integration around a bioengineered tooth root was seen at 30 days after transplantation ... [The] engrafted bioengineered tooth displayed physiological tooth functions such as mastication, periodontal ligament function for bone remodeling and responsiveness to noxious stimulations.

...

These findings indicate that whole tooth regenerative therapy is feasible through the transplantation of a bioengineered mature tooth unit. This study also provides the first reported evidence of entire organ regeneration through the transplantation of a bioengineered tooth.

The age of bad teeth, old teeth, and artificial teeth will soon enough be coming to a close, I think. For my money, the most interesting parts of the paper relate to the challenges inherent in coaxing suitable dental stem cells into growing into teeth that have the right shape. The methodology that the researchers found worked was as follows:

To generate the shape- and length-controlled bioengineered tooth unit so that a suitable size was obtained, [the] tooth germ was inserted into a ring-shaped size-control device and then transplanted into a subrenal capsule.

Width was controlled by placing a barrier around the growing material, and the length controlled by how long the tooth was grown for - though the researchers also touched on other potential means of fine-tuning tooth shape and size. I look forward to seeing how well this methodology works when they move on to human teeth.

More Transdifferentiation: Brain Cells to Heart Cells
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Demonstrations of transdifferentiation, converting one cell type directly into another, have been picking up of late. Like research into creating stem cells, it has the potential to enable a new generation of regenerative therapies, or make existing therapies more effective and less costly. Here is an example of the present state of research: "For the past decade, researchers have tried to reprogram the identity of all kinds of cell types. Heart cells are one of the most sought-after cells in regenerative medicine because researchers anticipate that they may help to repair injured hearts by replacing lost tissue. Now, [researchers] are the first to demonstrate the direct conversion of a non-heart cell type into a heart cell by RNA transfer. Working on the idea that the signature of a cell is defined by molecules called messenger RNAs (mRNAs), which contain the chemical blueprint for how to make a protein, the investigators changed two different cell types, an astrocyte (a star-shaped brain cell) and a fibroblast (a skin cell), into a heart cell, using mRNAs. ... The method the group used, called Transcriptome Induced Phenotype Remodeling, or TIPeR, is distinct from the induced pluripotent stem cell (iPS) approach used by many labs in that host cells do not have to be dedifferentiated to a pluripotent state and then redifferentiated with growth factors to the destination cell type. TIPeR is more similar to prior nuclear transfer work in which the nucleus of one cell is transferred into another cell where upon the transferred nucleus then directs the cell to change its phenotype based upon the RNAs that are made. "

Link: http://www.eurekalert.org/pub_releases/2011-07/uops-aco070811.php

Considering the Naked Mole Rat
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In light of the recent sequencing of the naked mole rat genome, here's a paper on why the species is of interest: "Reactive oxygen species (ROS), by-products of aerobic metabolism, cause oxidative damage to cells and tissue and not surprisingly many theories have arisen to link ROS-induced oxidative stress to aging and health. While studies clearly link ROS to a plethora of divergent diseases, their role in aging is still debatable. Genetic knock-down manipulations of antioxidants alter the levels of accrued oxidative damage, however, the resultant effect of increased oxidative stress on lifespan are equivocal. Similarly the impact of elevating antioxidant levels through transgenic manipulations yield inconsistent effects on longevity. Furthermore, comparative data from a wide range of endotherms with disparate longevity remain inconclusive. Many long-living species such as birds, bats and mole-rats exhibit high-levels of oxidative damage, evident already at young ages. Clearly, neither the amount of ROS per se nor the sensitivity in neutralizing ROS are as important as whether or not the accrued oxidative stress leads to oxidative-damage-linked age-associated diseases. In this review we examine the literature on ROS, its relation to disease and the lessons gleaned from a comparative approach based upon species with widely divergent responses. We specifically focus on the longest lived rodent, the naked mole-rat, which maintains good health and provides novel insights into the paradox of maintaining both an extended healthspan and lifespan despite high oxidative stress from a young age." The current best explanation for this state of affairs is the membrane pacemaker hypothesis, in which it is theorized that differences in chemical composition of cellular membranes affect their resilience to oxidative damage.

Link: http://www.ncbi.nlm.nih.gov/pubmed/21736541

Stem Cells Can Repair Other Cells By Donating Component Parts
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Every so often I run into an especially intriguing paper, and a recent open access work on the interaction between stem cells and other cells is a good example of the type. If you've been following stem cell research over the past decade, you'll know that one of the important questions has been how stem cell transplants cause regeneration. At present, the best answer appears to be some combination of creating new cells and issuing chemical signals, with much more of the latter taking place in most of the earlier therapies, such as stem cell transplants for heart disease.

