Fight Aging!

An article by Ben Goertzel over at h+ Magazine discusses the Russia 2045 initiative, a program I've noted on a couple of occasions. A few highlights:

For 3 days in late February, Russian businessman Dmitry Itskov gathered 500+ futurists in Moscow for a "Global Future 2045 Congress" - the latest manifestation of his "Russia 2045" movement. ... The occurrence of a conference like this in Russia is no big shock, of course. Russia has a huge contingent of great scientists in multiple directly Singularity-relevant areas; and it also has an impressively long history of advanced technological thinking . My dear departed friend Valentin Turchin wrote a book with Singularitarian themes in the late 1960s, and the Russian Cosmists of the early 1900s discussed technological immortality, space colonization and other futurist themes long before they became popular in the West.

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It's unclear from the online conference abstracts and other Russia 2045 materials just how much actual work is going in Russia on right now, explicitly oriented toward realizing the exciting visions Itskov describes; and it's also unclear to what extent Itskov's "Russia 2045" movement serves an active R&D role, versus a visionary and publicity role. It appears that most of the concrete science and engineering work at the conference was presented by scientists who had made their breakthroughs outside the context of the "Russia 2045" project; whereas Itskov and the other Russia 2045 staff were largely oriented toward high-level visioning. But of course, Russia 2045 is a new initiative, and may potentially draw more researchers into its fold as time progresses.

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Ray Kurzweil gave a fairly glowing report, noting "It was a well funded conference, funded by a number of major corporations in Russia..... There was significant representation from the mainstream press. The ideas were taken seriously. There were people from companies, from academe, from government.... The comparison to Humanity+ or the Singularity Summit is reasonable.... The people at the conference (about 500-600) were pretty sophisticated about all the issues you and I talk and write about."

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Clearly there are many smart scientists and engineers in Russia doing directly Singularity-relevant things; and Itskov's Russia 2045 organization seems to be doing a good job of attracting public and political attention to this work. What amount of concrete work is actually going on toward Itskov's list of grand goals is unclear to me at present, but certainly seems something to keep an eye on.

As Goertzel notes, there are the standard reasons for caution before becoming too taken by this project - but unlike the usual situation for an emerging initiative there is already a fair amount of money involved. So if we outsiders adopt a wait and see approach, matters will undoubtedly become more clear in time. Either there will be tangible progress, leading to more outreach and collaboration with the scientific community, or there will not. Either way it can be taken as a confirmation that the time is becoming right for far greater public support of longevity engineering: building longer healthy lives and attempting to reverse or effectively work around the consequences of aging.

An Australian program featuring researchers Aubrey de Grey and David Sinclair: "It feels like science fiction, but it's actually true. And we're really at the cutting edge, it's a really exciting time in the field right now. ... There's no such thing as ageing gracefully. I don't meet people who want to get Alzheimer's disease, or who want to get cancer or arthritis or any of the other things that afflict the elderly. Ageing is bad for you, and we better just actually accept that. As far as I'm concerned, ageing is humanity's worst problem, by some serious distance. ... Now if you think that's an overstatement, consider this: world-wide, a hundred and fifty thousand people die each day, two-thirds of them from ageing. That means potentially one hundred thousand people could be saved every day with therapies that combat ageing. ... Ageing is simply and clearly, the accumulation of damage in the body. That's all that ageing is. What it's going to take is development of thoroughly comprehensive regenerative medicine for ageing. That means medicine which can repair the molecular and cellular damage that accumulates in our bodies throughout life, as side effects of our normal metabolic processes. ... We do not know what humanity of the future is going to want to do. If thirty or fifty years from now people don't have the problems that we thought they might have, but we didn't develop those therapies, so those people have to die anyway, after a long period of decrepitude and disease, then they're not going to be terribly happy are they? That's why we have a moral obligation to develop these technologies as soon as possible."

Link: http://www.abc.net.au/catalyst/stories/3465499.htm

Via EurekAlert!: researchers have "explained how rapamycin, a drug that extends mouse lifespan, also causes insulin resistance. The researchers showed in an animal model that they could, in principle, separate the effects, which depend on inhibiting two protein complexes, mTORC1 and mTORC2, respectively. The study suggests that molecules that specifically inhibit mTORC1 may combat age-related diseases without the insulin-resistance side effect. ... The mTOR complexes, for mammalian (or mechanistic) target of rapamycin, are proteins that regulate cell growth, movement, and survival, as well as protein synthesis and transcription. Specifically, there are two mTOR complexes and one mTOR protein. The mTOR protein is the core of both complexes (mTORC1 and mTORC2), which behave differently based on their associated proteins. One or both of the mTOR complexes can be inappropriately activated in certain cancers, and dual-specific inhibitors are being developed as chemotherapeutic agents. Several theories have been put forward by researchers to explain the observations that patients receiving rapamycin are more prone to developing glucose intolerance, which can lead to diabetes. Chronic treatment with rapamycin impairs glucose metabolism and the correct functioning of insulin in mice, despite extending lifespan. The research team demonstrated that rapamycin disrupts mTORC2 in the mice, and that mTORC2 is required for the insulin-mediated suppression of glucose metabolism in the liver. On the other hand, they also demonstrated that decreasing mTORC1 signaling was sufficient to extend lifespan independently from changes in glucose metabolism. They used a mouse strain in which mTORC1 activity was decreased and saw that lifespan was extended by 14 percent, yet the animals had normal glucose metabolism and insulin sensitivity."

Link: http://www.eurekalert.org/pub_releases/2012-03/uops-dol032612.php

Advanced glycation end-products (AGEs) such as glucosepane are what you might think of as a sort of biological rust. They build up as an undesirable side-product of the chemistry of life and damage important molecular machinery in and around cells by sticking to molecules or sticking molecules together, making it impossible for them to do their jobs. The increase in AGE levels in the body with advancing age isn't a matter of straight accumulation over time - it's more dynamic than that, and the level of AGEs in the diet may play some role - but eventually it becomes enough to cause serious harm. Aging is little more than damage, and AGEs are one form of that damage.

The SENS Foundation is currently sponsoring research into therapies to break down glucosepane, what is probably the most important AGE in humans. I see that the UK-based research group has a few web pages devoted to their work, on one of which is offered some explanation as to why the drug industry isn't all that much help when it comes to building ways to tackle AGEs:

There are two difficulties with creating AGE-breaker drugs. Firstly, AGEs are chemical targets, not genes or proteins. Almost all of pharmaceutical research over the last 40 years has been orientated to finding drugs that interact with proteins, and with the genes that make those proteins. So we cannot call on the trillions of dollars of research and technology development that have created the modern drug industry to help us (very much - we can use some of it). Secondly, AGEs are pretty stable and tough. That is inevitable - they are in essence the physiological equivalent of the black stuff on the bottom of your baking tin - what is left after years of use and the dishwasher. (In the case of humans, 'the dishwasher' is an array of mechanisms that take care of nearly all the waste products of metabolism.) We know how to break them quite easily, but only using a process that would also dissolve every protein in your body. The trick is finding a way to cleave them and leave all the rest of you intact.

Here is a recently posted video from last year's SENS5 conference in which one of the research groups focused on AGEs discusses their work:

Advanced glycation end-products are a class of natural products that form non-enzymatically on exposed protein residues in the human body. AGEs accumulate as a result of normal metabolism and aging, and significant elevations in these molecules have also been observed in the plasma of patients with chronic diseases, such as diabetes, cancer, arthritis, cardiovascular disease, and others. Our laboratory is taking an orthodox approach to studying these materials; we have initiated a synthetic program to prepare AGE- adducts on large scale and in chemically homogenous form. This talk will describe ongoing efforts along these lines, with a particular focus on exploring a class of arginine-derived AGEs. Chemical and biological insight arising from these studies will also be discussed. It is our hope that this small molecule-based strategy will serve to shed new light on the role of AGEs in both healthy and disease physiology.

There's a range of research to indicate that gut bacteria are important in the relationship between metabolism and aging, though the situation in higher animals is probably far more complex than in nematode worms: "A powerful approach to understanding complex processes such as aging is to use model organisms amenable to genetic manipulation, and to seek relevant phenotypes to measure. Caenorhabditis elegans is particularly suited to studies of aging, since numerous single-gene mutations have been identified that affect its lifespan; it possesses an innate immune system employing evolutionarily conserved signaling pathways affecting longevity. As worms age, bacteria accumulate in the intestinal tract. However, quantitative relationships between worm genotype, lifespan, and intestinal lumen bacterial load have not been examined. We hypothesized that gut immunity is less efficient in older animals, leading to enhanced bacterial accumulation, reducing longevity. To address this question, we evaluated the ability of worms to control bacterial accumulation as a functional marker of intestinal immunity. ... We show that as adult worms age, several C. elegans genotypes show diminished capacity to control intestinal bacterial accumulation. We provide evidence that intestinal bacterial load, regulated by gut immunity, is an important causative factor of lifespan determination; the effects are specified by bacterial strain, worm genotype, and biologic age, all acting in concert. ... In total, these studies focus attention on the worm intestine as a locus that influences longevity in the presence of an accumulating bacterial population. Further studies defining the interplay between bacterial species and host immunity in C. elegans may provide insights into the general mechanisms of aging and age-related diseases."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22452899

Yet another study showing a correlation between chronic inflammation and abdominal fat: "Obesity-related increases in multiple inflammatory markers may contribute to the persistent subclinical inflammation common with advancing age. ... We used factor analysis to identify inflammatory factor(s) and examine their associations with adiposity in older adults at risk for disability. ... [Inflammatory markers] were measured in 179 participants from the Lifestyle Interventions and Independence for Elders Pilot (Mean ± SD age 77 ± 4 years, 76% white, 70% women). Body mass index, waist circumference, and total fat mass were assessed by anthropometry and dual-energy x-ray absorptiometry. ... Greater total and abdominal adiposity are associated with higher levels of an inflammatory factor related to CRP, IL-1ra, and IL-6 in older adults, which may provide a clinically useful measure of inflammation in this population. ... [The associations were determined] after adjusting for age, gender, race/ethnicity, site, smoking, anti-inflammatory medications, comorbidity index, health-related quality of life, and physical function. These associations remained significant after further adjustment for grip strength, but only waist circumference remained associated with inflammation after adjusting for total lean mass." Waist circumference is a better correlation with the amount of visceral fat packed around the organs in comparison to body mass index.

Link: http://www.ncbi.nlm.nih.gov/pubmed/22451470

Someone who didn't take note of the eagerness with which people throw money at the shams, fakes, and security blankets of the "anti-aging" marketplace might be forced to conclude that the world's inhabitants are on balance indifferent as to whether they live long or die young, whether they suffer for decades or live healthily some years down the line. There are many common sense health practices that people can undertake to maximize their remaining life expectancy and reduce the risk of age-related disease - and that's even before we start in on supporting research and development of rejuvenation biotechnology - but the majority don't do anywhere near as much as they might, and in consequence they come to suffer for it.

Are we a species whose dominant trait is actually nihilism? One wonders at times.

But the personal future of aging isn't the only thing that most people, judging by their actions, are indifferent to. We might also consider the preventable nature of well known conditions like cancer, to pick one example. Most people know that they should be exercising, they should not let themselves get fat, and they also know how to halve the risk of suffering cancer - but do they adopt the necessary changes in lifestyle? Largely no:

More than half of all cancer is preventable, and society has the knowledge to act on this information today ... What we know [is] that lifestyle choices people make and that society can influence in a number of ways - from tobacco use to diet and exercise - play a significant role in causing cancer. Specifically, the researchers cite data demonstrating that smoking alone is responsible for a third of all cancer cases in the United States. Excess body weight and obesity account for another 20 percent.

This all might be viewed as another facet of the difficulty faced by groups trying to do something about aging and age-related disease - which is to say trying to help people avoid a future that many to most seem to be largely indifferent to, judging by their actions. If a person doesn't care enough about their future trajectory to take basic, simple care of their health today, why would they care enough to donate money to medical research and development? Fortunately, it isn't necessary to persuade everyone - even a few tens of millions of casual supporters, a tiny fraction of the population of the world, could between them generate enough resources to carry the SENS research program to completion, for example. Cancer research is itself an example of what it looks like some decades after that initial group of casual supporter is amassed - once the ball starts rolling and achieves a critical mass, the research programs become accepted as a part of what is.

But we are still left wonder on the rationality of humans, and the degree to which the average person is prepared to let their future self suffer.

There is plenty of evidence to show that being overweight for any great length of time in life causes harm, either fairly directly by boosting levels of chronic inflammation, or because that fat tissue is associated with a lack of exercise and consequent development of vascular dementia, or for a range of other possible reasons. Here is another study on this topic: "High midlife body mass index (BMI) has been linked to a greater risk of dementia in late life, but few have studied the effect of BMI across midlife on cognitive abilities and cognitive change in a dementia-free sample. ... We investigated the association between BMI, measured twice across midlife (mean age 40 and 61 years, respectively), and cognitive change in four domains across two decades in the Swedish Adoption/Twin Study of Aging. ... Latent growth curve models fitted to data from 657 non-demented participants showed that persons who were overweight/obese in early midlife had significantly lower cognitive performance across domains in late life and significantly steeper decline in perceptual speed, adjusting for cardio-metabolic factors. Both underweight and overweight/obesity in late midlife were associated with lower cognitive abilities in late life. However, the association between underweight and low cognitive abilities did not remain significant when weight decline between early and late midlife was controlled for. ... There is a negative effect on cognitive abilities later in life related to being overweight/obese across midlife. Moreover, weight decline across midlife rather than low weight in late midlife per se was associated with low cognitive abilities." The weight decline association shows up in a range of studies on weight and health; one common conclusion is that it reflects the impact that more serious medical conditions - related to weight or otherwise - can have on people.

