A Preliminary Roadmap to Whole Brain Emulation
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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.

Unregulated Prices Fall, While Quality Improves
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A piece from the LEF Magazine that makes the points about modern medical research that most people don't think about: "the public today tolerates federal and state laws that enable pharmaceutical companies to conduct business as a virtual monopoly. The result is that Americans pay outlandish prices for mediocre drugs that are often laden with side effects. ... Unlike regulated prescription drugs, the cost of dietary supplements has plummeted over the past three decades. ... in a free market environment, technological breakthroughs that occurred in telecommunications will also happen in medicine. ... More frightening is the suffocating effect that regulation has on the discovery of life-saving therapies. Just imagine if advancement in clinical medicine progressed at the same rapid rate as telecommunications. If it did, we would probably have cures for most killer diseases today!" Heavily regulated markets are bloated, slow markets, in which the incentives are so set as to discourage progress. Present regulation is a very real threat to the future of your health and longevity.

Link: http://www.lef.org/magazine/mag2008/sep2008_Would-You-Tolerate-This-Abuse_01.htm

Incremental Improvements in Stem Cell Therapy
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Researchers continue to find ways to alter stem cells to produce better therapies: "Adult stem cells resemble couch potatoes if they hang out and divide in a dish for too long. They get fat and lose key surface proteins, which interferes with their movement and reduces their therapeutic potential. Now, via a simple chemical procedure, researchers have found a way to get these cells off the couch and over to their therapeutic target. To do this, they simply added a molecule called SLeX to the surface of the cells. The procedure took just 45 minutes and restored an important biological function. ... Delivery remains one of the biggest hurdles to stem cell therapy. The blood stream offers a natural delivery vehicle, but stem cells don't move through blood vessels normally after being expanded in culture. Our procedure promises to overcome this obstacle. ... Karp cautions that his lab's discovery must be validated in animals, before doctors can apply it in the clinic. He's collaborating with another lab to test the homing ability of the SLeX-dotted cells in mice."

Link: http://www.eurekalert.org/pub_releases/2008-10/hms-scp102908.php

Melatonin and Hidden Complexity
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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.

A Little More on IGF-1 and Growth Hormone
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Following up on a recent Fight Aging! post, more on the role of IGF-1 in longevity: "Using a mouse model relevant for humans, we showed that lifespan can be significantly extended by reducing the signaling selectively of a protein called IGF-I in the central nervous system. ... This caused growth retardation, smaller adult size, and metabolic alterations, and led to delayed mortality and longer mean lifespan. Thus, early changes in neuroendocrine development can durably modify the life trajectory in mammals. The underlying mechanism appears to be an adaptive plasticity of somatotropic functions allowing individuals to decelerate growth and preserve resources, and thereby improve fitness in challenging environments. ... continuously low IGF-I and low growth hormone levels favor extended lifespan and postpone age-related mortality. ... our results further challenge the view that administration of GH can prevent, or even counteract human aging. This knowledge is important since growth hormone is often prescribed to elderly people in an attempt to compensate the unwanted effects of aging."

Link: http://dx.doi.org/10.1371/journal.pbio.0060254

Ouroboros On Mitochondrial Uncouplers
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From Ouroboros: researchers "suggest that mitochondrial uncoupling is an effective mimic of [calorie restriction (CR)]. In mitochondria, the electron transport chain uses electrons from glucose and lipids to pump protons across a membrane. This proton gradient can be used to make energy in the form of ATP through oxidative phosphorylation. The process is kind of like generating hydropower. Uncouplers work by putting a leak in the dam, which lets water through without going to the generator. They 'uncouple' the electron transport chain from oxidative phosphorylation, thus reducing the efficiency of energy production. Although animals have uncoupling proteins (these proteins are important for thermogenesis, especially during hibernation), so far there are no known agonists. The researchers instead used low doses of the mitochondria uncoupler DNP. ... The DNP treated mice ate the same amount of food as control mice but had lower body mass [and] showed many phenotypes observed in calorie restricted mice. Like CR mice, DNP treated mice had higher rates of respiration with lower production of ROS. ... Most importantly, DNP treated mice showed an extended lifespan. This study suggests that mitochondrial uncouplers are an effective mimic of calorie restriction and might be a realistic therapeutic intervention for delaying aging and extending lifespan."