This paper looks at another mechanism that has been known for a while, but is far less well explored: a stem cell can form a thin connecting tunnel to a damaged cell and use that tunnel to donate some portion of its internal machinery. Cells are equipped with roving, self-replicating herds of organelles, including the recycling machines called lysosomes and energy generating machines called mitochondria - and sending some through the tunnel can help to restore proper functioning to some degree in the recipient cell. From the paper:

Although therapeutic effect of adoptive transfer of endothelial progenitor cells (EPC) has been well-substantiated, the actual engraftment is relatively low [usually averaging 1-2%] compared to a robust functional improvement of [blood vessel function]. ... This discrepancy explains an intense search for indirect mechanism(s) of vascular repair by EPC that could reconcile the scarcity of engrafted cells with the notable functional response.

...

Tunneling nanotubes (TNT) formation between cultured cells has been described and proved to be a viable mechanism of organellar exchange between the partners. This mechanism has been shown to account for mitochondrial transfer between adult stem cells and somatic cells and rescue their respiration. This mechanism is believed to play a significant role in intercellular communication, although it remains technically difficult to morphologically document it.

The researcher show that stem cells are very selective in which cells they choose to connect to, and that transfer of lysosomes appears to be just as effective in rescuing cellular recycling functions as mitochondrial transfer is in restoring energy generation. That suggests that this is a significant mechanism in the operation of stem cell therapies. Be sure to take a look at the photographs of cells donating components, which are quite striking.

The whole process well illustrates the truth that biology is always more complex than we'd like it to be. Damage to both mitochondria and lysosomes are strongly implicated as causes of degenerative aging, and it makes theorizing, design of therapies, and evaluation of potential therapies that much harder if cells are willing to promiscuously swap these components. You'll find background on mitochondrial damage and lysosomal decline as it relates to aging back in the archives:

Better Understanding Pluripotent Stem Cells
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Scientists are making steady progress in developing the foundational knowledge that will support the next generation of stem cell therapies: "researchers discovered the fate - or destination - of human pluripotent stem cells is encoded by how their DNA is arranged, and this can be detected by specific proteins on the surface of the stem cells. ... It's like going on secret trip. When you decide to go to Jamaica, you pack your toothbrush, underwear, and of course shorts, t-shirts and swimsuits. But if, at the last minute, you get rerouted to Alaska, you unpack a few things but the basic elements, like your toothbrush, are going to be the same. You may just trade the shorts and swimsuits for long pants and a sweater. ... Until now, common scientific belief has been that all pluripotent stem cells are equivalent and keep all options open at the same time. But that's really not the case. ... This study showed that pluripotent cells are not all equal. They are all pluripotent. You can force a cell that normally would love to become a neural cell to turn into blood, just like you can force the vacationer to go Alaska instead of Jamaica. They'll do it, but not very well and not happily. ... For the study, [the] research team found stem cells with roadmaps and specifically packed suitcases for the blood and neural destinations. The researchers discovered when they isolated these stem cells by new protein markers on the surface of cells, they were able produce a greater number of specialized cells - nearly five times as many blood cells and twelve times as many neural cells compared to when the stem cells had to be forced into those cell types."

Link: http://www.sciencedaily.com/releases/2011/07/110707121924.htm

Regenerative Medicine's Promising Future
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A commentary by researcher Anthony Atala: "Is it possible for humans to regenerate a damaged body part the way starfish and salamanders can? Will doctors one day be able to replace cancer-ridden organs with healthy ones engineered in a lab? Will lengthy waiting times for organ transplants eventually become a thing of the past? Whenever lecturing about the field of regenerative medicine, I always enjoy hearing questions like these from audience members as they excitedly imagine the future applications of regenerative medicine. In fact, scenarios like these aren't outside the realm of possibility. Regenerative medicine therapies are already helping small groups of patients through clinical trials; and scientists around the world are working both to expand the applications of these therapies and to bring them into more widespread use. The effort to harness the body's natural healing powers has been called a new frontier in medicine because it offers the promise to actually cure, rather than just treat, disease. It has a several components: injectable cell therapies to promote healing; replacement tissues and organs engineered in the lab; and the use of bio-compatible materials or small molecules to prompt tissue regeneration from within the body."

Link: http://www.cnn.com/2011/OPINION/07/10/atala.grow.kidney/

An Idea: Animating the Fable of the Dragon-Tyrant
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You're all, I hope, familiar with the Fable of the Dragon-Tyrant - easily the best modern fable about the scientific quest to build rejuvenation biotechnology and thereby defeat age-related frailty, suffering and death. If you have not yet read it, shame on you. Go and read it:

Once upon a time, the planet was tyrannized by a giant dragon. The dragon stood taller than the largest cathedral, and it was covered with thick black scales. Its red eyes glowed with hate, and from its terrible jaws flowed an incessant stream of evil-smelling yellowish-green slime. It demanded from humankind a blood-curdling tribute: to satisfy its enormous appetite, ten thousand men and women had to be delivered every evening at the onset of dark to the foot of the mountain where the dragon-tyrant lived. Sometimes the dragon would devour these unfortunate souls upon arrival; sometimes again it would lock them up in the mountain where they would wither away for months or years before eventually being consumed...