Link: http://www.ncbi.nlm.nih.gov/pubmed/22450854

Advances in biotechnology are greatly reducing the cost of performing broad analyses of metabolism - and so researchers are gathering ever more data on the various breeds of long-lived mice that have been created in recent years: "Significant advances in understanding aging have been achieved through studying model organisms with extended healthy lifespans. Employing (1)H NMR spectroscopy, we characterized the plasma metabolic phenotype (metabotype) of three long-lived murine models: 30% dietary restricted (DR), insulin receptor substrate 1 null (Irs1(-/-)), and Ames dwarf (Prop1(df/df)). A panel of metabolic differences were generated for each model relative to their controls, and subsequently, the three long-lived models were compared to one another. Concentrations of mobile very low density lipoproteins, trimethylamine, and choline were significantly decreased in the plasma of all three models. Metabolites including glucose, choline, glycerophosphocholine, and various lipids were significantly reduced, while acetoacetate, d-3-hydroxybutyrate and trimethylamine-N-oxide levels were increased in DR compared to ad libitum fed controls. Plasma lipids and glycerophosphocholine were also decreased in Irs1(-/-) mice compared to controls, as were methionine and citrate. In contrast, high density lipoproteins and glycerophosphocholine were increased in Ames dwarf mice, as were methionine and citrate. Pairwise comparisons indicated that differences existed between the metabotypes of the different long-lived mice models. Irs1(-/-) mice, for example, had elevated glucose, acetate, acetone, and creatine but lower methionine relative to DR mice and Ames dwarfs. Our study identified several potential candidate biomarkers directionally altered across all three models that may be predictive of longevity but also identified differences in the metabolic signatures. This comparative approach suggests that the metabolic networks underlying lifespan extension may not be exactly the same for each model of longevity and is consistent with multifactorial control of the aging process."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22225495

Not all tissue structures need to be tailored to the patient - indeed, most of the present tissue engineering industry is in fact directly serving the research and development community rather than clinics. Engineered tissue is used for a broad range of testing, for example, and many life science research programs can progress more effectively with access to tissue structures rather than cells in a petri dish. As costs fall, that becomes an ever more practical alternative, meaning that research becomes more efficient and faster. Behind these falling costs lies a world of automation and infrastructure, leading towards assembly lines that produce pieces of living tissue for use in research and medical development:

Artificial skin for use in transplants or to verify the safety of the active ingredients of drugs, cosmetics and chemicals is a rare commodity. It is currently produced manually on a laboratory scale, and cultivation takes six weeks. The production volume is therefore limited to 2,000 pieces of skin per month, each one only a square centimetre in size. At a lab in Germany's Fraunhofer Institute, automation technology supplier Festo has helped to marry process automation with skin cultivation. The company's automation specialists recently helped the lab change its systems to achieve faster skin cell production

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The new BioPoLiS organic production laboratory at the Fraunhofer IPA is home to what it says is the only facility in the world for the fully automatic in vitro production of up to 5,000 human skin models a month. The plant reflects the importance of bio-production, a combination of biology and automation technology. ... A particularly noteworthy feature is the continuous process chain. A single production line is used to handle cell extraction, cell proliferation, the cultivation of a three-dimensional tissue structure and cryonic preservation of skin models. Each process step is conducted without interrupting any of the others.

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The scientists involved in the project are not content merely to produce skin. They say they plan to develop the technology further in the next two years to the point where other types of tissue, such as cartilage, can also be produced automatically.

Tissue is machinery, and we humans have accumulated a great deal of experience in how to build large amounts of homogeneous, quality-controlled machinery in a short period of time. So there is every reason to think that mass production of tissue structures for research and regenerative medicine will result in industrial processes that have much in common with the automated assembly lines that produce appliances or cars. As demand increases, and especially if therapies that use standardized tissues rather than patient-specific tissues become widespread, then we will see a much more of this sort of thing. An industry of large, specialized tissue factories is not an unrealistic expectation for the 2020s, though I would imagine that such a factory will look a lot more like a hospital, clinic, or microchip fabrication plant on the inside than the name might suggest.

Some people have an objectively better metabolism than others when it comes to longevity - perhaps better mitochondrial DNA, perhaps less LDL cholesterol, for example: "Coronary atherosclerosis - a hardening of the arteries due to a build-up of fat and cholesterol - can lead to heart attacks and other forms of coronary heart disease (CHD). Lowering low-density lipoprotein (LDL), or 'bad' cholesterol, reduces the risk of CHD ... By the time most people begin treatment to lower LDL, CHD has often been quietly developing for decades. Because coronary atherosclerosis begins early in life, lowering LDL at a younger age may produce even greater reductions in the risk of CHD. Researchers sought to test this hypothesis by using genetic data to conduct a series of 'natural' randomized controlled trials involving over one million study participants. ... researchers used a novel study design called a Mendelian randomized controlled trial (mRCT) to study the effect of nine single-nucleotide polymorphisms (SNPs), or single-letter changes in DNA sequence, each of which is associated with lower levels of LDL cholesterol. Because each of these SNPs is allocated randomly at the time of conception, inheriting one of these SNPs is like being randomly allocated to a treatment that lowers LDL cholesterol beginning at birth. The researchers found that all nine SNPs were associated with a consistent 50-60 percent reduction in the risk of CHD for each 1 mmol/L (38.67 mg/dl) lower lifetime exposure to LDL cholesterol. "

Link: http://www.sciencedaily.com/releases/2012/03/120326133606.htm

Commonalities between many different forms of cancers will become increasingly important as biotechnology offers the ability to target them. They offer the prospect of a simplifying of cancer research and development, and far more cost-effective therapies - the big question is to what degree they exist at all: "A decade ago, biologist Irving Weissman [discovered] that leukemia cells produce higher levels of a protein called CD47 than do healthy cells. CD47, he and other scientists found, is also displayed on healthy blood cells; it's a marker that blocks the immune system from destroying them as they circulate. Cancers take advantage of this flag to trick the immune system into ignoring them. In the past few years, Weissman's lab showed that blocking CD47 with an antibody cured some cases of lymphomas and leukemias in mice by stimulating the immune system to recognize the cancer cells as invaders. Now, he and colleagues have shown that the CD47-blocking antibody may have a far wider impact than just blood cancers. ... What we've shown is that CD47 isn't just important on leukemias and lymphomas. It's on every single human primary tumor that we tested. ... Moreover, Weissman's lab found that cancer cells always had higher levels of CD47 than did healthy cells. How much CD47 a tumor made could predict the survival odds of a patient. ... To determine whether blocking CD47 was beneficial, the scientists exposed tumor cells to macrophages, a type of immune cell, and anti-CD47 molecules in petri dishes. Without the drug, the macrophages ignored the cancerous cells. But when the CD47 was present, the macrophages engulfed and destroyed cancer cells from all tumor types. Next, the team transplanted human tumors into the feet of mice, where tumors can be easily monitored. When they treated the rodents with anti-CD47, the tumors shrank and did not spread to the rest of the body. In mice given human bladder cancer tumors, for example, 10 of 10 untreated mice had cancer that spread to their lymph nodes. Only one of 10 mice treated with anti-CD47 had a lymph node with signs of cancer. Moreover, the implanted tumor often got smaller after treatment."

Link: http://news.sciencemag.org/sciencenow/2012/03/one-drug-to-shrink-all-tumors.html

The SENS Foundation, a non-profit focused on both the development of rejuvenation biotechnology capable of reversing aging and establishing a larger research community to achieve that goal more effectively, has released their 2011 annual report (PDF).

It's with great pleasure that I announce the release of our Annual Report for 2011. The report includes updates on all of our research projects, both at the Research Center in Mountain View, and at leading universities and institutions around the world. It reviews the success of SENS 5 and the expansion of our Academic Initiative, and summarises our financial situation through 2011. I hope that you enjoy reading it as much as we have enjoyed assembling it!

Some highlights from the PDF:

You might say that the past three years have been SENS Foundation's 'Mercury project' - our proof-of-concept phase - during which we've worked to establish the feasibility of our line of inquiry through our research, education, and outreach programs. And in this we have been successful. The Thiel Foundation's substantial and continued funding has been met both with broader-based support and more key individual backers. Edward James Olmos has volunteered to lend his voice to our message. Jason Hope's philanthropic gift has launched our glucosepane research program at Cambridge and Yale Universities. We've worked hard to build new collaborations and outreach opportunities, and 2012 will show a significant research project in every major category of damage in the SENS technological proposal.

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What has changed [in the SENS Foundation messaging] is the fact that we now have specific research, details, and ongoing proof-of-concept work to discuss. SENS Foundation has matured as an organization. We have moved well beyond the point of needing to defend the SENS platform as worth testing out in the laboratory; we have won that battle. Instead, we are discussing how SENS Foundation can best go about its work of building an industry and creating a comprehensive, practical suite of rejuvenation biotechnologies. And so, I no longer discuss and emphasize what the future might hold. Rather, I discuss and emphasize what is going on right now at the SENS Foundation Research Center in Mountain View, California, and in Foundation-funded laboratories across the world.

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We are delighted that SENS Foundation was able to make expenditures of $1,518,000 in 2011. This was an increase of over $400,000 from 2010, overwhelmingly in support of direct research and conference projects. ... We greatly appreciate the support of the many individuals who contributed to our mission. We would like to thank Peter Thiel, Jason Hope, the Methuselah Foundation, and all of our contributors and volunteers for their on-going generosity. We expect a significant increase in both revenues and expenses for 2012, as we begin to see distributions from a de Grey family trust, under a grant from SENSF-UK. This support will be in addition to the contributions we receive from other sources.

That last part there - very admirable. Would that we were all so dedicated.

By way of comparison with the 2010 report showed a $1 million budget or so for that year, about a third of which went to LysoSENS research - working on the foundation of a biomedical remediation strategy that could use bacterial enzymes to safely break down the age-related build up of harmful aggregates in the body. That build up is one of the fundamental causes of aging, but suitable biotechnologies such as biomedical remedication can and should be developed to address it. A successful technology platform for therapies will allow for both extension of healthy life span and restoration of health to those who are already damaged and suffering.

It has to be said, I'm pleased to see work on finding a safe agent to break down glucosepane moving forward. The lack of significant progress anywhere in the world on AGE breakers targeting the most common AGE - glucosepane - over the past decade has been enormously frustrating. It is one of the few areas of SENS in which the traditional and massive drug development industry is perfectly suited to the task. It may as well have had a big red target painted on it given the size of the market for a working drug that actually, legitimately, literally reversed skin aging - amongst other important body parts such as blood vessels - and yet nothing much has happened.

The world needs another ten SENS Foundations, collectively kicking the rest of the research community in the pants, demanding to know why the important work isn't being accomplished, and then making those big-budget groups look bad by creating real progress in biotechnology on a shoestring budget.

Hair color - and loss - is one of the aspects of aging that people care about too much in comparison to its effects on health. There are far more important degenerations to consider. Nonetheless, here is a report suggesting that better control over the cell signaling could restore lost hair color by directing pigment cells to get back to work: "We report the first case of progressive hair repigmentation associated with the use of lenalidomide in an elderly patient with multiple myeloma. The influence of lenalidomide on follicular melanogenesis may involve removing the inhibitory influences of some cytokines such as IL-1, IL-6 and TNF-α. In addition, certain endocrine effects of lenalidomide on the hypophyseal-adrenal axis could explain its action on hair pigmentation. We further hypothesize that lenalidomide may be capable of stimulating migration and/or differentiation of melanocytes to promote repigmentation of gray hair follicles. Pending the clarification of how hair repigmentation occurs with lenalidomide, our observation materializes the concept that hair graying may not be an irreversible process." This sort of brute force approach is, however, far less desirable than working to fix the underlying levels of cellular damage that lead to changed signaling and the decline of melanocyte activity in the first place.

Link: http://www.ncbi.nlm.nih.gov/pubmed/22440400

This research should be added to that showing that failure of systems in the body, such as stem cells, is as much a consequence of the overall bodily environment and the biochemical signals it generates as it is damage to the systems specifically: "People with kidney failure may think that they're better off getting a new kidney from a young and spry donor, but a recent study indicates that for those over 39 years old, the age of a live donor - ranging from 18 to 64 years - has an insignificant effect on the long-term health of a transplanted kidney. ... [Researchers] analyzed the survival of kidneys from donors of different age groups that were transplanted into recipients of different age groups. Their study included data from all adult kidney transplants from living donors that were performed in the United States from January 1988 to December 2003, with follow-up through September 2007. With the exception of recipients aged 18 to 39 years, who benefited the most when they received kidneys from donors aged 18 to 39 years, donor age between 18 and 64 years had minimal effect on the survival of transplanted kidneys. ... many patients will likely find that participating in living donor paired exchanges - and possibly receiving a kidney from an older-aged donor - is a better option than continuing to wait for a deceased donor transplant."

Link: http://www.eurekalert.org/pub_releases/2012-03/ason-lda031912.php

The first generation of the modern cryonics community, people who were middle-aged in the 1970s, is benefiting from the technologies and visions that they built. They founded a movement that has sustained itself for four decades in providing steadily improved cryopreservation services through organizations such as Alcor and the Cryonics Institute. The growth that would remake cryonics as from a non-profit community into a for-profit business with a healthy research and development arm has yet to happen, unfortunately, despite the clear need for the ability to preserve the brains and minds of those who will age to death before the advent of working rejuvenation biotechnology. But the present level of success is enough to provide a shot at renewed life in the future for the few who are determined enough and organized enough to take it.

I see that another of the early cryonics pioneers was cryopreserved recently:

Alcor Co-Founder Fred Chamberlain is Cryopreserved

Fred Chamberlain III who, with his wife Linda, incorporated Alcor in 1972, was cryopreserved by Alcor on March 22, 2012. One week earlier, Fred relocated from Florida to a Scottsdale hospice. This allowed us to watch over him and respond immediately when needed. We believe that Fred received an excellent cryopreservation. More details will be released later.

Linda Chamberlain has released a document to announce his cryopreservation and honor him.

Bon Voyage, Fred Chamberlain

Fred Chamberlain was a NASA-JPL electrical engineer working on the Mariner-Jupiter-Saturn mission in 1973 [and] was and is of absolutely critical importance to cryonics. While most people with more than a passing acquaintance with cryonics will associate his importance with the founding of Alcor, that is in reality only a surrogate marker for his deeper importance. Fred came on the scene in cryonics in what was unarguably its darkest hour. It had degenerated into little more than a fraudulent cult in California and, everywhere in the US, it had lost all vestiges of technical and scientific rigor.

When Fred discovered this in his role as Vice President of the Cryonics Society of California (CSC) he not only left CSC and founded Alcor, he and Linda Chamberlain established, for the first time anywhere, the practice of scientific, evidence based cryonics; cryonics based on the scientific method, on documentation of procedures, policies, cryopreservation protocols and rigorous patient case reports. He and Linda mandated not only scientific and technical accountability, but administrative, financial and legal accountability as well.

Until it does become an earnestly growing industry of many competing companies and millions of cryopreservations every year, cryonics can only work - in the sense of providing a good chance at safe preservation until such time as molecular nanotechnology and other advanced medical technologies can rebuilt and revive cryopreserved individuals - if the movement acts as a community. Maintaining the means of brain preservation for the long term is simply a new option in the general category of caring for elders whose bodies are failing them: this is something that well-balanced communities of humans have accomplished for a long time indeed. So provided that the cryonics movement can persevere as an ordinary, standard community of people with shared interests, as it has for the past 40 years, it should offer those who are cryopreserved a good chance of stability and safety for the decades between now and the advent of restorative technologies of the future.

But that growth is still a better option all round. So very many people go to the grave every day, people who might have chosen cryonics or plastination if those were options backed by a large, vocal industry with millions of customers.