Link: http://ouroboros.wordpress.com/2008/10/30/mitochondrial-uncouplers-mimic-the-effects-of-calorie-restriction/

On Risk and Acting Appropriately
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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.

Your Internal Antioxidant Systems
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While consuming antioxidants doesn't seem to do much good, the state of your internal antioxidant systems is very important to health and longevity. "In aerobic organisms, oxygen is essential for efficient energy production but paradoxically, produces chronic toxic stress in cells. Diverse protective systems must exist to enable adaptation to oxidative environments. Oxidative stress (OS) results when production of reactive oxidative species (ROS) exceeds the capacity of cellular antioxidant defenses to remove these toxic species. Epidemiological and clinical studies have linked environmental factors such as diet and lifestyle to cancer, diabetes, atherosclerosis, and neurodegenerative disorders. All of these conditions, as well as the aging process, are associated with OS due to elevation of ROS or insufficient ROS detoxification." You might recall that enhancing or replicating the effect of these internal systems has successfully extended mouse life spans.

Link: http://www.ncbi.nlm.nih.gov/pubmed/18955158

Complexities of Immune System Decline
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The decline of immune system function with age varies in degree from person to person. Here is one reason why some older folk suffer less than others. Perhaps there's something that can be done with this knowledge as researchers become more capable in cell manipulation: "the number of peripheral naive T-cells declines throughout life and they exhibit severe functional defects at advanced age. However, we have recently identified a non-regulatory CD8+CD45RO+ CD25+ T-cell subset that occurs in a subgroup of healthy elderly individuals, who still exhibit an intact humoral immune response following influenza vaccination. Here, we demonstrate that CD8+CD45RO+CD25+ T-cells share phenotypic and functional characteristics with naive CD8+CD45RA+CD28+ T-cells from young individuals, despite their expression of CD45RO. CD8+CD45RO+ CD25+ T-cells also have long telomeres and upon antigenic challenge, they efficiently expand in vitro and differentiate into functional effector cells. The expanded population also maintains a diverse T-cell receptor repertoire. In conclusion, CD8+CD45RO+CD25+ T-cells from elderly individuals compensate for the loss of functional naive T-cells and may therefore be used as a marker of immunological competence in old age."

Link: http://www.ncbi.nlm.nih.gov/pubmed/18953723

Some Papers on IGF-1 And Insulin in Aging
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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.

Lipids and Alzheimer's
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The brain is complex organ, and Alzheimer's is a complex disease: a wide range of strategies produce results that look promising while not addressing the root cause. Indeed, distinguishing symptoms from root causes in Alzheimer's is still an ongoing concern. Here is a potential strategy I have not seen mentioned before: "scientists working with laboratory mice have discovered that complete or partial removal of an enzyme that regulates fatty acid levels lessened the memory and learning deficits of Alzheimer's ... The most striking change we discovered in the Alzheimer mice was an increase in arachidonic acid and related metabolites in the hippocampus, a memory center that is affected early and severely by Alzheimer's disease ... an enzyme called group IVA phospholipase A2 (or PLA2) released arachidonic acid [in] the brain ... removal or even partial reduction of PLA2 prevented memory and learning deficits and other behavioural abnormalities in the Alzheimer mice." It is worth noting that PLA2 is upstream in biochemical signaling processes that lead to inflammation - I suspect this has more to do with inflammation than fatty acids per se.