I see that some folk across the way a little in the longevity science community have the great idea that a web animation of the fable should be produced - something that could be dropped into many, many websites and seen by a large audience.

My friend Kent Kemmish, at Halcyon Molecular, has offered to put up $50 for someone who does the best animated flash version of Nick Bostrom's classic essay "The Fable of the Dragon-Tyrant" ... Let's say that the challenge stands for one month, until August 7th. My other friend Kevin Fischer is also putting in $50 for a total of $100. Would anyone else be interested in adding to that purse?

I think that this is a good idea with a great deal of merit, but that these folk are not going about it in quite the right way. From my point of view, producing a fair animation - let's say something that looks like the silhouette stop-motion techniques used in some older Eastern European animations of folktales - is going to take a little organization, a few months in total elapsed time from start to finish, and at minimum a few thousand dollars. If you expect to pull in donations through word of mouth and in $50 increments, then this is exactly the sort of project you'd want to run via a tool like Kickstarter. You need some form of way to track and communicate with donors, a way to accept donations, and a web page to showcase your idea and progress to date - why build all that yourself, when you could use Kickstarter?

So the folk who are pushing this should pick a leader, have him set up and manage a Kickstarter project, produce a few specification documents and showy sample pictures, and then reel in enough in the way of funds to get started with a developer who has a good portfolio, found via a contract marketplace like oDesk or 99designs. That's the way this is done. A wide range of indie developers in the writing world use Kickstarter to crowdsource funding for their work using ransom models and other fundraising methods. An alternate approach to the one above is if someone with deeper pockets were to simply commission the work on the simple animated version of the fable, they could then place it in escrow until the costs were recouped through donations, and finally release it online.

Step one would be to validate the cost - and that's as simple as finding someone who builds animations for websites (in Flash, Canvas, or whatever the cool kids are using nowadays) and then asking.

Autologous Stem Cells Versus Angina
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Via EurekAlert!: "injections of adult patients' own CD34+ stem cells reduced reports of angina episodes and improved exercise tolerance time in patients with chronic, severe refractory angina (severe chest discomfort that did not respond to other therapeutic options). The phase II prospective, double-blind, randomized, controlled clinical trial was conducted at 26 centers in the United States ... The objective of the trial was to determine whether delivery of autologous (meaning one's own) CD34+ stem cells directly into multiple targeted sites in the heart might reduce the frequency of angina episodes in patients suffering from chronic severe refractory angina, under the hypothesis that CD34+ stem cells may be involved in the creation of new blood vessels and increase tissue perfusion. ... While we need to validate these results in phase III studies before definitive conclusions can be drawn, we believe this is an important milestone in considering whether the body's own stem cells may one day be used to treat chronic cardiovascular conditions. ... At six months after treatment, patients in the low-dose treatment group reported significantly fewer episodes of angina than patients in the control group (6.8 vs. 10.9 episodes per week), and maintained lower episodes at one year after treatment (6.3 vs. 11 episodes per week). Additionally, the low-dose treatment group was able to exercise (on a treadmill) significantly longer at six months after treatment, as compared with those in the control group (139 seconds vs. 69 seconds, on average)." If you want access to this sort of treatment now, and are resident in the US, going abroad as a medical tourist is your only realistic option. Otherwise you may still be waiting five or ten years from now: the FDA moves to approve treatments very slowly, when it moves at all.

Link: http://www.eurekalert.org/pub_releases/2011-07/nu-asc070711.php

Calorie Restriction Slows Fertility Decline
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Another example of calorie restriction slowing a specific aspect of the damage of aging: "restricting the caloric intake of adult female mice prevents a spectrum of abnormalities, such as extra or missing copies of chromosomes, which arise more frequently in egg cells of aging female mammals. ... We found that we could completely prevent, in a mouse model, essentially every aspect of the declining egg quality typical of older females. We also identified a gene that can be manipulated to reproduce the effects of dietary caloric restriction and improve egg quality in aging animals fed a normal diet, which gives us clues that we may be able to alter this highly regulated process with compounds now being developed to mimic the effects of caloric restriction. ... The long-term effects of a caloric restriction (CR) diet in humans are being investigated in ongoing studies, but some health improvements, including reductions in cholesterol levels and other cardiovascular risk factors, have already been reported. ... While the mechanisms by which caloric restriction produces its effects are still being investigated, several of the metabolic pathways involve a regulator of DNA transcription called PGC-1a, which is known to modulate genes involved in controlling mitochondrial number and function. [The researchers] also found that egg cells from female mice lacking a functional PGC-1a gene who were allowed to free feed through adulthood maintained the same egg-cell quality as seen in the CR mice. However, combining CR with PGC-1a inactivation did not increase the effects beyond those achieved separately, which suggests that the two approaches work in a common pathway."