The founder of the Russia 2045 initiative is interviewed here: "Dmitry Itskov is the founder of Global Future 2045, which recently held its first conference. The Russian entrepreneur gathered scientists from around the world to discuss many topics that will help achieve one goal: life extension. ... The main idea of the project and my mission is to help people, to eliminate disease and death probably in the future, to overcome the limitations of our body, and to help humanity grow out of the crisis. As for my personal background, I have always been in the IT business, internet technologies. I published a few internet newspapers in Russia, I produce internet TV channel, a kind of blog service, email service, so being in this business I have always been interested in science and technologies that can extend life. Of course, like anybody, I have seen death and diseases in my family, my grandparents have gone, I've always been thinking how can I personally help. I've also been interested in science and I've seen an example of scientists who haven't gone, who are with us, like Stephan Hawking. He can't even move, he can't even normally talk to people, so this experience inspired me, this made me think how can I participate and help people. I decided to launch such an initiative with the help of Russian scientists who I knew like me. What helped me was that talking to them I was pretty sure that if we launched a kind of a big technical project, a big social initiative, if we work together, if we make our thinking global, and if we are able to launch a global network, then there is a very big chance we make our dreams come true. ... [The Avatar initiative] is the main technological project of the initiative which consists of four steps. One is human-like robot controlled by brain-computer interface. ... the second part is about producing life support system for the human brain. ... The third part is reverse engineering for the brain." The fourth step is to replace the biological brain with an artificial system that is more durable and extendable - which is a long way out, but something that has to be accomplished carefully and thoughtfully to be anything other than an expensive form of suicide that happens to leave behind a copy of the original you. Acceptable means include slowly replacing neurons one by one with nanomachinery that replicates their function and data storage whilst interfacing with the remaining brain tissue - but again, this sort of technology is a long way out from where we stand now, and there are many other challenges to be overcome along the way.

Link: http://sciencefiction.com/2012/03/19/exclusive-interview-with-dmitry-itskov-founder-of-global-future-2045/

Researchers are slimming down the process of generating specific types of cell to order, turning the multi-step induced pluripotency processes of the last couple of years into a single step: researchers "have succeeded in obtaining somatic stem cells from fully differentiated somatic cells. [Scientists] took skin cells from mice and, using a unique combination of growth factors while ensuring appropriate culturing conditions, have managed to induce the cells' differentiation into neuronal somatic stem cells. ... Our research shows that reprogramming somatic cells does not require passing through a pluripotent stage. Thanks to this new approach, tissue regeneration is becoming a more streamlined - and safer - process. ... One factor in particular, called Brn4, which had never been used before in this type of research, turned out to be a genuine 'captain' who very quickly and efficiently took command of his ship - the skin cell - guiding it in the right direction so that it could be converted into a neuronal somatic stem cell. ... This interconversion turns out to be even more effective if the cells, stimulated by growth factors and exposed to just the right environmental conditions, divide more frequently. ... Gradually, the cells lose their molecular memory that they were once skin cells. ... It seems that even after only a few cycles of cell division the newly produced neuronal somatic stem cells are practically indistinguishable from stem cells normally found in the tissue. ... So far, insights are based on experiments using murine skin cells; the next steps now are to perform the same experiments using actual human cells. In addition, it is imperative that the stem cells' long-term behaviour is thoroughly characterized to determine whether they retain their stability over long periods of time."

Link: http://www.mpg.de/5548755/stem_cells_skin_cells

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

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

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

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

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

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

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

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

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

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

The aging of bacteria has been a topic of interest in the years since its discovery; firstly, it overturns the long-held assumption that bacteria are essentially immortal, and secondly it provides insight into the very early evolutionary origins of aging. Here is a recent update: "Evidence for aging in symmetrically dividing bacteria such as Escherichia coli has historically been conflicting. Early work found weak or no evidence. More recent studies found convincing evidence, but negative results are still encountered. Because bacterial aging is believed to result from non-genetic (e.g. oxidative) damage, we tested the possibility that the negative outcomes resulted from the lack of an extrinsic damage agent. We found that streptomycin, which produces mistranslated proteins that are more vulnerable to oxidation, was able to induce both damage and aging in bacterial populations. A dosage effect relating the level of damage to the concentration of streptomycin was observed. Our results explain the previous inconsistencies because all studies that failed to find evidence for bacterial aging did not use a damage agent. However, all studies that succeeded in finding evidence utilized fluorescent proteins as a visual marker. We suggest that aging in those studies was induced by the harmful effects of an extrinsic factor, such as of the proteins themselves or the excitation light. Thus, all of the previous studies can be reconciled and bacterial aging is a real phenomenon. However, the study and observation of bacterial aging requires the addition of an extrinsic damage agent."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22422756

A BBC News article: "It might seem unbelievable, but researchers can grow organs in the laboratory. There are patients walking around with body parts which have been designed and built by doctors out of a patient's own cells. ... There is a pressing need. A shortage of available organs means many die on waiting lists and those that get an organ must spend a lifetime on immunosuppressant drugs to avoid rejection. The idea is that using a patient's own stem cells to grow new body parts avoids the whole issue of rejection as well as waiting for a donor. ... Dr Anthony Atala [has] made breakthroughs in building bladders and urethras. He breaks tissue-building into four levels of complexity. 1) Flat structures, such as the skin, are the simplest to engineer as they are generally made up of just the one type of cell. 2) Tubes, such as blood vessels and urethras, which have two types of cells and act as a conduit. 3) Hollow non-tubular organs like the bladder and the stomach, which have more complex structures and functions. 4) Solid organs, such as the kidney, heart and liver, are the most complex to engineer. They are exponentially more complex, have many different cell types, and more challenges in the blood supply. ... We've been able to implant the first three in humans. We don't have any examples yet of solid organs in humans because its much more complex. ... One of the problems when you move to larger organs is the getting the blood supply to work, connecting arteries, capillaries and veins to keep the organ alive. It is why some researchers are investigating 'decellularisation' - taking an existing donated organ, stripping out the original cells and replacing them with new cells from the patient who will receive the organ."

Link: http://www.bbc.co.uk/news/health-16679010

The evolution of aging and longevity is a field in which it's still comparatively easy to make a mark and carve out an area of new theory. For most species it is still the case that ideas on their longevity are comparative unsettled: why they live as long as they do, what mechanisms may have determined their life span, and how it all fits in to the bigger picture of metabolism and the evolution of specific biological processes. There is far more data than any one group of researchers could hope to organize in a lifetime, and new information continues to flood in ever faster as the biotechnology revolution unfolds.

At some point this rich wealth of data starts to give rise to hypotheses that are more holistic: evolution as a system of systems linked by feedback loops, thousands of species interacting with one another in any given biome, and the evolution of each species highly connected to that of its peers. Embarking upon this level of modeling and understanding, all the way down to biomolecular processes, will keep evolutionary biologists busy for the next century or so, I'd imagine - and give them something to do with the staggering levels of computing power that will be available by that time.

Here is an interesting open access paper that gives a hint of the shape of this sort of future research, whilst considering the evolution of longevity amongst interacting species:

Various organisms (i.e., bacteria, fungi, plants and animals) within an ecosystem can synthesize and release into the environment certain longevity-extending small molecules. Here we hypothesize that these interspecies chemical signals can create [selective] forces driving the ecosystemic evolution of longevity regulation mechanisms.

In our hypothesis, following their release into the environment by one species of the organisms composing an ecosystem, such small molecules can activate anti-aging processes and/or inhibit pro-aging processes in other species within the ecosystem. The organisms that possess the most effective (as compared to their counterparts of the same species) mechanisms for sensing the chemical signals produced and released by other species and for responding to such signals by undergoing certain hormetic and/or [cellular housekeeping related] life-extending changes to their metabolism and physiology are expected to live longer then their counterparts within the ecosystem.

Thus, the ability of a species of the organisms composing an ecosystem to undergo life-extending metabolic or physiological changes in response [to] chemical compounds released to the ecosystem by other species: 1) increases its chances of survival; 2) creates selective forces aimed at maintaining such ability; and 3) enables the evolution of longevity regulation mechanisms.

So the researchers propose that such things as the ability of rapamycin (produced by soil bacteria) to extend life in mice or the beneficial effects of mammalian bile acid on yeast life span are late manifestations of cross-species evolutionary processes that have been going on since the very earliest epoch of multicellular life. The suggestion is that we should expect there to be a wide range of compounds produced by varied species that will have some beneficial effect on the life span of another species (such as by improving cellular housekeeping processes), because the existence of such relationships between species is a fundamental characteristic of diverse ecosystems produced by evolution.

Which is an interesting line of thought, and I look forward to seeing where it leads.

The second part of an article in CMAJ that shows off some of the subtle prejudices against cryonics that exist in the medical scientific community (such as in the choice of title) while attempting objectivity: "Although death and taxes are said to be the only two certainties in life, a small but vocal community takes issue with the inclusion of the former. There is, they say, the alternative of cryonics, in which a legally dead person is preserved at -196C in hopes that he will ultimately be revived and rejuvenated, once a cure for his ailment is found. And it's entirely consistent with the basic tenets of medicine, providers argue. ... Although it seems like an unusual and radical idea to many people, I think in the very truest sense of the term, this is conservative medicine. This is literally conserving a patient rather than giving up on them by today's standards of medicine. It's true a doctor can't do anything more for these people, but that doesn't mean the future cannot. ... Those interested in cryonics tend be optimistic, hopeful about technological developments and dissatisfied with an ordinary life span, says Ben Best, president of the Cryonics Institute. ... a miniscule chance is better than none, enthusiasts say. ... Nobody has come up with a better idea yet, so therefore myself, as well as some others, believe that cryonics is simply the second worst thing that can happen. You're going to die. You're going to stop breathing. Whether you be buried or cremated or cryopreserved, it's going to happen. There's nothing we can do about this now, but I know that if I'm cremated or buried, even if technology vastly increased, I'm never coming back. ... Enthusiasts are mystified that only a small segment of the general population has investigated the cryonic option. ... I don't know why there are far more people who don't sign up for cryonics arrangements. It's true that what we do is unorthodox and different, at least in 2012. But there are so many bizarre ideas out there which have no evidence to support them and get many, many people fascinated ... Yet we only have less than 1000 members after 40 years. ... People tend in my experience to kind of rely on this naturalistic [fallacy] that because people have always gotten older and died, therefore they should get older and die as a result of simply living longer."

Link: http://www.cmaj.ca/site/earlyreleases/20mar12_the-church-of-cryopreservation.xhtml

From an interview with Vernor Vinge at Wired: "First of all, I'm all for human life extension. In The Singularity is Near, I think, [Ray Kurzweil] has a nice discussion of the situation that a lot of essayists have where they say, 'Oh, we really don't want that. A wise and philosophical person realizes that life needs be limited, and that's a good thing,' these essayists say. He does a good job of criticizing that point of view, and I certainly agree with that. Furthermore, I think that a human lifespan of a thousand years with post-Singularity technology is easily doable. I think a lifespan of a thousand years would actually - Singularity aside - would do human society and human nature a great deal of good, and don't think it is that difficult, it probably can even be achieved without having a Technological Singularity. Life spans of 10,000 to 100,000 years, then you begin to look at what's involved, the humans that are involved, and how capable a human mind is of absorbing variety. ... The complaint or the criticism here is that the human mind has a certain level of ability to handle different sorts of complexity, and if you believe that you could go 100,000 years and not be turned into a repeating tape loop, well, then let's talk about longer period of time. How about a billion years, or a hundred billion years? At a hundred billion years, you're out there re-engineering the universe. The age of the universe becomes your chief longevity problem. But there's still the issue of, what would it be like to be you after that? This raises the point, which actually I'm sure is also on Ray's mind, that if you're going to last that long you have to become something greater, and the Singularity is ideally set up to supply that. So the people who are into the intelligence amplification mode of looking at these things, this all fits. And I'm not saying that in a critical and negative way, it does all fit, and it puts you in a situation where you are talking realistically about living very long periods of time, perhaps so long that you have to re-engineer the universe because the universe is not long-lived enough. At the same time, you have to be growing and growing and growing. I mean, intellectually growing. Now, if you look at that situation, it ultimately gets you, I think, to a very interesting philosophical point, which really I don't think was within the horizon of what people normally thought about two or three or four hundred years ago."

Link: http://www.wired.com/underwire/2012/03/vernor-vinge-geeks-guide-galaxy/

Mitochondria crowd your cells, roving descendants of ancient bacteria that were long ago co-opted to serve as power plants, turning food into adenosine triphosphate (ATP), the energy store chemical used to power cellular machinery. As a legacy of their bacterial origins, mitochondria carry their own DNA, separate from that in the cell nucleus. Making ATP is a messy business, creating all sorts of reactive molecules as byproducts, and that mitochondrial DNA is more vulnerable than the safely enclosed nuclear DNA. The balance of evidence strongly implicates mitochondrial DNA damage as one of the contributing causes of aging. A damaged gene can no longer be used as a blueprint for the process of gene expression that produces the protein machinery that is vital to the operation of a mitochondrion, and from there matters only go downhill - it's a long road that ends up at atherosclerosis, neurodegeneration, and many other forms of advanced age-related degeneration.

Thus finding ways to repair mitochondrial DNA (mtDNA) is of great importance - but this is still a minority field of science in comparison to stem cell medicine or cancer research. Nonetheless, mitochondrial repair has been attracting some attention in the past week, as an important new line of research made it to the press release and publicity stage. The technique demonstrated is not really repair, per se, more a method of working around damage to mitochondrial genes - but it looks to be a great improvement over existing methodologies in terms of cost, time, and difficulty. This may enable broader and faster progress towards therapies that can remove the harm caused by damaged mitochondria. You might peruse these recent posts for more details on the work:

• A General Method for Correcting Mitochondrial Mutations
• SENS Foundation on Recent Mitochondrial Research

The new method is a way to deliver more or less arbitrary RNA to mitochondria, which should allow for continued function even after mutational damage to important genes. Production of RNA is a first step in the convoluted process of gene expression - by which genes are used as a blueprint for proteins - so it's quite possible to skip the gene and start with the RNA. This shortcut is the basis for a range of modern life science research, and one obvious use is to correct for a missing or damaged gene: find a way to provide the patient with an ongoing supply of suitably crafted RNA molecules targeted to the right places in his or her cells and it won't matter that the gene is broken.

I should note that there are only thirteen genes in the mitochondria that are important for the purposes of this discussion, but the process of producing repairs or workarounds for each one has been hard, very different for each of them, slow, and difficult up until this point. A method that works in a very similar way for all of them is a big deal.

The researchers presented on their work in RNA last year at SENS5, and I see that the SENS Foundation volunteers moved up the presentation video in the queue for processing and posted it to YouTube today:

A decline in the function of mitochondria may contribute to the aging process and age-related disorders. A functional decline could arise from accumulated mtDNA mutations over time, leading to reduced oxidative phosphorylation and other untoward effects on mitochondrial activities. Strategies that restore mitochondrial function could potentially offset key aspects of aging decline. RNA import into mammalian mitochondria is considered essential for replication, transcription, and translation of the mitochondrial genome but the pathway(s) and factors that control this import are poorly understood.

