Beyond the era of biotechnology lies the era of pervasive computation and advanced nanotechnology, starting around 2030, I would imagine. Processing cycles will be ten thousand times more abundant than now and applications of molecular manufacturing will be tentatively emerging from the labs. This is the era in which the human brain will be reverse-engineered, the first strong artificial intelligences constructed, and perhaps most importantly, inroads made into the grail of radical life extension: incrementally replacing the biology of the brain with something more robust and damage-resistant.

I would get my neurons replaced (slowly, one at a time over time, to ensure continuity of the self) with some form of much more robust, easily maintained nanomachinery. That allows these sorts of engineering possibilities:

• Swapping out the body for whatever machinery of transport and support best minimizes risk
• Moving most of the business of life into simulation
• Physically separating my neurons while still remaining alive, conscious and active

It's that last point that's key, as physical locations have the same sort of issues with time, probability and bad events as people do. Meteorites happen, as do landslides, earthquakes and volcanoes. The way to reduce your risk function dramatically is to spread out. You can imagine a wireless brain (using whatever the most robust communications technology of the time happens to be be) scattered in a thousand separate locations across a continent, or the whole planet.

I notice that the Future of Humanity Institute has published a (PDF) roadmap to whole brain emulation (WBE) - a tiny step towards the visions outlined above. In intent it could be compared to SENS, or the work of Drexler, Freitas and others on the design of medical nanomachinery: a foundation of theory on which research strategies can be built.

As this review shows, WBE on the neuronal/synaptic level requires relatively modest increases in microscopy resolution, a less trivial development of automation for scanning and image processing, a research push at the problem of inferring functional properties of neurons and synapses, and relatively business‐as‐usual development of computational neuroscience models and computer hardware.

This assumes that this is the appropriate level of description of the brain, and that we find ways of accurately simulating the subsystems that occurs on this level. Conversely, pursuing this research agenda will also help detect whether there are low‐level effects that have significant influence on higher level systems, requiring an increase in simulation and scanning resolution.

There do not appear to exist any obstacles to attempting to emulate an invertebrate organism today. We are still largely ignorant of the networks that make up the brains of even modestly complex organisms. Obtaining detailed anatomical information of a small brain appears entirely feasible and useful to neuroscience, and would be a critical first step towards WBE. Such a project would serve as both a proof of concept and test bed for further development.

If WBE is pursued successfully, at present it looks like the need for raw computing power for real‐time simulation and funding for building large‐scale automated scanning/processing facilities are the factors most likely to hold back large‐scale simulations.

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A couple of papers to compare and contrast:

Melatonin in relation to the "strong" and "weak" versions of the free radical theory of aging:

While the data supporting a role for melatonin in forestalling aging and prolonging life span per se is not compelling, the findings related to melatonin's ability to reduce the severity of a variety of age-related diseases that have as their basis free radical damage is convincing.

Melatonin prevents age-related mitochondrial dysfunction in rat brain via cardiolipin protection

Melatonin has been shown to possess antioxidant properties and to reduce oxidant events in brain aging. .... We found [that a number of] mitochondrial parameters were significantly altered with aging, and that melatonin treatment completely prevented these age-related alterations. These effects appear to be due, at least in part, to melatonin's ability to preserve the content and structural integrity of cardiolipin molecules, which play a pivotal role in mitochondrial bioenergetics.

Which is interesting to say the least; I would have lumped melatonin in with all the other antioxidant supplements - just because a chemical happens to affect some aspects of your biochemistry doesn't mean that ingesting it is going to have any positive benefit.

I have to wonder at what complexity is hidden here: a mechanism completely prevents alterations in mitochondrial parameters, and yet doesn't do anything for life span? Compare that with antioxidant chemicals targeted directly to mitochondria, which lead to significant extensions of healthy life. Mitochondria are complex objects, and (a) the state of their membranes, (b) the working of their inner processing mechanisms, and (c) the effects they have on their cell are not linked in straightforward ways.

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The rational actor looks at risks to life and health ahead and acts to minimize those risks. Since we all have limited time and resources, we have to prioritize: we make lists, in our heads if nowhere else, putting the most likely and terrible outcomes up at the top. Highly unlikely but terrible outcomes don't receive much attention: meteors, lightning strikes, that sort of thing. Likely but merely unpleasant events might just be suffered as a cost of getting on with life: catching the flu is an obnoxious happenstance, but not particularly threatening for most of us. There are more important things to worry about while buying insurance and otherwise taking care of essentials.

So you end up with a list involving fires, car accidents, sudden implosion of the company you work for, that sort of thing. In that, most of us are not being terribly rational, as aging isn't on the list. It is absolutely going to happen, and it leads to the most terrible personal consequence possible - death - via numerous other very nasty personal consequences. Alzheimer's, heart disease, cancer, and all the rest. We all have a 100% chance of aging as things stand, and it's the worst thing that will happen to most of us. So why isn't it up near the top of that priority list?

On that subject, thoughts from a bioethicist I seem to be linking to a lot of late. Replace "we" with "I" and "society" with "an individual" and it works just fine:

the following four issues are vital:

1. The certainty of the harm (e.g. 0.1% vs 70% chance)
2. The severity of the harm (e.g. broken leg vs death)
3. The likelihood of mitigating the harm (e.g. 0.1% vs 70%)
4. The cost of mitigating the harm ($1 billion vs $1 trillion)

...