Link: http://www.laboratoryequipment.com/news-Calorie-Reduction-May-Prevent-Infertility-070811.aspx

Tissue Engineered Synthetic Trachea Successfully Transplanted
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It seems that this is a week for announcing significant progress in tissue engineering. You might recall that one of the groups involved in recellularization research transplanted a trachea into a human recipient a couple of years ago. The organ was from a donor, stripped of all its cells, and the remaining natural scaffold of the extracellular matrix repopulated with cells from the recipient. The end result was a transplanted organ that would not be rejected by the immune system. The same researchers have now gone one step further and successfully transplanted an entirely synthetic trachea grown from the patient's cells on an artificial scaffold - no donor organ required.

Surgeons have performed the first transplant operation using an organ wholly grown in a laboratory to give a man a new windpipe. The 36-year-old is recovering after surgeons implanted the world's first wholly lab-grown organ into his body.

...

Professor Paolo Macchiarini, a Spanish expert in regenerative medicine who led the groundbreaking operation, designed the Y-shaped synthetic trachea scaffold with Professor Alexander Seifalian, from University College London. The Y-shaped structure was made from a plastic-like "nanocomposite" polymer material consisting of microscopic building blocks. Two days after stem cells were placed into the scaffold they had grown into tracheal cells ready for transplantation. Since the organ was built from cells originating from the patient, there was no risk of it being rejected by his immune system.

In conjunction with lines of research like organ printing, this pace of work bodes well for the 2030s as a time in which failing or badly injured organs are no longer automatically fatal or the cause of lifelong disability for the young. There is still the question of how best to take advantage of this for the old, however: the frailty that comes with aging brings with it a much lower survival rate and success rate for major surgery - and any significant transplant is major surgery. Regrowth of organs alone is not the way to greatly extend the maximum human lifespan on a timescale that matters. Other technologies are needed as well:

There are many whole-body, multi-organ, or regional biochemical feedback and control loops in the body. There are types of age-related damage that involve the intracellular accumulation of biochemical junk - simply replacing cells doesn't get rid of that. If your only tool is bioprinting (which won't be the case, but let us think inside the box for a while here), then the solution to these problems starts to look like replacing more of the body at one time.

You can't just replace the brain, of course, which remains an important limiting factor and the real driving need for in situ repair technologies that operate at the level of cells, buildup of protein aggregates, and broken cellular machinery.

Aging and the Genetics of the Immune System
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The quality of the immune system in later years has a strong impact on mortality rates and frailty - and that quality varies with different genetic profiles. Thus it follows that among the genetic variants known to affect human longevity, some are involved with the immune system: "The ageing process is very complex. Human longevity is a multifactorial trait which is determined by genetic and environmental factors. Twin and family studies imply that up to 25% of human lifespan is heritable. The longevity gene candidates have generally fallen into the following categories: inflammatory and immune-related factors, stress response elements, mediators of glucose and lipid metabolism, components of DNA repair and cellular proliferation and mitochondrial DNA haplogroups. Because of the central role of HLA molecules in the development of protective immunity and the extraordinary degree of polymorphism of HLA genes, many studies have addressed the possible impact of these genes on human longevity. Most of the data available so far demonstrated a possible role of HLA class II specificities in human longevity but definitive evidence has remained elusive. Although the data are limited and controversial, it has been hypothesized that longevity could be associated with cytokine gene polymorphisms correlating with different levels of cytokine production, thereby modulating immune responses in health and disease. Because of the essential role of cytokines in immune responses, the regulation of cytokine gene expression and their polymorphic nature, the genetic variations of these loci with functional significance could be appropriate immunogenetic candidate markers implicated in the mechanism of successful ageing and longevity."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21726414

Exploring IFG-1 and Longevity
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Some work here on IFG-1, not to be confused with IGF-1, which is also of interest in longevity: "When researchers at the Buck Institute dialed back activity of a specific mRNA translation factor in adult nematode worms they saw an unexpected genome-wide response that effectively increased activity in specific stress response genes that could help explain why the worms lived 40 percent longer under this condition. ... Scientists have identified a number of so-called 'longevity' genes active in many species. However, the mechanisms by which those genes impact lifespan remain poorly understood. ... the majority of research involving those genes has focused on transcription, the first level of cellular activity whereby DNA produces RNA. This research focuses on translation, whereby RNA specifies the production of proteins. ... [Researchers] inhibited expression of the mRNA translation factor, IFG-1, in adult worms. IFG-1 is important for growth and development ... "Turning down ifg-1 expression flips a switch that turned down growth and reproduction, but increased their healthspan as well as their lifespan. ... Our primary interest is to understand the biological basis of aging. This will help identify molecular targets that can be used to develop therapeutics that would slow age-related diseases and extend the healthy years of life."