In recent studies we have shown a role for polynucleotide phosphorylase (PNPASE) in regulating the import of nuclear-encoded RNAs into the mitochondrial matrix. ... A mitochondrial RNA targeting signal was identified that enables the import of heterologous RNAs in a PNPASE-dependent manner. Combined, our studies show an unanticipated role for PNPASE in mediating the translocation of RNAs into mitochondria and provide a potential therapeutic route for halting or reversing the decline in mitochondrial function with aging.

In short, the researchers have found a mechanism that can be hijacked in order to import RNA into the mitochondria as desired.

Here is more evidence for modest benefits derived from common forms of minimal intermittent fasting, though as is often the case one may suspect that other associations with lifestyle choices cloud the picture: "Previously we discovered that routine periodic fasting was associated with a lower prevalence of coronary artery disease (CAD). Other studies have shown that fasting increases longevity in animals. A hypothesis-generating analysis suggested that fasting may also associate with diabetes. This study prospectively tested whether routine periodic fasting is associated with diabetes mellitus (DM). Patients (n = 200) undergoing coronary angiography were surveyed for routine fasting behavior before their procedure. ... Meta-analyses were performed by evaluation of these patients and 448 patients from a previous study. DM was present in 10.3% of patients who fasted routinely and 22.0% of those who do not fast. CAD was found in 63.2% of fasting and 75.0% of nonfasting patients, and in nondiabetics this CAD association was similar. Meta-analysis showed modest differences for fasters versus nonfasters in glucose concentrations (108 ± 36 vs 115 ± 46 mg/dl) and BMI (27.9 ± 5.3 vs 29.0 ± 5.8 kg/m(2)). In conclusion, prospective hypothesis testing showed that routine periodic fasting was associated with a lower prevalence of DM in patients undergoing coronary angiography. A reported fasting association with a lower CAD risk was also validated and fasting associations with lower glucose and BMI were found."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22425331

Another promising form of immunotherapy in mice: "researchers have trained mouse immune systems to eradicate skin cancer from within, using a genetic combination of human DNA from melanoma cells and a cousin of the rabies virus. The strategy, called cancer immunotherapy, uses a genetically engineered version of the vesicular stomatitis virus to deliver a broad spectrum of genes derived from melanoma cancer cells directly into tumors. In early studies, 60 percent of tumor-burdened mice were cured in fewer than three months and with minimal side effects. ... We believe that this new technique will help us to identify a whole new set of genes that encode antigens that are important in stimulating the immune system to reject cancer. In particular, we have seen that several proteins need to be expressed together to generate the most effective rejection of the tumors in mice. ... The immune system functions on a seek-and-destroy platform and has fine-tuned its capacity to identify viral invaders such as vesicular stomatitis virus. Part of the appeal of building cancer vaccines from the whole spectrum of tumor DNA is that tumors can adapt to the repeated attacks of a healthy immune system and display fewer antigens (or signposts) that the immune system can identify. Cancers can learn to hide from a normal immune system, but appear unable to escape an immune system trained by the vesicular stomatitis virus with the wide range of DNA used in the library approach. ... Nobody knows how many antigens the immune system can really see on tumor cells. By expressing all of these proteins in highly immunogenic viruses, we increased their visibility to the immune system. The immune system now thinks it is being invaded by the viruses, which are expressing cancer-related antigens that should be eliminated."

Link: http://www.eurekalert.org/pub_releases/2012-03/mc-mcr031912.php

Amongst the figures of the aging research community - which is pretty much still so small that everyone knows everyone else - there is one fairly prolific author of papers who argues that the mTOR gene is a major regulator of aging. This is an example of someone who sees aging as largely programmed rather than the result of stochastic damage at the level of cells and cellular protein machinery. I think that those folk have a tall hill to climb in order to make their case, based on present evidence, and this particular mTOR specialist might be seeing nails everywhere when the tool to hand is a hammer. But intelligent people can differ, and an important part of reading the scientific literature is to understand that there are ongoing and important differences of opinion under the hood - points are being argued, and most of those positions will ultimately be shown to be incorrect in some way, shape, or form.

In this open access paper, the fellow outlines his view of cellular senescence and how it emerges from a cell that has entered cell cycle arrest due to failing its checkpoints. You'll recall that cellular senescence is the fate awaiting old cells that someone are not removed - either by destroying themselves or being destroyed by the immune system. They are damaging to surrounding tissue and contribute to degenerative aging; their numbers grow rapidly in advanced age, probably due to decline in other systems and a rising level of damage in the body. The paper quoted below is educational and well worth reading, while bearing in mind that the overall case that he makes with regard to mTOR and programmed aging seems weak on the face of it.

Cell cycle arrest is not yet senescence. When the cell cycle is arrested, an inappropriate growth-promotion converts an arrest into senescence (geroconversion). ... As discussed in the article, cell cycle arrest is not yet senescence and senescence is not just arrest: senescence can be driven by growth-promoting pathways such as mTOR, when actual growth is impossible. ... This mechanism connects cellular senescence, organismal aging and age-related diseases.

...

You might notice that an accumulation of molecular damage was never mentioned in this article. It was unneeded. Cellular aging and geroconversion is not caused by accumulation of random molecular damage. Although damage accumulates, I suggest that the organism does not live long enough to suffer from this accumulation

...

One definition of organismal aging is an increase in the probability of death. Gerogenic cells (due to their hyper-activity and signal-resistance) may slowly cause atherosclerosis, hypertension, insulin-resistance, obesity, cancer, neurodegeneration, age-related macular degeneration, prostate enlargement, menopause, hair loss, osteoporosis, osteoarthritis, benign tumors and skin alterations. These conditions lead to damage - not molecular damage but organ and system damage. Examples include beta-cell failure, ovarian failure (menopause), myocardial infarction, stroke, renal failure, broken hips, cancer metastases and so on. These are acute catastrophes, which cause death. I suggest that by suppressing geroconversion, gerosuppressants will prevent diseases and extend healthy life span.

The part that stands out to me is this:

Cellular aging and geroconversion is not caused by accumulation of random molecular damage.

That is a claim that I think is already readily refuted by the available evidence. But don't let that stop you reading the paper; it's an interesting view on the accumulation of senescent cells, which are demonstrated to be an important factor in aging and worthy of more research attention - they do in fact contribute to the long list of conditions provided by the author above, and more besides.

If you read the whole thing, this outsider's view of cryonics at CMAJ illustrates a few of the subtle prejudices held in the medical and scientific community in the course of trying to be objective: "cryonics - the practice of preserving a legally dead person at a temperature far below freezing in hopes of someday being revived and rejuvenated after advances in science have provided a cure for their ailment. The appeal is self-evident, enthusiasts say. 'It certainly offers an opportunity, although remote and probably speculative, as an ambulance to the future so to speak. If I die from something that is not preventable today, maybe future technology will offer the means of reviving me, figuring out the condition I have and fixing it.' Yet, however appealing the notion of a second life may be, the number of people who've actually been frozen is miniscule: about 250, according to the Cryonics Institute, a cryonics services provider located in a regional township of the state of Michigan. ... But far more people appear interested in being frozen. Membership in the two biggest cryonics providers in the United States - the Cryonics Institute and the Alcor Life Extension Foundation in Scottsdale, Arizona - is close to 2000. ... The cryonics process involves draining a patient's fluids and replacing them with a vitrification solution, essentially a preservative cocktail of cryoprotectant chemicals such as dimethylsulfoxide, ethylene glycol, propylene glycol and glycerol that are believed to prevent ice crystal formation and reduce the extent of tissue damage that occurs after flesh is frozen. The corpse is allowed to cool and then dropped into liquid nitrogen for indefinite preservation at a brisk -196°C. Or as Ben Best, president of the Cryonics Institute, writes in an email 'the perfusion process involves replacing body water in cells, not just blood in the blood stream. By perfusing vitrification solution into the blood stream, there is an exchange of vitrification solution for water. Water is removed from the body (and tissues) as vitrification solution replaces it by the diffusion process. With vitrification solution in brain tissue (especially) there should be no ice formation whatsoever. The flesh is therefore vitrified, not frozen (freezing means ice). The patient is cooled under a computer controlled cooling box to liquid nitrogen temperature, not simply 'dropped' in liquid nitrogen.'"

Link: http://www.cmaj.ca/site/earlyreleases/19mar12_spending-eternity-in-liquid-nitrogen.xhtml

The SENS Foundation here comments on recent research that may make it easier to build therapies to treat mitochondrial DNA damage in order to remove its contribution to aging: "The UCLA group's approach is highly promising. Their work builds upon and may potentially supersede several previous approaches to the problem of mitochondrial mutations that occur as a result of the degenerative aging process, including allotopic protein expression, its optimization using [a mitochondrial targeting sequence], and the exploitation of the multiprotein RNA import complex (RIC) of the protozoal parasite Leishmania tropica (which the investigators characterize as 'requir[ing] the introduction of nonnative tRNAs with foreign protein factors or the transfer of a large multisubunit aggregate into cells, which is of low efficiency and difficult to reproduce in desirable disease-relevant settings' ... As compared to allotopic protein expression, an RNA-based approach has the theoretical advantage of abrogating the difficulties encountered thus far with the mitochondrial import of large and hydrophobic proteins. But as we suggested in discussion of their earlier, more discovery-phase research, allotopic protein and RNA approaches are not mutually exclusive: different mitochondrially-encoded proteins could be either allotopically expressed, or their mRNAs generated allopically and imported for in situ translation, depending on the ease or efficiency of each approach for the protein in question. ... For their part, Dr. Teitell's group is evidently optimistic, and have clearly moved beyond the basic science focus of their earlier report. ... In response to this report, SENS Foundation CSO Dr. Aubrey de Grey has said that 'If this is as good as it looks, I think it could be a real game-changer', and Dr. O'Connor and his team at the SENS Foundation RC are considering testing a construct based on Teitell's methods in a system that the RC has already generated and used for testing of allotopic expression of cytochrome B. The race is on -- as it should be, for the stakes are large. Large, age-related deletions in mtDNA are likely responsible for the systemic rise in oxidative stress with aging, and for localized but terrible pathologies of skeletal muscle and substantia nigra dopaminergic neurons in aging bodies. The obviation of these mutations is a desperate medical need, and biomedicine is shamed for every day that a solution is delayed. This new method must be tested and exploited to its limits, and all approaches must be trialed, until the fires of life are once again burning in rejuvenated cells, in bodies restored to their youthful prime."

Link: http://www.sens.org/node/2682

Stem cell populations in the body live in stem cell niches, each different type of stem cell with its own niche. The niche supplies the necessary environment and many of the cues that direct stem cell activity, and this is why changes in the niche are possibly more important than changes in stem cells themselves when it comes to the decline of stem cell activity with aging. That decline causes a sort of corrosion of your tissues as stem cells increasingly fail to keep up with maintenance and repair - but the evidence to date suggests that those stem cells are generally still capable of doing their jobs, provided they are given their marching orders:

Surprisingly, this age-related decline in stem cell potency may be somewhat reversible. A team of Howard Hughes Medical Institute (HHMI) researchers has found that in old mice, a several-week exposure to the blood of young mice causes their bone marrow stem cells to act "young" again. ... The researchers have not yet isolated the blood-borne factors that can switch old stem cells back to a more youthful state, but their results are consistent with other recent studies that show stem-cell aging may be reversible.

Thus we have to look at the aging of stem cells in the context of the niche and the rest of the body, and we have to look at regenerative medicine for the old in a holistic way. While throwing stem cells at every problem seems to be fairly beneficial, based on the successes to date in first generation stem cell transplant therapies, it isn't enough in and of itself. Putting good stem cells into an age-damaged environment is not using them to their best effect.

But this all comes back to the question of just what a stem cell niche is anyway, and why the changes of aging change the way in which stem cells act within the body. Here is a good open access paper that provides an introduction to the niche and its importance, with some examples of various different stem cell and niche types throughout the body:

What does the concept of the stem cell niche really mean today?

Ideas about stem cells, and how they behave, have been undergoing a lot of change in recent years, thanks to developments in visualizing, monitoring, and manipulating cells and tissues. ... the detailed mechanisms underlying niche function are extremely varied. Niches may be composed of cells, or cells together with extracellular structures such as the extracellular matrix (ECM). They may be sources of secreted or cell surface factors [that] control stem cell renewal, maintenance, or survival. They may consist of just a single cell type, or a whole host of interacting cells. They may derive from cells outside the stem cell's lineage, or they may derive primarily from the stem cell's own descendents. In general, there seems to be much more consensus about the fact that stem cells invariably need niches than about the specific mechanisms by which niches do their jobs.

Why should a stem cell need a special environment? This is a pertinent question, given that none of the elementary processes that stem cells rely upon - growing, dividing, differentiating - are unique to stem cells. We can easily imagine three classes of answers:

One possibility is that there are demands placed on stem cells that necessitate special support for viability. For example, the need, imposed by cellular immortality, to minimize the accumulation of genetic damage, may drive stem cells to adopt a peculiar metabolic state that might force them to rely upon other cells nearby for sustenance. This 'nutritive' function of the niche remains a formal possibility, but in most systems few experimental data in support of it have so far emerged.

A second possibility is that niches are agents of feedback control. Recent studies tell us that stem cell pools are not slavishly maintained at a constant size by fixed, asymmetric divisions, but are usually capable of expanding or contracting and, even under homeostatic conditions, may face large stochastic fluctuations. The varied growth factors and cell surface molecules produced by niche cells may share the common goal of controlling stem cell pools. If this is the case, then the niche might best be thought of not simply as an environment conducive to stem cell functioning, but as an apparatus for communicating information about the state of a tissue back to the stem cells that maintain it. An important question to address would then be how niches obtain and relay such information.

A third possibility is that niches are instruments of coordination among tissue compartments. Some of the best evidence for this view comes from work on the hair follicle niche ... There, stem and progenitor cells responsible for maintenance of epidermis, pigmentation, hair, and connective and adipose tissue all interact in close proximity. A need to achieve tight coordination among these different cell populations may be the overriding reason for complex organization of this niche. The possibility that other niches may also be hubs of inter-lineage coordination is certainly an idea worth investigating.

The best case scenario for the future is that enacting the Strategies for Engineered Negligible Senescence to repair the known forms of cellular and molecular damage that occur with aging will cause stem cell niches to largely take care of themselves. In other words, under this scenario it turns out that the second possibility outlined in the quote above is the principal role for niches, and thus repairing the biological damage of aging in the body will cause the command and control mechanisms for stem cell populations to return to a youthful state.