Aging increases one’s risk of disease and death. So the empirical evidence clearly shows that aging scores very high on (1) and (2). These facts alone show that aging is a BIG problem.

How about issues (3) and (4)? People are most likely to (mistakenly) assume aging research scores low on both these fronts. That is, people are skeptical that we can actually modify the biological processes of aging. But there are countless experiments in a variety of organisms that show aging is not immutable. And so the goal of retarding human aging scores reasonably well on (3). And once you add considerations (1) and (2) into the mix, it becomes evident that the current neglect of aging research is unjustified.

People will also falsely assume that (4) will require vast amounts of money. But here one must put things in their proper context. A lot of money compared to what? What we spend on national defence? National defense spending in the U.S. has reached approximately $1,600 per capita, compared to $97 per capita for federal spending on biomedical research (source)

Which I think is a fair summary of where things stand - aging is terrible, but those who would act to materially support longevity science don't believe that progress is possible, or that progress is cost-effective. Meanwhile, individuals pledge significant time and money for food, entertainment, and geopolitical machinations. You might want to refresh your memory as to the Strategies for Engineered Negligible Senescence (SENS) cost breakdown: a billion dollars over ten years to develop the medical technologies capable of rejuvenating aged mice in the laboratory, each of the seven branches of SENS requiring something like $15 million per year over that time.

Effective research is cheap compared to almost everything else connected with aging: the loss of wealth, deteriorating health, loss of contributing members of society, the elderly care infrastructure, and more. It's a great pity that support and fundraising lags so far behind the potential of longevity science.

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Mainstream research on the biochemistry of aging and longevity - with an eye to slowing down aging rather than repairing it - is at this time primarily focused on a small number of areas. One is the cluster of mechanisms and signaling pathways associated with insulin and insulin-like growth factor 1 (IGF-1). You might recall that a tenfold increase in nematode life span was engineered via manipulation of IGF-1, for example:

Reis' team discovered that a mutant in the insulin/ IGF-1 pathway of C. elegans slows development but ultimately produces adults he described as "super survivors," able to resist levels of toxic chemicals that would kill an ordinary worm. Although the adult lifespan of C. elegans is normally only two to three weeks, half of the mutant worms were still alive after six months, with some surviving to nine months.

While perusing PubMed, I noticed a couple of papers on insulin, IGF-1, and aging:

Insulin and aging

In invertebrates, signaling pathways homologous to mammalian insulin and insulin-like growth factor (IGF-1) signal transduction have a major role in the control of longevity. There are numerous indications that these pathways also influence aging in mammals, but separating the role of insulin from the effects of IGF-1 and growth hormone (GH) is difficult.

In mice, selective disruption of the insulin receptor in the adipose tissue extends longevity. Increases in lifespan were also reported in mice with deletion of insulin receptor substrate 1 (IRS1) in whole body or IRS2 only in the brain. GH deficiency or resistance in mutant mice leads to hypoinsulinemia and enhanced insulin sensitivity along with remarkably extended longevity.

These characteristics resemble animals subjected to calorie restriction. Studies of physiological characteristics and polymorphisms of insulin-related genes in exceptionally long-lived people suggest a role of insulin signaling in the control of human aging.

Role of the GH/IGF-1 axis in lifespan and healthspan: Lessons from animal models

Consistently, two interventions, caloric restriction and repression of the growth hormone (GH)/insulin-like growth factor-1/insulin axis, have been shown to increase lifespan in both invertebrates and vertebrate animal model systems. Caloric restriction (CR) is a nutrition intervention that robustly extends lifespan whether it is started early or later in life. Likewise, genes involved in the GH/IGF-1 signaling pathways can lengthen lifespan in vertebrates and invertebrates, implying evolutionary conservation of the molecular mechanisms.

Specifically, insulin and insulin-like growth factor-1 (IGF-1)-like signaling and its downstream intracellular signaling molecules have been shown to be associated with lifespan in fruit flies and nematodes. More recently, mammalian models with reduced growth hormone (GH) and/or IGF-1 signaling have also been shown to have extended lifespans as compared to control siblings. Importantly, this research has also shown that these genetic alterations can keep the animals healthy and disease-free for longer periods and can alleviate specific age-related pathologies similar to what is observed for CR individuals. Thus, these mutations may not only extend lifespan but may also improve healthspan, the general health and quality of life of an organism as it ages.

With the level of interest presently devoted to this subject, I imagine that a decade from now researchers will fully understand how IGF-1, insulin, growth hormone, and calorie restriction all fit together into the bigger picture of the natural range of metabolic processes in response to circumstances. Your diet and exercise choices change the way your biochemistry operates: the biochemical mechanisms by which this happens have a deep evolutionary history.

It seems evident that some large portion of the research community will continue to forge ahead with strategies to shift your metabolism into a better state for your long term health - replicating calorie restriction, or mutations known to be beneficial. This is not a path to radical extension of the healthy human life span, however. It will only produce modest gains. To move beyond the small goals, we have to aim to repair the damage of aging rather than just slow down its accumulation. It will be no harder to achieve from where we are now, and the rewards are far greater.