Link: http://www.sciencedaily.com/releases/2011/07/110705123340.htm

Growing A New Section of Small Intestine in Mice
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Publicity materials for a good-looking incremental advance from the tissue engineering community are doing the rounds in the press at the moment.

Researchers at The Saban Research Institute of Children's Hospital Los Angeles have successfully created a tissue-engineered small intestine in mice that replicates the intestinal structures of natural intestine - a necessary first step toward someday applying this regenerative medicine technique to humans.

...

Working in the laboratory, the research team took samples of intestinal tissue from mice. This tissue was comprised of the layers of the various cells that make up the intestine - including muscle cells and the cells that line the inside, known as epithelial cells. The investigators then transplanted that mixture of cells within the abdomen on biodegradable polymers or "scaffolding."

What the team wanted to happen did - new, engineered small intestines grew and had all of the cell types found in native intestine. Because the transplanted cells had carried a green label, the scientists could identify which cells had been provided - and all of the major components of the tissue-engineered intestine derived from the implanted cells. Critically, the new organs contained the most essential components of the originals.

The original paper is also available, for those who are interested. The normal caveats apply here - it's a promising advance for researchers to show that they can make lengths of intestine grow correctly inside a living mouse, using scaffolds seeded with cells. But bear in mind that this is only a demonstration: the new section of intestine isn't hooked up or being put under load. It'll be a few more years, I'd guess, before we see mice (or perhaps pigs) with tissue engineered and functional replacement small intestines.

If you'd like to learn more, I noticed an educational set of pages on the topic put up by the students at UCI:

In tissue engineering, there are two fundamentally different approaches that can be taken. The first is to replicate the organanatomically, with the expectation that the function of the engineered organ will therefore be the same. The second approach is simply to replicate its function. Researchers who aim to engineer intestine have adopted the anatomical approach with the key problems including the development of a muscular layer and neuronal innovation are major challenges to its success. On the other hand,if the aim is to develop an absorptive surface with neointestinal epithelium, it is possible to be more imaginative about how this can be achieved.
Shorter Telomeres, Higher Cancer Risk
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A confirming review of studies: "Telomeres play a key role in the maintenance of chromosome integrity and stability, and telomere shortening is involved in initiation and progression of malignancies. A series of epidemiological studies have examined the association between shortened telomeres and risk of cancers, but the findings remain conflicting. ... A dataset composed of 11,255 cases and 13,101 controls from 21 publications was included in a meta-analysis to evaluate the association between overall cancer risk or cancer-specific risk and the relative telomere length. ... The results showed that shorter telomeres were significantly associated with cancer risk compared with longer telomeres. ... Studies have showed that telomeres are critical for maintaining genomic integrity and that telomere dysfunction or shortening is an early, common genetic alteration acquired in the multistep process of malignant transformation. In addition, telomere dysfunction has been found to be associated with decreased DNA repair capacity and complex [cellular] abnormalities. Both of animal studies and clinical observations have shown that shorter telomeres were associated with increased risk of cancers, such as epithelial cancers. However, telomere shortening might play conflicting roles in cancer development. For example, the progressive loss of telomeric repeats with each cell division can induce replicative senescence and limit the proliferative potential of a cell, thus functioning as a tumor suppressor. But, once telomeres reach a critical length, it will result in chromosome break, causing genome instability and enhancing potential for malignant transformation."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3112149/

Making Better Cells for Tissue Engineering
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Altering cells used in tissue engineering so as to obtain a better result is a very viable prospect, as demonstrated in a recent investigation of tendon regeneration: "The basic function of tendon is to transmit force from muscle to bone, which makes limb and joint movement possible. Therefore tendons must be capable of resisting high tensile forces with limited elongation. ... the mechanical properties of tendons are related to the fibril diameter distribution, large fibrils could withstand higher tensile forces. ... In the healing tendon, a uniform distribution of small diameter collagen fibrils has been found with poorer mechanical properties than native tissue and shows no improvement of mechanical properties with time ... The present study for the first time demonstrated the use of a scaffold-free tissue engineered tendon model for investigating the biological function of collagen V in tendon fibrillogenesis. ... Conclusively, it was demonstrated that Col V siRNA engineered tenocytes improved tendon tissue regeneration. ... These findings present a good example of in vitro tissue engineering model for tendon biology investigation and may provide basis for future development of cell or gene therapy for tendon repair."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119690/

Naked Mole Rat Genome Sequenced
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Prioritizing the few exceptionally long-lived mammal species for full genome sequencing has been a few years in the making as a project, but I see that the researchers who initiated that effort have now completed the first item on their list:

Naked mole rat's genome 'blueprint' revealed

The industrious but unlovely naked mole rat is the latest creature to have its genome sequenced by scientists. A genetic blueprint for this bizarre-looking rodent could help researchers understand why it is so long-lived.