Damaged mitochondria cause problems because their electron transport chains, the core mechanism by which they generate power for the cell, stop working the right way. That leads to a situation in which sub-par mitochondria in a cell are not recycled despite being damaged, and since they replicate like bacteria the bad mitochondria take over the cell. It goes downhill from there, and this whole process is one of the fundamental causes of aging. Ways of addressing this situation include repairing the mitochondria directly or working around their damage by creating replacements for the damaged parts of mitochondrial protein machinery elsewhere in the cell. Here is another line of research that looks at trying to minimize the consequences of that damaged machinery by providing substitute components, but with a different focus: "Mitochondrial dysfunction (primary or secondary) is detrimental to intermediary metabolism. Therapeutic strategies to treat/prevent mitochondrial dysfunction could be valuable for managing metabolic and age-related disorders. Here, we review strategies proposed to treat mitochondrial impairment. We then concentrate on redox-active agents, with mild-redox potential, who shuttle electrons among specific cytosolic or mitochondrial redox-centers. We propose that specific redox agents with mild redox potential improve mitochondrial function because they can readily donate or accept electrons in biological systems, thus they enhance metabolic activity and prevent reactive oxygen species (ROS) production. These agents are likely to lack toxic effects because they lack the risk of inhibiting electron transfer in redox centers. ... This view has been demonstrated by testing the effect of several redox active agents on cellular senescence. Methylene blue (MB) appears to readily cycle between the oxidized and reduced forms using specific mitochondrial and cytosolic redox centers. MB is most effective in delaying cell senescence and enhancing mitochondrial function in vivo and in vitro. Mild-redox agents can alter the biochemical activity of specific mitochondrial components, which then in response alters the expression of nuclear and mitochondrial genes. We present the concept of mitochondrial electron-carrier bypass as a potential result of mild-redox agents, a method to prevent ROS production, improve mitochondrial function, and delay cellular aging. Thus, mild-redox agents may prevent/delay mitochondria-driven disorders."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22419586

Just as physical exercise is beneficial, so too is exercising the mind. This open access paper examines structured mental exercise as a basis for therapy that might do at least some good for neurodegenerative disease patients: "Non-pharmacological intervention of memory difficulties in healthy older adults, as well as those with brain damage and neurodegenerative disorders, has gained much attention in recent years. The two main reasons that explain this growing interest in memory rehabilitation are the limited efficacy of current drug therapies and the plasticity of the human central nervous system and the discovery that during aging, the connections in the brain are not fixed but retain the capacity to change with learning. Moreover, several studies have reported enhanced cognitive performance in patients with neurological disease, following non-invasive brain stimulation [i.e., repetitive transcranial magnetic stimulation and transcranial direct current stimulation to specific cortical areas]. The present review provides an overview of memory rehabilitation in individuals with mild cognitive impairment and in patients with Alzheimer's disease with particular regard to cognitive rehabilitation interventions focused on memory and non-invasive brain stimulation. Reviewed data suggest that in patients with memory deficits, memory intervention therapy could lead to performance improvements in memory, nevertheless further studies need to be conducted in order to establish the real value of this approach."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297818/

The industry that provides antioxidant supplements to the world has tremendous inertia: enormous income and a very loud voice, and thus little incentive to react to advances in scientific knowledge that might reduce that revenue stream if acted upon. So despite the scientific consensus that ingested antioxidants are not in fact wonderful for your health, and may even be modestly harmful over the long term, the larger players in the industry continue onward as though it's still 1992 outside their offices.

On the other side of the fence, the public at large keeps buying the products as though it's still 1992, just as blithely ignoring what the scientific community has to say on the matter. Everyone wants that silver bullet to be available now rather than tomorrow, and wants it badly enough to buy lead painted up to a nice sheen if that's all there is. All in all it's a good reminder that any institutional knowledge or common wisdom is likely to be a decade or two out of date - it takes time for information to percolate, even in this age of instant electronic overcommunication. There is seemingly so much that everyone has to say, day in and day out, and yet the important data still takes years to get from point A to point B.

Here is a good open access paper on antioxidants and just how far removed from reality the common wisdom is these days. I imagine it will take a few more years of authoring similar review papers for the point to start to sink in:

Antioxidants are assumed to provide numerous benefits, including better health, a reduced rate of aging, and improved exercise performance. Specifically, antioxidants are commonly "prescribed" by the media, supplement industry, and "fitness experts" for individuals prior to training and performance, with assumed benefits of improved fatigue resistance and recovery. This has provoked expansion of the supplement industry which responded by creation of a plethora of products aimed at facilitating the needs of the active individual. However, what does the experimental evidence say about the efficacy of antioxidants on skeletal muscle function? Are antioxidants actually as beneficial as the general populous believes? Or, could they in fact lead to deleterious effects on skeletal muscle function and performance?

...

Experimental evidence does not support the "common knowledge" that antioxidant treatment greatly improves exercise performance and recovery. On the contrary, studies with antioxidant supplementations generally show no effect on muscle function during and after exercise.

Less fat tissue is unambiguously good for you over the long term, and one side effect of calorie restriction is the loss of excess fat tissue - but that is only a side effect. More interesting stuff is going on at the level of cells and their mechanisms: "Caloric restriction (CR) slows the aging process and extends longevity, but the exact underlying mechanisms remain debatable. It has recently been suggested that the beneficial action of CR may be mediated in part by adipose tissue remodeling. Mammals have two types of adipose tissue: white adipose tissue (WAT) and brown adipose tissue (BAT). In this study, proteome analysis [was] performed on both WAT and BAT from nine month old male rats fed ad libitum or subjected to CR for six months. Our findings suggest that CR activates mitochondrial energy metabolism and fatty acid biosynthesis in WAT. It is likely that in CR animals WAT functions as an energy transducer from glucose to energy-dense lipid. In contrast, in BAT CR either had no effect on, or down-regulated, the mitochondrial electron transport chain, but enhanced fatty acid biosynthesis. This suggests that in CR animals BAT may change its function from an energy consuming system to an energy reservoir system. Based on our findings, we conclude that WAT and BAT cooperate to use energy effectively via a differential response of mitochondrial function to CR." It is worth noting that there are other signs that the biochemistry of fat tissue, and its effects on health, can be dramatically altered - see the research on fat in GHRKO mice, for example.

Link: http://www.ncbi.nlm.nih.gov/pubmed/22414572

One of the underlying mechanisms by which the advanced glycation endproducts (AGEs) that build up with age cause harm is through hammering on the receptor for AGEs, or RAGE. Some Alzheimer's researchers are looking into targeting RAGE in order to remove the contribution of AGEs to that condition, and it is possible that the results of their work may have more general application to AGEs in aging - though the best possible strategy would be to remove the AGEs rather than work around them: "Researchers have taken another crack at a promising approach to stopping Alzheimer's disease that encountered a major hurdle last year. ... scientists have developed a compound that targets a molecular actor known as RAGE, which plays a central role in mucking up the brain tissue of people with the disease. Scientists [synthesized] a compound that stops RAGE in mice - reversing amyloid deposits, restoring healthy blood flow in the brain, squelching inflammation, and making old, sick mice smarter. But the scientists caution that the work has a long way to go before it's considered as a possible treatment in people. ... A phase 2 study in 399 people of another compound designed to stop RAGE - which stands for Receptor for Advanced Glycation Endproducts - was halted prematurely in November when scientists had questions about the compound's safety at high doses, and after early results indicated that the compound was not helping patients with Alzheimer's disease. ... The benefits of blocking RAGE are even greater than has been realized. RAGE is central to many mechanisms that wreak havoc in the brains of people with Alzheimer's disease. It turns out that when you inhibit RAGE, you block molecules central to creating inflammation in the brain, and that is a major problem with Alzheimer's disease."

Link: http://www.urmc.rochester.edu/news/story/index.cfm?id=3440

A billion people will die between now and the earliest plausible date for the first package of rough and ready but working rejuvenation therapies - say twenty years from now. Another few decades will pass for the technology to work its way out to global availability at low cost, and the deaths by aging will continue in less fortunate regions while this happens. Even after aging is completely conquered, there will be an ongoing toll of death due to accidents and whatever passes for disease in the age of medical nanotechnology. Death isn't going away completely for we biological folk, no matter how well we do in the field of medicine in the foreseeable future: medicine can't wave away falling rocks.

Thus will always be a role for what we might term post-mortem critical care: technologies and services to preserve the fine structure of the brain and the mind it contains following death, and keep them preserved until such time as that patient can be restored to life. At present the only post-mortem critical care option is cryonics, with what looks like a fair few years to wait for technology to advance to the point of restoration, and thus an unknown chance of eventual success for any individual - but a significantly greater chance than is offered by the grave, of course. In contrast, in a future in which the technology to restore a preserved person exists, cryonics and other preservation technologies like plastination will occupy a more dynamic position in the medical toolkit, and patients might expect to wait in a preserved state only for transport to the nearest major population center.

At last year's SENS5 conference, Max More, CEO of cryonics company Alcor, gave this presentation on the future of his industry:

Cryonics involves the cryopreservation of humans as soon as possible after legal and clinical "death". Legal and clinical death differ importantly from biological death or true (irreversible) cessation of function. It is therefore a mistake to portray cryonics as an alternative to cremation or burial. It is true that cryopreserved people are not alive but neither are they dead. Cryonics should be seen as part of the field of life extension. Cryonics enables the transport of critically ill people through time in an unchanging state to a time when more advanced medical and repair technologies are available. Even after "longevity escape velocity" has been attained and aging has been largely tamed, cryonics will continue to be needed for people who die of accidents or diseases for which there is no cure at the time.

Here is a study claiming a noticeable impact on mortality rates from eating red meat. Weight is considered to some degree via body mass index, but I have to wonder if this only reflects a modest association of red meat consumption with other, less healthy lifestyle choices rather than an actual red-meat-based mechanism - as an obvious candidate mechanism for that isn't also present in all meat consumption isn't springing to mind: researchers "found that red meat consumption is associated with an increased risk of total, cardiovascular, and cancer mortality. The results also showed that substituting other healthy protein sources, such as fish, poultry, nuts, and legumes, was associated with a lower risk of mortality. ... [Researchers] observed 37,698 men from the Health Professionals Follow-up Study for up to 22 years and 83,644 women in the Nurses' Health Study for up to 28 years who were free of cardiovascular disease (CVD) and cancer at baseline. Diets were assessed through questionnaires every four years. ... One daily serving of unprocessed red meat (about the size of a deck of cards) was associated with a 13% increased risk of mortality, and one daily serving of processed red meat (one hot dog or two slices of bacon) was associated with a 20% increased risk. ... These analyses took into account chronic disease risk factors such as age, body mass index, physical activity, family history of heart disease, or major cancers. ... Replacing one serving of total red meat with one serving of a healthy protein source was associated with a lower mortality risk: 7% for fish, 14% for poultry, 19% for nuts, 10% for legumes, 10% for low-fat dairy products, and 14% for whole grains. The researchers estimated that 9.3% of deaths in men and 7.6% in women could have been prevented at the end of the follow-up if all the participants had consumed less than 0.5 servings per day of red meat."

Link: http://www.sciencedaily.com/releases/2012/03/120312162746.htm

Via ScienceDaily: researchers "have made early retina structures containing proliferating neuroretinal progenitor cells using induced pluripotent stem (iPS) cells derived from human blood. And in another advance, the retina structures showed the capacity to form layers of cells - as the retina does in normal human development - and these cells possessed the machinery that could allow them to communicate information. ... Put together, these findings suggest that it is possible to assemble human retinal cells into more complex retinal tissues, all starting from a routine patient blood sample. Many applications of laboratory-built human retinal tissues can be envisioned, including using them to test drugs and study degenerative diseases of the retina such as retinitis pigmentosa, a prominent cause of blindness in children and young adults. One day, it may also be possible replace multiple layers of the retina in order to help patients with more widespread retinal damage. ... We don't know how far this technology will take us, but the fact that we are able to grow a rudimentary retina structure from a patient's blood cells is encouraging, not only because it confirms our earlier work using human skin cells, but also because blood as a starting source is convenient to obtain."

Link: http://www.sciencedaily.com/releases/2012/03/120313185232.htm

This is an era of data in the sciences - endless, vast stores of data, with more pouring in constantly from new studies. In most fields the infrastructure to manage that data is still under construction; in the life sciences, for example, the rapid advance of bioinformatics and biotechnology in general has outpaced the strategies for data management. The data infrastructure is lacking, even as it is being built up rapidly. This has consequences on the efficiency of research and the speed of progress, but researchers are not blind to this present state of affairs.

Here, for example, Maria Konovalenko of the Science for Life Extension Foundation presents at last year's SENS5 conference, calling for better and more systematic management of data in longevity research initiatives - which is effectively a form of advocacy for lowering the cost of exchange of information between research groups.

Traditionally evaluation of age-related changes is performed by physiological, functional and psychological tests, by visual examination and some biochemical analyses. There is a big gap between the molecular data of aging and their implementation in practice mainly because aging data is scarce and it gets lost in the stream of bio-medical knowledge. As we know only a few databases exist that concern the molecular aspects of aging and none of them describes age-related changes and phenotype context like cell type or tissues.

We propose creation of an open web-based Integrated Information System on Aging Biomarkers. The goals of the System: 1. Systematization of data on age-related changes happening on various levels of organization in humans and model animals 2. Systematization of experimantal data on interventions in aging processes in model animals 3. Integration of clinical data on the impact of various interventions on aging processes in patients 4. Creation of a basis for modeling of aging processes, therapeutic interventions and their impact on patients' health and longevity

When development of life extending therapies begins in any earnest way (as opposed the present expensive dabbling with metabolic manipulation to slightly slow aging), it will be necessary to start keeping score and measuring well. Even before then, and as I pointed out above, there is more data than can easily be made useful at this time - that has to change in order to build a better foundation for the next generation of research projects.