Link: http://www.medicalnewstoday.com/articles/126012.php

Calorie Restriction Delays Mitochondrial Damage
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Another win for the practice of calorie restriction: "According to the "mitochondrial theory of aging" the lifelong accumulation of various kinds of damage to mitochondrial DNA (mtDNA) has been related to the age-dependent mitochondrial bioenergetic dysfunction. Caloric restriction (CR) diet is able to prevent or delay the onset of several age-related damages to mtDNA. The effects of aging and CR on the presence of abasic sites and single-strand breaks of the sugar-phosphate backbone in mtDNA have been analyzed [in a] region of brain mtDNA from young and old ad libitum-fed and old CR-treated rats. The region [is] is highly damaged in the old ad libitum-fed animals with respect to the young ones, whereas in the CR rats it shows a much lower extent of damage. The data confirm, at single nucleotide resolution, the protective effect of CR on the age-related mtDNA damage." Damage to mitochondrial DNA appears to provide an important contribution to degenerative aging - we would expect this process to be slowed in calorie restriction, and here is confirmation.

Link: http://www.ncbi.nlm.nih.gov/pubmed/18946734

Rejuvenation Research For October 2008
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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.
The Immortality Trap
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Too many discussions of radical life extension veer off into the immortality trap - at which point things degenerate into hair splitting and angels dancing on the head of a pin. Talking about immortality has little relevance to the practical objective of reversing degenerative aging in humans. Over at Depressed Metabolism you'll find an example of how this tends to progress, followed by these thoughts: "Although speculation about how immortality may affect human psychology can be intriguing, our limited knowledge about the universe and lack of empirical observations of actual immortals make this a highly speculative affair, leaving much room for injecting personal feelings and wishful thinking. ... Few philosophers against immortality argue that today's lifespan is too long. Which again raises the question, how long is too long? Ultimately, such an answer can only be answered empirically by the individuals who will live a much longer lifespan than those living today." It comes back to practical concerns in the end: I, for one, am in favor of getting the job done first and pontificating later, when there is all the time in the world to do so.

Link: http://www.depressedmetabolism.com/2008/10/22/the-secular-case-against-immortality/

Screening For Longevity Drugs
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From Ouroboros: "The observation that long-lived and relatively healthy animals can be obtained by simple genetic manipulation prompts the search for chemical compounds that have similar effects. Since aging is the most important risk factor for many socially and economically important diseases, the discovery of a wide range of chemical modulators of aging in model organisms could prompt new strategies for attacking age-related disease such as diabetes, cancer and neurodegenerative disorders ... Long-lived organisms tend to be resistant to many types of stress, whereas short-lived organisms tend to be stress sensitive. This happy coincidence allows us to screen for longevity mutants by looking for stress resistance rather than long life ... it's quite impressive that so many different antioxidants of so many different types can confer thermotolerance and increased longevity [in nematode worms], and suggests that perhaps the association between antioxidants and longevity may have never had much to do with oxidation as such, but rather with some as-yet-uncovered connection between antioxidants and the activation of stress response pathways."

Link: http://ouroboros.wordpress.com/2008/10/27/discovering-lifespan-extension-drugs-by-screening-for-stress-resistance/

Differential Aging
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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.

Another Organ Successfully Grown From Scratch
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From Reuters: "Researchers have discovered stem cells in the prostates of mice and grown complete prostates from them ... human beings have similar stem cells in their prostates, although they have so far not grown human prostate glands from the cells. ... The research team [first] found a marker, a protein, that would differentiate prostate stem cells from other cells in the prostate. This marker, C-117, can also be found in the human prostate ... Other stem cell experts said they doubted Genentech would try to grow human prostates but might use the finding for research into prostate cancer and other prostate conditions. This is a compelling and important study providing strong evidence not only for the presence of stem cells in the adult prostate, but a way to identify them. This extends the number of adult organs in which such tissue-specific stem cells have been found, including skin, brain, mammary glands, and the gut. ... whether you need to regenerate a new prostate is a moot point, since the prostate simply gives the aging male population serious medical problems. However, it is a widely held view that cancers originate from normal stem cells, so this discovery will be a significant boost to prostate cancer research."