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The latest Rejuvenation Research is available online; I'm interested to note the contribution of another "social justice"-style bioethicist. Regular positive engagement with the ideas and goals of longevity science is a fairly recent phenomenon for that portion of the social studies crowd; while their ideas are just as contemptuous of freedom as the root of progress here as everywhere else, I view diversification as progress. There is some truth in the view that libertarian cliques get things started, but their goal only becomes a movement when the socialist masses finally join in with a clamor of "you must," "we should," and "there ought to be a law!"

It is usually the case that you will see sentences containing "should" and "we" in this way when you're being sold up the river. There exists some group of people who think you should live your life a certain way, regardless of your opinions on the matter, and this is a little of the manner in which they build up a rhetoric to justify their eventual use of force and constraint of law. Assumptions of inclusion and unity via "we" and assumptions of authority via "should." Neither are true; you're not a member of their little group unless you choose to be, and there is no authority beyond that which you grant them of your own choice.

Here's the social science paper that prompted this line of discussion:

The Normative Dimensions of Extending the Human Lifespan by Age-Related Biomedical Innovations:

The current normative debate on age-related biomedical innovations and the extension of the human lifespan has important shortcomings. Mainly, the complexity of the different normative dimensions relevant for ethical and/or juridicial norms is not fully developed and the normative quality of teleological and deontological arguments is not properly distinguished.

This article addresses some of these shortcomings and develops the outline of a more comprehensive normative framework covering all relevant dimensions. Such a frame necessarily has to include conceptions of a good life on the individual and societal levels. Furthermore, as a third dimension, a model for the access to and the just distribution of age-related biomedical innovations and technologies extending the human lifespan will be developed. It is argued that such a model has to include the different levels of the general philosophical theories of distributive justice, including social rights and theories of just health care. Furthermore, it has to show how these theories can be applied to the problem area of aging and extending the human lifespan.

It is unfortunate that human cultures seem so hardwired for inefficiency and waste - so much time spent on trying to justify coercion of others to attain your personally favored goals. Human nature is what it is, for now at least: best to keep plugging away at the problems you care about and do your best to hold up a decent set of standards by persuading rather than coercing.

Even if we could draft the masses to work to defeat aging, we should not do it; that would make us no better than those deathists who would set the agency of government to block research and mandate age-related death to their schedule.

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The human body is not a homogeneous mass, but rather a networked collection of very different structures and systems. Unsurprisingly, then, aging affects different tissues at different rates. This is just the same as in any engine, simple or complex: some components tend to fail due to accumulated damage more rapidly than others. For example:

The 80-year-old Norwegian received a cornea transplant fifty years ago, a piece of tissue now 123 years old that still works today. It could be the oldest eye, or even human body part, still functioning or to have ever been in use for so long. ... He had a cornea transplanted into his right eye in 1958, from a man born in June 1885. At the time it was expected to work for only 5 years. However, Reuters report that the procedure has been in use since the early 20th century. That means there could be even older corneas out there.

There is no profound lesson to be learned here, but this another useful example to present to people unfamiliar with the bounds of life span and survival in the natural world. If tortoises, whales, and this cornea can all manage such lengthy survival, it encourages the belief that medical research can engineer the same for human life in general. It is easier for people to accept that a goal can be accomplished based upon the evidence of a near example already in existence than in the absence of any example at all.

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What biological systems trigger the beneficial effects of calorie restriction? The response to limited calorie intake is an evolutionary adaptation to periods of famine that extends longevity in most species tested so far. The mechanisms that determine whether or not to trigger this response are still under investigation, but some intriguing results are surfacing. Last year, scientists demonstrated that sense of smell is important for calorie restriction in flies:

A team of scientists [found] that the average life span of fruit flies on restricted diets decreased when they were exposed to food odors. The findings [suggest] that the flies are "actually perceiving the environment," thinking they are in a nutrient-rich place and then their bodies are "adaptively responding to it."

A recent experiment demonstrates the opposite effect in nematode worms, another favored experimental animal:

Many animals live longer when raised on low calorie diets. But now [researchers] have shown that they can extend the life spans of roundworms even when the worms are well fed - it just takes a chemical that blocks their sense of smell.

...

it's possible that sensory perception cues have important metabolic consequences independent of what we actually eat. "Emerging evidence suggests that core metabolic pathways that modulate lifespan in worms also modulate lifespan in vertebrates such as mice and perhaps humans. Sensory pathways might also be fairly universal. In an ancient common ancestor, these pathways might have caused metabolic adjustments that affect lifespan. That could be reflected in our own biology."

It wouldn't be surprising to uncover some influence on the metabolic changes of calorie restriction from sensory systems in more complex animals like us - but whether or not it exists and is significant is pure speculation at this stage. It does present another possible place to start looking for ways to trick the body into enacting these changes independently of diet, however.

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Another thoughtful post from In Search of Enlightenment; always interesting to see how the other half of the healthy life extension community presents and interprets the ideas we hold in common:

When people ask me what I am working on I inevitably mention aging and the aspiration to retard human aging. This provokes many different responses. The most common response is a sense of surprise that we might actually be able to do something about aging. This is of course understandable, for if one had not been following the field of biogerontology for the past few years one might assume that aging is immutable, for that was a common belief. But this belief has been proven wrong- aging is not immutable.

Once I note this people often persist in their scepticism, and express doubt that we could actually develop a technology that could slow aging in humans (rather than just in mice). Again, this scepticism is understandable, indeed some scepticism is warranted. But I often ask them how much scepticism they have about finding a cure for cancer, or reversing climate change. And when it comes to these issues they are pretty optimistic about the likelihood that these goals could be achieved.