Studies of correlations between longevity, mortality, and specific single nucleotide polymorphisms (SNPs) in humans are becoming more common, but as this one demonstrates they reinforce just how complicated the genetics of metabolism and longevity are. There are many, many correlations with small effects, the majority of which are different in different human populations: "Here we explore association with human longevity of common genetic variation in three major candidate pathways: GH/IGF-1/insulin signaling, DNA damage signaling and repair and pro/antioxidants by investigating 1273 tagging SNPs in 148 genes composing these pathways. In a case-control study of 1089 oldest-old (age 92-93) and 736 middle-aged Danes we found 1 pro/antioxidant SNP, 5 GH/IGF-1/INS SNPs, and 5 DNA repair SNPs to be associated with longevity after correction for multiple testing. In a longitudinal study with 11years of follow-up on survival in the oldest-old Danes we found 2 pro/antioxidant SNPs, 1 GH/IGF-1/INS SNP and 3 DNA repair SNPs to be associated with mortality in late life after correction for multiple testing. ... No formal replications were observed when investigating the 11 SNPs from the case-control study in 1613 oldest-old (age 95-110) and 1104 middle-aged Germans. ... In conclusion, the present candidate gene based association study, the largest to date applying a pathway approach, not only points to potential new longevity loci, but also underlines the difficulties of replicating association findings in independent study populations and thus the difficulties in identifying universal longevity polymorphisms."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22406557

A therapy that can robustly correct any mitochondrial DNA mutation throughout the body can be turned into a way to rejuvenate the stochastic damage of aging that occurs to the thirteen important mitochondrial genes not replicated in the cell nucleus. If asked to wager, based on the evidence I'd suggest that mitochondrial damage is the largest individual contribution to aging, which is why it's important to see progress on fixing it or making it irrelevant. So this, I think, is a development worth watching: "Researchers [have] identified, for the first time, a generic way to correct mutations in human mitochondrial DNA by targeting corrective RNAs ... I think this is a finding that could change the field. We've been looking to do this for a long time and we had a very reasoned approach, but some key steps were missing. Now we have developed this method and the next step is to show that what we can do in human cell lines with mutant mitochondria can translate into animal models and, ultimately, into humans. ... Gene therapy is often used to express proteins that can treat the cause of a variety of diseases. In this case, [researchers] developed a strategy to target and import specific RNA molecules encoded in the nucleus into the mitochondria and, once there, to express proteins needed to repair mitochondrial gene mutations. First, the research team had to figure out a way to stabilize the reparative RNA so that it was transported out of the nucleus and then localized to the mitochondrial outer membrane. This was accomplished by engineering an export sequence to direct the RNA to the mitochondrion. Once the RNA was in the vicinity of the transport machinery on the mitochondrial surface, then a second transport sequence was required to direct the RNA into the targeted organelle. With these two modifications, a broad spectrum of RNAs were targeted to and imported into the mitochondria, where they functioned to repair defects in mitochondrial respiration and energy production in two different cell line models of human mitochondrial disease. ... This study indicates that a wide range of RNAs can be targeted to mitochondria by appending a targeting sequence with or without a mitochondrial localization sequence, to provide an exciting, general approach for overcoming mitochondrial genetic disorders."

Link: http://www.sciencedaily.com/releases/2012/03/120312152645.htm

The Brain Preservation Foundation, a group with very sensible goals, runs a technology prize:

The nonprofit Brain Preservation Foundation (BPF) hereby officially announces a cash prize for the first individual or team to rigorously demonstrate a surgical technique capable of inexpensively and completely preserving an entire human brain for long-term (>100 years) storage with such fidelity that the structure of every neuronal process and every synaptic connection remains intact and traceable using today's electron microscopic (EM) imaging techniques.

As regular readers will know, the data of the mind is encoded in the fine structure of the brain. If we could find a low cost way of preserving the brain - and the mind it contains - then people could opt for preservation with the hope of later restoration to life through the far more advanced technology that will emerge in the decades ahead. As a vision it beats the grave, rot, and certain oblivion, and I've argued that we are barbarians for not putting far more effort into preventing the tens of millions of permanent deaths each and every year.

The two current competitors for the BPF technology prize, cryonics spin-off technology company 21st Century Medicine and collaborating scientists in the Max Planck Institute and other research centers, recently put out updates on their progress. You can see images of preserved brain tissue at the BPF website, created with the quite different technologies used by the two teams:

Our first team, led by Shawn Mikula (working in the laboratory of Winfried Denk at the Max Planck Institute in Heidelberg), has developed a whole mouse brain chemical preservation and plastic embedding technique. ... As part of the Brain Preservation Technology Prize competition, Dr. Mikula has agreed to demonstrate the quality of ultrastructure preservation which his protocol can achieve.

...

21st Century Medicine's main research has been focused on the cryopreservation of transplantable organs (kidney, heart) and toward decreasing the toxicity of the process to such organs. However, as part of the Brain Preservation Technology Prize competition, they have agreed to demonstrate the quality of ultrastructure preservation that their low temperature vitrification technique can achieve when applied to whole rabbit brains.

Here then are examples of the two most plausible avenues to long-term preservation of the mind's structure: plastination on the one hand and vitrification at low temperatures on the other. The latter is practiced by present day cryonics providers, as the cryonics community has always focused on low temperature storage, but this is something of a historical accident, I think. Future competitors to the present day cryonics industry may well employ plastination techniques - and competition is always good, as it generates progress and better service.

A lot of people are going to run out of time even under the best case scenarios for the development of rejuvenation biotechnologies capable of reversing aging. A billion lives every twenty years, give or take, a staggering number. But they don't have to die, permanently and irrevocably - suffering what is known as information theoretic death. For so long as the mind is successfully preserved, a person can wait for the molecular nanotechnologies and other advanced medical technologies of the future to be developed and used: that person has a chance at a life in the future, and that is far more than can be said for those who have gone to the grave.

We lose the dead forever today because too few people care enough to do something about it, to build an industry capable of offering preservations at a cost comparable to funerary services. A great deal of growth lies between today's cryonics community and a world-spanning competitive industry that can place tens of millions of people into storage every year, however, and it is to our collective shame that such a thing seems very implausible at this time.

Heat shock proteins (HSPs) are important in cellular housekeeping, the processes of removing and repairing damage - and given how important these processes are to longevity, it's no surprise that we see associations between HSP levels and longevity. Researchers have been investigating how to build therapies based on boosting HSPs in recent years, but here is a different point of view: research to show that insulin resistance reduces HSP levels, which may be another one of the ways in which being fat and sedentary enough to become insulin resistant harms your health: "Heat shock protein (HSP)70 decreases with age. Often aging is associated with coincident insulin resistance and higher blood glucose levels, which also associate with lower HSP70. We aimed to understand how these factors interrelate through a series of experiments using vervet monkeys (Chlorocebus aethiops sabaeous). Monkeys fed low-fat diets showed no association of muscle HSP70 with age, but levels were highly heritable. Insulin resistance was induced in vervet monkeys with high-fat diets, and muscle biopsies were taken after 0.3 or 6 years. HSP70 levels were significantly greater after 0.3 years but were significantly lower following 6 years of high-fat diet. Associations with glucose also switched from being positive to strikingly negative with increasing insulin resistance. In conclusion, a low-fat diet may preserve tissue HSP70 and health with aging, whereas high-fat diets, insulin resistance, and genetic factors may be more important than age for determining HSP70 levels." Which is good news for those folk who make an effort to maintain health and fitness into old age, as insulin resistance and weight gain are avoidable consequences of lifestyle for the vast majority of people.

Link: http://www.ncbi.nlm.nih.gov/pubmed/22403054

Mice with the myostatin gene removed grow more muscle, and researchers have been looking into therapies for muscle wasting based on this mechanism for a number of years. Here is another confirmation that myostatin is involved in age-related changes in muscle mass and strength via its effect on stem cells: "Human aging is accompanied by a progressive loss of muscle mass (sarcopenia). We tested the hypothesis that older males (OMs, 70±4 yr, n=9) would have a blunted myogenic response to a physiological stimulus compared to younger controls (21±3 yr, n=9). Subjects completed an acute bout of intense unilateral muscle loading. Young healthy males matched for body mass and activity level served as the control group. Muscle biopsies and blood were obtained before and at 3, 24, and 48 h after muscle loading. The muscle stem cell response was analyzed ... OMs had 35% fewer basal stem cells and a type II fiber-specific impairment in stem cell content and proliferation. Myogenic determination factor staining and cell cycle analysis illustrated a severely blunted progression through the myogenic program. Myostatin protein and mRNA were 2-fold higher in OMs. Stem cell-specific myostatin levels were not different at baseline; however, there were 67% more myostatin-positive type II-associated stem cells in OMs at 24 h. These data illustrate an age-related impairment of stem cell function in a fiber type-specific manner. The greater colocalization of myostatin with stem cells provides a mechanism for the impaired myogenic capacity of aged muscle."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22403007

With advancing age - and accumulating damage - the immune system moves into a state wherein it is constantly roused and on alert, exacting a toll on the integrity of tissue and cells through its signaling and activity, but also ineffective at actually tackling pathogens, senescent cells, precancerous cells, and other things that should be destroyed. So you have constant chronic inflammation and all its downsides with none of the compensatory immune activity boost that comes with short-term inflammation in the young. Researchers have given the name "inflammaging" to this progressive and increasingly harmful disarray of the immune system, and you'll find a few introductions to inflammaging as a concept back in the Fight Aging! archives.

Below is an open access paper that gives an overview of inflammaging and how it relates to some of the forms of cellular damage that cause aging. In this paper, the researchers paint a picture of inflammaging derived from root causes that involve mitochondrial damage and progressive failure of autophagy to clear out that damage, two line items that have been examined a fair number of times here in the past - under the Strategies for Engineered Negligible Senescence (SENS) viewpoint these two are amongst the fundamental, root causes of aging.

Inflammaging: disturbed interplay between autophagy and inflammasomes

In 2000, Franceschi et al. coined the term "inflammaging" in order to refer to a low-grade pro-inflammatory status appearing during the aging process. They emphasized the role of macrophages as well as cellular stress and genetic factors in the generation of the inflammaging condition. In addition, they hypothesized that this inflammatory environment could predispose the organism to the development of several age-related diseases. During recent years, this scenario has been confirmed by a plethora of experimental evidence. ... Interestingly, the aging process is simultaneously accompanied by both the features accelerating inflammaging and the counteracting, so-called anti-inflammaging characteristics. It seems that the balance between these opposite forces controls the outcome of the aging process, either leading to frailty and degenerative diseases or a healthy old age and longevity.

...

The aging process is associated with a decline in autophagic capacity which impairs cellular housekeeping, leading to protein aggregation and accumulation of dysfunctional mitochondria which provoke reactive oxygen species (ROS) production and oxidative stress.

Recent studies have clearly indicated that the ROS production induced by damaged mitochondria can stimulate intracellular danger-sensing multiprotein platforms called inflammasomes. [As a result of inflammasome activity, signaling molecules called] cytokines provoke inflammatory responses and accelerate the aging process by inhibiting autophagy.

There has been some good progress in recent years in pulling things together in the big picture - and the more that we see the mechanisms of SENS featured, the better to my eyes. That ways lies increased support for rejuvenation biotechnology that will actually work to reverse aging, rather than the present mainstream course of aiming to slow down aging just a little sometime in next few decades.

The immune system falls apart with age in ways that are as much a matter of configuration as wear and tear - it is a machine in which the programming runs awry, leading it to do the wrong things at the wrong time, or just do nothing when it should be doing something. This activity leads to damage, which in turn accelerates aging: "Immune aging is associated with loss of critical immune functions, such as host protection from infection and malignancy. Unexpectedly, immunosenescence also renders the host susceptible to inflammation, which may translate into tissue-damaging disease as the senescent immune system loses its ability to maximize inflammatory protection while minimizing inflammatory injury. On the other hand, chronic inflammation associated with immune-mediated disease represents a profound stress factor for the immune system, affecting cellular turn-over, replication and exhaustion. Immune cell longevity is tightly connected to the functional integrity of telomeres which are regulated by cell multiplication, exposure to oxidative stress and DNA repair mechanisms. Lymphocytes are amongst the few cell types that can actively elongate telomeres through the action of telomerase. In patients with the autoimmune disease rheumatoid arthritis (RA), telomerase deficiency is associated with prematurity of immune aging. Patients with RA have other defects in DNA repair mechanisms, including the kinase Ataxia telangiectasia mutated (ATM), critically involved in the repair of DNA double strand breaks. ATM deficiency in RA shortens lymphocyte survival. Dynamics of telomeric length and structure are beginning to be understood and have distinct patterns in different autoimmune diseases, suggesting a multitude of molecular mechanisms defining the interface between chronic immune stimulation and progressive aging of the immune system."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22396899

Via EurekAlert!: "Alzheimer's disease is characterized by abnormal deposits in the brain of the protein Amyloid-ß, which induces the loss of connections between neurons, called synapses. Now, scientists [have] discovered that specific antibodies that block the function of a related protein, called Dkk1, are able to completely suppress the toxic effect of Amyloid-ß on synapses. ... Dkk1 is elevated in the brain biopsies of people with Alzheimer's disease but the significance of these findings was previously unknown. Scientists [have] found that Amyloid-ß causes the production of Dkk1, which in turn induces the dismantling of synapses (the connections between neurons) in the hippocampus, an area of the brain implicated in learning and memory. ... scientists conducted experiments to look at the progression of synapse disintegration of the hippocampus after exposure to Amyloid-ß, using brain slices from mice. They were able to monitor how many synapses survived in the presence of a specific antibody which targets Dkk1, compared to how many synapses were viable without the antibody. The results show that the neurons that were exposed to the antibody remained healthy, with no synaptic disintegration."

Link: http://www.eurekalert.org/pub_releases/2012-03/ucl-sdt030512.php

If you've been reading Fight Aging! for a while, you'll recall that I've discussed organized crowdsourcing of funding of life science research - and longevity science in particular - for a few years now. This is a concept whose time has come: the Internet is providing great transparency and insight into all fields of endeavor, the cost of biotechnology has fallen rapidly to the point at which graduate students and a few tens of thousands of dollars can accomplish meaningful novel research, and crowdsourcing is achieving critical mass in other markets.

So we have ventures like Kickstarter, which is making a name for itself in art, publishing, and manufacturing projects. That is an example of a successful marketplace, where workers and funders can come together to raise sums comparable to pre-angel investments in start up companies - but on their own terms, and usually far better terms.

If you can raise money for books, art projects, and widgets, why not for discrete life science research projects with determined goals? The LongeCity (previously the Immortality Institute) crowd have been trying this for some years, with a great deal of success considering the limited audience of this community in comparison to the audience available through Kickstarter. It is sad but true that far more people are brought to a state of excitedly opening their wallets for the development of an iPhone widget than for any sort of biotechnology project, even one that will contribute to the reversal of aging.

But regardless, the groundwork is laid - this is the time for growth in crowdsourced funding. For the scientific community, the remaining piece of the puzzle at this time would seem to be a viable first marketplace, some Kickstarter-for-science that captures an audience and replicates the success of Kickstarter in this field. Once that is done a single time, then the idea will be accepted by the public and many such ventures can blossom.

Today, I see a fairly professional offering is put forward as a contender: Petridish:

Petridish lets you fund promising research projects and join first hand in new discoveries. World famous researchers post projects and expeditions that need your help to get off the ground. Each project has a minimum threshold it must hit in pledges, or it will not be funded. Backers in successful projects join the team and get insider rewards such as: Early access to news about progress and findings, souvenirs from the field, acknowledgements in journals, naming rights for new discoveries, or the ability to join an expedition in person.

Crowdsourced funding is a tremendously powerful tool for minority research fields - such as the rejuvenation biotechnology of the SENS Foundation. This is true for exactly the same reasons that make it a powerful tool for indie publishers and other entities largely removed from the traditional funding sources in their industry. In fact, the history of the SENS Foundation and Methuselah Foundation has been one long crowdsourced funding effort, launched by the early interest of the transhumanist community and carried onward by a broader community of people who value longer lives enough to do something about it.

What an organization like Petridish can bring to the table, if successful, is a larger audience and a formalism of the crowdsourced funding process that enables it to proceed much more smoothly - and more successfully. There are economies of scale that emerge quite quickly if you want to break down your fundraising into ten small programs rather than one big one, but it takes something like a Petridish or a Kickstarter to make this work well.

