Fight Aging!

A documentary film entitled The Singularity will be released tomorrow. It is the latest in a line of works from recent years to examine the near future of technology and its implications: a convergence of biotechnology, ever-increasing computing power, and molecular nanotechnology means that we will become capable of engineering ourselves to much the same degree as we presently choose to engineer our surroundings. Why would we stick with the flaky, error-prone, and short-lived evolved version of human biology when far better and more cost-effective replacements can be built?

Here is a short review:

Doug Wolens' latest documentary, released 1 November, captures the argument between the two sides. The Singularity takes the form of a series of intercut interviews, with animations illustrating various points (intentionally or not, they're a little reminiscent of how entries in the fictional Hitchhiker's Guide to the Galaxy were depicted in the classic BBC television adaptation).


Wolens' subjects include, unsurprisingly, people like Kurzweil himself, roboticist Cynthia Breazeal, and gerontologist Aubrey de Grey. But Wolens also interviews people not normally associated with the speculative edge of artificial intelligence and biomolecular engineering, such as Richard A. Clarke, the former chief counterterrorism advisor to the U.S. National Security Council, and the current U.S. secretary of defense, Leon Panetta.

While The Singularity doesn't cover a great deal of ground that's new to anyone already familiar with the concept, it does provide crisp snapshots of the current state of the debate and many of the main players.

The most vocal proponents of the technological singularity as a concept tend to focus on artificial intelligence and machine capabilities rather than advances in biotechnology. This is fair enough: the original definition is one of recursively self-enhancing artificial intelligence rather than any other technology. When biology does become involved, the picture that is often brought to the table is one of blurring the line between biology and machinery, between a living entity and its tools. We will merge with our machines - but again, the view there is very much focused on expanding the boundaries and capabilities of the human mind.

In past years, I've pointed out that the likely timescales here put reverse engineering the brain by brute force simulation as a contemporary to meaningful progress in the first true rejuvenation biotechnology - of the sort envisaged in the Strategies for Engineered Negligible Senescence. Development of both will be underway in earnest in the late 2020s through the 2030s: the key to that timing is the minimum level of processing power needed for brain simulation on the one hand versus an optimistic hope for the future of SENS funding on the other. What this suggests is that we'll be a fair way down the road of working out how to repair aging and better maintain the biology we have long before we can enjoy any of the myriad potential economic and research benefits of strong artificial intelligence - such as the ability to create legions of cheap, tireless knowledge workers to order.

One can argue about whether the 2030s will see significant man-machine mergers, such as engineered protein machinery and nanorobot swarms in the body for medical applications, such as surrogate immune systems - though by now it is becoming clear that any future nanoscale robot stands a good chance of being an artificial cell, bacterium, or cell component rather than a tiny device made of precision-placed carbon atoms. Brain interfaces driven by similar nanomachinery don't seem likely to be out of the laboratory by then, however: understanding the structure and mechanisms of the brain sufficiently well at a low level to accomplish this task will be a research effort still in full swing two decades from now, and no doubt consuming many multiples of present levels of funding.

The past few paragraphs were a long-winded way of saying that work on the more machine-focused side of technologies envisaged for the technological singularity is not as important as straightforward biotechnology, or at least not to my eyes. First things first: building the first generation of therapies to repair and reverse the damage that causes aging needs to happen the old-fashioned way. No waiting around for strong AI and mind enhancements to make the research happen faster - that technology isn't going to arrive in time for us.

Antagonistic pleiotropy describes a situation in which a gene provides both benefit and drawback under different circumstances. In evolutionary considerations of aging the usual context for this situation is that a gene is selected because it provides competitive advantages in youth, when reproduction is taking place, and then becomes harmful later in life when evolutionary pressure is much reduced. Here researchers take a measure of the prevalence of this phenomenon in yeast:

The genes responsible for inherited diseases are clearly bad for us, so why hasn't evolution, over time, weeded them out and eliminated them from the human genome altogether? Part of the reason seems to be that genes that can harm us at one stage of our lives are necessary and beneficial to us at other points in our development. [Researchers now] report that antagonistic pleiotropy is very common in yeast, a single-celled organism used by scientists to provide insights about genetics and cell biology.

"In any given environment, yeast expresses hundreds of genes that harm rather than benefit the organism, demonstrating widespread antagonistic pleiotropy. The surprising finding is the sheer number of such genes in the yeast genome that have such properties. From our yeast data we can predict that humans should have even more antagonistic pleiotropy than yeast."

Yeast has about 6,000 genes, about 1,000 of which are essential - eliminate any of them and the organism dies. [Researchers] worked with a set of 5,000 laboratory strains of yeast in which one non-essential gene had been deleted from each strain. [They] grew all 5,000 strains together in a single test tube and compared the growth rates of each strain. This side-by-side comparison allowed them to determine which genes were beneficial (increased growth rate) and which ones were harmful (decreased growth rate) under the six environmental conditions.

The researchers found that for each of the six conditions, on average, the yeasts expressed about 300 genes that slowed their growth and were therefore classified as harmful. Deleting those genes resulted in more rapid growth. But many of the genes that were harmful under one set of environmental conditions proved to be beneficial under another, demonstrating widespread antagonistic pleiotropy.

Link: http://www.ns.umich.edu/new/releases/20928-genetic-tradeoff-harmful-genes-are-widespread-in-yeast-but-hold-hidden-benefits

The mitochondria in our cells generate damaging oxidative byproducts as a result of their operation, and that is the first step in a long process that contributes to degenerative aging. Researchers have shown that localizing antioxidants to the mitochondria can reduce this damage and thus modestly slow aging and extend life in laboratory animals.

Most antioxidants do not find their way to mitochondria, however, and have no effect on long term health or aging. Thus there has been some interest in recent years in designing compounds that do localize to mitochondria. One research group works on the mitochondrially targeted antioxidant SkQ1 and related compounds, and these scientists continue to conduct a range of studies in laboratory animals:

Here we evaluated the effect of the mitochondria-targeted antioxidant SkQ1 on markers of aging in the old OXYS rats, a unique animal model of accelerated senescence and age-related diseases, as well as normal Wistar rats. ... we compared effects of SkQ1 [on] age-dependent decline in blood levels of leukocytes, growth hormone (GH), insulin-like growth factor-1 (IGF-1), testosterone, dehydroepiandrosterone (DHEA).

Our results indicate that when started late in life, treatment with SkQ1 [not] only prevented age-associated hormonal alterations but partially reversed them. These results suggest that supplementation with low doses of SkQ1, even in chronologically and biologically aged subjects seem to be a promising strategy to maintain health and retard the aging process.

Link: http://impactaging.com/papers/v4/n10/full/100493.html

Aubrey de Grey of the SENS Foundation is an advocate for the development of rejuvenation biotechnology; he gives a great many presentations in the course of any given year, mostly in Europe and the US. Earlier this month he was invited to the University of Delaware by the Socratic Club there to talk about the Strategies for Engineered Negligible Senescence (SENS). Video of the presentation was recently uploaded to YouTube:

Dr. Aubrey de Grey from the SENS Foundation gives a talk on regenerative medicine at the University of Delaware on October 2, 2012. He is introduced by Marvin Whitaker, who is President of the Socratic Club and is a PhD student in the Department of Political Science and International Relations at the University of Delaware. This event was hosted by the Socratic Club and co-hosted by the University of Delaware's Center for Science, Ethics, and Public Policy.

I'll note that a great many other videos of presentations, lectures, and interviews with de Grey have made their way to YouTube over the past five or six years. This is the age of the moving image, it seems: resist it at your own risk. It is enough to make we poor scriveners, typesetters, and readers feel like throwbacks to an earlier, more Dickensian era.

More seriously, it is worth considering that some channels in the grand, many-threaded, endless conversation that is our culture have little to do with the written word. Television is one of these, a ruthless stamp of uniformity fallen upon the vast diversity of oral traditions that preceded it. But the centralized broadcast model of television is being overtaken in importance by dirt-cheap video recording, editing, and delivery - everyone can join in, and videos become just another way to converse. This sea change is enabled by the internet and its associated computing and software technologies, and shows no signs of slowing down.

The technology ecosystems that allow for easy personal video distribution enable a growth in grassroots advocacy. I'd argue this to be the case because they offer an easier path to becoming a persuasive, widely-heard advocate than the traditional route that involves learning how to write well and convincingly. Learning to write is a considerably harder and more drawn out a process, in my experience at least. Wherever a particular goal becomes less costly in time and money you will see more people achieve that end.

I don't think we're far enough down this path of video as a medium for communication to see how it will eventually settle down to something approaching maturity, but it is worth keeping an eye on successful advocates and talking heads in that arena, if only to see what can be achieved when people put their minds to it.

Following on from a recent post on exercise and the aging brain, here is yet another study to show that improvements in cognitive function can be brought about by regular exercise and its consequent effects on body composition, metabolism, and other line items. Use it or lose it, as they say:

A regular exercise routine can make you fitter than ever - mentally fit. In a new study, previously sedentary adults were put through four months of high-intensity interval training. At the end, their cognitive functions - the ability to think, recall and make quick decisions - had improved significantly.

Blood flow to the brain increases during exercise. The more fit you are, the more that increases. The pilot [study] looked at adults, average age 49, who were overweight and inactive. [Researchers] measured their cognitive function with neuropsychological testing, as well as their body composition, blood flow to the brain, cardiac output and their maximum ability to tolerate exercise.

The subjects then began a twice-a-week routine with an exercise bike and circuit weight training. After four months - not surprising - their weight, body mass index, fat mass and waist circumference were all significantly lower. Meanwhile, their capacity to exercise (measured by VO2 max) was up 15 per cent.

Most exciting, [cognitive function] had also increased, based on follow-up testing. These improvements were proportional to the changes in exercise capacity and body weight. Essentially, the more people could exercise, and the more weight they lost, the sharper they became.

Link: http://www.eurekalert.org/pub_releases/2012-10/hasf-eis102212.php

Induced pluripotent stem cells (IPSCs) are reprogrammed cells - such as those obtained from a skin sample - and are similar to embryonic stem cells in the sense that it should be possible to generate any form of cell from them. They offer the capacity to easily generate unlimited numbers of patient-specific cells, or build tissue and organ structures from scratch. Each type of tissue or cell requires different chemical instructions, growth environments, and technical strategies to be discovered and then refined, however - and there are a few hundred types of cell in the human body. Here, researchers report on progress on generating cartilage from IPSCs:

[Researchers have] engineered cartilage from induced pluripotent stem cells that were successfully grown and sorted for use in tissue repair and studies into cartilage injury and osteoarthritis. ... [This] suggests that induced pluripotent stem cells, or iPSCs, may be a viable source of patient-specific articular cartilage tissue.

Articular cartilage is the shock absorber tissue in joints that makes it possible to walk, climb stairs, jump and perform daily activities without pain. But ordinary wear-and-tear or an injury can diminish its effectiveness and progress to osteoarthritis. Because articular cartilage has a poor capacity for repair, damage and osteoarthritis are leading causes of impairment in older people and often requires joint replacement.

One challenge the researchers sought to overcome was developing a uniformly differentiated population of chondrocytes, cells that produce collagen and maintain cartilage, while culling other types of cells that the powerful iPSCs could form.

To achieve that, the researchers induced chondrocyte differentiation in iPSCs derived from adult mouse fibroblasts by treating cultures with a growth medium. They also tailored the cells to express green fluorescent protein only when the cells successfully became chondrocytes. As the iPSCs differentiated, the chondrocyte cells that glowed with the green fluorescent protein were easily identified and sorted from the undesired cells.

The tailored cells also produced greater amounts of cartilage components, including collagen, and showed the characteristic stiffness of native cartilage, suggesting they would work well repairing cartilage defects in the body.

Link: http://www.dukehealth.org/health_library/news/duke-researchers-engineer-cartilage-from-pluripotent-stem-cells

The October 2012 issue of Rejuvenation Research is available online. I notice that the editorial in this issue comments on a recent Scientific American article in a useful fashion. That article examined the two positions on strategy held by by researchers in the mainstream of aging science, most of whom look to achieve only a modest slowing of aging through their work. Or at least, these are positions held in that portion of the community interested in extending life spans at all, which is probably at this point a majority but by no means all of the field:

One group believes lifespan can be extended by limiting diseases one at a time. ... The other group believes the actual underlying aging pathway itself can be slowed.

These positions within the mainstream are distinct from those of the smaller Strategies for Engineered Negligible Senescence (SENS) camp and like-minded allies, researchers who seek to repair and reverse the root causes of aging rather than just slow it down a bit. The SENS viewpoint is in need of greater attention, however, as it remains overlooked by those who paint the field with broad brush strokes.

One point of this exercise is to note that there exists more than just the one strategic debate in aging research: it's isn't only a matter of arguing for the goal of rejuvenation versus the goal of slowing aging, though I see that as the most important of all such divisions in the scientific community, the debate that will determine whether those of us in middle age now will benefit from a meaningful extension of healthy life span. After all, the battle over whether or not to intervene at all in aging is still being fought to some degree, depressingly enough: until comparatively recently the scientific community would neither discuss nor sanction any discussion of engineering greater human longevity. Remember that this community is far from a monolith, however, and every position has its varied internal factions and smaller rifts.

In any case, here is a pertinent quote from the Rejuvenation Research editorial, penned by Aubrey de Grey:

The September 2012 issue of Scientific American includes a commentary contrasting two approaches to combating aging. Like almost all general-audience piece, and despite the best efforts of most experts in the field, it highlights the goal of life extension rather than stressing that any longevity benefits will be a side effect of health benefits ... The value of the article, though diminished thereby, is still substantial, in that it provides a clear description of the contrast between the "combat one disease at a time" approach generally taken by geriatricians and the holistic "combat aging itself" approach favored by most biogerontologists.

As those readers familiar with my work will know, I view both such approaches as highly unlikely to deliver substantial postponement of age-related ill health in the remotely foreseeable future, but not for the reasons generally given by the proponents of the other approach. Geriatricians reject combating of "aging itself" because they don't generally view aging as a medical condition at all, but instead merely view chronological age as a risk factor for various types of ill health. Biogerontologists, conversely, reject the "one disease at a time" approach because they believe that there will always be something - the very same "aging itself," of course - that will be a source of exponentially accelerating ill health however many specifics are defeated.

The SENS perspective is that it is inaccurate and misleading to draw a sharp distinction between "aging itself" and the specific aspects of age-related ill health, first because where one draws that distinction is arbitrary - Are foam cells atherosclerosis yet, for example? Are fatty streaks? - and second because the lifelong changes that drive ill health, and thus hold the the only logical claim to be lumped under the term "aging," are themselves not aspects of any meaningful unitary process, but are instead relatively independent processes occurring as side-effects of different aspects of metabolism.

Advanced glycation endproducts (AGEs) are a class of undesirable metabolic byproduct. The level of AGEs in the body rises with age and causes harm through a variety of mechanisms, such as by excessively triggering certain cellular receptors or gluing together pieces of protein machinery by forming crosslinks, thus preventing them from carrying out their proper function.

In past years a number of efforts were undertaken to develop drugs that can safely break down at least some forms of AGE. Early promising candidates in laboratory animals failed in humans because the most harmful forms of AGE are different for short-lived versus long-lived mammals - so what benefits a rat isn't of much utility for we humans. So far little progress has been made towards a therapy for the dominant type of AGE in humans, glucosepane, sad to say, as there is comparatively little interest in this field of research.

Here is a recent paper commenting on the potential utility of AGE-beaker drugs:

Reducing sugars can react nonenzymatically with the amino groups of proteins to form Amadori products. These early glycation products undergo further complex reactions, such as rearrangement, dehydration, and condensation, to become irreversibly cross-linked, heterogeneous fluorescent derivatives, termed advanced glycation end products (AGEs).

The formation and accumulation of AGEs have been known to progress in a normal aging process and at an accelerated rate under diabetes. Nonenzymatic glycation and cross-linking of proteins not only leads to an increase in vascular and myocardial stiffness, but also deteriorates structural integrity and physiological function of multiple organ systems.

Furthermore, there is accumulating evidence that interaction of AGEs with a cell-surface receptor, receptor for AGEs (RAGE), elicits oxidative stress generation and subsequently evokes inflammatory, thrombogenic, and fibrotic reactions, thereby being involved in atherosclerosis, diabetic microvascular complications, erectile dysfunction, and pancreatic β-cell apoptosis.

Recently, AGE cross-link breakers have been discovered. Therefore, removal of the preexisting AGEs by the breakers has emerged as a novel therapeutic approach to various types of diseases that develop with aging. This article summarizes the potential clinical utility of AGE cross-link breakers in the prevention and management of age- and diabetes-associated disorders.

Link: http://dx.doi.org/10.1089/rej.2012.1335

Epigenetics has become an important component of the study of aging: how genetic regulation changes in response to cellular and molecular damage. One of the mechanisms of this regulation is the acetylation of histones: researchers evaluate the way in which this changes with aging, leading to changes in gene expression, altered levels of key protein machinery in tissues, and changes in the operation of biological systems in the body. Some research groups are in search of epigenetic alterations that might be reversed through therapy to produce beneficial effects:

Aging increases the vulnerability of aging white matter to ischemic injury. Histone deacetylase (HDAC) inhibitors preserve young adult white matter structure and function during ischemia by conserving ATP and reducing excitotoxicity.

In isolated optic nerve from 12-month-old mice, deprived of oxygen and glucose, we show that pan- and Class I-specific HDAC inhibitors promote functional recovery of axons. This protection correlates with preservation of axonal mitochondria. The cellular expression of HDAC 3 in the central nervous system (CNS), and HDAC 2 in optic nerve considerably changed with age, expanding to more cytoplasmic domains from nuclear compartments, suggesting that changes in glial cell protein acetylation may confer protection to aging axons.

Our results indicate that manipulation of HDAC activities in glial cells may have a universal potential for stroke therapy across age groups.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23050648

Mitochondria, the cell's herd of bacteria-like power plants, occupy an important position in processes of aging, metabolism, and many age-related conditions. Mitochondria produce damaging reactive oxidative molecules as a side-effect of their operation, and these can cause all sorts of havoc - such as by damaging mitochondrial DNA in ways that can propagate throughout the mitochondrial population of a cell, causing it to run awry and harm surrounding tissue. This happens ever more often as we age, and is one of the principle contributions to degenerative aging.

It is worth noting that a greater ability of mitochondria to resist this sort of self-inflicted oxidative damage is theorized to explain much of the longevity of many species that are unusually long-lived for their size - such as bats, naked mole-rats, and so forth.

Thus the researcher community is increasingly interested in finding ways to target therapies to mitochondria: to slow oxidative damage, fix that damage, repair other issues such as genetic disorders in mitochondrial DNA, or alter mitochondrial operation as a way of manipulating cellular behavior and metabolic processes. Building such a therapy usually means attaching a payload molecule to a delivery molecule or particle that will be (a) taken up by a cell, passing through the cell membrane, and then (b) swallowed by a mitochondrion within the cell, passing through that mitochondrion's membranes.

A range of different research groups are working on varied forms of delivery technology. Compare, for example, the repurposed protein machinery of rhTFAM with various plastinquione compounds or polymer nanoparticles. Or, more deviously, genetic engineering that makes a cell nucleus produce and export proteins to that cell's mitochondria. There are many others.

Diversity is a good thing - though of course not all of these strategies are equal in the sort of interventions that they can support. There is a world of difference between introducing more antioxidants into the mitochondria so as to blunt their creation of damaging, reactive byproducts and introducing new genes to repair damage to mitochondrial DNA. The former only gently slows the inevitable, while the latter reverses and repairs the harm done.

In any case, here is a paper representative of work taking place in the targeted antioxidant camp, much of which is taking place in Moscow research centers. Given a few years of promising studies, they are going on to explore the space of possible related compounds, in search of drug candidates that might do as well or better as those discovered to date.