It's a long post and covers a lot of ground, so read the whole thing. The more people writing seriously on these issues, the better - and even more so when the community of writers displays a wide plurality of backgrounds and philosophies. These are signs of progress in the breadth of support for longevity research.

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One of the more interesting recent developments in tissue engineering is recellularization: removing all the cells from an organ, leaving only the extracellular matrix as a blueprint, and then repopulating that blueprint with cells from the patient who will receive the finished tissue. It's a clever way around our present inability to grow organs from scratch, or generate nanoscale scaffolds as complex as the extracellular matrix. As an added bonus, organs and tissue from animals can be used as the basis for a transplant.

I noticed a press release today that delves a little more into ongoing recellularization work outside the US, by a different group to that receiving the more recent press attention:

The three scientists were nominated for the development and successful transplantation of tissue engineered biological cardiac valves for children, which grow with the patients ... The "decellularised and re-colonised pulmonary valves" developed by Haverich and his team provide child patients with significantly improved chances of survival and a better quality of life. In Europe around 1,200 heart valve transplants a year are performed on children. The mechanical heart valves normally used in these operations have the disadvantage that they require lifelong blood thinning treatment and are susceptible to infections. The biological heart valves from pigs or cows used as an alternative are again only of limited durability. Children with heart valve defects therefore normally have to undergo multiple operations - with all the physical and psychological pressures and risks this entails.

Haverich and his colleagues, on the other hand, use heart valves that are "grown" from the young patient's natural body cells. To do this, a valve from a human or animal donor is removed of all cells using tissue engineering, so that only its outer framework remains. This valve matrix is then colonised with cells that have been obtained from the blood of the recipient and propagated. Within a few weeks, a quasi-natural heart valve then emerges in this bioreactor, that exhibits no rejection response or other faults, but instead grows with the patient after the implantation.

Recellularization makes xenotransplantation a much more viable technology to fill the tissue engineering gap prior to the ability to grow complex organs from scratch. Transplanting complex organs on demand is still a secondary target in the grand scheme of things, however - transplants are traumatic affairs, as for any major surgery. What we really want is sufficient control over our own cells that we can direct them to completely repair and regenerate existing organs.

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One of the effects of oppressive regulation in medical research is that animals have better access to cutting edge therapies than people:

Veterinary science continues to provide the shining example of where we could be with even just a little less waste, less socialism and less pointless, self-serving bureaucracy.

In the race to perfect 'regenerative medicine,' stem cell therapy for animals is ahead of treatment for humans because it is not so strictly regulated. It's not experimental - it's here. ... There are no side effects and no problems with rejection, because the patient is also the cell donor. ... I don't see any reason why humans aren't doing it."

Here is another example of the sort of work presently taking place in veterinary medicine, but that is many (government-enforced, largely unnecessary) trials away from reaching human clinics:

Tendon injuries can be career-killers for horses: only 5 to 15 percent of those with damaged tendons will ever make it back to the track, he says. But a novel treatment that Casey developed - injecting adult tendon cells grown in a lab into horses’ injured core lesions - has had remarkable success. The first 10 of 14 horses treated have returned to intensive training, and seven of these racers are back in full competition, he says. “We’re putting back natural tissue into a defect that has formed,” says Casey. “It’s minimally invasive. So far so good.”

...

They’re looking to take their findings in regenerative medicine in animals and apply them to humans. Think new treatments for stubborn injuries to areas like the Achilles tendon and rotator cuff. “Before the rotator cuff goes, we would be able to put tenocytes back into the tear and help heal,” says Casey.

Before that happens, however, there’s work to do, Casey says, including safety studies to determine that once injected, cells stay where they’re supposed to and don’t travel. Another would be to determine that the cellular signaling message to “turn on” or divide gets “turned off” again. Therapy Cells has hired a legal team in Washington, D.C. to work toward approval from the U.S. Food and Drug Administration. “It will revolutionize how you treat tendon injuries,” predicts Casey.

Casey says he and his team will await guidance from the FDA about the next steps to take. “But our first target is to hopefully gain FDA approval and in short order have human applications in human tendons,” he says. If that day arrives, he may finally end up with patients who can actually talk to him about their treatment.

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Following up on a post from a few days back on the benefits that the discovery of induced pluripotency is bringing to stem cell research, I thought I'd point out this article:

The first reports of the successful reprogramming of adult human cells back into so-called induced pluripotent stem (iPS) cells, which by all appearances looked and acted liked embryonic stem cells created a media stir. But the process was woefully inefficient: Only one out of 10,000 cells could be persuaded to turn back the clock.

Now, a team of researchers led by Juan Carlos Izpisua Belmonte at the Salk Institute for Biological Studies, succeeded in boosting the reprogramming efficiency more than 100fold, while cutting the time it takes in half. In fact, they repeatedly generated iPS cells from the tiny number of keratinocytes attached to a single hair plucked from a human scalp.

For a variety of reasons, technical and otherwise, inducing pluripotency in adult cells is within the present capacity of many more laboratories and researchers than embryonic stem cell research. More researchers means faster progress - as illustrated above. I expect to see a great deal of progress in the broader field of controlling our cells resulting from this line of work over the next few years.