Scientists sequence DNA of cancer-resistant rodent

For the first time, scientists have sequenced the genome of the naked mole-rat to understand its longevity and resistance to diseases of ageing. Researchers will use the genomic information to study the mechanisms thought to protect against the causes of ageing, such as DNA repair and genes associated with these processes. To date, cancer has not been detected in the naked mole-rat. Recent studies have suggested that its cells possess anti-tumour capabilities that are not present in other rodents or in humans. Researchers at Liverpool are analysing the genomic data and making it available to researchers in health sciences, providing information that could be relevant to studies in human ageing and cancer.

Dr Joao Pedro Magalhaes, from the University of Liverpool's Institute of Integrative Biology, said: "The naked mole-rat has fascinated scientists for many years, but it wasn't until a few years ago that we discovered that it could live for such a long period of time. It is not much bigger than a mouse, which normally lives up to four years, and yet this particular underground rodent lives for three decades in good health. It is an interesting example of how much we still have to learn about the mechanisms of ageing. We aim to use the naked mole-rat genome to understand the level of resistance it has to disease, particularly cancer, as this might give us more clues as to why some animals and humans are more prone to disease than others. With this work, we want to establish the naked mole-rat as the first model of resistance to chronic diseases of ageing."

It will likely take a few years for the first interesting results to emerge from the genomic data - grants must be written, teams formed, studies carried out. Science, while fast, isn't yet instant. While researchers have a good idea as where in naked mole rat biochemistry they should be looking for both cancer resistance and longevity, molecular biology is an inordinately complex field of study. On the longevity side of the house, the composition of cellular membranes appears to be of greatest interest. You might look back into the Fight Aging! archives at these posts:

The membrane pacemaker hypothesis predicts that long-living species will have more peroxidation-resistant membrane lipids than shorter living species.

Resistance to oxidative damage is of particular importance in mitochondria, cellular power plants that progressive damage themselves with the reactive oxygen species they produce as a byproduct of their operation - and that gives rise to a chain of further biochemical damage that spreads throughout the body, growing ever more harmful as you age. Less damage to the mitochondria should mean slower aging, and thus more resistant mitochondrial membranes should also mean slower aging.

Cycles of Interest in Cryonics
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A long and interesting post at Chronosphere: "I think that most who seriously study the history of cryonics will conclude that there appear to be cycles of activism and interest. There is nothing remarkable in this: the same is true in almost any area of human undertaking. ... . What can be learned from a careful analysis of [Alcor membership from 1972 to 2010]? Is there a discernible reason why growth in membership became nearly exponential, briefly, during the early 1980s? ... there is now nearly 50 years of cryonics history. That's a substantial baseline, and if you chart the progress of cryonics over that time by almost any measure, and you look at the primary historical record, you'll immediately notice that in no way has cryonics behaved as it was predicted to do by the first generation of cryonicists (or for that matter, by any subsequent generation). ... Beyond these basic observations, if we want to understand if there are any reasons for 'bad' or 'good' intervals on these, or other indices of how cryonics has performed over time, we will necessarily have to have recourse to history. Did anything happen of historical note to jump start Alcor's growth in the 1980s? If so, what was it, and can anything be learned from examining the historical record in detail that might prove useful in assisting the growth of Alcor, and more generally the growth of cryonics, today? Do the pauses in growth and the occasional downturns that are in evidence to varying degrees in all of these charts mean anything? If so, are there lessons for us?"