Novel penetrating cations for targeting mitochondria

Novel penetrating cations were used for a design of mitochondria-targeted compounds and tested in model lipid membranes, in isolated mitochondria and in living human cells in culture. Rhodamine-19, berberine and palmatine were conjugated by aliphatic linkers with plastoquinone possessing antioxidant activity. These conjugates (SkQR1,SkQBerb, SkQPalm) and their analogs lacking plastoquinol moiety (C12R1,C10Berb and C10Palm) penetrated bilayer phospholipid membrane in their cationic forms and accumulated in isolated mitochondria or in mitochondria of living cells due to membrane potential negative inside.

Reduced forms of SkQR1, SkQBerb and SkQPalm inhibited lipid peroxidation in isolated mitochondria at nanomolar concentrations. In human fibroblasts SkQR1, SkQBerb and SkQPalm prevented fragmentation of mitochondria and apoptosis induced by hydrogen peroxide.

The novel cationic conjugates described here are promising candidates for drugs against various pathologies and aging as mitochondria-targeted antioxidants and selective mild uncouplers.

As a footnote I should remind folk that everyday antioxidant supplements do nothing for long-term health, and certainly don't end up in your mitochondria when you ingest them.

Microbes in the digestive system seem to have some influence on aging, insofar as they interact with the immune system, epigenetic regulation of nearby tissues, and so forth. In effect they act almost like an additional organ or biological system. Researchers are very much in the early stages of trying to understand how microbial life in the body fits in to the bigger picture of metabolism and aging - which is already very complex, and likely to become more so:

The ageing process affects the human gut microbiota phylogenetic composition and its interaction with the immune system. Age-related gut microbiota modifications are associated with immunosenescence and inflamm-ageing in a sort of self-sustaining loop, which allows the placement of gut microbiota unbalances among both the causes and the effects of the inflamm-ageing process.

Even if, up to now, the link between gut microbiota and the ageing process is only partially understood, the gut ecosystem shows the potential to become a promising target for strategies able to contribute to the health status of older people. In this context, the consumption of pro/prebiotics may be useful in both prevention and treatment of age-related pathophysiological conditions, such as recovery and promotion of immune functions ... Moreover, being involved in different mechanisms which concur in counteracting inflammation, such as down-regulation of inflammation-associated genes and improvement of colonic mucosa conditions, probiotics have the potentiality to be involved in the promotion of longevity.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23079287

There are numerous ways in which lifestyle choices can damage long-term health and lower life expectancy, but smoking remains one of the more effective, on a par with becoming obese:

The Life Span Study (LSS) was initiated in 1950 to investigate the effects of radiation, tracking over 100,000 people. However, most received minimal radiation exposure, and can therefore provide useful information about other risk factors. Surveys carried out later obtained smoking information for 68,000 men and women, who have now been followed for an average of 23 years to relate smoking habits to survival.

The younger a person was when they started smoking the higher the risk in later life. Older generations did not usually start to smoke until well into adult life, and usually smoked only a few cigarettes per day. In contrast, Japanese born more recently (1920-45) usually started to smoke in early adult life, much as smokers in Britain and the USA.

These differences in smoking habits are reflected in the mortality patterns. Smokers born before 1920 lost just a few years. In contrast, men born later (1920-45) who started to smoke before age 20 lost nearly a decade of life expectancy, and had more than double the death rate of lifelong non-smokers, suggesting that more than half of these smokers will eventually die from their habit. Results on the few women who had smoked since before age 20 were similar.

In addition to studying the risk of smoking, the researchers were able to examine the benefits of stopping. As elsewhere, those who stopped smoking before age 35 avoided almost all the excess risk among continuing smokers, and even those who stopped around age 40 avoided most of it.

Link: http://www.eurekalert.org/pub_releases/2012-10/bmj-st1102412.php

One of the many ways in which FDA regulation corrupts research and development in medicine is the creation of a strong financial incentive to reuse existing drugs. It's much less expensive to obtain regulatory approval for a new marginal use of a drug already approved for other uses than it is to obtain regulatory approval for a completely new drug or other medical technology that might be far better. This discourages real progress in favor of something that only looks a little like progress: many of the existing stable of drugs are decades old, yet resources that might otherwise go to breaking new ground are instead poured into shoving these old square pegs into as many round holes as possible.

Given this it should be no great surprise to see that as work on the biology of calorie restriction has progressed, an increasing amount of time and money has been devoted to attempts to reuse existing drugs as calorie restriction mimetics - i.e. to find approved drugs that produce at least some of the same changes in metabolism, and with as few side-effects as possible. One of these drugs is metformin, but as I noted in a post earlier this year, it really isn't much to write home about, given that results from a range of studies are all over the map. It may or may not be useful or beneficial, and certainly doesn't show the clear benefits to health and life expectancy produced by calorie restriction itself:

Studies of the potential antiaging effects of antidiabetic biguanides, such as metformin, are still experimental for obvious reasons and their results are currently ambiguous.

Today I thought I'd direct your attention to a recent paper that shows metformin failing to do much for fly life spans:

Activation of AMPK by the Putative Dietary Restriction Mimetic Metformin Is Insufficient to Extend Lifespan in Drosophila

The biguanide drug, metformin, commonly used to treat type-2 diabetes, has been shown to extend lifespan and reduce fecundity in C. elegans through a dietary restriction-like mechanism via the AMP-activated protein kinase (AMPK) and the AMPK-activating kinase, LKB1.

We have investigated whether the longevity-promoting effects of metformin are evolutionarily conserved using the fruit fly, Drosophila melanogaster. We show here that while feeding metformin to adult Drosophila resulted in a robust activation of AMPK and reduced lipid stores, it did not increase lifespan in either male or female flies. In fact, we found that when administered at high concentrations, metformin is toxic to flies. Furthermore, no decreases in female fecundity were observed except at the most toxic dose. Analysis of intestinal physiology after metformin treatment suggests that these deleterious effects may result from disruptions to intestinal fluid homeostasis.

Thus, metformin appears to have evolutionarily conserved effects on metabolism but not on fecundity or lifespan.

Nonetheless, money continues to flow for this and similar work.

Videos of the presentations given at this year's Singularity Summit have yet to emerge online, but while we're waiting here is a report on the event:

Kurzweil took the stage on Saturday afternoon to deliver the summit's keynote address. "The singularity is near," he began quietly, a grin slowly spreading across his face. "No, it isn't here yet, but it's getting nearer," he said to laughs and applause. He spoke extemporaneously for over an hour, his presentation a mix of statistics, time series graphs, personal anecdotes, and predictions.

Computing ability and technological innovation have been increasing exponentially over the past few decades, he argued, alongside similar increases in life expectancy and income. "All progress stems from the law of accelerating returns," he proclaimed. He discussed his latest project - an attempt to reverse-engineer the human brain. "Intelligence is at the root of our greatest innovations: genetics, nanotechnology, and robotics. Once we master artificial intelligence, unimaginable new frontiers will open up."

After his talk, a man stood up and looked Kurzweil in the eye. "I'm in my 60s like you," he said, his voice faltering. "Do you think we'll make it?" It took me a few seconds to realize they were talking about immortality and I felt chills in that moment. "Life expectancy tables are based on what happened in the past," responded Kurzweil without skipping a beat. "In 25 years, we'll be able to add one year of life for every year that passes. We have a very good chance of making it through."

I should note that I believe Kurzweil's timelines for rejuvenation biotechnology are only possible if $300 million or more in dedicated research funding turns up at the SENS Foundation's front door tomorrow, thereby ensuring a good shot at demonstrating rejuvenation in old laboratory mice by the mid-2020s. As things stand progress towards the necessary technologies is far slower - not because it cannot be done, but because there is comparatively little interest in doing it, and therefore little funding.

One of the deep puzzles of our age is how a multi-billion-dollar "anti-aging" industry, full of enthusiasm but providing nothing that significantly impacts aging, can exist alongside the near absence of interest in funding research that will produce therapies capable of reversing the progression of aging. There are strange tides at work in the psychology surrounding aging and longevity.

Link: http://www.policymic.com/articles/16546/human-immortality-singularity-summit-looks-forward-to-the-day-that-humans-can-live-forever

Members of the cryonics community gathered for the Alcor-40 conference last week. Here is a report on the event:

I was expecting some excellent talks on the current state of cryonics technology, from the particulars of preservation via vitrification with powerful cryoprotectants, to the pragmatics of transitioning a recently deceased body from the site of death to Alcor's facilities. And the talks on these topics were indeed worthwhile, giving me faith that, in spite of quite limited funding for research and operations, Alcor is steadily improving all dimensions of their practice. Alcor's new CEO Max More started in the position fairly recently, and from what I can tell he's been doing a very professional job.

What surprised me was the depth of the talks on longevity science and neuroscience. One definitely got the feeling that cryonics is not nearly as marginalized as it was a decade ago or even five years ago, and is now accepted as a reasonable pursuit by a rapidly increasing subset of the scientific community.

Of course, this is part of a larger trend of the gradual mainstreaming of transhumanist technologies. AGI and nanotechnology, for example, were laughed at by most academics in relevant fields just 10-20 years ago. Now they are much more broadly acknowledged as valid and important pursuits, though there are still differences in vision between the maverick advocates and the interested folks in the academic mainstream.

Link: http://www.kurzweilai.net/report-from-the-alcor-40-conference

There is a strong correlation between exercise - or level of physical activity - and the pace at which the brain declines. One of the plausible connecting mechanisms is the quality of blood vessels and level of blood flow in the brain, both of which suffer in sedentary people. Other possible candidates include the pace at which new brain cells are created, and the pace of decline in the portions of the immune system that support brain tissue. Both of those are also impacted by exercise.

Unfortunately the downward spiral of degenerative aging is compounded by the fact that exercise and eventually any meaningful physical activity become increasingly hard to undertake. The erosion of muscle mass and strength, and rising frailty due to other causes, can accelerate the decline of mental capacity by indirectly attacking the physical foundations of the brain's operation. All of our biological systems are intertwined, after all.

Equally, correlations between brain and body aging can be looked upon as the result of a general decline in robustness: if there is more cellular and molecular damage throughout the body, then you would expect to see that, on average, greater physical and cognitive decline occur together in the same individual. More damage means a greater loss of function.

Here is a recent paper that touches on the strong relationship between frailty, exercise, and cognitive decline:

Poor Physical Performance and Dementia in the Oldest Old: The 90+ Study

The 90+ Study is a population-based, longitudinal, epidemiologic study of aging and dementia performed at the University of California, Irvine, from January 1, 2003, through November 30, 2009. .., A total of 629 participants from The 90+ Study were included in the study. The mean age was 94 years, and most (72.5%) were women.

All-cause dementia [was] was the main outcome measure. ... Odds of dementia in relation to the physical performance measures were estimated by logistic regression after adjustment for age and sex.

Poor physical performance in all measures was significantly associated with increased odds of dementia. ... We found a strong cross-sectional relationship between poor physical performance and dementia in people 90 years and older.

You might also look at the paper that was referenced in one of yesterday's posts, in which all sorts of physical changes in the aging brain are less progressed in people who exercise more. A great many similar studies have amassed over the years.

Neuroprotective lifestyles and the aging brain

Increased participation in leisure and physical activities may be cognitively protective. Whether activity might protect the integrity of the brain's white matter, or reduce atrophy and white matter lesion (WML) load, was examined in the Lothian Birth Cohort 1936, a longitudinal study of aging.

Associations are presented between self-reported leisure and physical activity at age 70 years and structural brain biomarkers at 73 years. For white matter integrity, principal components analysis of 12 major tracts produced general factors for fractional anisotropy (FA) and mean diffusivity. Atrophy, gray and normal-appearing white matter (NAWM) volumes, and WML load were assessed.

A higher level of physical activity was associated with higher FA, larger gray and NAWM volumes, less atrophy, and lower WML load. The physical activity associations with atrophy, gray matter, and WML remained significant after adjustment for covariates, including age, social class, and health status.

The decline of the immune system is an important component of aging, and one of the causes of that decline is persistent infection by common herpesviruses such as cytomegalovirus (CMV). This is near harmless in the short term, but over time more and more of the limited repertoire of immune cells are devoted to the futile attempt to clear out CMV - and ever less are left free to tackle other threats.

One possible solution is to destroy the CMV-specialized immune cells to free up space. This is a very plausible goal, given advances in targeted cell killing technologies emerging from the cancer research community. But here, scientists measure the cost of CMV infection in laboratory animals - more motivation for research groups that might be trying to build a therapy:

Persistent CMV infection has been associated with immune senescence. To address the causal impact of lifelong persistent viral infection on immune homeostasis and defense, we infected young mice systemically with HSV-1, murine CMV, or both viruses and studied their T cell homeostasis and function.

Herpesvirus(+) mice exhibited increased all-cause mortality compared with controls. Upon Listeria-OVA infection, 23-mo-old animals that had experienced lifelong herpesvirus infections showed impaired bacterial control and CD8 T cell function, along with distinct alterations in the T cell repertoire both before and after Listeria challenge, compared with age-matched, herpesvirus-free controls.

Herpesvirus infection was associated with reduced naive CD8 T cell precursors above the loss attributable to aging. ... To our knowledge, this study for the first time causally links lifelong herpesvirus infection to all-cause mortality in mice and to disturbances in the T cell repertoire, which themselves correspond to impaired immunity to a new infection in aging.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23087407

We humans are long-lived for our size when compared with other mammals. One possible explanation is the grandmother hypothesis, suggesting that evolutionary selection favored survival to increasing age because older members of a social group can increase the survival chances of their grandchildren. As for all hypotheses there are arguments against it, but here researchers have created simulations to support the concept:

The simulations indicate that with only a little bit of grandmothering -- and without any assumptions about human brain size - animals with chimpanzee lifespans evolve in less than 60,000 years so they have a human lifespan. Female chimps rarely live past child-bearing years, usually into their 30s and sometimes their 40s. Human females often live decades past their child-bearing years. The findings showed that from the time adulthood is reached, the simulated creatures lived another 25 years like chimps, yet after 24,000 to 60,000 years of grandmothers caring for grandchildren, the creatures who reached adulthood lived another 49 years - as do human hunter-gatherers.

Based on earlier research, the simulation assumed that any newborn had a 5 percent chance of a gene mutation that could lead to either a shorter or a longer lifespan. The simulation begins with only 1 percent of women living to grandmother age and able to care for grandchildren, but by the end of the 24,000 to 60,000 simulated years, the results are similar to those seen in human hunter-gatherer populations: about 43 percent of adult women are grandmothers. The new study found that from adulthood, additional years of life doubled from 25 years to 49 years over the simulated 24,000 to 60,000 years.

The competing "hunting hypothesis" holds that as resources dried up for human ancestors in Africa, hunting became better than foraging for finding food, and that led to natural selection for bigger brains capable of learning better hunting methods and clever use of hunting weapons. Women formed "pair bonds" with men who brought home meat. Many anthropologists argue that increasing brain size in our ape-like ancestors was the major factor in humans developing lifespans different from apes. But the new computer simulation ignored brain size, hunting and pair bonding, and showed that even a weak grandmother effect can make the simulated creatures evolve from chimp-like longevity to human longevity.

Link: http://www.sciencedaily.com/releases/2012/10/121023204142.htm

Mitochondria are a roving herd of power plants that exist in every cell, storing energy in chemical form for use in powering cellular processes. They are the remnants of symbiotic bacteria-like organisms, and so bear their own DNA that encodes much of the protein machinery needed for their operation. Unfortunately, this mitochondrial DNA (usually abbreviated as mtDNA) sits right next to processes that generate reactive byproducts, and is far less protected than the DNA in the cell nucleus. It becomes damaged over time in ways that spiral out to harm the cell, harm surrounding tissue, and ultimately cause some fraction of degenerative aging.

Thus fixing mitochondrial DNA damage is an important line item for any future rejuvenation toolkit. Seven years ago, there was an unofficial claim of the ability to replace mitochondrial DNA in a laboratory animal using a methodology known as protofection. There has not been a great deal of progress on this front since then however: to the best of my knowledge, no-one else has managed to replicate that result. Yet that research group and others continue to work on the mechanisms used: so what's going on here?

At its heart, protofection is a cargo delivery method, and the cargo consists of gene sequences to be inserted into mitochondria - such as extra copies of important genes that tend to get damaged, causing mitochondrial dysfunction. The delivery mechanism is a protein assembled of various parts that enable it to (a) cross cell membranes, (b) be transported into the interior of mitochondria within the cell, and (c) participate in the normal processes of DNA replication. Thus a cargo of mitochondrial genes attached to this basic assembly will be carried to mitochondria and then added to the mitochondrial DNA that is already present.

This delivery protein is known of late as recombinant human mitochondrial transcription factor A (rhTFAM), and in older materials such as those used for the unfinished Open Cures protofection protocol as PTD-SODMLS-Mature TFAM:

PTD stands for Protein Transduction Domain. This part of the protein facilitates its ability to cross lipid membranes.

SODMLS stands for Superoxide Dismutase Mitochondrial Localization Signal. This domain targets mitochondria specifically. In the literature, the term MTD (Mitochondrial Transduction Domain) is used in place of PTD + SODMLS indicating that the MTD is the part of the protein that causes it to enter cellular mitochondria.

TFAM refers to human mitochondrial transcription factor A. This protein plays several roles in the mitochondria. It participates in mtDNA transcription, replication and maintenance. It also non-specifically binds to mtDNA which is the property we want to exploit as we attempt to pull pristine mtDNA into mitochondria which contains damaged DNA.

In recent years, it seems that the core protofection research group has dropped the use of rhTFAM as a carrier and are instead focused on exploring how it might be used in and of itself, without any cargo, as a therapy for mitochondrial conditions. It so happens that rhTFAM boosts mitochondrial activity in some ways, and progressive mitochondrial dysfunction is implicated in a range of age-related conditions, especially in the brain. Even marginal therapies here could have meaningful market value.

You might look on this as one of the more subtle ways in which the present US regulatory structure for medical research and development distorts the undertaking of science. The FDA only permits clinical applications for specific named conditions, and thus anything other than the development of treatments for late-stage disease becomes either too expensive or outright forbidden. Treatment of aging falls into the latter category, as aging is not recognized as a medical condition that should be treated. So research efforts that might have some application to aging are sidelined into the development of marginal therapies for one specific disease, often type 2 diabetes, rather than what are arguably far more important applications.

But back to rhTFAM: here is a recent paper that illustrates the present research direction. It is an evaluation of rhTFAM as a therapeutic agent intended to galvanize mitochondria, rather than as a means of delivering mitochondrial DNA to fix damage.

RhTFAM treatment stimulates mitochondrial oxidative metabolism and improves memory in aged mice

To treat mitochondrial deficiencies, we have developed recombinant human mitochondrial transcription factor A (rhTFAM). TFAM is an essential component of the mitochondrial DNA replication and expression machinery ... RhTFAM enters the mitochondrial compartment of cells rapidly and can also transport mtDNA cargo into mitochondria.

RhTFAM stimulates mitochondrial biogenesis of human cells modeling sporadic Parkinson's disease or containing high abundance mtDNA mutations of Leber's hereditary optic neuropathy (LHON) or Leigh syndrome. RhTFAM treatment of cells exposed to parkinsonian neurotoxins restores ATP deficiencies and reduces oxidative stress. Systemic treatment of young adult mice with rhTFAM stimulates mitochondrial biogenesis, increases respiration in brain, heart and muscle, increases brain mitochondrial ATP synthesis and reduces oxidative stress damage to proteins.

These desirable properties of rhTFAM suggest that it might improve bioenergetic deficiencies produced as a consequence of aging. To test that possibility, we treated aged mice with rhTFAM in a manner similar to our prior study of treating young adult mice. We observed stimulation of mitochondrial biogenesis and mtDNA gene expression in the absence of any apparent systemic toxicity. Increases in mitochondrial oxidative metabolism were mirrored by improvements in Morris water maze performance in aged mice, including platform acquisition (learning) and platform location recall (memory), and increases in brain protein levels of BDNF and synapsin. These findings support beneficial use of rhTFAM in human aging and development for experimental use of rhTFAM in humans.