I believe that the SENS Foundation folk should contact the Petridish folk and set something up: there is no shortage of discrete, interesting projects that the Foundation would like to undertake, and I think this would be an excellent test of the waters. This is the future of small to mid-sized project funding, both in the sciences and elsewhere: if you want enthusiastic, knowledgeable supporters, then you have to get them more involved in the nuts and bolts of your work - in the small victories and accomplishments that are the foundation of the bigger picture. This is the best way to do that.

You'll find some thoughts on incentives, politicians, and longevity science over at h+ Magazine. I don't agree with all of them, but then my views on the state as a millstone hung upon the neck of medical progress are known: "After finding out I was an economist, [Aubrey de Grey] effectively challenged me to work out what we should want politicians to do ... With over 150,000 people dying every day, I hope governments would respond to the animal experiments by accelerating our journey to [actuarial] escape velocity through massively increasing funding for longevity medical research, because the cost of dying this year goes way up if it causes you to just miss out on the chance to live long enough to live forever. But since a rational world would already make abolishing death a top priority, we can't count on politicians automatically doing this. Still (as I will explain at the end of this article) people will likely be made aware of any inevitable approach to escape velocity which should cause at least some voters to reward politicians who increase taxpayer support for medical research. ... Once we actually reach escape velocity, U.S. politicians would face enormous political pressure to make the necessary medical treatments available to all Americans, regardless of income. The U.S. government might well do this by limiting how much companies could charge for the needed medicines. Predicting this, pharmaceutical companies would have fewer incentives to develop the cures in the first place."

Link: http://hplusmagazine.com/2012/02/28/the-politics-of-medical-immortality/

Via EurekAlert!: "This paper reports the discovery of one of the first targeted drugs specifically developed to reverse fibrosis and regenerate the kidney. We're optimistic about the benefits, but the real proof will come from clinical testing. ... In the kidneys and other organs, fibrosis develops from normal repair mechanisms that do not stop. Scar tissue slowly builds up and replaces the working cells of the organ. In 2003, [researchers] reported that the destructive fibrosis in mice can be countered by the human protein BMP-7, originally named for its ability to spur bone growth. ... However, the large protein needs to be injected or surgically implanted and, therefore, is not useful for long-term treatment protocols. Probing deeper into the biology of the kidney, they identified the protein Alk3 [and] based on the details about the molecular interaction between the BMP protein and the ALK receptor, [scientists] developed a class of small functional peptides, including THR-123, which then underwent further testing. ... This receptor must be present for the new molecule to function ... Working through the receptor, the molecule suppressed inflammation, cell death and fibrosis formation, as well as reversing established fibrosis and allowing kidneys to regenerate functional cells ... Further experiments showed that the test drug worked even better in the mice when given in combination with ACE inhibitors, the anti-hypertensive drugs now considered a standard therapy for chronic kidney disease which work by targeting another molecular process. ... Targeting the receptor not only stops fibrosis, it removes established fibrosis, and it works in combination with an existing drug used in patients. The next step is to test this molecule in the clinic."

Link: http://www.eurekalert.org/pub_releases/2012-03/bidm-stk030712.php

The near future of organ transplants will become very varied, as a range of different viable types of technology are presently undergoing active development. A short list looks much like this:

• Incremental progress in old-style organ transplants, such as improving the donation system, allowing organs to be stored outside the body for longer periods of time, and so forth.
• Decellularization, in which a donor organ is stripped of cells, leaving only the scaffold of the extracellular matrix. The scaffold is repopulated from the patient's cells, removing the possibility of immune rejection and need for immunosuppressant drugs.
• Electromechanical and bioartificial organs, including hearts, lungs, and kidneys, continue to improve at a good pace. New types of small artificial organ are becoming possible thanks to advances in materials science.
• Creating organ tissue and scaffolds from scratch through a variety of methods, such as the 3-D printing pioneered by a number of groups.
• Xenotransplantation, the use of animal organs for human patients, is also becoming more viable as a near-term prospect.
• Lastly, there are the researchers who aim to rebuild damaged organs in situ through manipulation of stem cells and signaling processes in normal regeneration.

There will be a great deal of innovation and healthy competition over the next two decades before this larger cycle of technological progress in medicine settles down to a few mature and tried and tested ways of fixing broken and age-damaged organs in the body.

To add to the list of strategies, I noticed an article today on a possible middle path between old-style donor transplants (immunosuppressant drugs and all) and the near future of organs that are populated by the patient's own stem cells. It may be possible to use the knowledge acquired by stem cell researchers to date in order to minimize or completely remove the risk of immune rejection of a donor organ:

In a standard kidney transplant, the donor agrees to donate their kidney. In the approach being studied, the individual is asked to donate part of their immune system as well. The process begins about one month before the kidney transplant, when bone marrow stem cells are collected from the blood of the kidney donor using a process called apheresis. The donor cells are then sent to the University of Louisville to be processed, where researchers enrich for "facilitating cells" believed to help transplants succeed. During the same time period, the recipient undergoes pre-transplant "conditioning," which includes radiation and chemotherapy to suppress the bone marrow so the donor's stem cells have more space to grow in the recipient's body.

Once the facilitating cell-enriched stem cell product has been prepared, it is transported back to Northwestern, where the recipient undergoes a kidney transplant. The donor stem cells are then transplanted one day later and prompt stem cells to form in the marrow from which other specialized blood cells, like immune cells, develop. The goal is to create an environment where two bone marrow systems exist and function in one person. Following transplantation, the recipient takes anti-rejection drugs which are decreased over time with the goal to stop a year after the transplant.

...

Less than two years after her successful kidney transplant, 47-year-old mother and actress Lindsay Porter of Chicago, is living a life that most transplant recipients dream of - she is currently free of anti-rejection medications and says at times, she has to remind herself that she had a kidney transplant. ... Doctors are hopeful that Porter will not need immunosuppressive drugs long-term, given her progress thus far.

You might look on this as creating a form of engineered chimerism. We know that some animals and humans exist with, for example, multiple blood types and genetically distinct systems in their body as a result of the fusion of two zygotes in the womb. These individuals don't seem to suffer any great harm from being chimeric, which might be taken as a promising sign for the long-term prospects of this form of stem cell medicine.

Most known cancer suppression genes and mutations shorten life in laboratory mice, as they suppress the mechanisms of cell replication needed to maintain tissues. There are exceptions that have emerged as researchers find more sophisticated methods of genetic engineering to work around these limitations, but this life-extending example of gene engineering seems to be more straightforward than most: "Mice with an extra dose of a known anti-cancer gene lose weight even as their appetites grow. Not only that, but [the] animals also live longer, and that isn't just because they aren't getting cancer, either. ... One of the animals' youthful secrets is hyperactive brown fat, which burns energy instead of storing it. The findings add to evidence that tumor suppressors aren't designed only to protect us against cancer, the researchers say. They also point to new treatment strategies aimed to boost brown fat and fight aging. ... Tumor suppressors are actually genes that have been used by evolution to protect us from all kinds of abnormalities. ... In this case, the researchers studied a tumor suppressor commonly lost in human cancers. Mice with an extra copy of the gene known as Pten didn't get cancer, but that's not the half of it. Those mice were also leaner, even as they ate more than controls ... That suggested that the animals were experiencing some sort of metabolic imbalance - and a beneficial one at that. Cancer protection aside, the animals lived longer than usual. They were also less prone to insulin resistance and had less fat in their livers. Those benefits seem to trace back to the fact that those Pten mice were burning more calories thanks to overactive brown fat."

Link: http://www.sciencedaily.com/releases/2012/03/120306131252.htm

Here is one of many clear signs to show that chronic inflammation is something to be avoided: "Inflammation, oxidative damage, and platelet activation are hypothesized biological mechanisms driving the disablement process. The aim of the present study is to assess whether biomarkers representing these mechanisms predicted major adverse health-related events in older persons. ... Data are from 2,234 community-dwelling nondisabled older persons enrolled in the Health Aging and Body Composition study. Biomarkers of lipid peroxidation, platelet activation, and inflammation (serum concentrations of interleukin-6) were considered as independent variables of interest and tested in Cox proportional hazard models as predictors of (severe) mobility disability and overall mortality. ... The sample's (women 48.0%, whites 64.3%) mean age was 74.6 (SD 2.9) years. During the follow-up (median 11.4 years), 792 (35.5%), 269 (12.0%), and 942 (42.2%) events of mobility disability, severe mobility disability, and mortality occurred, respectively. ... Only interleukin-6 showed significant independent associations with the onset of all the study outcomes. ... The inflammatory marker interleukin-6 is confirmed to be a robust predictor for the onset of negative health-related events."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22389462

The Institute for Evidence Based Cryonics is hosting a symposium in Portland in July:

On Saturday July 7, 2012, the Institute for Evidence Based Cryonics and Cryonics Northwest will organize a symposium on cryonics and brain-threatening disorders in Portland, Oregon. The symposium will start at 09:00 am at the offices of Kaos Softwear. Entrance to the event is free.

Some background is provided in another post at the Institute website:

Conventional wisdom in life extension circles is that making cryonics arrangements allows one to benefit from rejuvenation technologies that are not available during one's existing lifespan. Aside from the risk of high-impact accidents or getting lost at sea, there is one challenge that some cryonicists will face when they grow older; the debilitating consequences of brain-threatening disorders.

One of the unfortunate effects of the increase in human lifespan is a corresponding increase in late-onset identity-destroying brain disorders. We know that some patients at the existing cryonics organizations were cryopreserved after advanced Alzheimer's disease. Some cryonics organization members who developed Alzheimer's disease were not preserved at all, due to lapsed insurance and/or cryopreservation arrangements.

The main challenges and risks associated with low-temperature preservation of the brain after death relate to (a) overbearing regulation that prevents sensible end of life decisions and increases risk of a poor preservation, and (b) your removal from the scene as a willful actor, capable of defending your own interests. Neurodegenerative conditions like Alzheimer's are a special case of point (b) - you are still alive, but become incapable of monitoring affairs to ensure that the course of action you desire is carried out.

All the data of your mind may still be largely intact, as appears to be the case for Alzheimer's until late in its progression, or it may be progressively and irrevocably destroyed by a disease that will have largely consumed you by the time it kills your body. Either way, a lot of entirely disreputable things happen behind closed doors when family members are close to death and cannot look out for themselves - I'm sure we can all recall a tale or two. Which is all fine and well if it's just an inheritance fight, but when it means the difference between your brain and the data of your mind preserved well at Alcor or rotting away to guaranteed oblivion ... well, that's a much bigger deal.

These are challenges, given that the best we can do today is to try change the laws that prevent voluntary euthanasia, support research into biotechnologies that can repair the brain, and live an exceedingly healthy life. Many of these issues relating to the brain and cryopreservation could be dealt with if Western governments didn't force people to live to the bitter end, no matter the personal cost. On the general health side of things, it is true that fit older folk don't tend to suffer Alzheimer's, which appears to be just as much a lifestyle disease as type 2 diabetes for most people. There are still any number of other degenerations, however, and even the best kept body and brain deteriorate progressively until death.

So, as people tend to point out, support of cryonics is not a complete alternative to support of medical biotechnology - people who will not live to see the advent of true rejuvenation biotechnologies should still be very interested in medical progress in regenerative medicine and other fields likely to support therapies and methods of preventation for the degeneration of the brain with aging.

Even marginally better control over the actions of cells can improve regenerative processes in the body: "Scientists were able to unpick the process of how different cells in the liver are formed. When the liver is damaged it produces too many bile duct cells and not enough cells called hepatocytes, which the liver needs to repair damaged tissue. They found they could increase the number of hepatocyte cells - which detoxify the liver - by encouraging these cells to be produced instead of bile duct cells. Understanding how liver cells are formed could help to develop drugs to encourage the production of hepatocytes to repair liver tissue. This could eventually ease the pressure on waiting lists for liver transplants. ... The production of hepatocyte cells was increased by altering the expression of certain genes in early stage liver cells. ... This research helps us know how to increase numbers of cells that are needed for healthy liver function and could pave the way for finding drugs that help liver repair. Understanding the process in which cells in the liver are formed is key in looking at ways to repair damaged liver tissue."

Link: http://www.crm.ed.ac.uk/news/press/boosting-cell-production-could-help-treat-liver-disease

Another of a number of research groups here works towards repair of damaged corneas with stem cells: researchers "have used defective corneas obtained ... [to show] how human stem cells can be caused to develop into what are known as 'epithelial cells' after 16 days' culture in the laboratory and a further 6 days' culture on a cornea. It is the epithelial cells that maintain the transparency of the cornea. ... Similar experiments have been carried out on animals, but this is the first time that stem cells have been grown on damaged human corneas. It means that we have taken the first step towards being able to use stem cells to treat damaged corneas ... If we can establish a routine method for this, the availability of material for patients who need a new cornea will be essentially unlimited. Both the surgical procedures and the aftercare will also become much more simple." While this is not the first time that stem cells have been used to repair a cornea, this sort of infrastructural work that aims to reduce cost of materials and improve efficiency of a therapeutic process is nonetheless an important step along the way to making a new therapy widely available.

Link: http://www.sciencedaily.com/releases/2012/03/120305160818.htm

Short term predictions for the future, such as looking at the next ten years, are especially challenging; the random nature of life and circumstance tends to dominate on that timescale, which means the trends that can be picked up from various 30-60 year time frames are not so helpful as guidelines for progress. One good day or one bad day for a developer or fundraiser somewhere in the world can can spiral outward to move a due date for new technology a few years in either direction, but that sort of stochastic noise evens out over longer periods of time.

I've pondered the late 2030s to early 2040s in past years - which are still enough business cycles removed from here and now to expect a certain evening out of the uncertainties of progress. But what about the next round number between here and there: 2020? That is a more challenging and uncertain prospect, but here are some thoughts:

• There will be a $5 million per year budget devoted to SENS-like research by a single organization. That may be the SENS Foundation, or it may be an existing organization whose leadership have become SENS-sympathetic.
• The first batch of results from SENS Foundation research into removal of cellular aggregates will be somewhere in the middle of the Big Pharma pipeline, having been licensed out for development.
• Simple stem cell transplant therapies will finally be available in the US without the FDA trying to shut them down - re-injection of largely unmodified stem cells from the patient to treat arthritic joints, for example. Look to what is available today for veterinary practice to see what will be available legally for humans in 2020. More sophisticated therapies will only be available in overseas clinics, and the best of those will be far better and far more effective.
• No group will have yet doubled the life span of a mouse, and nor will there be any available means to do so. Yet.
• The research community will have accomplished solid life span studies in normal mice for removal of senescent cells and partial correction of mitochondrial DNA damage. Both will be shown to extend life, but not by as much as we'd all like - and researchers will still be looking into why. Nonetheless, these are some of the first life span studies to involve repair biotechnologies to reverse aging, rather than alterations of metabolism to slow aging.
• Decellularization of donor organs followed by transplant will have been made to work successfully for all major soft internal organs of the body in laboratory mammals.
• A research group will have printed, from scratch, a full, functioning animal heart, kidney, or liver, and transplanted it successfully into a recipient lab animal.
• A service somewhere in the world will offer culturing and implant of replacement natural teeth grown from dental pulp stem cells.
• Cancer immunotherapies are still largely in the lab in the US, but first generation immunotherapy treatments - such as granulocyte transplant therapy - are widely available through medical tourism, and are becoming a hot topic of conversation in the cancer community due to their effectiveness.
• Amateur groups organize online and offline to produce crowdsourced DIYbio lab protocols for personal improvement through biotechnology - the logical next step for self-help health engineers. This might range from engineering your own tailored probiotics or mouth bacteria at the low end, to groups trying to produce a gene therapy to boost muscle mass at the high end.