Link: http://www.reuters.com/articlePrint?articleId=USN2237531420081022

On Clearing Amyloid-Beta
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At a level somewhere between root cause and symptoms, Alzheimer's is a failure of the mechanisms that clear out amyloid beta (AB) from a healthy brain. Amyloid creation and destruction is a rapid, dynamic process - but if clearance falls just a little behind, then Alzheimer's will develop. So a strategy one step better than patching up symptoms is to somehow improve natural clearance: researchers "discovered that the activity of a potent AB-degrading enzyme can be unleashed in mouse models of the disease by reducing its natural inhibitor cystatin C (CysC). All of us produce AB proteins in the brain. However, in most people, the proteins never build up to dangerous levels because they are cleared away by enzymes that destroy them. Previously Dr. Gan's laboratory had shown that cathepsin B (CatB) is such an AB-degrading enzyme. ... The activity of CatB is regulated by the protease inhibitor CysC. By reducing CysC activity, the scientists were able to unleash the AB-degrading power of CatB, effectively preventing the build-up of AB in [mice]."

Link: http://www.eurekalert.org/pub_releases/2008-10/gi-gsf102008.php

Searching For the Triggers of Calorie Restriction
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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.

Ancient Considerations of Aging and Longevity
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In 350 BC, Aristotle wrote "The reasons for some animals being long-lived and others short-lived, and, in a word, causes of the length and brevity of life call for investigation. The necessary beginning to our inquiry is a statement of the difficulties about these points. For it is not clear whether in animals and plants universally it is a single or diverse cause that makes some to be long-lived, others short-lived. Plants too have in some cases a long life, while in others it lasts but for a year. Further, in a natural structure are longevity and a sound constitution coincident, or is shortness of life independent of unhealthiness? Perhaps in the case of certain maladies a diseased state of the body and shortness of life are interchangeable, while in the case of others ill-health is perfectly compatible with long life." Slow progress in the investigation of aging and longevity in the centuries since has never been due to a lack of interest, but rather the lack of capable technology. Now that we have the needed biotechnology, isn't it time to move vigorously forward and finish the job?

Link: http://classics.mit.edu/Aristotle/longev_short.html

More On CR Differences Between Species
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As Ouroboros notes, researchers are beginning to uncover differences in the mechanisms of calorie restriction (CR) between species. This lends support to the evolutionary arguments that CR, while demonstrated to be very good for human health, isn't going to extend maximum human life span to the same degree it does in mice. "Decreased IGF-1 levels are associated with increased lifespan. Calorie restriction is also associated with increased lifespan. In rodents, CR is associated with decreased IGF-1 levels, leading to the (still unproven) hypothesis that the effects of CR are mediated by modulation of the IGF-1 axis. In humans, however, the situation is slightly different: As in rodents, the human IGF-1 pathway contains several genes that appear to regulate longevity. The longevity benefits of CR are still under study, but it does appear that certain types of fasting regimens have protective effects against e.g. tumor growth. According to this new study, however, CR has no effect on the levels of functional, circulating IGF-1 [in humans] - so while IGF-1 may regulate longevity and CR may protect against cancer and other age-related maladies, it doesn't appear that CR mediates its effects via IGF-1."

Link: http://ouroboros.wordpress.com/2008/10/22/calorie-restriction-and-igf-1-in-rodents-vs-humans/

More Thoughts From a Pro-Longevity Bioethicist
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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.

Masters of Our Own Fates
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As this open access paper illustrates, the future of our health is largely in our hands - the vast majority of us are not fated by our genes, but instead by how well we look after our health: "The study sample consisted of 24,043 participants (49.7% women) consisting of 11,186 complete same-sex twin pairs ... Information on retirement [events], including disability pensions (DPs) with diagnoses, was obtained from the Finnish nationwide official pension registers. Correlations in liability for [twins] and discrete time correlated frailty model were used to investigate the genetic liability to age at disability retirement. ... A moderate genetic contribution to the variation of disability retirement due to any medical cause was found. The genetic effects appeared to be stronger at younger ages of disability retirement suggesting the increasing influence of environmental factors not shared with family members with increasing age." Largest amongst those "environmental factors" are, I suspect, levels of exercise and calorie intake over the years.