There are a lot of good references in the paper for those who want to look into other recent publications on this topic. For a broader context, you might compare the research discussed here with some other recent advances that might be of use in repairing or replacing mitochondria - this is far from the only line of research that might turn out to win the day:

• A Way to Insert New Mitochondria into Cells
• Nanoparticles to Reliably Target Mitochondria
• A General Method for Correcting Mitochondrial Mutations

Much of the stem cell research community is engaged in determining the recipes needed to create large numbers of specific types of cell for specific therapeutic uses. There are a few hundred different types of cell in the human body, so you'll periodically see announcements such as this as successes are achieved:

A new approach for generating large numbers of circulatory system cells, known as vascular endothelial cells (VECs), from human amniotic-fluid-derived cells (ACs) is reported ... The strategy, which shows promise in mice, opens the door to establishing a vast inventory of VECs for promoting organ regeneration and treating diverse vascular disorders.

VECs line the entire circulatory system, including the heart and blood vessels, and they help to control blood pressure, promote the formation of new blood vessels, and support the regeneration and repair of injured organs. A wide range of vascular diseases stem from dysfunctions in VECs, so generating healthy cells for transplantation in patients would represent an attractive treatment strategy. But past stem cell strategies have fallen short: VECs derived from stem cells are unstable and tend to convert to nonvascular cells, and they do not increase rapidly in number, limiting their potential for clinical use.

To overcome these limitations, [researchers] developed a safe approach for producing a large number of stable VECs from amniotic cells, which are extracted during routine amniocentesis procedures and thus represent a steady source of cells. To reprogram amniotic cells into mature and functional VECs, called rAC-VECs, the researchers turned specific genes on and off using members of the E-twenty-six family of transcription factors - proteins that bind DNA and are important for VEC development.

The rAC-VECs resembled human adult VECs in that they expressed the normal set of vascular-specific genes. When rAC-VECs were transplanted into the regenerating livers of mice, they formed stable, normal, and functional blood vessels.

Link: http://www.eurekalert.org/pub_releases/2012-10/cp-tvd101212.php

Regular exercise, much like calorie restriction, has a beneficial effect on near all measures of aging in humans - though unlike calorie restriction it doesn't increase maximum life span in laboratory animals. Here is a reminder that decline in brain function is slowed by exercise:

The new research included about 700 people living in the United Kingdom who all had brain scans when they reached the age of 73. Three years earlier, at age 70, the study participants were questioned about the leisure and physical activities they engaged in. People in the study who reported being the most physically active tended to have larger brain volumes of gray and normal white matter, and physical activity was linked to less brain atrophy. Regular exercise also appeared to protect against the formation of white matter lesions, which are linked to thinking and memory decline.

[In another study, researchers] recruited 120 older inactive adults with no evidence of dementia. ... Half began a modest exercise routine that included walking at a moderate pace for 30 to 45 minutes, three times a week. The other half did stretching and toning exercises. A year later, MRI brain scans showed that a key region of the brain involved with memory, known as the hippocampus, was slightly larger in the walking group, while it has shrunk slightly in the non-aerobic stretching group.

"The old view is that as we get older our brains become less malleable and less able to change. The new view is that it remains plastic even very late in life. We were able to show positive change after just one year of moderate-intensity physical activity."

Link: http://www.webmd.com/healthy-aging/news/20121022/exercise-protects-aging-brains-better

Mortality determines society. By this I mean that the function describing mortality rate by age in humans acts as a filter to determine the sort of societies that can exist and support themselves. A high mortality rate reduces the range of societies that can exist. The mechanisms at play in this relationship are economic in the broadest sense: a mix of population growth, division of labor, effectiveness in recording and transmitting knowledge, time preference, establishment of sufficient capital for more than just subsistence living. Consider the difference between the late paleolithic era and classical Greek civilization, for example, and think on why they are different.

In terms of mortality, the immediately noticeable difference between the classical era and prehistory is an upsurge in the number of people who reached old age - a reduction in the omnipresent violence between small groups, and a marginal improvement in medicine. As a general rule you don't find the bones of old people in early human archaeology: so few of them made it past 40 as to be close to absent entirely as a class. Mortality rates in classical Greek and early Roman times were horrific by modern standards, but enormously improved over those of prehistory.

Thus as a consequence there were both old people and a certain expectation of reaching old age - which means a rise in planning ahead and an increase in available capital. A longer vision breaks through destructive cycles of economic behavior that take place on shorter timescales. As one example, people cultivate their property more effectively if they think that it must last for longer under their stewardship, more readily resisting short-term gains that come at the cost of long-term gains. This incentive has operated throughout human history, whenever average life spans rose. A later example can be seen in the simultaneous rise of life span and economic well-being in 17th and 18th century England:

If life cycle inspiration was present in rural England in the 18th century, farmers who were becoming aware that old people were gradually living for longer periods must have been more concerned about their own means of subsistence in the future. This may have been an important stimulus to reduce consumption, increase savings and take into account longer horizons.

Various destructive cycles of poverty to wealth to poverty exist for all time scales of human behavior and all population densities. A greater expected span of life doesn't make them go away entirely, but it does mean that more people will be around to suffer the consequences of ill-thought action - and as a result, endeavor to understand and avoid the acts that lead to suffering they see in others. Don't eat your own seed corn; be the ant rather than the grasshopper; don't cut down the whole forest; engage in trade rather than slavery; shun destruction in favor of construction; allow the merchant class to exist; and so forth. You might see the commonality here: it is restraining the urge to obtain short-term gains that harm the prospects for long-term gain.

One important thing to note is that all historical progress in expanding the range of possible human societies has come about without greatly altering the maximum human life span. It was possible to live to more than a century without modern medicine and in the presence of pervasive disease and violence - that outcome was just enormously unlikely for any given individual. Improved mortality rates led to a growth in the number of old people and their influence.

I submit that this largely unchanged outer limit to life span is why we can look back on thousands of years of politics to see the same patterns repeated over and again. Regions rise and fall. Empires form and decline. Countries become wealthy and then poor. Democracies slide into authoritarianism. Currencies are steadily debased and destroyed. Known and enumerated forms of governance arise over and again, and fail in the same ways each time. The patterns repeat because throughout history expectations regarding the outer limits of personal stewardship and responsibility remained set at something less than a century. It is that span of time that drives choices made between cultivating future growth versus squandering it for present advantage - and even drives whatever incentive exists to understand that you are taking one of those paths rather than the other.

After all, economics as a professional body of knowledge and theory only really evolved into the forms we'd recognize today in the wake of 17th to 18th century gains in longevity, after the rise and fall of physiocracy as a flawed means to explain the wealth or poverty of nations and how that related to human behavior.

Just as paleolithic hunter-gatherer groups were stuck in their own limited range of sustainable human societies, their choices and cultural evolution over time driven by high mortality rates at all ages and the near absence of elders, so are we also stuck in our own, larger range of possible societies. Our present span of life limits us to what we see. Where wealth, freedom, and the rule of law necessary to create wealth arise, they corrode over time as successive generations forget how and why their good fortune came about: they eat their own seed corn. We can see this happening in the US, somewhere past the mid-point of the process, and all somewhat analogous to the decline of the Roman Republic, at least insofar as root causes are considered: successful republics have a way of falling into empire and authoritarian rule, accompanied by massive military and welfare spending. Bread, circuses, and the legions.

All humans of our maximum life span and adult mortality rates low enough to allow for societies of cities and writing have found themselves trapped within the wheel of time I described above: the rise and fall of polities that takes place over centuries, poverty to wealth to poverty, or tribes to civilization to tribes. It is the consequence of our dominant short-termisms; where our time preference fails the test; where we squander our own potential.

The human condition has been bounded in this way for a very long time indeed, since the first cities arose more than 6,000 years ago, but it will not continue for much longer. In this age of biotechnology the transition from age-bounded life spans of a century to accident-bounded life spans of thousands of years will happen in the course of mere decades. Entire populations will stop dying as therapies capable of repairing the cellular and molecular damage of aging become widely available. Degenerative aging will become a controlled medical condition, warded and defeated like smallpox and others in the past century.

The wheel of time will be broken. Those who stand at the beginning and the height of empire will be the very same individuals who must also stand at its decline: their horizons will extend, and so the shape of empire will be quite different, if it comes about at all. How will this play out, this grand restructuring of all the incentives that lurk at the base of human societies? What new forms of society will emerge as possibilities given widespread radical life extension? These are open questions: the changes to human life span that lie ahead are dramatically different in character to those that have occurred in the past. The gulf in mortality and life span that likely lies between us and the humanity of the 22nd century is far greater than that separating paleolithic hunter-gatherers from the classical Greeks. Further, it will occur in a comparative eyeblink - a single generation will stand with one foot in each world.

Yet the wheel of time will be broken, and this seems to me to be a good thing.

The small cryonics industry provides a method of low-temperature storage after death, with the aim of preserving the fine structure in brain tissue that stores the data of the mind. Cryopreserved people can wait out the development of sufficiently advanced applications of molecular nanotechnology that are capable of restoring them to active life. Over the decades since the first cryonics providers were established the industry has not grown greatly, but it is nonetheless the only option other than the grave available to the billions who will die prior to the advent of biotechnologies to reverse aging.

In a better world, cryonics providers would be as commonplace as funeral homes and near everyone would be preserved. But there are only a small number of active organizations: a couple in the US, a more recently launched project in Russia, and a few others in various stages of early development.

At present it looks like an initiative to launch a cryonics provider in Australia is nearing fruition. Here is a recent article on this effort:

Milton first heard about cryonics as a kid, through reading science fiction, but only became seriously interested four years ago, while researching life-extension techniques. One night he attended a meeting of the Cryonics Association of Australasia (CAA) in a cafe in the city, where he met Peter Tsolakides, a retired manager for ExxonMobil, the oil company. At the meeting, both men were disappointed to discover that there was no cryonics facility in Australia. If you wanted to get frozen, you had to go to the USA. This is not impossible - the Cryonics Institute, in Michigan, has six Australians in cryopreservation, and the Alcor Life Extension Foundation, in Arizona, has two - but it is certainly inconvenient. You either had to be aware you were on the way out and get on a plane, quickly, or wait till you had de-animated and have someone, usually an obliging member from CAA, pack you in ice and mail you over. Either way, it was a logistical nightmare, and so Milton and Tsolakides decided to start a local operation.

That was in 2009. Since then, Stasis has recruited 11 investors, each of whom has agreed to put in $50,000. This money will fund the construction of the facility, which should be complete by 2014, and pay for the investors' cryonic suspension, when the time comes. Milton, who works from home, spends his time liaising with NSW Health, which has been "very supportive", and, more recently, scouting for suitable land sites. "We are currently looking for a couple of acres in regional NSW - Yass, Wagga Wagga, Goulburn ... It has to be a low-risk area for natural disasters, like bushfires, earth tremors or flooding, and it needs to be somewhere with reliable power, sealed access and liquid nitrogen delivery routes, because liquid nitrogen is essential."

Link: http://www.brisbanetimes.com.au/lifestyle/deep-freeze-20121015-27lqf.html

The most important strategic debate in aging science is over how to go about producing therapies for aging. The present dominant camp believes that only minimal progress is possible in the near term, and that altering the operation of metabolism is one of the few viable methods: they are aiming to gently slow aging, such as by replicating some of the beneficial changes that occur in calorie restriction.

The minority position in this debate looks to build therapies capable of true rejuvenation, reversal of aging by repairing the cellular and molecular damage that causes aging. This is a path that should prove no harder, will produce far better results, but yet remains unpopular in the research community. If we want to see meaningful progress towards engineered longevity in our lifetimes, it is the path that will have to win out, however.

The mainstream position has its own internal debates over strategy, as a recent article illustrates, while taking a swipe at the repair-based approach along the way:

In the current issue of Scientific American, author Katherine Harmon takes a brief look at two schools of thought in the field of human lifespan expansion science. One group believes lifespan can be extended by limiting diseases one at a time. Focusing on the top two, cancer and heart disease, they beleive will go a long way. "If we can focus on the major causes of death - cancer, cardiovascular disease - if we can really conquer those diseases and replace parts of the body if they wear out, that is the best possible outcome," gerontologist Sarah Harper is quoted as saying.

The other group believes the actual underlying aging pathway itself can be slowed. This camp is represented by Dr . S. Jay Olshanksy at the University of Chicago. He believes that even if diseases are eliminated, cells and organs will age and degenerate and people will still age and die, perhaps some number of fixed years later. Olshansky is said with colleagues to be launching a "Manahttan-style project to slow aging" whose primary goal is to extend healthy lifespan by seven years in the next decade or two. Since disease risk doubles every seven years, slowing aging by seven years will reduce diseases by half.

The aim of this group is to find compounds that slow aging. No specific mention was made in the article of Dr. Aubrey de Grey and his SENS Foundation and his premise that age-related damage can be fixed and aging reversed and halted. His efforts are derided by associating one his quotes that the first person to live to 150 has already been born to "pseudoscience backwater, swamped with snake oil and short-lived hopes."

The snake oil abounds amidst the lies and frauds of the "anti-aging" market of course, but it's simple laziness to associate serious scientific efforts like SENS with snake oil salesmen just because both groups say that they want to greatly extend healthy life.

Link: http://extremelongevity.net/2012/10/22/how-we-may-soon-all-live-to-100/

Chronic inflammation is a bad thing, walking hand in hand with the frailties and degenerations of aging. Rising inflammation contributes to a very broad range of fatal age-related conditions, and the progressive decline of the immune system itself causes ever greater chronic inflammation, even as it fails to protect the body from pathogens and errant cells. Further, visceral fat tissue is a potent source of inflammation, and this is one of the mechanisms thought to link excess fat with lowered life expectancy and greater risk of age-related disease.

There is plenty in the Fight Aging! archives on the subject of inflammation and its role in aging. To pick a handful of examples:

• Avoid Chronic Inflammation
• Inflammation and the Damage of Aging
• The Importance of Inflammation in Aging
• More Visceral Fat Means More Inflammation
• Inflammation and Life Span Differences Between Species

Some of the best known genetically engineered mutant mice with extended longevity are those in which growth hormone and its receptor are suppressed. They are small, need careful husbanding because they don't generate enough body heat to survive well on their own, and live 60-70% longer than ordinary members of their species. As noted in the following review paper, reduced inflammation has some role to play in this extended healthy life span:

Growth hormone, inflammation and aging:

The last 200 years of industrial development along with the progress in medicine and in various public health measures had significant effect on human life expectancy by doubling the average longevity from 35-40 to 75-80. There is evidence that this great increase of the lifespan during industrial development is largely due to decreased exposure to chronic inflammation throughout life. There is strong evidence that exposure of an individual to past infections and the levels of chronic inflammation increase the risk of heart attack, stroke and even cancer.

Centenarians represent exceptional longevity in human populations and it is already known that many of these individuals are escaping from major common diseases such as cancer, diabetes etc. There is ongoing interest in investigating the mechanisms that allow these individuals to reach this exceptional longevity. There are several animal mutants used to study longevity with hope to determine the mechanism of extended lifespan and more importantly protection from age related diseases. In our laboratory we use animals with disruption of growth hormone (GH) signaling which greatly extend longevity.

Mutant animals characterized by extended longevity provide valuable tools to study the mechanisms of aging. Growth hormone and insulin-like growth factor-1 (IGF-1) constitute one of the well-established pathways involved in the regulation of aging and lifespan. Ames and Snell dwarf mice characterized by GH deficiency as well as growth hormone receptor/growth hormone binding protein knockout (GHRKO) mice characterized by GH resistance live significantly longer than genetically normal animals.

During normal aging of rodents and humans there is increased insulin resistance, disruption of metabolic activities and decline of the function of the immune system. All of these age related processes promote inflammatory activity, causing long term tissue damage and systemic chronic inflammation. However, studies of long living mutants and calorie restricted animals show decreased pro-inflammatory activity with increased levels of anti-inflammatory adipokines such as adiponectin. At the same time, these animals have improved insulin signaling and carbohydrate homeostasis that relate to alterations in the secretory profile of adipose tissue including increased production and release of anti-inflammatory adipokines.

This suggests that reduced inflammation promoting healthy metabolism may represent one of the major mechanisms of extended longevity in long-lived mutant mice and likely also in the human.

Spermidine has been noted to boost autophagy and promote greater longevity to some degree in laboratory animals. Its activities are in the process of being advanced by some researchers as candidate drug mechanisms for slowing aging. Given that, it makes sense for researchers to investigate spermidine levels in longer lived individuals to see if there is any association:

Polyamines (putrescine, spermidine and spermine) are a family of molecules deriving from ornithine, through a decarboxylation process. They are essential for cell growth and proliferation, stabilization of negative charges of DNA, RNA transcription, translation and apoptosis.

Recently, it has been demonstrated that exogenously administered spermidine promotes longevity in yeasts, flies, worms and human cultured immune cells. Here, using a cross-sectional observational study, we determined whole-blood polyamines levels from 78 sex-matched unrelated individuals divided into three age groups: group 1 (31-56 years, N=26, mean age: 44.6±6.07), group 2 (60-80 years, N=26, mean age: 68.7±6.07) and group 3 (90-106 years, N=26, mean age: 96.5±4.59).

Polyamines total content is significantly lower in group 2 and 3 compared to group 1. Interestingly, this reduction is mainly attributable to the lower putrescine content. Group 2 displays the lowest levels of spermidine and spermine. On the other hand, [nonagenarians and] centenarians (group 3) display significant higher median relative percentage content of spermine with respect to total polyamines, compared to the other groups.

For the first time we report polyamines profiles from whole blood of healthy [nonagenarians and] centenarians, and our results confirm and extend previous findings on the role of polyamines in determining human longevity. However, although we found an important correlation between polyamines levels and age groups, further studies are warranted to fully understand the role of polyamines in determining life-span. Also, longitudinal and nutritional studies might suggest potential therapeutic approaches to sustain healthy aging and to increase human life-span.

Link: http://dx.doi.org/10.1089/rej.2012.1349

Tissue engineers have been inching closer to building a kidney from stem cells in the past couple of years. Here is a recent example of the ongoing work in this field:

Investigators can produce tissues similar to immature kidneys from simple suspensions of embryonic kidney cells, but they have been unsuccessful at growing more mature kidney tissues in the lab because the kidneys' complicated filtering units do not form without the support of blood vessels.

Now, from suspensions of single kidney cells, [researchers] have for the first time constructed "organoids" that can be integrated into a living animal and carry out kidney functions including blood filtering and molecule reabsorption. Key to their success was soaking the organoids in a solution containing molecules that promote blood vessel formation, then injecting these molecules into the recipient animals after the organoids were implanted below the kidneys. The organoids continued to mature and were viable for three to four weeks after implantation.

Link: http://www.sciencedaily.com/releases/2012/10/121018184850.htm

Many dubious arguments are fielded in support of aging and involuntary death: every status quo, no matter how terrible, gathers its supporters. This is one of the deeper flaws inherent in human nature, the ability to mistake what is for the most desirable of what is possible. A hundred thousand deaths each and every day and the suffering of hundreds of millions is the proposal on the table whenever anyone suggests that human aging should continue as it is.

Massive campaigns of giving and social upheaval have been founded on the backs of a hundredth of this level of death and pain - but the world has a blindness when it comes to aging. Such is the power of the familiar and the long-standing: only heretics seek to overturn it, no matter how horrid and costly it is.

Nonetheless, this is an age of biotechnology in which aging might be conquered. There are plans and proposals, set forth in some detail, and debate over strategy in the comparatively small scientific community focused on aging research. So arguments over whether the development of means of rejuvenation should take place at all, reserved for philosophers and futurists in the past, now have concrete consequences: tens of millions of lives and untold suffering whenever progress is delayed. It should always be feared that a society will somehow turn to block or impede research into therapies for aging - worse and more outright crimes have been committed in the past by the members of so-called civilized cultures.