Ultimately, the aim is to be able to understand and control the mechanism of potency - thus enabling any cell to be transformed into any other type of cell. The result of all this work would be low cost, efficient regenerative medicine. Age-damaged or injured tissue? No problem, just grow a fresh, undamaged replacement in culture from your own healthy cells.

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While differences in mitochondria are clearly very important to aging and longevity, this is not the case for all specific differences between your mitochondria and those of the person next to you. For example, take a look at this paper that draws on the Ashkenazi Jewish centenarian study:

Association of mitochondrial haplogroup J with longevity has been reported in several population subgroups. While studies from northern Italy and Finland, have described a higher frequency of haplogroup J among centenarians in comparison to non-centenarian, several other studies could not replicate these results and suggested various explanations for the discrepancy.

...

There does not exist a universal association of mitochondrial haplogroup J with longevity across all population groups.

It is not at all unreasonable to expect differences in mitochondria between genetic subgroups of the same species to influence longevity - even for the comparatively tiny biochemical changes involved in differentiating one haplogroup from another. Mitochondria are the engines of our cells, and numerous experiments have shown that altering their effective output of damaging free radicals can greatly influence healthy life in mammals. I can envisage future decades in which mitochondrial replacement is not just a matter of preventing the age-related degeneration caused by damaged mitochondria, but also upgrades your birth mitochondria to a more robust version - either discovered somewhere else in the human species or engineered de novo based on what is known at the time.

For all that, these are early days in the underlying science, and haplogroup J doesn't appear to be an important difference.

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There closer scientists look, the more ways they find for our aging stem cells to fail. Since stem cells are necessary to repair ongoing wear in our tissues, their loss of function is an important contributer to degenerative aging. My attention was drawn today to a novel discovery: a malfunction in the mechanisms of cell replication and differentiation that doesn't look much like any of the more familiar ways in which cells fail with age.

Asymmetric division of adult stem cells generates one self-renewing stem cell and one differentiating cell, thereby maintaining tissue homeostasis. A decline in stem cell function has been proposed to contribute to tissue ageing, although the underlying mechanism is poorly understood. Here we show that changes in the stem cell orientation with respect to the niche during ageing contribute to the decline in spermatogenesis in the male germ line of Drosophila.

Throughout the cell cycle, centrosomes in germline stem cells (GSCs) are oriented within their niche and this ensures asymmetric division. We found that GSCs containing misoriented centrosomes accumulate with age and that these GSCs are arrested or delayed in the cell cycle. The cell cycle arrest is transient, and GSCs appear to re-enter the cell cycle on correction of centrosome orientation.

On the basis of these findings, we propose that cell cycle arrest associated with centrosome misorientation functions as a mechanism to ensure asymmetric stem cell division, and that the inability of stem cells to maintain correct orientation during ageing contributes to the decline in spermatogenesis. We also show that some of the misoriented GSCs probably originate from dedifferentiation of spermatogonia.

So, translated to English from the Scientese: there is a fiddly, complex structure within stem cells upon which their most vital function - the generation of new cells - depends. This structure, the centrosome, only works when in the right relationship with the surrounding stem cell niche. As flies get older, more and more of stem cells fall out of this correct relationship.

Interestingly, we already know that the stem cell niche, the tissue in which stem cells are sustained, is important in the decline of stem cell function with aging - it's wrong to think of stem cells in isolation. The real mechanism in your body consists of an entire stem cell population plus the signaling and support mechanisms of the niche in which they are sustained. It's all connected.

This new finding will no doubt have scientists scratching their heads and digging in deeper. Are misaligned centrosomes a cause or effect - a symptom of other cellular damage, or a stand-alone form of decline? It will be interesting to find out.

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As regular readers already know, damage to your mitochondrial DNA is important to the aging process. It is the first step in a chain of events that leads to dysfunctional mitochondria, damaged tissues, and processes run awry in the body. You might want to follow that link and read the introduction if this is new to you.

Some effects of accumulated mitochondrial damage are more direct than others: in age-related retinal disease for example.

Mitochondria are central to retinal cell function and survival. There is increasing evidence to support an association between mitochondrial dysfunction and a number of retinal pathologies including age-related macular degeneration (AMD), diabetic retinopathy and glaucoma.

The past decade has highlighted mitochondrial genomic instability as an important factor in mitochondrial impairment culminating in age-related changes and age-related pathology. This represents a combination of the susceptibility of mitochondrial DNA (mtDNA) to oxidative damage ... This random cumulative mtDNA damage leads to cellular heteroplasmy and, if the damage affects a sufficient proportion of mitochondria within a given cell, results in loss of cell function and greater susceptibility to stress.

mtDNA damage is increased in the neural retina and RPE with aging and appears to be greatest in AMD. It thus appears that the mitochondrial genome as a weak link in the antioxidant defenses of retinal cells and that deficits in mitochondrial DNA (mtDNA) repair pathways are important contributors to the pathogenesis of retinal degeneration. Specifically targeting mitochondria with pharmacological agents able to protect against oxidative stress or promote repair of mtDNA damage may offer potential alternatives for the treatment of retinal degenerations such as AMD.