Link: http://chronopause.com/index.php/2011/07/04/casual-conversation-a-remembrance-of-things-past/

More on Stem Cell Aging and Environmental Cues
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Researchers are making inroads into showing that stem cell decline with aging is a function of the surrounding environment - you might recall the experiments in which old mice were given young blood, for example. Here is another research report: "Increasing studies have demonstrated the importance of extrinsic cellular factors on the aging of adult stem cells. Aged mouse spermatogonial stem cells have been transplanted into young recipient hosts for over three years without any decline in function. Serum from old mice markedly induces embryonic stem cell dysfunction. However, the effects of the aged environment on [mesenchymal stem cell (MSC)] senescence and function have not yet been reported. In the present study, the young and the old systemic milieu were mimicked by adding 20% [young rat serum (YRS) and old rat serum (ORS)] into the culture medium respectively. The results show that the ORS culture clearly promoted senescence and [reactive oxygen species] production in the MSCs compared with those cultured with YRS. The proliferation and survival ability of the MSCs were also significantly inhibited in the ORS group compared with that in the YS group. Therefore, ORS induces MSC senescence, as well as inhibit their proliferation and survival ability."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119703/

Biomarkers of Aging and Age-Related Conditions
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The Russian side of the longevity science community, largely associated with the Science for Life Extension Foundation, produces very slick, professional materials on the science of aging and how we might intervene to extend healthy human life. Unfortunately, many of the large posters on the fundamental science are in Russian, and only slowly make their way into English. As they usually appear online as images rather than PDFs, and are generally filled with scientific terminology, they are not particularly amenable to automated translation.

But it is worth keeping an eye out for the ones that do get translated. See, for example, this recent post from Alexey Moskalev, run through the Google Translate service:

To chart some of the biomarkers of aging and age-related pathologies. English had to do double duty and make it easier to find literature supporting the scheme. Thanks to the designer of the Fund "Science for Life Extension" and Olga Martyniuk.

Google Translate won't let you download the image attached to that post directly, unfortunately, so here's a copy for you to admire. Click on it for the full size version:

You might also look at a recent discussion on biomarkers from last month. There are many aspects of our biochemistry that are known to change in characteristic ways with aging, but as of yet very very few than might be used to accurately either measure current age or predict remaining life expectancy. That is a real challenge for groups that want to develop therapies to bring aging under medical control: how does a researcher quickly verify that he has a therapy that works if there is no measurement that can be made to show effectiveness after a couple of months of treatment? The wait and see approach might be borderline acceptable in mice - and even there it takes years and adds huge costs to studies - but it won't work in humans.

The Search for Ways to Spur Stem Cells into Action
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Based on work to date, it should be expected that there are effective ways to provoke existing stem cell populations in the body into greater feats of healing than normally take place. This research is an example of the type: "Injecting proteins similar to insulin directly into the heart can cause damaged cells to repair themselves and begin regenerating again, researchers said. Tests on pigs showed that the dormant cells could begin regrowth following a 'regenerative medicine' treatment using certain growth factors - naturally occurring proteins which cells use to communicate with their environment. Experts from Liverpool John Moores University (LJMU) said the four-year study presented a 'significantly different' therapy to those currently being developed by scientists. The findings, produced with teams from Italy and Spain, could lead to simple and affordable treatments for heart attacks. ... this new approach by LJMU could ultimately lead to a clinical myocardial regenerative therapy which is effective, simple, affordable, readily and widely available and easy to apply and compatible with the current clinical standard of cardiac care. ... the research shows that injecting growth factors IGF-1 and HGF caused significant 'anatomical, histological and physiological' regeneration of damaged hearts and 'sets the path' for testing clinical trials. Another member of the LJMU BioStem research team, Dr Georgina May Ellison, said funding had been secured for clinical tests of the new method to begin at the Vall d'Hebron University Hospital in Barcelona."

Link: http://www.telegraph.co.uk/health/healthnews/8611634/Scientists-mend-broken-hearts.html

The Goal: Bring Aging Under Medical Control
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Reuters reports on a recent presentation by Aubrey de Grey of the SENS Foundation: "'I'd say we have a 50/50 chance of bringing aging under what I'd call a decisive level of medical control within the next 25 years or so,' de Grey said in an interview before delivering a lecture at Britain's Royal Institution academy of science. .... And what I mean by decisive is the same sort of medical control that we have over most infectious diseases today. ... De Grey sees a time when people will go to their doctors for regular 'maintenance,' which by then will include gene therapies, stem cell therapies, immune stimulation and a range of other advanced medical techniques to keep them in good shape. ... The idea is to engage in what you might call preventative geriatrics, where you go in to periodically repair that molecular and cellular damage before it gets to the level of abundance that is pathogenic. ... For some, the prospect of living for hundreds of years is not particularly attractive, either, as it conjures up an image of generations of sick, weak old people and societies increasingly less able to cope. But de Grey says that's not what he's working for. Keeping the killer diseases of old age at bay is the primary focus. ... This is absolutely not a matter of keeping people alive in a bad state of health. This is about preventing people from getting sick as a result of old age. The particular therapies that we are working on will only deliver long life as a side effect of delivering better health."

Link: http://www.reuters.com/article/2011/07/04/us-ageing-cure-idUSTRE7632ID20110704

Two Months Left Until the SENS5 Conference
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The fifth Strategies for Engineered Negligible Senescence (SENS) Conference, SENS5, draws closer. It will be held from 31st August to 4th September at Queens' College in Cambridge - so there's still time to register.