One of the arguments put forward in favor of a continuation of aging and mass death is that without the threat of impending personal extinction we'd collapse into stagnation and indolence. As the argument goes, only death and an explicitly limited future gives us the incentive to get anything done, and so all progress depends upon aging to death. I state the proposition crudely, but this is the essence of the thing, flowery language or no.

This is a terribly wrong way of looking at things: it denies the existence of desire independent of need. It casts us as nothing more than some form of Skinner box, unable to act on our own. This is another example of the way in which many humans find it hard to look beyond what is to see what might be: we live in a state of enforced urgency because we are all dying, because the decades of healthy life are a time of frantic preparation for the decline and sickness that comes later. It is normal, the everyday experience, for all of us to know we are chased by a ticking clock, forced to put aside the things that we would rather do in favor of the things that we must do. We cannot pause, cannot follow dreams, cannot stop to smell the roses.

Some people seem to manage these goals, but only the lucky few - and then only by twining what they would like to do with what they must do. It's hard to achieve that end, and it is really nothing more than an ugly compromise even when obtained. Yet like so much of what we are forced into by the human condition, it is celebrated. One more way in which what is triumphs over what might be in the minds of the masses.

Given many more healthy years of life in which to do so, we would lead quite different lives. Arguably better lives, not diverted by necessity into a long series of tasks we do not want to undertake, carried out for the sake of what will come. We could follow desire rather than need: work to achieve the aims that we want to achieve, not those forced on us. Because of aging and death, we are not free while we are alive - and in any collection of slaves there are those who fear the loss of their chains. The longer they are enslaved, the less their vision of freedom. Sadly, in the mainstream of our culture, it is those voices that speak the loudest.

Some of the effects of aging are driven by signaling changes in important parts of our biochemistry - such as in stem cell niches, collections of cells that provide necessary support to the stem cells that maintain and repair tissue. Niches increasingly act to suppress the stem cells they contain in response to rising levels of cellular and other damage connected to aging. The stem cells themselves also suffer damage, and this evolved response is likely a way to minimize the risk of cancer at the cost of maintaining tissues, but the declining function of the stem cells so far seems to be far more a property of signals from the niche.

In the course of investigating this and similar effects, researchers have been moving blood between young and old mice. Transfusions and joining the bloodstreams of young and old mice are a way to change the signaling environment in order to see what the effects are. The outcome is that a range of measures of aging are reversed:

Experiments on mice have shown that it is possible to rejuvenate the brains of old animals by injecting them with blood from the young. ... blood from young mice reversed some of the effects of ageing in the older mice, improving learning and memory to a level comparable with much younger animals.

[Researchers] connected the circulatory systems of an old and young mouse so that their blood could mingle. This is a well-established technique used by scientists to study the immune system called heterochronic parabiosis. When [researchers] examined the old mouse after several days, [they] found several clear signs that the ageing process had slowed down. The number of stem cells in the brain, for example, had increased. More important, [they] found a 20% increase in connections between brain cells.

One of the main things that changes with ageing are these connections, there are a lot less of them as we get older. That is thought to underlie memory impairment - if you have less connections, neurons aren't communicating, all of a sudden you have [problems] in learning and memory. ... the young blood most likely reversed ageing by topping up levels of key chemical factors that tend to decline in the blood as animals age. Reintroduce these and [all] of a sudden you have all of these plasticity and learning and memory-related genes that are coming back.

Link: http://www.guardian.co.uk/science/2012/oct/17/young-blood-reverse-effects-ageing

In recent years a few research groups have been working on a class of antioxidant compounds that can be ingested but nonetheless target themselves to mitochondrial in our cells. These compounds extend life in laboratory animals, probably by soaking up reactive free radical compounds emitted by mitochondria in the course of their operation, and thus preventing some of the damage that mitochondria cause to themselves. This damage is significant in aging, one of the root causes of degeneration and age-related disease.

It is worth noting that all of the commonly available antioxidant compounds you can buy and ingest do nothing for life span or health, according to many, many studies. They don't target mitochondria, and in fact probably even cause some harm by blocking hormetic processes that use free radical signaling to boost repair mechanisms in tissue.

Here is a paper providing more data on the effects of the best known class of mitochondrially targeted antioxidant:

Previously, extremely low [concentrations] of the mitochondria-targeted plastoquinone derivative SkQ1 (10-(6'-plastoquinonyl) decyltriphenylphosphonium) were shown to prolong the lifespan of male and female Drosophila melanogaster by about 10%. Using long-term monitoring of SkQ1 effects on the Drosophila lifespan, we analyzed different integral parameters of Drosophila survival and mortality under SkQ1 treatment. Meta-analysis was used to evaluate the average SkQ1 effect measured in terms of standard deviation. The effect appeared to be 0.25 for females and 0.18 for males.

The SkQ1 effects on the Drosophila lifespan were reproducible over six years and showed no relationship to fluctuations in the mean lifespan of the w ( 1118 ) line used in the experiments, methods of preparation and administration of the drug, seasons, or calendar years. Adding SkQ1 to fly food was associated with a reduction in early mortality and a decrease in random variation in lifespan. [The data] indicated that feeding flies SkQ1 reduced the rate of fall of fly vitality and, consequently, slowed aging. These findings indicated that the SkQ1 effect on lifespan was associated with both elevation of life quality and slowing of aging.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23073710

Cells become senescent after many divisions or after suffering some forms of damage. They cease dividing and leave the cell cycle. Most are destroyed, either by the mechanisms of programmed cell death or by the immune system, but unfortunately some remain, and their numbers grow with time. The presence of senescent cells harms surrounding tissues, and the more senescent cells that exist the greater the harm. In this, cellular senescence - or rather the accumulation of senescent cells - is one of the root causes of degenerative aging.

What to do about this? Much of the past discussion here at Fight Aging! has focused on efforts to destroy senescent cells - to pick up the slack and eliminate those senescent cells overlooked by existing mechanisms in our biology. Periodically sweeping these cells from the body should prevent their accumulation from ever reaching damaging levels. See those posts from the archives, for example:

• A Demonstration of the Merits of ApoptoSENS
• Needed: a Robust Way of Identifying Senescent Cells
• A Way to Target Senescent Cells

Destruction is one approach, but there is another: researchers could seek a practical way to reverse cell senescence. I would be the first to suggest that this will prove far more challenging than simply destroying the errant cells, but there are some hints that researchers might have to do this for at least some of the cells in the brain. If a significant portion of the neurons that store the data of the mind become senescent, then we can't just forge ahead with global destruction of everything that looks like a senescent cell.

So how do you go about rescuing a senescent cell, and more importantly do so in a way that can be undertaking in a living body rather than only in a petri dish cell culture? Here is a paper that looks at the senescent cell issue in aging from this perspective:

Rejuvenation of senescent cells - the road to postponing human aging and age-related disease?

Senescent cells characterized by the presence of [various senescence markers] accumulate in tissues of aged animals and humans as well as at sites of pathology. It is believed that cellular senescence evolved as a cancer barrier since non-proliferating senescent cells cannot be transformed to neoplastic cells. On the other hand senescent cells favor cancer development, just like other age-related pathologies, by creating a low grade inflammatory state due to senescence associated secretory phenotype (SASP).

Reversal/inhibition of cellular senescence could prolong healthy life span, thus many attempts have been undertaken to influence cellular senescence. The two main approaches are genetic and pharmacological/nutritional modification of cell fate. The first one concerns cell reprogramming by induced pluripotent stem cells (iPSCs), which in vitro is effective even in cells undergoing senescence, or derived from very old or progeroid patients. The second approach concerns modification of senescence signaling pathways just like TOR-induced by pharmacological or with natural agents.

However, knowing that aging is unavoidable we cannot expect its elimination, but prolonging healthy life span is a goal worth serious consideration.

If you watch the field for long enough, you gain a certain sense for sentences that were added to appease conservative funding sources or elder laboratory peers, and that last line above is a classic of the type. For a long time it was very harmful to future career prospects in the field to talk openly about therapies for aging, and while that is far from the case today, some remnants of that former wall of silence remain. That it existed at all is unconscionable - exactly as though the cancer research community or other major part of the medical science establishment did nothing but watch and calibrate the degree of pain, suffering and death caused, rather than try to work towards cures.

The processes of aging are unavoidable in our present biology - but that says nothing about how well we can intervene. The processes of rust are unavoidable in cars, but if you maintain a car well enough it can last indefinitely. The same principle applies in the engineering of greater longevity for living organisms: the regular application of therapies to repair the forms of cellular and molecular damage that cause aging, thereby keeping its consequences at bay for so long as those therapies are continued. That is the intermediate term goal for biotechnology and medicine.

We live longer than our ancestors thanks to our greater wealth and more advanced technology: risk of death is reduced at all ages, the level of damage suffered due to infectious disease and other causes is lowered throughout life, and inroads made into means of alleviating age-related disease. When it comes to effects across a life span, however, our extended lives are so far largely incidental, a side effect of improvements in medicine and quality of life that were introduced to satisfy other, more short-term goals.

This shows that aging and life span is very plastic - it can be changed, and is very readily changed. On the other hand, it tells us next to nothing about what lies ahead, as the rejuvenation biotechnology of the future will be an entirely different beast from the medicine of the past. Only now is the research community deliberately trying to manipulate the processes of aging, or repair the biological damage that causes degeneration. Given this shift in what is possible, projecting past trends to the future is unwise: the deliberately engineered changes in longevity of tomorrow will not look like the incidental benefits that slowed aging yesterday.

Here is an article on recent research that seeks to quantify the degree of improvement in human life expectancy that has occurred in recent centuries - you might want to look at the paper itself since it is open access.

It's said that life is short. But people living in developed countries typically survive more than twice as long as their hunter-gatherer ancestors did, making 72 the new 30, according to new research. Most of the decline in early mortality has occurred in the past century, or four generations, a finding that calls into question traditional theories about aging.

But there's a larger message from the research: Our estimates about the limits of human lifespans may be too low. The study findings "make it seem unlikely that there is a looming wall of death ... which kills off individuals at a certain age" because of genetic mutations that build up as we age.

For example, hunter-gatherer humans were about 100 times more likely to die before age 15 than today's residents of Japan and Sweden. And the study says hunter-gatherers were as likely to die at age 30 as Japanese people are at age 72. But the human lifespan didn't grow gradually over thousands of years. The big jump occurred after 1900 in what the study authors call a "rapid revolutionary leap."

In the big picture, the research challenges the idea that genetic mutations over a lifetime prevent humans from living very long ... Without changing our genetic code at all, we have all of this improvement in mortality at these ages where these mutations should kill us off. And we got all this improvement without 'fixing' any of these mutations that are predicted to cause our bodies to break down in various ways.

Link: http://health.usnews.com/health-news/news/articles/2012/10/15/big-rapid-gains-made-in-human-lifespan-study

An enormously complex web of genes and protein machinery controls the operation of metabolism, a layered nest of interactions and feedback loops. It is thus possible for many different genetic alterations to extend life by working through the same basic mechanism. The example here involving fibroblast growth factor 21 is a newly discovered change that seems to work through a known life extension method involving suppression of growth hormone, used in the past to extend life by 60-70% in mice.

Restricting food intake has been shown to extend lifespan in several different kinds of animals. In our study, we found transgenic mice that produced more of the hormone fibroblast growth factor-21 (FGF21) got the benefits of dieting without having to limit their food intake. Male mice that overproduced the hormone had about a 30 percent increase in average life span and female mice had about a 40 percent increase in average life span.

FGF21 seems to provide its health benefits by increasing insulin sensitivity and blocking the growth hormone/insulin-like growth factor-1 signaling pathway. FGF21 is a hormone secreted by the liver during fasting that helps the body adapt to starvation. It is one of three growth factors that are considered atypical because they behave like hormones. ... Previous research has found that FGF21 can reduce weight in obese mice. The mice that overproduced FGF21 in this latest study were lean throughout their lives and remained lean even while eating slightly more than the wild-type mice.

The hormone does have some downsides: FGF21 overproducers tended to be smaller than wild-type mice and the female mice were infertile. While FGF21 overproducers had significantly lower bone density than wild-type mice, the FGF21-abundant mice exhibited no ill effects from the reduced bone density.

Link: http://www.utsouthwestern.edu/newsroom/news-releases/year-2012/october/starvation-hormone-mangelsdorf-kliewer.html

If it takes another 40 years to defeat aging through advances in biotechnology, the construction of therapies designed to prevent and repair the biological damage that causes aging, more than two billion people will die between now and then. Most of those fatalities will be caused by aging and the panoply of fatal conditions it creates, the end result of the fact that evolution largely favors faster adaptation for a species over greater length of reproductive life for individuals. Evolutionary pressures don't care about the endless suffering, pain, and destruction that they produce - but we, the product of those pressures, can care. Moreover, we can choose to do something about it.

Hence medical science, which is at its root the fight to defeat death and suffering. That said, much of our present society seems slow to come around to the realization that of course - of course! - the goals of medicine include the defeat of aging. Aging is just another of the many complex medical conditions that we should oppose and eliminate precisely because it causes pain and suffering. It should be up near the forefront of all research, as it and its consequences claim more than 100,000 lives each and every day.

But even under the most optimistic of scenarios, such as those in which the SENS program for rejuvenation biotechnology is fully funded starting tomorrow, billions will age to death before the research community can develop the first therapies capable of meaningful rejuvenation. There is something that can be done to address this issue, for all that almost as little effort is made here as for ways to cure aging: long-term preservation of the dead, accomplished in ways that prevent destruction of the fine structures in the brain that store the mind.

At present, the only way to preserve your mind on death is through cryonics, or low-temperature storage with vitrification of tissue. Legal obstacles make it harder than it needs to be to obtain a good preservation, and as noted above the long-standing cryonics industry is a thin thread rather than the mighty river of effort it would be in a more just and sane world. Billions have died since cryonics became a viable commercial product, of which only a few hundred have been successfully preserved.

They can wait out the coming decades, wait out the development of medical nanotechnologies that can reverse the processes of cryopreservation. Time is on their side in this age of rapid progress, assuming that the living community of enthusiasts and professionals can continue to ensure a long-term continuity of service.

A possible future alternative to cryopreservation is plastination, a different methodology for fixing a cell's structure all the way down to the finest details. No organizations analogous to the cryonics industry yet exists to offer plastination services, but that may only be a matter of time. Competition is healthy in any field of human endeavor.

Below is quoted a long article by a plastination advocate, published a few weeks back. It delves into some of the details regarding what exactly has to be preserved in the brain in order to preserve the mind, regardless of the method chosen, and where the uncertainties still remain. If you're interested in the scientific nuts and bolts of preserving the mind for the future, then you should find this quite interesting.

I should note in passing that this fellow sees the end goal of preservation as a record, not an individual in stasis: the preserved mind is a collection of data that can later be recreated as an active individual when the technology exists to run a human mind in software emulation. This is not a desirable goal from my point of view: a copy of you is not you, and restoring the preserved original tissue via suitably advanced medical nanomachinery is the desired end result. There are people who strongly favor one side or another or have no great care, but both end goals require the same quality of preservation. The data has to be there for a good restoration, regardless of how that restoration comes about, so (fortunately) philosophical debate over what constitutes personal identity has little impact on this stage of research and development, which can focus entirely on tangible, measurable issues:

Preserving the Self for Later Emulation: What Brain Features Do We Need?

To preserve the self for later emulation in a computer simulation, what brain features do we need? We can distinguish three distinct information processing layers in the brain:

1. Electrical Activity ("Sensation, Thought, and Consciousness")
These brain features are stored from milliseconds to seconds, in electrical circuits.

2. Short-term Chemical Activity (Short- and Intermediate-term Learning - "Synapse I")
These brain features are stored from seconds to a few days in our neural synapses (synaptome), by temporary molecular changes made to preexisting neural signaling proteins and synapses.

3. Long-term Molecular Changes (Long-term Learning - "Nucleus and Synapse II")
These are stored from years to a lifetime in our neuron's connectome, nucleus (epigenome) and synaptome, by permanent molecular changes to neural DNA, the synthesis of new neural proteins and receptors in existing synapses, and the creation of new synapses.

At present, it is a reasonable assumption that only the third layer, where long-term durable molecular changes occur, must be preserved for later memory and identity reanimation. The following overview of each of these layers should help explain this assumption.

The detailed sections of the article that follow that introduction defy easy piecemeal quoting, but it's very readable - dive in and see what you think.

Parkinson's disease is caused by excessive loss of cells in the small population of dopamine-generating neurons. This is an exaggerated version of a loss that we all suffer due to the wear and tear of aging: many age-related conditions are of this nature, aggravated or more rapidly occuring versions of the same damage that everyone suffers. So all people lose some of the cells that generate the neurotransmitter dopamine, just not enough for that loss to become a named and known medical condition. But even this more modest loss of dopamine neurons causes functional decline in the brain, as researchers here demonstrate - with the intent to show that drugs that deliver dopamine to the brain could at least partially compensate for this decline:

Activation of the hippocampus is required to encode memories for new events (or episodes). Observations from animal studies suggest that, for these memories to persist beyond 4-6 hours, a release of dopamine generated by strong hippocampal activation is needed. This predicts that dopaminergic enhancement should improve human episodic memory persistence also for events encoded with weak hippocampal activation.

Here, using pharmacological functional MRI (fMRI) in an elderly population in which there is a loss of dopamine neurons as part of normal aging, we show this very effect. The dopamine precursor levodopa led to a dose-dependent (inverted U-shape) persistent episodic memory benefit for images of scenes when tested after 6 hours, independent of whether encoding-related hippocampal fMRI activity was weak or strong (U-shaped dose-response relationship). This lasting improvement even for weakly encoded events supports a role for dopamine in human episodic memory consolidation, albeit operating within a narrow dose range.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23055489

Following on from last week's news, it seems the Glenn Foundation for Medical Research is establishing a brace of new laboratories for the study of aging, joining those formed a few years back. Which is to say that the Foundation is reinforcing some of the existing leading lights in aging and longevity science, and in the process of delivering sizable grants is setting up new, named research centers. This time it's the turn of researchers at the Albert Einstein College of Medicine:

Albert Einstein College of Medicine of Yeshiva University has received a $3 million grant from the Glenn Foundation for Medical Research to establish the Paul F. Glenn Center for the Biology of Human Aging Research. The grant will fund research to translate recent laboratory and animal discoveries into therapies to slow human aging.

"Paul F. Glenn has been a visionary in aging research for more than 30 years," said Ana Maria Cuervo, M.D., Ph.D., co-director of the new center, the Robert and Renee Belfer Chair for the Study of Neurodegenerative Diseases, and professor of developmental and molecular biology, of anatomy and structural biology and of medicine at Einstein. "Some of us got to know him when we were still graduate students and he came to scientific conferences to see the data as it was being developed. Paul's personal approach to science has made a big difference to many of us in the field of aging research and has contributed to the career development of many young investigators."

The funding, in the form of pilot and feasibility study grants, is targeted to several specific research projects: uncovering the genetic and epigenetic mechanisms that protect humans against aging and age-related diseases, testing the effectiveness of the first-generation pro-longevity therapies, and developing novel preventive and therapeutic interventions against cellular aging in humans.

Cuervo, you might recall, led the demonstration of reversal of lysosomal decline in the aging liver a few years back, making old mouse livers function as well as when young.

Link: http://www.sacbee.com/2012/10/15/4913069/einstein-establishes-the-paul.html

Threads of research aimed at reverse engineering the brain overlap at the edges with both longevity science and strong artificial intelligence. The knowledge and efforts required to simulate a human brain will probably help work aimed at building the means to repair and rejuvenate an aging brain, and certainly provide a path to the development of artificial minds. When it comes to fixing the damage of aging in the human brain, the research community may find that some combination of repair biotechnologies in the SENS model and unleashing stem cells to do their work is sufficient, even in an absence of full understanding of the processes by which the brain ages and degenerates. But more knowledge never hurts.