The dysfunctional regulatory regime for medical research in most developed nations ensures that significant funding is only available for applications of science to named diseases. Much of the limited groundwork presently taking place to develop a way to repair mitochondrial DNA is actually aimed at specific gene defects associated with specific forms of hereditary blindness, for example. This is the perverse result of the incentives in place: potentially revolutionary science is corralled and herded down alleys of limited application. No developer will invest in a revolution when the government prevents them from selling the results of their labor - and for every example you hear about, a hundred take place in silence. The real cost is what you don't see - researchers working towards what is possible rather than what is permitted.

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The 4th Strategies for Engineered Negligible Senescence (SENS) conference will be held a little less than a year from now in Cambridge, England, with registration opening at the end of this year. Mark your calendars:

The purpose of the SENS conference series, like all the SENS initiatives (such as the journal Rejuvenation Research and the Mprize), is to expedite the development of truly effective therapies to postpone and treat human aging by tackling it as an engineering problem: not seeking elusive and probably illusory magic bullets, but instead enumerating the accumulating molecular and cellular changes that eventually kill us and identifying ways to repair -- reverse -- those changes, rather than merely to slow down their further accumulation.

The meeting will comprise invited talks, short oral presentations of submitted abstracts, and poster sessions. There will be no concurrent sessions. Talks will take place in the Fitzpatrick Lecture Hall. Poster sessions will take place each evening in the conservatory adjacent to the bar, with the customary free alcohol.

You might want to take a look at the archives for SENS3, the last conference in the series, for examples of what to expect - the presentation videos are especially worthy of attention. Additionally, you'll find links to SENS3 conference reports back in the Fight Aging! archives.

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The more time you spend thinking about aging, longevity science, and a future in which aging can be repaired, the further you move away from the mindset shared by most people in the world. At times it can be a challenge to recall that, yes, you lived in a "pro-aging trance" back in the day, accepting that growing old and dying was just the way of things. It's a part of the very human tendency to see the world as it is, continuing forever: at some level, we're hardwired to reject all prospects for change as being somewhat ridiculous. So we grow up in the world that is, and comparatively few people spend much time looking beyond that to the world that could be.

Anyway, this line of thinking is prompted by an interesting post over at In Search of Enlightenment:

Those who have read some of my academic work, or past entries on this blog, will know I am an advocate of longevity science. I am very interested in hearing the arguments and reactions people have to the aspiration to slow human aging, for I myself shared some of these reservations when I first began thinking about these issues. But over time I realized that many of my initial reactions or concerns to longevity science where either misinformed or focused on concerns that are, in the big picture of things, minor when compared to the enormous benefits of extending healthy life.

So here I want to reflect a bit on some of the issues that arose in our class discussion and debate concerning tackling human aging.

It's a long post. Setting aside the redistributive economic viewpoint, it covers a lot of useful ground in the ongoing discussion about aging and extending the healthy human life span.

From the long term perspective, longevity science is still in the earliest stages of building a foundation of support. The handful of multi-million dollar philanthropic initiatives presently taking place are a few seedlings in the middle of an empty field: the final engineered longevity research community will be - must be - vast by comparison. It will look very much like the cancer research or regenerative medicine communities today.

When talking about progress over decades, the most important part of that progress is not the year in which scientific progress reaches a tipping point - although that helps - but it is the year in which advocacy and education reaches a tipping point. Significant progress occurs when a large number of people want it to occur: up until that point matters tends to move slowly. This means that we should pay more attention to the way we used to think, back in the day. How did we wake from our pro-aging trances? That event has to be repeated many millions of times over the next decade if a large community and effective community of supporters, researchers, and fundraisers is to arise.

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As I've noted in the past, it's essential to keep an eye on progress in infrastructure in science and research. When costs are lowered and easy of use increases, more people join the research community, and those already achieve existing goals more rapidly. New goals, previously too costly to consider, become attainable. Cost of infrastructure is the foundation upon which a research community takes form and makes progress.

Cost isn't just a matter of dollars, of course, though it all boils down to dollars and time in the end. You have to consider the skills of potential researchers - is the technique too hard for most? Also the equipment needed for a given strategy: do many laboratories already have it in place, and thus have no need to invest money before research can commence? Improvement can be as much a matter of making new strategies work for existing staff and equipment as inventing a new and cheaper methodology.

I noticed an article today that gives a very good idea of the level of benefit brought to the regenerative medicine community by the development of induced pluripotent stem (iPS) cells. To refresh your memory as to what these are:

A pluripotent cell can create all cell types except for extra embryonic tissue

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Induced pluripotent stem cells, commonly abbreviated as iPS cells or iPSCs, are a type of pluripotent stem cell artificially derived from a non-pluripotent cell, typically an adult somatic cell, by inducing a "forced" expression of certain genes. Induced Pluripotent Stem Cells are believed to be identical to natural pluripotent stem cells, such as embryonic stem cells in many respects

As the article notes, many more laboratories are equipped and ready to work with iPS cells than with embryonic stem cells:

He said he's amazed at how quickly scientists have begun exploring the use of the reprogrammed skin cells he reported on last year. "People are jumping in very rapidly, much more rapidly than they did 10 years ago" after the initial discovery of embryonic stem cells, Thomson said.

In all, 812 labs in dozens of countries have requested the materials needed to reprogram ordinary cells into iPS cells, said Addgene, a Massachusetts-based repository for research supplies. By contrast, a half-dozen or so labs started working with embryonic stem cells in the months after his landmark 1998 paper, Thomson said.