There are many other things that might happen between now and then that would be a big deal if they came to pass, but seem to be a roll of the dice in terms of odds - or at least I've no idea what the odds are. For example, will researchers figure out how to recreate salamander-style limb and organ regeneration in higher animals? That may or may not be possible with any ease, and the answers might be right around the corner or might take another twenty years to work themselves out. Or, to pick another example, researchers find a definitive gain-five-to-ten-years-absolutely-for-certain longevity mutation or therapy in humans. That seems pretty unlikely, but you never know.

Equally, SENS might acquire a Russian backer with exceedingly deep pockets - perhaps unlikely, but everyone else seems to have one. Any sort of large influx of interest or funds tends to throw off all the predictions for SENS and other nascent programs; the uncertain nature of fundraising is one of the reasons why near term predictions are so hard.

The aggregation of α-synuclein that contributes to Parkinson's disease has been blocked in an animal model of the condition, which is promising but needs much more testing: researchers "report the development of a novel compound known as a 'molecular tweezer,' which in a living animal model blocked α-synuclein aggregates from forming, stopped the aggregates' toxicity and, further, reversed aggregates in the brain that had already formed. And the tweezers accomplished this without interfering with normal brain function. ... finding a therapy that targets only the aggregates is a complicated process ... In Parkinson's, for example, the protein implicated in the disorder, α-synuclein, is naturally ubiquitous throughout the brain. ... Its normal function is not well understood, but it may play a role in aiding communication between neurons. The trick, then, is to prevent the α-synuclein protein aggregates and their toxicity without destroying α-synuclein's normal function, along with, of course, other healthy areas of the brain. [The researchers used] a particular molecular tweezer he had developed called CLR01. Molecular tweezers are complex molecular compounds that are capable of binding to other proteins. Shaped like the letter 'C,' these compounds wrap around chains of lysine, a basic amino acid that is a constituent of most proteins. Working first in cell cultures, the researchers found that CLR01 was able to prevent α-synuclein from forming aggregates, prevent toxicity and even break up existing aggregates. ... The researchers next tried their tweezers in a living animal, the zebrafish ... Using a transgenic zebrafish model for Parkinson's disease, the researchers added CLR01 and used fluorescent proteins to track the tweezer's effect on the aggregations. They found that, just as in cell cultures, CLR01 prevented α-synuclein aggregation and neuronal death, thus stopping the progression of the disorder in the living animal model."

Link: http://scienceblog.com/52489/parkinsons-disease-stopped-in-animal-model/

The stifling regulation attending medical research and development ensures that veterinary medicine is years ahead of human medicine: "Products in the veterinary medical space can be brought to market more rapidly, iterated upon more rapidly, and therefore improved more rapidly. With owners eager to try new treatments, lower barriers to entry for new products, and far less risk of lawsuits dogs and other pets offer great advantages for development of therapies. ... Owners of pets who try assorted stem cell therapies, gene therapies, and the like have information that is now not being collected systematically. That's a great lost opportunity and the opportunity will grow with each new treatment that reaches the veterinary market. If vets could also report information then test results could be combined with owner observations (e.g. did Fido start running again after stem cells injected into joints?) then the efficacy (or lack of efficacy) of therapies could be discovered much more rapidly. This ties into a bigger problem: As things stand today truly objective medical research is much rarer than generally appreciated. We need basically open source medical research with large amounts of data collected independent of companies that develop drugs and other treatments. Given enough software and some group (could be mostly volunteers) to manage a web site to collect pet medical histories many others could analyze the data. Pets are also great for research information collection because with pets privacy isn't a big consideration. My guess is most people won't mind having their pet's medical history made public if they can see a benefit for their current and future pets and for humans as well. Given public availability of the data a far larger number of people with requisite training in statistics, medicine (veterinary or otherwise), and biological sciences could do analyses and discover patterns in the data."

Link: http://www.futurepundit.com/archives/008542.html

At the end of a post on the science of aging, filmmaker Robert Kane Pappas says the following on the goal of greatly extending human life:

Actual age reversal was something - that, when I first heard of it 5 years ago - I put in the category of time travel and ghosts. [But] after 5 years of interviewing the researchers and poking around labs with my camera, it is not a question of if but when. The general population has little idea of what is about to befall them.

Which is both true and a problem. From an advocate's point of view, I'd say that unless a much larger portion of the public gains an understanding of longevity, the level of support will not rise far enough to generate the large sums of money needed for meaningful progress within the next 20 to 30 years. Outside of stem cell medicine and cancer research, the necessary research programs to build rejuvenation biotechnology are somewhere between fringe, anemic, and non-existent, relatively speaking - and it's only the dedicated efforts of groups like the Methuselah Foundation and SENS Foundation that have boosted these research projects to be more than non-existent. The present few million dollars a year is a lot in one sense, but a drop in the bucket in comparison to the the hundred of millions that are necessary for real progress.

Given that, I feel I can say that if the first fruits of longevity science come as a surprise to the world at large, to the average fellow in the street, then those advances will likely be faltering and far less imposing than might have been possible. On the large scale progress in science and medical technology is a numbers game: the more public support there is, the easier it becomes to raise funding, the more researchers become interested in working in the field, and the more entrepreneurs step forward ... and the wheel turns faster as a result. To gain that greater public support requires persuasion, communication, and education - informal and otherwise - are thus it is these line items that are the roots of progress when looking at breadth of society and a length of decades.

And still, today, the public is indeed largely oblivious to longevity science - not at all aware of the possibility that biotechnologies already envisaged in some detail could be rejuvenating the old 20 to 30 years from now. That future is uncertain: it depends on many more people grasping the idea and the potential, and doing their part to help provide the research community with a full head of steam and major funding.

The membrane pacemaker hypothesis suggests that longevity differences between species are largely determined by the resistance to oxidative damage exhibited by important cell membranes - such as those in mitochondria. Here is some evidence to suggest that this holds up within a species too: "Membrane unsaturation plays an important role in the aging process and the determination of inter-species animal longevity. Furthermore, the accumulation of oxidation-derived molecular damage to cellular components particularly in the nervous and immune systems over time leads to homeostasis loss, which highly influences age-related morbidity and mortality. In this context, it is of great interest to know and discern the degree of membrane unsaturation and the steady-state levels of oxidative damage in both physiological systems from long-lived subjects. In the present work, adult (28 ± 4 weeks), old (76 ± 4 weeks) and exceptionally old (128 ± 4 weeks) BALB/c female mice were used. Brain and spleen were analysed for membrane fatty acid composition and specific markers of protein oxidation, glycoxidation and lipoxidation damage ... The results showed significantly [higher membrane resistance to lipid peroxidation and lower lipoxidation-derived molecular damage brain and spleen in] exceptionally old animals when compared to old specimens ... In addition, the higher levels of the glycoxidation-derived marker observed in exceptionally old animals, as well as in adult mice, could be considered as a good indicator of a better bioenergetic state of these animals when compared to the old group. In conclusion, low lipid oxidation susceptibility and maintenance of adult-like protein lipoxidative damage could be key mechanisms for longevity achievement."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22367548

An open access commentary at Impact Aging: "There is a lively discussion going on as to whether oxidative stress is or is not a cause of (accelerated) aging, fuelled to a significant extent by the finding from Arlan Richardson's group that mice heterozygous for the mitochondrial superoxide dismutase SOD2 showed increased oxidative stress, increased cancer incidence but not accelerated ageing. A new twist to this story was introduced recently when it was shown that connective tissue-specific SOD2 knockouts developed multiple signs of progeria including short lifespan, associated with up-regulation of the cell senescence marker p16INK4A. Mitochondrially generated oxidative stress is both an established cause and a relevant consequence of cell senescence, frequencies of senescent cells in connective tissue increase during mice aging, and destruction of senescent cells can 'cure' some age-related tissue dysfunction. A paper by Judith Campisi's and Simon Melov's groups recently published in Aging now further explores the connection between oxidative stress, cell senescence and aging. The authors demonstrate that mitochondrial dysfunction occurs in the epidermis of old (2 years) mice ... These data enforce two central hypotheses in the field, namely that of mitochondrial dysfunction as a cause of cell senescence, and of cell senescence as a relevant contributor to mammalian aging ... However, a fascinating question remains: Is it really Reactive Oxygen Species (ROS) arising from mitochondria that promote cellular senescence in this model?"

Link: http://impactaging.com/papers/v4/n2/full/100432.html

I first noticed the Russia 2045 initiative late last year, and remarked on it as a contrasting approach to achieving agelessness. A diversity of initiatives is a good thing in any field of human endeavor:

To my eyes, the most interesting aspect of this Russia 2045 initiative is that, unlike any other serious proposal I'm aware of, their focus is on getting out of biology and into machine bodies as rapidly as possible. ... In essence, this is a course to throw away as much of the body as possible as soon as possible - a path based on a different set of preconceptions about difficulty and efficiency on the road leading to an artificial brain hosting a once-biological human mind. If aiming for life spans of thousands of years, this is the exactly same place we'll get to in the end even if we start out by maintaining our biological bodies and brains for as long as possible through rejuvenation biotechnologies.

In essence the Russia 2045 strategy swaps most of the challenges and research goals of rejuvenation biotechnology for a different set of challenges and research goals regarding brain-machine interfaces, supporting the brain outside the body, and maintaining the brain against aging while doing it. Whether this makes for an easier problem space is very open to debate.

But on with the more recent news: there was a Global Future 2045 conference last month, organized by the same group:

"Global Future 2045" is a nonprofit organization with the goal of creating a network community with the world's leading scientists in the field of life extension and to support them as an investment hub, contributing to various projects.

You should peruse the presentation videos, as they give a fair idea as to the focus: to transcend biology as rapidly as possible, and outline the details of that path in much the same spirit as the SENS platform discusses how to retain one's biology in good working condition for as long as desired.

A Wired article provides a little more background on this organization and its backer:

Dmitry Itskov, a 31-year-old Russian media mogul, [has] a massive, sci-fi-esque venture of his own ... Itskov's plan: Construct robots that'll (within 10 years, he hopes) actually store a human's mind and keep that consciousness working. Forever. "This project is leading down the road to immortality," Itskov, who founded New Media Stars, a Russian company that runs several online news outlets, tells Danger Room. "A person with a perfect Avatar will be able to remain part of society. People don't want to die."

...

Until now, most of the work on Itskov's Avatar has taken place in Russia, where he claims to have hired 30 researchers - all of them paid out of his own deep pockets. Now, Itskov plans to take the mission global. "I want to collaborate with scientists from around the world," he says. "This is a new strategy for the future; for humanity."

As a technology program that requires a great deal of research, this project will succeed for the long term only if it expands out into the broader scientific community: relationships built, knowledge exchanged, interest spurred. Pointed, narrow-focus programs within well-funded small groups can achieve their milestones, but they cannot build enough to change the world without large numbers of other participants joining in, competing, filling in the gaps, and building on top of the foundations. This is true of all ventures that aim that high - if the first step is vision, and the second step obtaining resources, then the last is persuasion.

In any case, I look forward to seeing how this develops. The world needs more earnest, vocal people out to build their slice of the science fiction future and persuade as many others as will listen.

We are far from the first generation to have looked at the state of science and postulated that we can significantly extend human life span through some specific means - but we are the first generation to have possession of the necessary scientific knowledge to be correct in our evaluation. That we have this knowledge is why you can't just look at the long history of predictions of longevity and say "we're just another generation that will be disappointed - it's all more of the same." The past is a great place to look if you want to predict the future of politics, but a terrible resource for predicting the future of technology. There is an enormous difference between the state of life science of today and the nascent biotechnology of the 1970s and advocates like Timothy Leary - and not to mention the science of the early 20th century as is referenced in this article: "It might seem as if a magic [longevity-enhancing] pill isn't so far off. But before we get too cheery about the prospects for these discoveries, it's useful to be reminded of the many longevity 'breakthroughs' that have come and gone in the past. One such potential advance was hailed in the November 1929 issue of Technology Review, in an essay called 'Forestalling Death: The Cow's Contribution to Human Longevity' ... In the previous 125 years, Tobey observed, average life span had risen from the low 30s to the upper 50s. This was primarily due to reductions in infectious disease and in the infant death rate ... It wasn't enough to simply reduce a threat such as infectious disease - it was imperative that we find something we could add to our lives, or maybe simply increase our intake of something we were already consuming. He felt recent research might have uncovered just such a substance. ... He pointed to recent experiments at Columbia University, wherein one set of rats had been given an 'adequate diet' of one-sixth dried whole milk and five-sixths whole wheat. An 'optimal diet' group, meanwhile, received double the milk and less wheat. The average duration of life was almost exactly ten percent greater in those subjects receiving the optimal diet ... Is it possible that we have had the fountain of youth within our grasp throughout the ages that man has been seeking this liquid phantasm? Milk has always been recognized as the one most nearly perfect food ... but apparently it possesses hitherto undreamed of virtues." And so on: the end result is more of the oral fixation that seems to so dominate our culture - in the popular imagination everything of significance must be something that we put in our mouths and consume. Most important medicine, of course, is nothing of the sort.

Link: http://www.technologyreview.com/biomedicine/39630/

Another potential method to treat or minimize the progession of sarcopenia: researchers "report that a family of protein transcription factors, called 'Forkhead (Fox0)' plays a significant role in the regulation of skeletal muscle mass. Specifically, they found that interfering with the activity of these transcription factors prevents muscle wasting associated with cancer and sepsis, and even promotes muscle growth. This discovery is likely to be relevant to any disease, condition or lifestyle that leads to muscle wasting, including voluntary inactivity. [Researchers] genetically inhibited the activity of 'Forkhead boxO' proteins, or 'FoxO,' in the skeletal muscle of healthy control mice, septic mice, and mice with cancer. The loss of muscle mass in those with cancer and sepsis was significantly decreased by inhibition of FoxO activity. In healthy control animals inhibiting FoxO activity caused an increase in muscle cell size which occurred as a result of protein synthesis. ... FoxO proteins may provide a target for therapies aimed at reducing muscle wasting and thus improving the quality of life and survival rates for patients with many different diseases."

Link: http://www.eurekalert.org/pub_releases/2012-02/foas-nwn022912.php