Considering the very long term, we will need to understand the workings of the brain and become very capable at emulating them in order to progressively replace the neurons of a flesh brain with more durable and resistant machinery. Given present mortality rates for perfectly healthy young individuals, we might live for thousands of years if protected from aging by suitable biotechnologies. To last longer, we'd need to change ourselves - such as through replacement of the body. But that all lies a long way past the field of immediate and pressing problems related to aging. First things first.

Nonetheless, efforts like the Allen Institute for Brain Science and the Human Brain Project are worth keeping an eye on:

The brain, with its billions of interconnected neurons, is without any doubt the most complex organ in the body and it will be a long time before we understand all its mysteries. The Human Brain Project proposes a completely new approach. The project is integrating everything we know about the brain into computer models and using these models to simulate the actual working of the brain. Ultimately, it will attempt to simulate the complete human brain. The models built by the project will cover all the different levels of brain organisation - from individual neurons through to the complete cortex. The goal is to bring about a revolution in neuroscience and medicine and to derive new information technologies directly from the architecture of the brain.

The Human Brain Project will impact many different areas of society. Brain simulation will provide new insights into the basic causes of neurological diseases such as autism, depression, Parkinson's, and Alzheimer's. It will give us new ways of testing drugs and understanding the way they work. It will provide a test platform for new drugs that directly target the causes of disease and that have fewer side effects than current treatments. It will allow us to design prosthetic devices to help people with disabilities. The benefits are potentially huge. As world populations grow older, more than a third will be affected by some kind of brain disease. Brain simulation provides us with a powerful new strategy to tackle the problem.

You might take a few minutes to peruse the Human Brain Project web site, and take a look at the various PDFs they have available for download. It all makes for interesting reading. One of the points to take away is that potentially transformative research programs are cheap when compared to the budgets of nation states: the Human Brain Project seeks something on the order of $1.5 billion for their vision. The Strategies for Engineered Negligible Senescence is on the order of a $1 billion over a decade for a good shot at realizing rejuvenation in a mouse - all the necessary biotechnologies made ready to the point at which clinical development for humans could begin.

Importantly, and thanks to ongoing progress in technology, the amounts needed for these and similar projects have fallen to a level at which motivated high net worth individuals can - individually - decide to shape these fields, as Paul Allen is doing in the case of brain research. There are hundreds of such people in the world, and all of them are just as subject to aging, frailty, and age-related disease as the rest of us. We're still waiting for someone to decide that SENS is the rational use for large-scale resources, but I think that this is only a matter of time and persuasion.

One fairly standard definition for aging is an increase in mortality rate over time. You are said to age if you become increasingly likely to die in any given interval of time. There is an interesting twist, however: researchers have shown that in short-lived species such as flies there appears to be a point in very late life at which mortality rate stops increasing - i.e. aging, by this definition, ceases.

There is some debate as to what this tells us, and how useful in might be in terms of informing aging research or practical applications of biotechnology to extend life. For example, the evidence for any such late-life plateau for mortality rates in humans is tenuous to non-existent. Does it even exist outside very short-lived species?

Here is a further commentary on late-life plateaus in mortality rate and evolutionary considerations of aging:

Too often, aging is thought of as an inevitable accumulation of damage to cells, as something common to all organisms and across all adult ages, or as a physiological process. These ways of thinking about aging limit aging research. We should instead understand aging as an evolutionarily derived condition, dependent entirely on the pattern of the force of natural selection.

In late adult life, the forces of natural selection no longer differentiate between age classes. At these late ages, there is no effective force of natural selection. This leads to a corresponding absence of consistent changes in fecundity and mortality. One prediction of the evolutionary theories is that other fitness characters, such as male virility, should also stabilize in late life. Following the virility of 1000 individual male D. melanogaster, I found that, as expected, male virility also reached a plateau in late life. This result conforms to the predictions of the evolutionary theories of late life.

Late life is therefore a period in which mortality, fecundity, and virility all plateau. ... These results suggest that late life physiology is distinct from that of aging, and that the absence of change in the effective forces of selection in late life, leads to paradoxical transitions in physiology as cohorts enter late life. From these results, I infer that the periods of aging and late life are different physiologically as a result of the very different ways in which they experience selective forces.

Link: http://dx.doi.org/10.3389/fgene.2012.00187

Important things remain to be learned of the regenerative capacity of various mammal species - such as the way in which rats can regrow large sections of the bladder. Researchers investigate mechanisms of natural regeneration with an eye to finding ways to reproduce exceptional examples of regrowth in human biochemistry. Here, scientists suggest that regeneration of the bladder in rodents is a better avenue of investigation than the well known regeneration of the liver that even we humans are capable of:

Subtotal cystectomy (STC; surgical removal of ~75% of the rat urinary bladder) elicits a robust proliferative response resulting in complete structural and functional bladder regeneration within 8-weeks. ... Although regeneration per se occurs throughout the animal kingdom, there are large disparities in the degree of regeneration observed between species (e.g., amphibian versus mammalian) let alone amid organs (e.g., liver versus kidney). The extensive attention focused on regenerative medicine is understandable given the enormous potential for repair and/or replacement of old, damaged or diseased cells, tissues and organs; such as the diseased and dysfunctional bladders that are the subject of this report.

The liver is very efficient in repairing or regenerating its mass, which occurs as a direct result of the proliferation of all the existing cells from the remaining liver remnant, but is mainly driven by mature hepatocytes, which will re-enter the cell cycle to restore the liver. The entire process, which is usually referred to as regeneration, is completed within a couple weeks, depending upon the mammalian species. However, the process is more accurately termed compensatory hyperplasia.

These well established observations regarding liver re-growth stand in contrast to rodent bladder regeneration, which occurs over a longer time frame (8 weeks rather than 2 weeks), and moreover, results in a regenerated bladder that structurally and functionally is essentially identical to the native bladder which it replaced. More specifically, the bladder capacity and bladder wall thickness (as well as the presence of all three layers; urothelium, muscularis propria and lamina propria) of the regenerated bladder are indistinguishable from the previous native bladder, and moreover, the animals are entirely continent. To our knowledge, bladder regeneration therefore holds a unique position with respect to its regenerative potential, as there is no other mammalian organ capable of this type of regeneration.

Link: http://dx.doi.org/10.1371/journal.pone.0047414

So the future of medicine is golden, biotechnology is in the throes of a vast expansion of capabilities and free-fall in costs, and we have a good idea as to how to go about reversing aging - if the research community would just stop tinkering with efforts to merely slow down aging and get on with achieving the all-round better goal of rejuvenation. We should all donate money and time to help out, because it's not as though we can take it with us and irreplaceable time is ticking away. A shot at lifespans of centuries and longer is coming, with not so much time left in which to reach for that goal.

Putting all of that to one side for the moment, there is the arguably less important question of how to optimize heath and life span given the present poor tools to hand. Many people spend a great deal of time talking and debating on this topic, immersing themselves in the world of what presently exists, and giving little thought to what might lie ahead. A vast industry caters to people who think they've found the better mousetrap when it comes to personal health and aging. They're all wrong, of course, but that doesn't stop the flow of commerce.

The sad truth of the matter is that it's simple and easy to achieve the 80/20 result in health and longevity within the bounds of the tools we have available to us today, provided you're starting out as a basically ordinary, healthy individual. Exercise regularly, the 30 minutes daily of aerobic exercise that has been recommended by physicians since way back when, and practice calorie restriction with optimal nutrition - i.e. eat a sane diet, not very much of it, and obtain the necessary levels of micronutrients while doing so. There's also the matter of not harming yourself greatly, but just as I shouldn't have to mention avoidance of knives and falling rocks, I shouldn't have to mention things like giving up smoking.

These things are not rocket science. They are widely known and most have been advocated for centuries. The supporting statistical data is far better now than at any point in the past, and so you have no excuses: if you're not adopting these practices then it is because you have decided to accept a shorter life expectancy and greater odds of ill health in exchange for the dissipations that you presently enjoy. No-one's perfect, right?

But here is an interesting thing about trying to reliably forge ahead beyond the 80/20 point in personal health, in search of the optimum level of improvement: it's next to impossible to go further or reliably measure that you have gone further. The research community has expended billions without being able to determine how you can do that - so what makes you think that you can do any better given your far more limited resources? Metabolism and its interactions are so very, very complex. We can list with some confidence what is good for you, but talking about what is optimal is far beyond present capabilities.

For example, to pick one line item, let us consider calorie restriction. It works amazingly well in short-lived animals and improves short-term measures of human health far more than any presently available medical technology can manage. But once we get to an examination of longer lived animals (such as we primates) over the long term, it starts to become much harder to pin down the best, most optimal way to do things - certainly, the present primate studies are beginning to look as though they will generate as much ambiguity as data.

Dietary Restriction: critical cofactors to separate healthspan from lifespan benefits

Dietary restriction (DR), typically a 20-40% reduction in ad libitum or "normal" nutritional energy intake, has been reported to extend lifespan in diverse organisms including yeast, nematodes, spiders, fruit flies, mice, rats and rhesus monkeys. The magnitude of the lifespan enhancement appears to diminish with increasing organismal complexity. However, the extent of lifespan extension has been notoriously inconsistent, especially in mammals.

Recently, Mattison et al. report that DR does not extend lifespan in rhesus monkeys in contrast to earlier work of Colman et al. Examination of these papers identifies multiple potential confounding factors. Among these are the varied genetic backgrounds and composition of the "normal" and DR diets. In the monkeys, the correlation of DR with increased healthspan is stronger than that seen with lifespan, and indeed may be separable. Recent mechanistic studies in Drosophila implicate non-genetic cofactors such as level of physical activity and muscular fatty acid metabolism in the benefits of DR. These results should be followed up in mammals. Perhaps levels of physical activity among the cohorts of rhesus monkeys contributes to inconsistent DR effects.

To understand the maximum potential benefits from DR requires differentiating fundamental effects on aging at the cellular and molecular levels from suppression of age-associated diseases, such as cancer. To that end, it is important that investigators carefully evaluate the effects of DR on biomarkers of molecular aging, such as mutation rate and epigenomic alterations. Several short-term studies show that humans may benefit from DR in as little as 6 months, by achieving lowered fasting insulin levels and improved cardiovascular health.

Optimized healthspan engineering will require a much deeper understanding of DR.

That last sentence is worth considering at length - but remember that the 80/20 win for personal health is still right here, easily achieved. Instead of trying to go further in a presently impossible attempt at optimization, a better use of that time and energy lies in supporting research and development of rejuvenation biotechnology. Even a magically optimized personal health program would not allow most people to live to 100 with today's technology - the only way that the vast majority of us will get to see a three digit birthday cake is through progress in longevity science and its clinical applications.

So if you're going to spend any effort on this whole living longer in good health thing, spend it wisely. Don't chase rainbows.

Much like mammals, bivalve molluscs exhibit a very wide range of life spans. At the known outer end stands the arctic quahog at more than four centuries, and much studied in recent years so as to understand the roots of its longevity. That research project is still ongoing, as are similar comparative studies of aging and longevity in a range of other species.

Here, researchers compare resistance to various forms of physical stress and damage in different bivalve species. As you might expect from the view of aging put forward earlier today, longer-lived species are more resistant to most forms of damage:

Bivalve molluscs are newly discovered models of successful aging. Here, we test the hypothesis that extremely long-lived bivalves are not uniquely resistant to oxidative stressors (eg, tert-butyl hydroperoxide, as demonstrated in previous studies) but exhibit a multistress resistance phenotype.

We contrasted resistance (in terms of organismal mortality) to genotoxic stresses (including topoisomerase inhibitors, agents that cross-link DNA or impair genomic integrity through DNA alkylation or methylation) and to mitochondrial oxidative stressors in three bivalve mollusc species with dramatically differing life spans: Arctica islandica (ocean quahog), Mercenaria mercenaria (northern quahog), and the Atlantic bay scallop, Argopecten irradians irradians (maximum species life spans: more than 500, more than 100, and ~2 years, respectively).

With all stressors, the short-lived A i irradians were significantly less resistant than the two longer lived species. Arctica islandica were consistently more resistant than M mercenaria to mortality induced by oxidative stressors as well as DNA methylating agent nitrogen mustard and the DNA alkylating agent methyl methanesulfonate. The same trend was not observed for genotoxic agents that act through cross-linking DNA. In contrast, M mercenaria tended to be more resistant to epirubicin and genotoxic stressors, which cause DNA damage by inhibiting topoisomerases.

To our knowledge, this is the first study comparing resistance to genotoxic stressors in bivalve mollusc species with disparate longevities. In line with previous studies of comparative stress resistance and longevity, our data extends, at least in part, the evidence for the hypothesis that an association exists between longevity and a general resistance to multiplex stressors, not solely oxidative stress.

In mammals, you might look to the naked mole rat as an analogous species: very resistant to all sorts of biological and cellular damage, and extremely long-lived in comparison to similar sized rodent species.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23051979

Here is a framework for thinking about aging and longevity: various forms of low-level biological damage accrue as a result of the operation of metabolism, degrading organs and tissues and ultimately causing death. Where natural selection favors longer-lived individuals, mechanisms will evolve to repair, minimize, or resist the effects of this damage. So aging is driven by damage, but genetic programs interact with that damage, evolved to try to do something about it.

Thus we could expect to be able to manipulate life span either by repairing damage or by altering the programs. The former approach should produce far more effective means of healthy life extension, however, including rejuvenation of the old. In comparison, and from what we've seen so far in longevity science, modestly slowing aging is about the best we can expect from the near future of genetic and metabolic alterations.

In spite of exciting new insights into regulatory mechanisms that modulate the aging process, the proximal cause of aging remains one of the unsolved big problems in biology. An evolutionary analysis of aging provides a helpful theoretical framework by establishing boundary conditions on possible mechanisms of aging. The fundamental insight is that the force of natural selection diminishes with age. This does not preclude senescence (age-related decrease in individual fitness) from occurring in natural populations. Senescence can develop because some genes have non-separable, but typically different or opposite, functions in reproductive-age and in old individuals. Such genes, selected according to their "youthful" function, may thus impose a distinct senescent phenotype in old age.

In general, however, unless a controversial formulation of group selection is invoked, traits that would become manifest only in old age cannot evolve. This precludes the evolutionary emergence of aging programs, which have been sometimes postulated to exist in analogy to developmental and other biological programs. (By the same token, selective pressure that diminishes with age would also prevent extreme longevity from evolving, if "extreme" denotes a potential life span much longer than that imposed by extrinsic mortality in a given environment.) This and other arguments against the existence of an aging program have been discussed previously.

The evolutionary perspective sketched out above does not specify the mechanisms that underlie aging, but it helps to narrow down the possibilities. As already discussed, an evolved deterministic aging program can be ruled out, perhaps with the exception of specific niche situations. In the absence of adaptive life-curtailing processes driven by a putative aging program, we are left with untargeted pro-aging, destabilizing phenomena which, in principle, may range from purely stochastic to side-effects of "legitimate" biochemical pathways. These destabilizing forces are counteracted by evolved, and genetically controlled, longevity assurance (or repair/maintenance) processes. The interplay of these countervailing forces determines the life span.

While I have previously presented my detailed interpretation of this model, its central tenets bear repeating: (a) the destabilizing processes that drive aging are neither evolved nor adaptive; (b) in contrast, longevity assurance mechanisms are under genetic control; (c) together, these two opposing forces determine life span; (d) the average life span of a species is set by evolving longevity assurance mechanisms so as to optimize reproductive success under environmental conditions typical for that species.

Link: http://dx.doi.org/10.3389/fgene.2012.00189

Stem cell therapies offer all sorts of possible ways to intervene in disorders of the brain and nervous system: the evidence suggests that, as for other parts of the body, there is a lot that can be achieved by dropping in a bunch of fully functional cells of the right type and letting them get to work. Or, alternately, by finding ways to stimulate existing cell populations into working harder.

Most of these approaches fall into the category of patches: increasing the pace of repair and recreation of destroyed resources, but doing little to address the underlying reasons for damage and destruction. As a strategy this is second-rate, especially in the brain, but it is how the mainstream of medical research proceeds. In part we can blame regulatory bodies for the focus on patching end results rather than preventing root causes: the way in which requirements and costs are imposed on the development of new therapies leads to a situation in which it the less expensive (and in some cases only) path is to build treatments for late stage disease.

Damage to myelin, the sheathing for axons in nerve cells, is at the root of a number of serious medical conditions. As is the case for most of our biology the integrity of myelin declines with age; some fraction of the age-related decline in cognitive function that occurs for everyone is thought to stem from progressively less effective myelination in the brain. A number of research groups are engaged in ongoing work with stem cells aimed at the repair of myelin, and here is one example:

Stem Cells Myelinate Human Brain

Neural stem cells transplanted into the brains of people with Pelizaeus-Merzbacher disease (PMD) can differentiate and begin producing the myelin sheaths that these patients lack, according to results of a Phase I clinical trial. ... If the stem cell transplants do ultimately demonstrate benefit, they could help more than just PMD patients ... There's a wide range of possible myelin disorders that could be targeted, including demyelinating disorders like multiple sclerosis and preterm babies at risk for cerebral palsy due to white matter injury.

Here, as in many other cases, a therapy is under development for use with specific named diseases - but it might also prove helpful as a treatment for aging, as an attempt to retard loss of cognitive function. Yet there is no path to legally produce therapies for general use in all old people in the US: the FDA doesn't recognize treatment of aging as a legitimate use of medicine, and short a revolution there's little hope of changing that situation through existing paths. Until this changes, a great deal of promising work will be sidetracked into narrow usage for late stage specific diseases, and any real progress towards clinical applications for aging will have to happen outside the US research community.

One line of research into treatments for neurodegenerative disorders involves spurring the brain to establish new neural connections to replace those that have been damaged or lost. This seems like an inferior strategy in comparison to trying to identify and remove root causes, one that can only delay the inevitable, but it's nonetheless a fairly entrenched field of work.

Here is an example of this sort of research - and note that as for other similar efforts there are hints that an induced increase in neural plasticity would be beneficial for cognitive function in all older individuals:

Researchers have developed a new drug candidate that dramatically improves the cognitive function of rats with Alzheimer's-like mental impairment. Their compound, which is intended to repair brain damage that has already occurred [by] rebuilding connections between nerve cells.

[The scientists] have been working on their compound since 1992, when they started looking at the impact of the peptide angiotensin IV on the hippocampus, a brain region involved in spatial learning and short-term memory. ... angiotensin IV, or early drug candidates based on it, were capable of reversing learning deficits seen in many models of dementia. The practical utility of these early drug candidates, however, was severely limited because they were very quickly broken down by the body and couldn't get across the blood-brain barrier.

Five years ago, [the scientists] designed a smaller version of the molecule [called] Dihexa. Not only is it stable but it can cross the blood-brain barrier. An added bonus is it can move from the gut into the blood, so it can be taken in pill form. The researchers tested the drug on several dozen rats treated with scopolamine, a chemical that interferes with a neurotransmitter critical to learning and memory. Typically, a rat treated with scopolamine will never learn the location of a submerged platform in a water tank, orienting with cues outside the tank. After receiving the [drug], however, all of the rats did, whether they received the drug directly in the brain, orally, or through an injection.

[The researchers] also reported similar but less dramatic results in a smaller group of old rats. In this study the old rats, which often have difficulty with the task, performed like young rats. While the results were statistically valid, additional studies with larger test groups will be necessary to fully confirm the finding.

Link: http://www.eurekalert.org/pub_releases/2012-10/wsu-pad101012.php

Nature here notes progress towards tissue engineering of replacement thyroid glands and a demonstration of the ability to repair the thyroid in situ:

The thyroid is the latest in a growing list of body parts that can now be 'fixed' in mice, with the potential to treat diseases from diabetes to Parkinson's ... Progress has been very rapid over the past decade. In recent years we've seen a number of very important studies in which mouse stem cells have been converted to a desired cell type that has then been shown to be functional in vivo, and to confer benefits in mouse models of human diseases.