Progress along this path will be much more rapid than the progress we've seen in the past decade. This is exactly the sort of acceleration needed if we are to see cultured replacement organs and other radical applications of regenerative medicine in emerging from the labs a decade from now.

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The Immortality Institute's Folding@Home prize contest enters its third quarter:

The 2nd quarter of the F@H prize competition came to a close September 30th and it was been another blowout quarter in terms of team success. During the 2nd quarter the Longevity Meme team rose from position 167 to 124 (as of Sept 24th) while PPD output increased 200% (up to an average of 160,000).

The 3rd quarter competition is now in swing (all competitor’s scores were reset to zero October 1st) and even more prize money is up for grabs due to generous support from the Life Extension Foundation. Not only has the prize amount for the top twelve competitors increased, a 13th prize has been added – to be randomly awarded to one folder who is outside of the top 12. To top it all off, the Life Extension Foundation has offered a free 6 month LEF membership to all of the F@H prize registrants

Competitors are earning their prizes by contributing unused processor cycles from their computers to the Stanford Folding@Home project.

The process of protein folding, while critical and fundamental to virtually all of biology, in many ways remains a mystery.

Moreover, when proteins do not fold correctly (i.e. "misfold"), there can be serious consequences, including many well known diseases, such as Alzheimer's, Mad Cow (BSE), CJD, ALS, Huntington's, Parkinson's disease, and many Cancers and cancer-related syndromes.

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Folding@home is a distributed computing project - people from throughout the world download and run software to band together to make one of the largest supercomputers in the world. Every computer takes the project closer to our goals.

It's easy to jump on in and compete:

1. Go to the Stanford Folding@home website and download the folding client to your computer (or PS3), link: http://folding.stanford.edu/English/Download

2. Enter the number 32461 (Longevity Meme team number) in the “team number” box when installing the Folding@home client.

3. Register as a “Registered User” or “Member” at the Immortality Institute and affirm your participation in the competition by making an initial post in this forum: http://www.imminst.org/forum/index.php?showtopic=20898. This step is required as the Institute will be paying the prize money to the winners through Paypal. You must have a Paypal account in order to receive your winnings. Also, if you already registered during the 1st or 2nd quarter, there is no need to register again.

Winners will be determined by how many points are accumulated over the course of three months as reported at the Stanford Folding@home statistics site. The 3rd quarter of competition begins at 12:00 a.m. Eastern daylight time (U.S.) October 1st and ends at 12:00 midnight, Eastern daylight time, on December 31st.

What are you waiting for?

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Research in recent years has made it clear that the composition of the membranes in your cells - the relative proportions of proteins and amino acids that make up their structure - has a lot to do with how long you live. When comparing longevity between species, at least. This is the membrane pacemaker theory of longevity:

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

Mitochondria, the power plants of your cells, generate damaging reactive oxygen species (ROS) in the course of their operation: ROS will race off to damage the first thing they can find by reacting with it, such as a cell membrane. Mitochondria themselves have membranes, and are first in line to be damaged by the ROS they generate. Eventually damage accumulates and cascades to change the surrounding cellular environment very much for the worse. This process is an important root cause of degenerative aging.

This is why those species more resistant to the damaging effects of reactive oxygen species live longer than their peers. A good example is the naked mole rat, which lives eight times longer than similarly sized rodent species.

With this theme in mind, I noticed an open access paper today that looks at membrane composition differences a little closer to home: in the mitochondria of primates:

The mitochondrial (mt) gene tree of placental mammals reveals a very strong acceleration of the amino acid (AA) replacement rate and a change in AA compositional bias

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the rate acceleration in the simian lineage is accompanied by a marked increase in threonine (Thr) ... his Thr increase involved the replacement of hydrophobic AAs in the membrane interior [and] analysis reveals a statistical significant positive correlation between Thr composition and longevity in primates.

Even in primates, the composition differences are important - no doubt altering the process of ROS damage and mitochondrial dysfunction that contributes to aging. It reinforces just how central our mitochondria are to aging and longevity, and how vital it is to speed research into repairing damaged mitochondria in humans.

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Mathematical models of the way in which the world works, built from observed data and then manipulated to discover patterns, can teach us a great deal. The reliability theory of aging is one result of this approach: it doesn't tell us the exact mechanisms that cause us to age, but still sheds a lot of light on what those mechanisms could be. For example:

Living organisms seem to be formed with a high initial load of damage, and therefore their lifespan and aging patterns may be sensitive to early-life conditions that determine this initial damage load during early development. The idea of early-life programming of aging and longevity may have important practical implications for developing early-life interventions promoting health and longevity.

I noticed a paper today in which researchers modeling the Gompertz-Makeham law of mortality come to the same conclusion from the opposite direction in the modeling space. The important thing to remember here is that we all start with some non-zero mortality rate as a result of what reliability theory calls the high initial load of damage. Aging is then the increase in our current mortality rate as time goes by and we become more damaged.

A key goal of gerontology is to discover the factors that influence the rate of senescence, which in this context refers to the age-dependent acceleration of mortality, inversely related to the morality rate doubling time. In contrast factors that influence only initial mortality rate are thought to be less relevant to the fundamental processes of aging.

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Of particular interest, [our] improved estimates indicate that most genetic manipulations in mice that increase lifespan do so by decreasing initial mortality rate, not rate of senescence, whereas most genetic manipulations that decrease lifespan surprisingly do so by increasing the rate of senescence, not initial mortality rate.