The purpose of the SENS conference series, like all the SENS initiatives (such as the journal Rejuvenation Research), is to expedite the development of truly effective therapies to postpone and treat human aging by tackling it as an engineering problem: not seeking elusive and probably illusory magic bullets, but instead enumerating the accumulating molecular and cellular changes that eventually kill us and identifying ways to repair - to reverse - those changes, rather than merely to slow down their further accumulation. This broadly defined regenerative medicine - which includes the repair of living cells and extracellular material in situ - applied to damage of aging, is what we refer to as rejuvenation biotechnologies.

The program of presentations links to a range of interesting abstracts describing some of the important work that has taken place in the couple of years since SENS4, such as:

Tissue engineering of the liver using decellularised scaffolds

Here, we describe the fabrication of three-dimensional, naturally derived scaffolds with an intact vascular tree. ... The vascular network was used to reseed the scaffolds with human fetal liver and endothelial cells. These cells engrafted in their putative native locations within the decellularized organ and displayed typical endothelial, hepatic and biliary epithelial markers, thus creating a liver-like tissue in vitro.

MitoSENS: Allotopic expression of mitochondrial genes using a co-translational import strategy

The mitochondrion contains its own genome and encodes 13 proteins that are essential for the respiratory chain to function properly, [but] somatic mutations also accumulate in the mitochondria with normal aging. ... Thus far, we have stably transfected 5 of the 13 mitochondrial genes into the nuclear genome of human cell lines and are characterizing the expression and function of these exogenously expressed genes.

I also note that the group in Florida who are running a trial of granulocyte transplant therapy for cancer - based on the impressive results achieved by Zheng Cui - will also be presenting. On the whole, the program is well worth browsing. If you are interested in this field of science and biotechnology and you are not yet signed up for the conference, you should give some thought to attending.

A Novel View of Stem Cell Decline
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An open access paper: "One of the most important and complex diseases of modern society is metabolic syndrome. This syndrome has not been completely understood, and therefore an effective treatment is not available yet. We propose a possible stem cell mechanism involved in the development of metabolic syndrome. This way of thinking lets us consider also other significant pathologies that could have similar [or shared biological pathways], like lipodystrophic syndromes, progeria, and aging. All these clinical situations could be the consequence of a progressive and persistent stem cell exhaustion syndrome (SCES). The main outcome of this SCES would be an irreversible loss of the effective regenerative mesenchymal stem cells (MSCs) pools. In this way, the normal repairing capacities of the organism could become inefficient. ... Stem cell restoration has already demonstrated therapeutic activities in certain systems. For example, it is known that after a stroke, endogenous stem cells are mobilized from the bone marrow in an attempt to heal the damaged neural tissue. Most interestingly, a recent study demonstrated that stroke patients who exhibit a high level of stem cell mobilization have better functional outcomes as opposed to patients with a lower mobilization. ... If [MSCs exhaustion syndrome] is true, then a stem cell therapy approach could be feasible. For instance, ex vivo expansion and reinfusion of MSCs from the patient's own or from allogeneic donors, as evidence shows that MSCs are not immunogenic at all, have been already tested in many clinical trials .... In the best case scenario, MSCs therapy could retard the onset of irreversible lesions associated with metabolic syndrome or at least partially improve those already present."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3118295/

On Longevity Insurance
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It is worth watching the prevalence of longevity insurance offerings, as this is a measure of the degree to which the actuarial community and insurance industry believes that increases in human life span will happen in the near future, but that they will not be large. For the insurer, longevity insurance is a bet on earlier than anticipated death: "Most people buy life insurance to protect against the risks of dying too soon. Now, there are new products offering the same protection if you live too long. It's known as longevity insurance, and there's clearly a huge market for it: Life expectancies are on the rise, cushy pensions are on the decline, and most people don't have enough savings to carry them through two decades or more of retirement. This is not lost on insurance companies, which would like you to think about the product as a pension of sorts - albeit one that you have to buy with your own money. ... But what happens if Merck invents the magic pill and we all live until 105? ... Continued improvements in medicine that allow people to live longer could create losses on our individual annuity business. but these would be more than offset by higher gains on the life insurance. ... Still [if] something like that were to happen, 'at some point, capacity might be limited.'" Companies that bet against large increases in longevity are likely to suffer greatly in decades to come - which is unfortunate for the rest of us, because these concerns are large enough to run to the nearest government for a bailout, and thus we all end up paying for collective bad bets.

Link: http://bucks.blogs.nytimes.com/2011/06/28/longevity-insurance-buying-down-the-risks-of-living-too-long/

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