[Researchers] first genetically engineered embryonic stem cells to express two proteins - NKX2-1 and PAX8 - that are expressed together only in the thyroid. When these cells were grown in Petri dishes in the presence of thyroid-stimulating hormone, they turned into thyroid cells. Thyroid cells, however, have to be organized into a particular three-dimensional shape before they can work. They need to form small, spherical follicles containing a cavity in which iodide - a component of some hormones produced in the thyroid gland - can be concentrated before being absorbed and used for hormone synthesis. Remarkably, the stem-cell-derived thyroid cells spontaneously grouped into follicles similar to those in an intact thyroid gland [and] the follicles were able to trap iodide and synthesize thyroid hormones.

The next step was to see how these follicles would function in live mice, and to assess their potential to correct hypothyroidism. This condition was induced in mice with an injection of radioactive iodine that accumulated in their thyroid glands, causing the tissue to wither away. Four weeks later, once hypothyroidism had been established, the mice received a graft of stem-cell-derived thyroid follicles. Out of nine mice treated in this way, eight showed complete rescue - their thyroid hormones returned to normal levels.

Link: http://www.nature.com/news/thyroid-is-latest-success-in-regenerative-medicine-1.11574

I was recently asked for pointers on where to look for historical data on aging and longevity research: the number of active biogerontologists, a count of laboratories dedicated to aging research, levels of public and private funding, and other measures that might be taken as proxies for progress (or at least growth in the field). Unfortunately I don't have anything more than the first sketches of a guide to hand: assembling this sort of data for any industry is a fair-sized task. There are plenty of questions without ready answers, especially when it comes to the for-profit side of aging research, where the participants don't tend to publish easily discovered summaries.

Some obvious starting points exist, however. The International Aging Research Portfolio (IARP), for example, is an initiative that aims to make data on aging research easily available. The present focus there is on funding, but that data can be broken down by laboratory, region, researcher, and date. There are some trend tools to help produce visualizations.

When looking that over, bear in mind that the IARP data is mined from available databases of public research funding, which probably amounts to ~30-40% of life science and medical research funding in the US. I'm not sure whether that general figure holds for aging research as a field, or whether it is at all representative of other regions of the world that lack the weight of NIH funding. Embarrassingly, I knew the origin of that 30-40% estimate some years ago, but the details have slipped my mind and I can no longer track it down. You might try digging through sources such as NSF publications on funding levels to see what can be gleaned.

In a search for historical funding data or the demography of biogerontologists, it makes sense to look for research papers where the authors have done the legwork to establish private funding levels or other historical data that's harder to come by. It's possible that such papers exist for aging research, the results of past interest on someone's part. This is a comparatively small field with little commercial activity as of yet, however, so I'm not optimistic on the chances of finding more than patchy data. Google Scholar and PubMed are good starting points for this line of investigation.

Speaking of PubMed, the tools there allow one to casually research the historical pace of publication in a given field, as any search of the PubMed database shows a histogram of results by year. This is of course heavily weighted towards more recent papers, as electronic publication is a comparatively recent advance. Most of the published history of research has yet to be digitized and added to this resource. It should be possible to filter out this bias by taking the results of general searches such as "science" or "research" as a baseline, however.

Between 1981 and 2011, we can see the following results for papers that match these search terms:

Which is food for thought, even if it is an overly simplistic comparison: I didn't take the time to filter by journal topics, for example, so as to cut out papers on the aging of rock or longevity of flowers. Nonetheless, it suggests that aging research is being outproduced by other fields, but there is a strong and growing interest in the biology of longevity. The latter point fits with what I know of the recent history of this field.

It is hard to link numbers on research funding to actual progress, however. A healthy, large, and well-funded research community is a necessary prerequisite for progress, but these sorts of high level statistics don't say much about whether that community is actually working productively. When it comes to government funding, that's always a concern - but it's not as though the private sector is immune from barking up the wrong tree for years on end. The entities involved there have more of an immediate incentive to correct misallocation of resources, however, while government misallocation can continue for decades - and is, as we speak.

As regular readers will know, there is an enormous difference between working on ways to slow aging and working on ways to reverse aging. The former path means that we will gain little benefit from longevity science in our lifetimes. The latter path is the only way forward that might produce ways to rejuvenate the old before we age to death. Both research and development strategies may wind up costing similar amounts and take similar lengths of time to develop prototypes and laboratory demonstrations. Both look exactly the same when you're counting researchers, labs, and dollars. But one leads to certain death, and the other to the possibility of living for thousands of years.

If any of the folk out there have other suggestions for metrics or where to dig up data, feel free to add a comment.

Trying to safely slow down aging, usually by developing drugs to replicate some of the metabolic and epigenetic alterations caused by calorie restriction or exercise, is an immensely complicated undertaking. Success will be slow in coming, and the end result will be of little use for those already old - so other than an increase in the understanding of how metabolism and aging relate to one another, we should not expect this field of research to contribute much to the bottom line of our own longevity.

Nonetheless, this is the mainstream of research into longevity science and where most of the money goes. That state of affairs will have to change in favor of a focus on the more practical path of repairing biochemical damage associated with aging, with the aim of creating biotechnologies that can reverse the root causes of aging and thus bring about some degree of rejuvenation.

Here is an example of the sort of complications that arise when attempting to adjust metabolism. Interventions that are beneficial at one point in life may be harmful at others, and may further interact poorly with one another to produce a net harmful effect even though they are individually beneficial:

We tested the effects of a Class I histone deacetylase inhibitor (HDAcI) (sodium butyrate, NaBu) on the longevity of normal- and long-lived strains of Drosophila melanogaster. We report that this HDAcI has mixed effects in the normal-lived Ra strain in that it decreases mortality rates and increases longevity when administered in the transition or senescent spans, but decreases longevity when administered over the health span only or over the entire adult lifespan. It has dose-dependent effects when administered over the entire larval+adult life span. Only deleterious effects are noted when administered by either method to the long-lived La strain.

This apparently contradictory set of results is, however, what would be expected if the gene regulatory mechanisms affected by NaBu were those intimately involved in inducing gene expression patterns characteristic of a healthy senescence. Thus "mid- to late-life" drugs may have different stage-specific effects on different genomes of a model organism. A different HDAcI (suberoylanilide hydroxamic acid, SAHA) administered to the normal-lived strain showed similar late-life extending effects, suggesting that this is not an isolated effect of one drug.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23044027

You'll recall that researchers recently demonstrated that they could slow or reverse stem cell decline with age by manipulating FGF2 - in the satellite cell population that maintains muscle tissue, at least. Based on their work, the researchers proposed that stem cell aging involves issues with dormancy and recuperation. Because of certain changes in signaling in the supporting stem cell niche, stem cell populations in old muscles are not able to remain dormant sufficiently well to maintain their numbers and functionality.

Here is a commentary on this research, placing it into the context of other ongoing investigations into the causes of stem cell decline with aging and consequent loss of tissue integrity:

Gradual declines in tissue homeostasis, function, and regenerative ability are hallmarks of the aging process. Tissue-specific adult stem cells are the primary components of tissue regeneration and homeostasis. Therefore, an attractive theory to explain the age-associated decline in these processes centres around the effects of aging on stem cell function. The current debate focuses on the very nature of how stem cells age. Is the decline in stem cell function with age a cell autonomous change that happens due to the cumulative detrimental effects of DNA damage, epigenetic changes, or metabolic and mechanical stresses over time? Or is it an environmentally induced process whereby a perfectly functional stem cell is instructed to behave in a dysfunction manner by an aging niche or systemic milieu?

A recent [study] proposes a unique mechanism whereby a signal from the aged niche causes a cell autonomous and persistent change in the ability of a stem cell to maintain the quiescent state, which, over time, leads into impaired tissue regenerative capacity. ... aged satellite cells display an increased propensity to [leave quiescence, enter] the cell cycle and to undergo apoptotic cell death. ... What is particularly intriguing about environmental theories of stem cell aging is that they imply that the functional changes that occur in stem cells as they age are potentially reversible when the cells are placed in a 'young' environment.

This report also touches on another issue that is commonly debated: the role of stem cell number in the effects of aging on tissue function and regeneration. The reported effects of aging on stem cell number vary widely across different stem cell populations but also within the satellite cell literature. [The authors here] report reduced satellite cell numbers in aged animals and attribute that decline to the functional changes they describe: [increases] in cycling and cell death. They propose that functional changes of aged satellite cells, which have previously been shown to impair muscle regeneration, are further exacerbated by declining stem cell numbers. It will be interesting to determine if the maintenance of stem cell number can overcome their functional deficits to prevent an age-related decline in regenerative potential.

Link: http://www.nature.com/emboj/journal/vaop/ncurrent/full/emboj2012281a.html

The concepts and ideology relating to egalitarianism and social justice are associated with advocates and a community largely hostile to engineered human longevity. To the lay egalitarian extending healthy life looks like more inequality in the making, so they oppose longevity science for the same reasons they oppose every new idea that they believe might benefit the wealthy first of all: death for everyone before inequality for anyone is, depressingly, pretty much exactly where they stand. You can see manifestations of this line of thought in resource allocations and rationing forced on some regions by centralized planning in medicine - such as the "fair innings" argument in the UK, used to justify moving resources away from medical provision to the old.

To be clear, in that sort of situation it is the centrally planned, command and control Soviet-style institutions of clinical medicine that are the problems - rationing and fierce arguments over who should feed from the trough are only symptoms. These are outgrowths of the other line item that walks hand in hand with egalitarianism: the urge to power. Egalitarian ideals cannot be enacted without the power to force people to do what they would not otherwise have done: along this road lies socialism, fascism, communism. Any flavor of authoritarianism in medicine, as in all other human endeavors, inevitably destroys in the incentives for progress, good service, and quality that exist in a market. It doesn't matter how good the original intentions were, the end result is never in doubt; only how long it takes to destroy the wealth and progress that previously existed.

In any case, opposition to human life extension based on an assumption that it will create greater inequality is not uncommon. Egalitarians age, suffer, and die just like the rest of us, however, and we are now entering an era in which the research community might develop biotechnologies to reverse aging. Egalitarians thus have a strong incentive to either selectively abandon their convictions or find a way to advocate for work on rejuvenation biotechnology within their philosophies. As a topic, this has cropped up a number of times in the past here at Fight Aging!. See, for example:

• Radical Egalitarianism in Defense of Engineered Longevity
• Egalitarians and Engineered Longevity
• Longevity Science and the Social Justice Viewpoint

Here are more thoughts on the moral imperative to develop ways to defeat aging and age-related suffering, as seen from the egalitarian viewpoint of imposed obligations and duties. The use of aging as a term here is somewhat loose, but the point that is being made should be clear nonetheless:

The Duty to Extend the "Biological Warranty Period" (Part 1)

Over the coming months I intend to post a few thoughts that I am developing for a new paper on the duty to extend the human "biological warranty period" (via retarding the rate of molecular and cellular decline).

...

Writing in 1971, Singer wanted to bring attention to the neglected issue of global poverty, and the duties the affluent have to mitigate the disadvantage of those in distant lands. The fact that the vulnerable live very far away does not erode the strength of the moral duty to aid them. Many aspects of Singer's argument are important for my project, though my specific topic is different from his (i.e. tackling aging rather than poverty).

...

For the 21st century, I think the aging of the human species is *THE* challenge of our times. Unlike poverty, which is a problem it is easy for most people to perceive as a problem (even if they do not do enough to tackle it), one has to do a great deal of work to make vivid the magnitude of the challenges of global aging. ... Because it is difficult to grasp the magnitude of the harms of senescence most people simply take the current rate of aging, and the diseases and disability that result from it, as "a given". As if aging is natural, and death from aging something that has always happened to our species. But both of these assumptions are wrong. The aging of a species is not in fact natural, it is an artifact - a product of human intervention. The only species that age on this planet are those that humans protect from predation and starvation so that they live longer lives, and eventually expire the biological warranty period imposed by evolution through natural selection. Once a population begins to outlive the biological warranty period, there is an explosion in the prevalence of chronic disease, pain and disability. And this is the scenario of humanity today.

The Duty to Extend the "Biological Warranty Period" (Part 2)

So the argument I intend to develop in this new paper will be an exercise in empirical ethics. It takes seriously the reality that the aging populations of today face novel health challenges (e.g. high prevalence of chronic disease and disability) never experienced before in human history. The moral landscape thus needs to adapt to reflect this novel empirical reality. I begin with a basic moral principle - the duty to aid - and explore the implications empirical considerations from demography, evolutionary biology and biogerontology have for the way we think the duty to aid should be employed in the early 21st century.

What is the context of the human species today? Human populations are aging. Our populations are living longer lives than they ever have in human history, and we are having fewer children. The phenomenon of global aging will have a profound impact on the demands of morality.

In the real world, unfortunately, the widespread adoption of ideas relating to egalitarianism, positive rights, and enforced obligation tends to lead to bad end points, such as the former Soviet Union or the current state of medical regulation in Europe and the US - where it is illegal to try to produce a commercial therapy for aging, for example.

We humans are sadly somewhat hardwired to approve of enforcement of egalitarian ideals, through threat and violence if necessary. This evolved instinct for equality stands in opposition to the incentives and freedom required for rapid generation of wealth and technological progress throughout a society - if you can't keep the rewards of your labor, why work harder? If any reward due to success in a risky endeavor (such as medical research and clinical development) is partially confiscated for redistribution, there will be fewer groups willing to undertake that risk. And so forth.

It is worth noting that the incentives of individuals involved in these examples were all for better services, faster progress towards new medical technologies, and higher quality products - and yet in the name of equality and fairness they collaborated to create a system that harms these goals or makes them impossible. That should stand as a grim warning to those of us who would like to think that rejuvenation biotechnology is enough of a grail to overcome these tendencies toward destruction, stasis, and poverty.

Spurring the brain to produce new neurons more rapidly than it ordinarily does may be a useful form of therapy for a range of conditions - and also quite possibly something you'd want turned on as a matter of course, if it manifests the same sort of benefits to cognitive health as are produced by drugs that induce greater neural plasticity.

Here, researchers note an alternative to manipulating stem cell populations into building new neurons - instead work to convert some of the supporting cells in the brain into neurons:

"This work aims at converting cells that are present throughout the brain but themselves are not nerve cells into neurons. The ultimate goal we have in mind is that this may one day enable us to induce such conversion within the brain itself and thus provide a novel strategy for repairing the injured or diseased brain."

The cells that made the leap from one identity to another are known as pericytes. Those cells, found in close association with the blood vessels, are important for keeping the blood-brain barrier intact and have been shown to participate in wound healing in other parts of the body. ... Further testing showed that those newly converted neurons could produce electrical signals and reach out to other neurons, providing evidence that the converted cells could integrate into neural networks.

"While much needs to be learnt about adapting a direct neuronal reprogramming strategy to meaningful repair in vivo, our data provide strong support for the notion that neuronal reprogramming of cells of pericytic origin within the damaged brain may become a viable approach to replace degenerated neurons."

Link: http://www.eurekalert.org/pub_releases/2012-10/cp-nhn092812.php

There is a fair amount of research linking general health with the pace at which brain function declines with age: the less robust you are, the more likely you are to get dementia. We can look at the structural integrity and level of age-related decline in blood vessels in the brain as one possible mechanism to link such things as exercise and fitness to brain health, but there are undoubtedly others.

Here researchers look at links between lung health and brain function. Lung health, at least in the way it was measured in this study, may be a good marker for the sort of general robustness that both allows for and is improved by exercise:

Researchers used data from a Swedish study of aging that tracked participants' health measures for almost two decades. An analysis of the data with statistical models designed to show the patterns of change over time determined that reduced pulmonary function can lead to cognitive losses, but problems with cognition do not affect lung health.

The study sample consisted of 832 participants between ages 50 and 85 who were assessed in up to seven waves of testing across 19 years as part of the Swedish Adoption/Twin Study of Aging. ... Lung function was measured in two ways: forced expiratory volume, or how much air a person can push out of the lungs in one second, and forced vital capacity, the volume of air that is blown out after a deep inhalation.

"The logical conclusion from this is that anything you could do to maintain lung function should be of benefit to fluid cognitive performance as well. Maintaining an exercise routine and stopping smoking would be two primary methods. Nutritional factors and minimizing environmental exposure to pollutants also come into play."

Though this study does not explain what a loss of pulmonary function does to the brain, the researchers speculated that reduced lung health could lower the availability of oxygen in the blood that could in turn affect chemicals that transmit signals between brain cells.

Link: http://www.sciencedaily.com/releases/2012/10/121008144258.htm

Every tissue in the body has its corresponding population of stem cells or other progenitor cells that renew and repair it. These cells reside in a stem cell niche, a specialized set of cells that form an environment to regulate and control stem cell behavior. As the research community learns more, it is becoming apparent that changes and damage in the stem cell niche contributes more to the decline of stem cell function with age than any damage to the stem cells themselves.

Research along these lines tends to proceed cell type by cell type, however, and it's not always useful to generalize what is learned in muscle - perhaps the best studied tissue when it comes to stem cell biology - to all other tissue types in the body. But for the importance of stem cell niches, the same sort of behavior shows up in a number of different tissues: old stem cells transferred to a young niche act as though young, and young stem cells transferred to an old niche act as though old.

This dynamic is why the regenerative medicine community is going to have to figure out how to address the mechanisms of aging insofar as they affect stem cells: for a cell therapy to be effective in an old person, the aging of niches has to be reversed or at the very least worked around in some way.

Here is a recent open access paper that shows a stronger contribution to age-related decline from the niche than from the stem cells in another type of tissue:

Aging induced decline in T-lymphopoiesis is primarily dependent on status of progenitor niches in the bone marrow and thymus

The notion of aging-induced defects in the stem-cell niche rather than in the stem cells themselves, leading to system wide failure has been recently recognized in many systems, such as aging in oocytes/ovary, sperm/testis, and muscles. However, this scenario has not been widely accepted in T-lymphoid system aging.

Age-related decline in the generation of T cells is associated with two primary lymphoid organs, the bone marrow (BM) and thymus. Both organs contain lympho-hematopoietic progenitor/stem cells (LPCs) and non-hematopoietic stromal/niche cells.

Murine model showed this decline is not due to reduced quantities of LPCs, nor autonomous defects in LPCs, but rather defects in their niche cells. However, this viewpoint is challenged by the fact that aged BM progenitors have a myeloid skew - [the undesirable tendency to differentiate into myeloid cells rather than lymphoid cells].

By grafting young wild-type (WT) BM progenitors into aged IL-7R-/- hosts, which possess WT-equivalent niches although LPCs are defect, we demonstrated that these young BM progenitors also exhibited a myeloid skew. We, further, demonstrated that aged BM progenitors, recruited by a grafted fetal thymus in the in vivo microenvironment, were able to compete with their young counterparts, although the in vitro manipulated old BM cells were not able to do so in conventional BM transplantation.

Both LPCs and their niche cells inevitably get old with increasing organismal age, but aging in niche cells occurred much earlier than in LPCs by an observation in thymic T-lymphopoiesis. Therefore, the aging induced decline in competence to generate T cells is primarily dependent on status of the progenitor niche cells in the BM and thymus.

In the near term, working around this sort of issue for the purpose of stem cell therapies provided to old patients will probably involve finding and manipulating a limited number of signal pathways or epigenetic changes. This will to some degree override the effect of an old niches on resident or transplanted stem cells.

In the long term, however, the root causes of stem cell niche dysfunction must be addressed. At this time, we have no reason to believe that they are any different from the general causes of aging - accumulated damage of the various sorts outlined in the Strategies for Engineered Negligible Senescence. The system of tissue maintenance based on stem cells has evolved to decline in the face of increasing dysfunction, most likely as a way to reduce the risk of cancer. A range of controlling mechanisms linked to cell activity and tissue regeneration appear to manage a trade-off between risk of cancer (more activity) and aging by tissue decline (less activity).

The range of stem cell therapies now moving from the lab to the clinic - via the slow, expensive, and largely unnecessary regulatory process of clinical trials - are a long way advanced from the state of the art even as recently as a decade ago. Use of a patient's own cells, engineered and manipulated to improve the chances of a successful outcome, is the new standard.