This is a rather interesting conclusion, and certainly a novel way of looking at the varied gene-engineered mice strains that live longer, healthier lives. It suggests that some mutations are building better mice at the outset, but doing little to the aging process. Is this actually the case? More research is needed.

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Taking care of the health basics - a good physician, exercise, diet, and supplementation - in a steady, reliable way makes a real difference in the long term. It is probably possibly to swing the end of your life twenty years one way or another at today's level of medical technology. That is just the result of choices you make and resulting changes in health and level of biochemical damage sustained over the years - no magic involved.

Here's a study offered as one more piece of evidence for the benefits of keeping on top of commonplace health matters:

Following up on growing evidence that higher levels of conscientiousness are associated with greater health protection, the authors conducted a meta-analysis of the association between conscientiousness-related traits and longevity.

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Using a random-effects analysis model, the authors statistically combined 20 independent samples. In addition, the authors used fixed-effects analyses to examine specific facets of conscientiousness and study characteristics as potential moderators of this relationship.

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Higher levels of conscientiousness were significantly and positively related to longevity. ... Associations were strongest for the achievement (persistent, industrious) and order (organized, disciplined) facets of conscientiousness. ... Results strongly support the importance of conscientiousness-related traits to health across the life span.

If you let things go, the consequences will come back and bite you in years to come, cutting your life short and increasing your chances of missing out on the development of real, working rejuvenation medicine.

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Here is a review with some interesting implications:

Hematopoietic stem cells (HSCs) are defined by their ability both to self-renew and to give rise to fresh blood cells throughout the lifetime of an animal. The failure of HSCs to self-renew during aging is believed to depend on several intrinsic (cell-autonomous) and extrinsic (non-cell-autonomous) factors. In this review, we focus on how dysregulation of reactive oxygen species (ROS) and disruptions of genomic stability can impair HSC functions.

Recently, it was shown that long-term self-renewing HSCs normally possess low levels of intracellular ROS. However, when intracellular ROS levels become excessive, they cause senescence or apoptosis, resulting in a failure of HSC self-renewal. Repression of intracellular ROS levels in HSCs by treatment with an antioxidant that scavenges ROS can rescue HSC functions, indicating that excess ROS levels are at the root of HSC failure.

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Further investigations on the molecular mechanisms of ROS regulation and on the manipulation of excess ROS levels could lead to the development of novel therapeutics for hematopoietic diseases, regenerative medicine, and the prevention of leukemia.

Rising levels of ROS with age are due to dysfunctional mitochondria. Could it be that the steady accumulation of mitochondrial damage - and the rising levels of ROS that result from that damage - contributes to shutting down stem cells in addition to all the other issues it causes?

Targeting antioxidants to stem cells in additional to cellular mitochondria begins to sound like something worth trying in mice. Will it extend healthy life by keeping stem cells active for longer, or will increased stem cell activity bring more and earlier cancer due to the other damage caused by mitochondrial ROS? If the root problem is the reactive oxygen species, tackling that problem first might be more effective than trying to keep cellular system running in the face of the ROS assault.

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The evolution of aging is a fascinating topic: why do we age, and why do we age the way we do? Why are some species near-immortal, so far as we can measure, while others come and go in the blink of an eye? How is it that we live far longer than many of our nearest relatives in the animal kingdom, but nowhere near as long as we'd like? You'll find a number of posts on that topic back in the archives:

• On the Inevitability of Aging
• Ageless Animals, Absent Immortality, Evolutionary Biology and Aging
• Evolution, Longevity and the Grandmother Hypothesis
• Ouroboros on the Evolution of Extreme Longevity
• Mitochondrial Optimization and the Evolution of Human Longevity

And so forth. The latest batch of SAGE Crossroads podcasts looks at the evolution of aging. I think you'll find them interesting.

#51 - Evolution of Aging - What are the prominent theories of how we age?

Daniel Perry discusses a few of the major theories of aging. He also tells us why it's important to understand these theories and how they impact aging research.

#52 - Evolution of Aging - Accounting for aging across species

KYLE JENSEN: Now do you know why the species, the aging in species, is vastly different?

STEVEN AUSTAD: No, that’s ultimately the question we hope to answer because if you look at the natural world the difference in aging between the shortest lived and longest lived species is vastly greater than that we can create in the laboratory. So, we feel like nature is providing us with good examples and all we need to do is figure out the key mechanisms that differ between the short and the long lived species.

#53 - Evolution of Aging - What is the developmental drift theory?

The idea of developmental drift is that a developmental pathway that’s used to make healthy tissue in normal animals is not maintained in old age. In our case, there is a developmental pathway that has three regulators, L5 - L6 - L3, whose normal job is to make particular tissues in the young worm in the intestine, and these three regulators are no longer maintained in the old worm, and so one of the developmental regulators turns down and two turn up in old age, and these become unbalanced.

When these become unbalanced, the transcription factors become unbalanced and they cause myriad downstream changes in gene expression that are detrimental to the worm. All of this happens in old animals, that is after the force of natural selection has gone away. Everything we’re talking about are things that happen to the homeostatic processes when nature no longer cares about homeostasis.

These are, I should emphasize, representative viewpoints from the mainstream of aging research - wherein scientists believe that altering metabolism to slow aging is the only viable path forward.

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