As I've noted in the past, the stem cell research community must solve the issue of age-related decline in stem cell function in order to build effective therapies, as most of the medical conditions that need this sort of regenerative treatment only occur in the old:

Canadian heart-attack survivors will get first crack at an experimental therapy that's moving into clinical trials early next year. The treatment is believed to be the first in the world to test the ability of a patient's own stem cells, genetically engineered to have extra-strong healing powers, to repair damaged tissue caused by a heart attack.

To date, more than 2,000 heart-attack survivors, mostly in Europe, have received experimental injections of stem cells, often ones taken from their own bone marrow. However, the overall degree of improvement in the patients' heart function has been disappointingly modest. That has led some researchers to think the stem-cell system itself might age and lose its effectiveness in older people.

To solve this problem, [researchers have] come up with a way to turn back the biological clock of aging stem cells by genetically reprogramming them to have stronger healing properties. The theory is that these younger, more potent stem cells could grow enough new blood vessels to improve, if not fully restore, the heart's ability to pump blood.

In fact, previous studies have suggested that stem-cell therapy can still improve a patient's quality of life even if the overall improvement to heart function is incremental. "There's less development of heart failure, less hospital readmission, less bypass (surgery) and better survival. The data suggest you don't need to fully normalize. You just need to stabilize to such a degree that you're unlikely to go down that slippery slope."

Link: http://www.vancouversun.com/health/health/7342140/story.html

In recent years the Glenn Foundation for Medical Research has established a number of laboratories focused on aging research, building and funding an infrastructure to help grow and sustain this scientific community. The Foundation has donated modestly to SENS research to reverse aging in the past, but these laboratories are firmly in the mainstream of biogerontology. The researchers involved typically investigate mechanisms of aging and ways to slow aging only - this being the slow, hard road ahead that will never lead to methods of rejuvenation. Here is news of the latest:

Under a new $3 million grant from the Glenn Foundation for Medical Research, Princeton University researchers will study the biology of aging and healthspan. The grant will establish the Paul F. Glenn Laboratories for Aging Research at Princeton under the leadership of Coleen Murphy, associate professor of molecular biology and the Lewis-Sigler Institute for Integrative Genomics. The funding will support pioneering collaborative work by faculty members in neuroscience, computer science, computational biology, physics and mathematics on the biological mechanisms that control the aging process.

"While great progress has been made in the identification of general longevity regulators, most aging research is focused on late-life physical or biochemical characteristics, such as loss of movement or death," said Murphy, whose cutting-edge research on age-related declines in memory and reproductive ability has received support from several important sources. "Early aging has not been as well studied. I believe that careful quantification of behavioral characteristics will allow us to better analyze these early declines as well as to assess therapeutic improvements."

Link: http://www.princeton.edu/main/news/archive/S34/93/77Q68/index.xml

Here is a recently posted video in which SENS Foundation cofounder Aubrey de Grey discusses the mechanisms of aging and what to do about them:

Aubrey de Grey is a well-known researcher on the process of ageing. He sees ageing as a disease and believes science will soon be able to slow it down so that we'll have more time for science to advance even further so we can fix the cellular damages of ageing and - maybe one day - live forever.

"Live forever" is such a clumsy shortage for agelessness achieved through medical technology, given that you'd have to put in a lot of work to push much past a few thousand years in a human body - even with a risk function for fatal accidents that is small compared to the present day. But you can't exactly stop people from using the phrase.

The video above was published by Basil Gelpke, who is also behind Human 2.0, a DVD release that examines the prospects for engineered longevity, among other topics of interest to transhumanists. It's subtitled in German, but is English language:

The human being will be the first species able to understand its own blueprint. The rapidly increasing knowledge of genetics, nanotechnology, robotics, and AI will dwarf everything philosophers, scientists, science fiction writers and other visionaries have ever conceived. Human life without disease and possibly even without death doesn't seem impossible anymore.

The development of artificial replacements proceeds in parallel with tissue engineering as a way to build replacement parts for damaged corneas. Here, publicity materials tout recent progress in artificial corneas:

ArtCornea is based on a polymer with high water-absorbent properties. [Researchers] have added a new surface coating to ensure anchorage in host tissue and functionality of the optic. The haptic edge was chemically altered to encourage local cell growth. These cells graft to the surrounding human tissue, which is essential for anchorage of the device in the host tissue. The researchers aimed to enlarge the optical surface area of the implant in order to improve light penetration beyond what had previously been possible ... Once ArtCornea is in place, it is hardly visible, except perhaps for a few stitches. It's also easy to implant and doesn't provoke any immune response

The specialists have also managed to make a chemically and biologically inert base material biologically compatible for the second artificial cornea, ACTO-TexKpro. [They] achieved this by selectively altering the base material, polyvinylidene difluoride, by coating the fluoride synthetic tissue with a reactive molecule. This allows the patient's cornea to bond together naturally with the edge of the implant, while the implant's inner optics, made of silicon, remain free of cells and clear. The ACTO-TexKpro is particularly suitable as a preliminary treatment, for instance if the cornea has been destroyed as a consequence of chronic inflammation, a serious accident, corrosion or burns.

TexKpro and ArtCornea [were] first tested by the doctors in the [laboratory] in vivo in several rabbits. After a six month healing process, the implanted prostheses were accepted by the rabbits without irritation, clearly and securely anchored within the eye. Tests carried out following the operation showed that the animals tolerated the artificial cornea well. [Clinical trials will] soon commence at the Eye Clinic Cologne-Merheim.

Link: http://www.fraunhofer.de/en/press/research-news/2012/october/artificial-cornea-gives-the-gift-of-vision.html

Wired is running a photo essay on cryonics, the low-temperature preservation technique that intends to preserve the structure of the mind sufficiently well for patients to be restored to life by future technology:

The Prospect of Immortality is a six-year study by UK photographer Murray Ballard, who has traveled the world pulling back the curtain on the amateurs, optimists, businesses and apparatuses of cryonics.

"It's not a large industry," says Ballard, who visited the Alcor Life Extension Foundation in Phoenix, Arizona; the Cryonics Institute in Detroit, Michigan; KrioRus in Moscow, Russia; and Suspended Animation Inc in Boytan Beach, Florida; among others.

Cryonics is the preservation of deceased humans in liquid nitrogen at temperatures just shy of its boiling point of -196°C/77 Kelvin. Cryopreservation of humans is not reversible with current science, but cryonicists hypothesize that people who are considered dead by current medical definitions may someday be recovered by using advanced future technologies.

Stats are hard to come by, but it is estimated there are about 2,000 people signed up for cryonics and approximately 250 people currently cryopreserved. Over 100 pets have also been placed in vats of liquid nitrogen with the hopes of a future recovery.

Link: http://www.wired.com/rawfile/2012/10/murray-ballard-cyronics/

A toolkit for producing true rejuvenation in humans will require a range of different therapies, each of which can repair or reverse one of the varied root causes of degenerative aging. Research is underway for all of these classes of therapy, but very slowly and with very little funding in some cases. The funding situation spans the gamut from that of the stem cell research community, where researchers are afloat in money and interest, to the search for ways to break down advanced glycation endproducts (AGEs), which is a funding desert by comparison, little known or appreciated outside the small scientific community that works in that field.

While bearing in mind that progress in projects with little funding is unpredictable in comparison to that of well-funded projects, I think that we can still take a stab at a likely order of arrival for various important therapies needed to reverse aging. Thus an incomplete list follows, running from the earliest to the latest arrival, with the caveat that it is based on the present funding and publicity situation. If any one of the weakly funded and unappreciated lines of research suddenly became popular and awash with resources, it would probably move up in the ordering:

1) Destruction of Senescent Cells

Destroying specific cells without harming surrounding cells is a well-funded line of research thanks to the cancer community, and the technology platforms under development can be adapted to target any type of cell once it is understood how to target its distinctive features.

The research community has already demonstrated benefits from senescent cell destruction, and there are research groups working on this problem from a number of angles. A method of targeting senescent cells for destruction was recently published, and we can expect to see more diverse attempts at this in the next few years. As soon as one of these can be shown to produce benefits in mice that are similar to the early demonstrations, then senescent cell clearance becomes a going concern: something to be lifted from the deadlocked US regulatory process and hopefully developed quickly into a therapy in Asia, accessed via medical tourism.

2) Selective Pruning and Support of the Immune System

One of the reasons for immune system decline is crowding out of useful immune cells by memory immune cells that serve little useful purpose. Here, targeted cell destruction can also produce benefits, and early technology demonstrations support this view. Again, the vital component is the array of mechanisms needed to target the various forms of immune cell that must be pruned. I expect the same rising tide of technology and knowledge that enables senescent cell targeting will lead to the arrival of immune cell targeting on much the same schedule.

Culling the immune system will likely have to be supported with some form of repopulation of cells. It is already possible to repopulate a patient's immune system with immune cells cultivated from their own tissues, as demonstrated by the limited number of full immune system reboots carried out to cure autoimmune disorders. Alternatives to this process include some form of tissue engineering to recreate the dynamic, youthful thymus as a source of immune cells - or more adventurous processes such as cultivating thymic cells in a patient's lymph nodes.

3) Mitochondrial Repair

Our mitochondria sabotage us. There's a flaw in their structure and operation that causes a small but steadily increasing fraction of our cells to descend into a malfunctioning state that is destructive to bodily tissues and systems.

There are any number of proposed methods for dealing with this component of the aging process - either repairing or making it irrelevant - and a couple are in that precarious state of being just a little more solidity and work away from the point at which they could begin clinical development. The diversity of potential approaches in increasing too. Practical methods are now showing up for ways to put new mitochondria into cells, or target arbitrary therapies to the interior or mitochondria. It all looks very promising.

Further, the study of mitochondria is very broad and energetic, and has a strong presence in many areas of medicine and life science research. While few groups in the field are currently engaged in work on mitochondrial repair, there is an enormous reservoir of potential funding and workers awaiting any method of repair shown to produce solid results.

4) Reversing Stem Cell Aging

The stem cell research field is on a collision course with the issue of stem cell aging. Most of the medical conditions that are best suited to regenerative medicine, tissue engineering, and similar cell based therapies are age-related, and thus most of the patients are old. In order for therapies to work well, there must be ways to work around the issues caused by the aged biochemistry of the patient. To achieve this end, the research community will essentially have to enumerate the mechanisms by which stem cell populations decline and fail with age, and then reverse their effects.

Where stem cells themselves are damaged by age, stem cell populations will have to be replaced. This is already possible for many different types of stem cell, but there are potentially hundreds of different types of adult stem cell - and it is too much to expect for the processes and biochemistry to be very similar in all cases. A great deal of work will remain to be accomplished here even after the first triumphs involving hearts, livers, and kidneys.

Much of the problem, however, is not the stem cells but rather the environment they operate within. This is the bigger challenge: picking out all the threads of signalling, epigenetic change, and cause and effect that leads to quieted and diminished stem cell populations - and the resulting frailty as tissues are increasingly poorly supported. This is a fair sized task, and little more than inroads have been made to date - a few demonstrations in which one stem cell type has been coerced into acting with youthful vigor, and a range of research on possible processes and mechanisms to explain how an aging metabolism causes stem cells to slow down and stop their work.

The stem cell research community is, however, one of the largest in the world, and very well funded. This is a problem that they have to solve on the way to their declared goals. What I would expect to see here is for a range of intermediary stopgap solutions to emerge in the laboratory and early trials over the next decade. These will be limited ways to invigorate a few aged stem cell populations, intended to be used to boost the effectiveness of stem cell therapies for diseases of aging.

Any more complete or comprehensive solution for stem cell aging seems like a longer-term prospect, given that it involves many different stem cell populations with very different characteristics.

5) Clearing Advanced Glycation Endproducts (AGEs)

AGEs cause inflammation and other sorts of mischief through their presence, and this builds up with age. Unfortunately, research on breaking down AGEs to remove their contribution to degenerative aging has been a very thin thread indeed over the past few decades: next to no-one works on it, despite its importance, and very little funding is devoted to this research.

Now on the one hand it seems to be the case that one particular type of AGE - glucosepane - makes up 90% or more the AGEs in human tissues. On the other hand, efforts to find a safe way to break it down haven't made any progress in the past decade, though a new initiative was launched comparatively recently. This is an excellent example of how minimally funded research can be frustrating: a field can hover just that one, single advance away from largely solving a major problem for years on end. All it takes is the one breakthrough, but the chances of that occurring depend heavily on the resources put into the problem: how many parallel lines of investigation can be followed, how many researchers are working away at it.

This is an excellent candidate for a line of research that could move upward in the order of arrival if either a large source of funding emerged or a plausible compound was demonstrated to safely and aggressively break down glucospane in cell cultures. There is far less work to be done here than to reverse stem cell aging, for example.

6) Clearing Aggregates and Lysomal Garbage

All sorts of aggregates build up within and around cells as a result of normal metabolic processes, causing harm as they grow, and the sheer variety of these waste byproducts is the real challenge. They range from the amyloid that features prominently in Alzheimer's disease through to the many constituents of lipofuscin that clog up lysosomes and degrade cellular housekeeping processes. At this point in the advance of biotechnology it remains the case that dealing with each of the many forms of harmful aggregate must be its own project, and so there is a great deal of work involved in moving from where we stand today to a situation in which even a majority of the aggregates that build up with age can be removed.

The most promising lines of research to remove aggregates are immunotherapy, in which the immune system is trained or given the tools to to consume and destroy a particular aggregate, and medical bioremediation, which is the search for bacterial enzymes that can be repurposed as drugs to break down aggregates within cells. Immunotherapy to attack amyloid as a treatment for Alzheimer's is a going concern, for example. Biomedical remediation is a younger and far less funded endeavor, however.

My expectation here is that some viable therapies for some forms of unwanted and harmful metabolic byproducts will emerge in the laboratory over the next decade, but that will prove to be just the start on a long road indeed. From here it's hard for me to guess at where the 80/20 point might be in clearing aggregates: successfully clearing the five most common different compounds? Or the ten most common? Or twenty? Lipofuscin alone has dozens of different constituent chemicals and proteins, never mind the various other forms of aggregate involved in specific diseases such as Alzheimer's.

But work is work: it can be surmounted. Pertinently, and again, the dominant issue in timing here is the lack of funding and support for biomedical remediation and similar approaches to clearing aggregates.

One of the handful of genetic alterations shown to extend life in mice is removal of adenylyl cyclase 5 (AC5). Researchers have noted in the past that this seems to share mechanisms with the longevity induced by calorie restriction - indeed, it is suspected that many of the varied known ways of altering laboratory animals to extend healthy life are in fact different methods to activate the same few base changes in metabolism. Here is another paper on this topic:

Adenylyl cyclase type 5 knockout mice (AC5 KO) live longer and are stress resistant, similar to calorie restriction (CR). AC5 KO mice eat more, but actually weigh less and accumulate less fat compared to [wild type] mice. CR applied to AC5 KO result in rapid decrease in body weight, metabolic deterioration and death. These data suggest that despite restricted food intake in CR, but augmented food intake in AC5 KO, the two models affect longevity and metabolism similarly.

To determine shared molecular mechanisms, mRNA expression was examined genome-wide for brain, heart, skeletal muscle and liver. Significantly more genes were regulated commonly rather than oppositely in all the tissues in both models, indicating commonality between AC5 KO and CR.

Gene Ontology analysis identified many significantly regulated, tissue-specific pathways shared by the two models, including sensory perception in heart and brain, muscle function in skeletal muscle, and lipid metabolism in liver. Moreover, when comparing gene expression changes in the heart under stress, the glutathione regulatory pathway was consistently upregulated in the longevity models but downregulated with stress. In addition, AC5 and CR shared changes in genes and proteins involved in the regulation of longevity and stress resistance, including Sirt1, ApoD and olfactory receptors in both young and intermediate age mice. Thus, the similarly regulated genes and pathways in AC5 KO and CR [suggest] a unified theory for longevity and stress resistance.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23020244

SENS Foundation cofounder Aubrey de Grey is a tireless advocate for engineering the end of aging, and steers the work taking place on the foundations of rejuvenation biotechnology at the Foundation's research center and in a halo of allied laboratory groups. He gives a great many presentations on the work and goals of the Foundation in the course of any given year, and here is an article noting one such recent event at Princeton University:

The seminar, called "The Science and Ethics of Eliminating Aging," was sponsored by the University's Center for Human Values and chaired by bioethics professor Peter Singer. De Grey presented his research on anti-aging therapy, promoted his vision for a world in which humans do not experience the negative effects of aging and evaluated the benefits of and objections to this future society.

De Grey began his presentation by defining aging. He said his foundation does research on ways to limit damages done to the human body by natural metabolic processes and that he hopes the research will allow them to identify a physical state in which one could perpetually "look and feel and function like a young adult." There are seven specific types of damage aging does to the body, de Grey noted. Although solutions to these have not been reached, he described a scientific breakthrough his group achieved several months ago; a study they had performed showed increased viability of cells in a culture, which he said could have implications for stopping the damage that causes cardiovascular disease.

De Grey then described the feasibility and societal benefits of successful development of anti-aging technology. He said his research suggests a "50-50 chance of developing these therapies within the next 25 years to a level of sophistication that will confer ... robust human rejuvenation."

On a slide comparing two pictures, de Grey simply summarized his views on the positives and negatives of anti-aging: one of young people at play labeled "Fun" and another of a sickly senior citizen labeled "Not Fun." Therefore, he argued that everyone - from biologists to journalists to ordinary citizens practicing advocacy - should work to achieve successful anti-aging solutions.

Finally, de Grey suggested that a society in which people live indefinite life spans would have a higher quality of life. He noted that critics argue that indefinite life spans would lead to overpopulation and that living forever might not be desirable. However, those are not reasons to halt research into anti-aging solutions and those are ethical questions best decided by future generations, he said. "Even if we did have a problem [arising from anti-aging development] and humanity had a choice to make ... that's a choice humanity of the future is entitled to make for itself rather than having that choice imposed on it by our not choosing to develop these therapies," de Grey said.

Link: http://www.dailyprincetonian.com/2012/10/04/31380/

Senescent cells lurk in our tissues: these cells have exited the cell cycle and passed their sell-by date, but have not been destroyed as they should be, either by the internal processes of programmed cell death or by that portion of the immune system that watches for errant cells. Senescent cells behave badly, secreting chemicals that degrade surrounding tissue and harm nearby cells. In this way their presence contributes to degenerative aging.

As you become older the mechanisms keeping a lid on the number of senescent cells start to fail: there is more damage in cells and the immune system begins to run down, for example. The number of senescent cells grows inexorably, and the more of them there are, the more harm they cause. Thus any toolkit of therapies that aims to treat aging has to include some way of destroying senescent cells or reversing cell senescence.

Last year, researchers demonstrated that the onset of age-related degeneration in mice can be delayed by culling senescent cells. The method used was convoluted, however, and involved gene therapy - which makes it a poor candidate for anything other than demonstrating that removal of senescent cells is a good thing. There's no building a near-term therapy from that work.

The path to building a useful and straightforward therapy that kills senescent cells is pretty clear, however. There are any number of ways to kill a cell; the trick lies in picking out the cells you want to kill from the forest of their peers. Fortunately, the cancer research community has been very focused on this problem for many years now: how to deliver any of the proven cell-killing drugs to a specific set of cells that look slightly different from their neighbors without harming any of those neighbors. The past decade has seen great strides in the development of nanoparticles that can carry a payload, attached to some form of biological machinery capable of discriminating between cells based on one or more aspects of their surface chemistry. Flood the body with suitable nanoparticle delivery systems and they will find and kill only the cells you want to kill.

Cell surface chemistry is complex and far from black and white, of course. Nonetheless, work on targeting and delivery mechanisms is progressing rapidly in the laboratory. The results are very relevant to our desire to selectively and safely destroy senescent cells, and the real challenge here lies in the reliable identification of senescent cells. As noted last year, we need a robust way of identifying senescent cells; that is the one vital ingredient not yet in place that will allow all that cell-killing expertise present in the cancer research community to be turned to senescent cells.

It was only a matter of time, however, and here we have a first attempt at a targeting mechanism for senescent cells - which is exciting news if it pans out and the chemical signature of senescence that the researchers focused on here is a good distinguishing mark throughout the different tissue types in the body:

"The nanodevice that we have developed consists of mesoporous nanoparticles with a galactooligosaccharide outer surface that prevents the release of the load and that only selectively opens in degenerative phase cells or senescent cells. The proof of concept demonstrates for the first time that selected chemicals can be released in these cells and not in others," says Ramón Martínez Máñez, researcher at the IDN Centre - Universitat Politècnica de València and CIBER-BBN member.

José Ramón Murguía, a researcher at the Instituto de Biología Molecular y Celular de Plantas (UPV-CSIC) and also a CIBER-BBN member, explains that senescence is a physiological process of the body to eliminate aged cells or ones with alterations that may compromise their viability. "When we are young senescence mechanisms prevent, for example, the appearance of tumors, the problem is that with age senescent cells accumulate in organs and tissues, disrupting their proper functioning. The elimination of these cells would slow down the appearance of diseases associated with aging. Our work shows that we can develop a targeted therapy against these cells," says Murguía.

The researchers have evaluated the utility of the new nanodevices in primary cell cultures derived of patients with accelerated aging syndrome dyskeratosis congenita (DC). Such cultures show a high percentage of senescence characterized by elevated levels of beta-galactosidase activity, an enzyme characteristic of senescent state. "The aging cells overexpress this enzyme so we have designed nanoparticles that open when detected and release their contents in order to eliminate senescent cells, prevent deterioration or even reactivate for their rejuvenation"

Different people age at different rates. Efforts have long been underway to find a reliable, effective way to measure physiological age in order to relate that to remaining life expectancy and mortality rate. Without a biomarker of aging that can be easily measured, it will remain very challenging to evaluate future therapies that intervene in the aging process: how do you know whether a particular medical technology worked, or whether it worked better or worse than a competing therapy?

The wait and see approach for determining effects on life span requires years and millions of dollars in mouse studies, while finding a definitive answer in humans is out of the question on the time scales involved here. The whole field of medicine will be transformed over the next two decades, but it would take much longer than that to even begin to answer simple questions as to effects of prospective rejuvenation therapies in humans.

Telomeres are protective caps at the end of chromosomes. Their length is determined by a number of dynamic lengthening and shortening processes, but on average tends to erode with age or ill health. Thus telomere length has been proposed as a biomarker of aging, but as this paper shows simple measures of average telomere length are not all that useful in and of themselves:

The search for biomarkers of aging (BoAs) has been largely unsuccessful to-date and there is widespread skepticism about the prospects of finding any that satisfy the criteria developed by the American Federation of Aging Research. This may be because the criteria are too strict or because a composite measure might be more appropriate. Telomere length has attracted a great deal of attention as a candidate BoA. We investigate whether it meets the criteria to be considered as a single biomarker of aging, and whether it makes a useful contribution to a composite measure.

Using data from a large population based study, we show that telomere length is associated with age, with several measures of physical and cognitive functioning that are related to normal aging, and with three measures of overall health. In the majority of cases, telomere length adds predictive power to that of age, although it was not nearly as good a predictor overall. We used principal components analysis to form two composites from the measures of functioning, one including telomere length and the other not including it. These composite BoAs were better predictors of the health outcomes than chronological age. There was little difference between the two composites.

Telomere length does not satisfy the strict criteria for a BoA, but does add predictive power to that of chronological age. Equivocal results from previous studies might be due to lack of power or the choice of measures examined together with a focus on single biomarkers. Composite biomarkers of aging have the potential to outperform age and should be considered for future research in this area.

In this context, you may want to look at another recent paper where the authors suggest that more sophisticated measures of telomere dynamics, such as counting changes in the proportion of very short telomeres, are in fact good biomarkers of aging.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23028820

One of the reasons that nerves regenerate poorly has to do with the way in which the immune system responds to traumatic injury. In essence its behavior tends towards the formation of scar tissue that blocks nerve regrowth rather than allowing for regeneration. With greater understanding of the underlying mechanisms, researchers can try to change this state of affairs:

By altering activity of the macrophage cells that respond to injuries, researchers dramatically increased the rate at which nerve processes regrew. Influencing the macrophages immediately after injury may affect the whole cascade of biochemical events that occurs after nerve damage, potentially eliminating the need to directly stimulate the growth of axons using nerve growth factors.

Macrophages can exist in several different phenotypes depending on the signals they receive. Among the macrophage phenotypes are two classes - M2a and M2c - that encourage healing. [The] research team used an interleukin 4 (IL-4) cytokine to convert macrophages within the animal model to the "pro-healing" phenotypes. They placed a gel that released IL-4 into hollow polymeric nerve guides that connected the ends of severed animal sciatic nerves that had to grow across a 15 millimeter gap to regenerate. The IL-4 remained in the nerve guides for 24 hours or less, and had no direct influence on the growth of nerve tissue in this short period of time.

Three weeks after the injury, the nerve guides that released IL-4 were almost completely filled with re-grown axons. The treated nerve guides had approximately 20 times more nerve regeneration than the control channels, which had no IL-4-treated macrophages. Research is now underway to develop the technique for determining how soon after injury the macrophages should be treated, and what concentration of IL-4 would be most effective.

Link: http://www.eurekalert.org/pub_releases/2012-10/giot-ssi100212.php

I don't often talk about anything related to the overlap between supplements and aging. For one, that entire industry is irrelevant given the scope of regenerative medicine and rejuvenation biotechnology: the future is deliberately designed and targeted medical technologies, not the lingering remnants of past medical practices influenced by oral fixation and magical thinking. You can't fix anything of significance in human aging by digging around for found compounds to stick into your mouth - that is characteristic of the just-about-up-to-dealing-with-infections medicine of the last millennium, and the sooner this model ceases to dominate the public imagination the better.

Secondly, there are any number of vocal resources out there that talk about nothing but naturally occurring things that you can stick into your mouth. Many of them want to sell you those naturally occurring things, and of those folk a sizable contingent spend their time making loud and unsupported claims with regard to their products and human aging. Unfortunately there is so much money in that business that sense and ethics largely fled a long time ago.

Lastly, nothing you can presently buy, consume, or wear is anywhere near as effective as either exercise or calorie restriction when it comes to health over the long term. Science tells us that much, with a great weight of evidence, and anyone claiming otherwise has a tall hill indeed to climb to make any sort of a case. They try nonetheless, day in and day out, and merchant voices often outweigh those of the scientific community in our popular culture when it comes to the relationship between people, medicine, and aging.

So I don't often talk about anything related to supplements. It isn't productive. Still, occasionally research does show up to suggest that there might be meaningful benefits to some form of therapy using a common supplement or food item. It's pretty rare, however - next to nonexistent. The only one springing to mind right this instant is the evidence suggesting that the body processes the essential amino acid luceine increasingly poorly with aging. This contributes to the muscle wasting of sarcopenia, but, unlike nearly all such issues, can be staved off by adding more luceine to the diet.

Again, let me emphasize that this sort of situation is rare. It is almost never the case that a specific progressive failure in the body's biochemistry can be ameliorated by sticking more of something related to the failure into your mouth. Biology is far more complex than that - imagining that you can affect a specific portion of your biochemistry in some desired way by consuming one of the compounds involved in a reaction somewhere in the process is basically a form of magical thinking.

So that all said as a sort of preamble, let me point you to a study on zinc-related mechanisms that's presently doing the rounds, with links to the publicity release and the paper:

A new study has outlined for the first time a biological mechanism by which zinc deficiency can develop with age, leading to a decline of the immune system and increased inflammation ... The study was [based on findings in laboratory mice]. It found that zinc transporters were significantly dysregulated in old animals. They showed signs of zinc deficiency and had an enhanced inflammatory response even though their diet supposedly contained adequate amounts of zinc.

When the animals were given about 10 times their dietary requirement for zinc, the biomarkers of inflammation were restored to those of young animals.

"We've previously shown in both animal and human studies that zinc deficiency can cause DNA damage, and this new work shows how it can help lead to systemic inflammation. Some inflammation is normal, a part of immune defense, wound healing and other functions. But in excess, it's been associated with almost every degenerative disease you can think of, including cancer and heart disease. It appears to be a significant factor in the diseases that most people die from."

If a progressively disarrayed zinc metabolism does impact inflammation and immune function in a fairly general way, one would expect to see some beneficial effect on life span from suitably zinc-fortified diets. You might look at another recent paper for an example of researchers pumping extra zinc into laboratory animals to see what happens - I'm sure that there's much more out there from past decades if you care to go digging.

In any case, I note this research for its rarity rather than its potential utility. At the end of the day, how much zinc you put into your diet will not swing your life span by anywhere near as much as even a mediocre level of progress towards biotechnologies that can repair the root causes of aging. As a culture, we need to tear ourselves away from the propaganda of the supplement industry and the fascination with dietary tinkering: none of that will save lives or meaningfully deal with the fact that we're all aging to death.

Biotechnology is where we must look to the future of medicine: gene therapies, ways to precisely alter specific cellular components, targeted nanoparticles to remove senescent cells, stem cell engineering, tailored bacterial enzymes to break down unwanted intracellular waste products - these and many similar lines of research are the future and the path to living in good health for many more years than were available to our ancestors.

Cryonics provider Alcor is becoming more transparent and communicative under CEO Max More, which I see as a good thing. One of the long-term challenges faced by Alcor (and all cryonics providers, for that matter) relates to the common model for customer membership and setting prices, insofar as that is impacted by increasing costs brought on by inflation that takes place over the decades that elapse between a customer initially signing up and later being cryopreserved. It's hard to solve that problem gracefully without a great deal of dialog with the customer community, as it basically boils down to either losing a bunch of money, thus endangering the business, or asking customers to pay more than they originally agreed to:

The 2012 Strategic Meeting took place from Friday September 7 until Sunday September 9. All Alcor directors attended in person, as did Alcor president Max More. The Strategic Meeting is the annual, intensive review of the organizations priorities and performance. You will find a more extensive discussion of several of the outcomes in a forthcoming issue of Cryonics magazine, but here are the main resolutions and priorities on which agreement was reached:

...

As minimum requirements for funding of cryopreservation inevitably go up over time, members who did not take out insurance well over the minimum of the day - or who do not regularly add to their savings in the form of a trust or other fund reserved for cryopreservation - may find it difficult to meet new, higher minimums. For older members, adding to life insurance may be too expensive or not an option. Other assets may be illiquid yet substantial, real estate being a common example. At the meeting, the board and president discussed alternative funding methods and resolved further to pursue possible options.

If cryonics is to become more widely accepted in the general scientific community, we need to add to existing evidence for the effectiveness of our procedures. One way to do this is to gather more data during all stages of stabilization, transport, and cryoprotection. We can also gather evidence of the quality and effectiveness of brain perfusion and structural preservation by routine CT scanning of neuro patients and by conducting biopsies of spinal cord and possibly other samples for all patients. The board expressed general support for carefully moving forward with this, ensuring that members understand what we propose to do.

Link: http://www.alcor.org/blog/?p=2645

A replacement liver (or thymus or other organ) doesn't necessarily have to look like or be structured in the same way as the original - it just has to do the same job as the original. This is perhaps more obvious in the development of wholly artificial electromechanical organs than for tissue engineering, but it's still the case there as well.

Here is some interesting research that illustrates this point. In some cases specialized cell populations within an organ's structure are the important component of that organ, and thus to replace the organ's functions it is sufficient for those cells to exist in some useful location:

Lymph nodes can provide a suitable home for a variety of cells and tissues from other organs, suggesting that a cell-based alternative to whole organ transplantation might one day be feasible. [Researchers] showed for the first time that liver cells, thymus tissue and insulin-producing pancreatic islet cells, in an animal model, can thrive in lymph nodes despite being displaced from their natural sites.

In the study, [researchers] tested the possibility of using lymph nodes, which are abundant throughout the body and have a rich blood supply, as a new home for cells from other organs in what is called an "ectopic" transplant. They injected healthy liver cells from a genetically-identical donor animal into lymph nodes of mice at various locations. The result was an enlarged, liver-like node that functioned akin to the liver; in fact, a single hepatized lymph node rescued mice that were in danger of dying from a lethal metabolic liver disease. Likewise, thymus tissue transplanted into the lymph node of mice that lacked the organ generated functional immune systems, and pancreatic islet cell transplants restored normal blood sugar control in diabetic animals.

"Our goal is not necessarily to replace the entire liver, for example, but to provide sufficient cell mass to stabilize liver function and sustain the patient's life. That could buy time until a donor organ can be transplanted. Perhaps, in some cases, ectopic cell transplantation in the lymph node might allow the diseased organ to recover."

Link: http://phys.org/news/2012-09-liver-cells-insulin-producing-thymus-grown.html

Eyes are an unusual body part: they are a part of the nervous system, yet are non-vital, and further are easily accessible. The internals of the eye can be easily inspected without the need for invasive procedures. Eyes are prone to a number of well-studied progressive disorders, such as the varieties of macular degeneration, that seem very amenable to treatment through stem cell therapies.

So given all of this, and especially the point about accessibility, we might expect regeneration in the eye to be a proving ground for a class of techniques and therapies aimed at structures in the nervous system. It should be easier and less costly to make progress in therapies aimed at rebuilding damaged vision than for repair of other portions of the nervous system. Over the years this sort of difference in cost tends to add up to incrementally faster research and development.

A recent publicity release makes this point:

"The eye is a transparent and accessible part of the central nervous system, and that's a big advantage. We can put cells into the eye and monitor them every day with routine non-invasive clinical exams," Tsang says. "And in the event of serious complications, removing the eye is not a life-threatening event."

The work in question involved the creation of induced pluripotent stem cells (iPS cells), which were then used to generate a population of retinal cells, photoreceptors that respond to light by sending signals back to the optic nerve. These newly created photoreceptor cells can then be deposited into a damaged retina to take over the function of local cells that are dead or genetically damaged:

In their study, the researchers injected the iPS-derived retina cells into the right eyes of 34 mice that had a genetic mutation that caused their retina cells to degenerate. In many animals, the human cells assimilated into mouse retina without disruption and functioned as normal retina cells well into the animals' old age. Control mice that got injections of saline or inactive cells showed no improvement in retina tests.

"Our findings provide the first evidence of life-long neuronal recovery in a preclinical model of retinal degeneration, using stem cell transplant, with vision improvement persisting through the lifespan," Tsang says. "And importantly, we saw no tumors in any of the mice, which should allay one of the biggest fears people have about stem cell transplants: that they will generate tumors."

Tsang hopes to begin a clinical trial for macular degeneration patients in the next three years, after more preclinical testing in animal models.

As you can see, matters are progressing rapidly in this field. Ten years ago, people were getting terribly excited about simple advances in transplanting stem cells laboriously purified from donor tissue. Yet now no-one bats an eye when researchers create perfectly matched stem cells as needed from a patient skin sample, manipulate them to create arbitrary types and amounts of cell to order, and then put them to use in ways that may successfully repair a broad range of serious medical conditions.

These are interesting times that we live in. Ten years from now, we can be sure that the presently sophisticated manipulation of stem cells will seem pretty crude and backward in comparison - perhaps because researchers will have figured out how to direct existing stem cell populations in the body to take the required actions without the need for any sort of processing and cell production outside the body.

Still, there is a lot of back-filling that has yet to happen. It remains the case that there are hundreds of varied types of cell in the body, the bulk of which seem to be varieties of nerve cell. The research community is far from possessing the recipes needed to produce each and every type of cell on demand given a pluripotent cell to start with. Developing that set of protocols will be a fairly laborious process, even distributed between the world's laboratories as it is, and that is but one of the tasks which will likely differ greatly for each of the types of cell.

There is a forking of the way in aging research, and it matters greatly which path comes to dominate: whether the mainstream (a) continues as in the past, ignoring all mention of engineered longevity and doing nothing more than investigating aging, (b) focuses on limited ways to slow aging, largely in the name of compression of morbidity while trying to minimize talk of extended life spans, or (c) works on ways to reverse and repair the root causes of aging, with the explicit goal of extending healthy and maximum human life spans.

Of these options only (c) will greatly help those of us who will need ways to repair the damage caused by aging a few decades from now. Ways to slow aging do little for people who are already old. Unfortunately very little of the research community is presently interested in or working on repair of the root causes of aging - though that faction is larger today than in the past, thanks to persistent advocacy and organizations like the Methuselah Foundation and SENS Foundation.

This article shows us what failure will look like: what the end goal will be some decades from now if the "only work to slow aging" and "don't talk about extending life" factions continue to dominate the research community:

Dame Linda Partridge, a geneticist at University College London, claimed drugs will soon be available which can lower the risk of diseases like cancer and dementia by tackling the root cause - age itself. Rather than promising immortality, taking the drugs from middle age or earlier could dramatically shorten the period of illness and frailty that we typically experience before we die.

Speaking at the EMBO life sciences meeting in Nice, France this week Dame Linda said several existing drugs have already been shown to have unexpected and welcome side effects, such as aspirin which reduces the risk of cancer. Other therapies will be produced that mimic the effects of a severely restricted diet, which animal studies suggest can protect against a host of age-related conditions including heart disease and diabetes, she said.

Speaking after her keynote lecture, she said: "One obvious approach in trying to deal with the very rapidly increasing incidence of age related diseases is to tackle the underlying aging process itself, because it is the major risk factor. What we want is, rather than a lingering period of ill health, to have a fairly sudden death when it comes. We are not talking about immortality, we are trying to get rid of that period of ill health that people get towards the end of their lives, to hold off age related disease for longer."

Link: http://www.telegraph.co.uk/science/science-news/9573755/Pill-for-healthy-ageing-available-within-a-generation.html

One of the reasons that the adaptive immune system declines with age is that too much of its limited resources become devoted to uselessly chasing persistent herpesviruses like CMV. But there are other mechanisms at work too - not just a depletion of cells ready to act, but a decline in these cells' ability to act.

So we have research such as this, in which scientists chase down age-related molecular mechanisms that hold back the effectiveness of immune cells, and try to reverse them:

Circulating T-helper cells fall into two broad categories. "Naïve" T-helper cells have never encountered an antigen before (as in the case of, say, a rare or emerging pathogen or a new vaccine), but are capable of wheeling into action once they do. It takes a week or two to reach full tilt. "Memory" T-helper cells have previously been exposed to an antigen. These cells are long-lived and narrowly fixed on that particular antigen. They can rapidly transition to an activated state should the same antigen ever cross their path again. That's why prior exposure - through infection or a vaccine - renders us more resistant.

[Researchers] showed that faulty regulation in memory T-helper cells, due to aging-related increased levels of a protein called DUSP4, inhibits the activation of those cells, with their consequent failure to ignite a good B-cell (antibody-producing) response. This time around, the investigators uncovered a similar effect with a related protein, DUSP6, on naïve T-helper cells. In test tubes, they compared blood cells drawn from people ages 20-35 versus 70-85 in response to stimulation. In naïve T-helper cells (but not in memory cells), there were age-associated differences in a specific chain of biochemical events involved in the cells' activation, proliferation and differentiation. Laboratory tests showed that the culprit behind the cells' fecklessness in older people was DUSP6, [with levels that were] much higher in older people's naïve T-helper cells.

Further experimentation revealed that DUSP6's increase in aging naïve T-helper cells was caused by an age-associated easing up on a brake pedal called miR-181a, one among hundreds of small molecules made of RNA (called microRNA) that regulate proteins' production. ... Artificially boosting miRNA-181a levels in naïve human T cells caused DUSP6 levels to plummet, commensurately increasing those cells' readiness to activate on exposure to a given dose of influenza vaccine. In contrast, artificially increasing the levels of DUSP6 blocked the beneficial effects of heightened miR-181a levels.

Link: http://www.sciencedaily.com/releases/2012/09/120930142113.htm