Link: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2566596

Inflammation, Leucine, and Sarcopenia
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Researchers who linked an age-related failure in the ability to process the amino acid leucine to progressive muscle loss, or sarcopenia, continue to search for the root cause: "Because aging is associated with changes in oxidative status, we hypothesized that reactive oxygen species-induced oxidative damage may be involved in the impairment of the anabolic effect of leucine with age. The present study assessed the effect of antioxidant supplementation on leucine-regulated protein metabolism in muscles from adult and old rats. ... In old rats, the ability of leucine to stimulate muscle protein synthesis was significantly decreased compared with adults. This defect was reversed when old rats were supplemented with antioxidants [but it] was not related to increased oxidative damage ... These effects could be mediated through a reduction in the inflammatory state, which decreased with antioxidant supplementation. Antioxidant supplementation could benefit muscle protein metabolism during aging, but further studies are needed to determine the mechanism involved and to establish if it could be a useful nutritional tool to slow down sarcopenia with longer supplementation." Given a weight of evidence for the ineffectiveness of ingested antioxidants, a reduction in inflammation and the widespread damage it causes sounds more plausible.

Link: http://www.ncbi.nlm.nih.gov/pubmed/18932012

A Look at More Recellularization Work
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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.

Immune Cells Versus Cancer
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The use of immune cells to attack cancer has been going on for many years, but it's only recently that biotechnology has become inexpensive and sophisticated enough to understand why early immunotherapies only sometimes worked. Via EurekAlert!: "One treatment option for patients with late-stage melanoma involves removing natural cancer-fighting T cells from the tumor, expanding their numbers in culture dishes, and then re-infusing them into the patient. This strategy - called adoptive immunotherapy - causes tumor regression in about half the patients treated, some of whom survive for decades without relapse. ... Among the cells taken from a patient who has remained tumor-free for more than a decade, [researchers] found naturally-arising T cells that recognized a new protein, which they dubbed "meloe-1." Meloe-1, the group found, is highly expressed in melanoma cells but not in normal skin cells or in other types of cancer. When they looked at the transferred cells from the other patients, they found meloe-1-specific T cells in 5 of the 9 patients who remained relapse-free, but in none of the 21 patients who relapsed." This sort of knowledge, categorized by cancer type, will lead to highly efficient immunotherapies in the years ahead.

Link: http://www.eurekalert.org/pub_releases/2008-10/rup-tcr100908.php

Ouroboros on Aging Research in Yeast
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Yeast has long been important in aging research: "The budding yeast Saccharomyces cerevisiae has been a valuable model system in biogerontology, dating back to the very earliest years of the modern synthesis of molecular genetics with the study of lifespan regulation. From yeast we first learned about the sirtuins, and it continues to teach us much about the mechanisms of lifespan extension by calorie restriction. ... An under-appreciated feature of yeast aging is that [a] yeast cell can die either by necrosis or by programmed cell death - i.e., apoptosis or something very much like it. That comes as a surprise to those of us who grew up thinking of apoptosis as a kind of 'noble sacrifice' made by a damaged cell in the context of a tissue or organ: damage leads to cancer, but not if it leads to cell death first; hence, there's a survival benefit to the organism if individual cells 'voluntarily' die in response to certain types of stress. But with no body to protect, why would a single-celled organism undergo apoptosis?"

Link: http://ouroboros.wordpress.com/2008/10/20/apoptosis-in-yeast/

Veterinary Medicine Gets the Best Stuff First
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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.

Exercise and the Aging Brain
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Exercise is much like calorie restriction in that there are few aspects of aging not improved by its practice. From RedOrbit: a review of research "finds that consistent aerobic exercise can prevent age-related decline in brain function, and may even help reverse aging of the brain. ... Moderate physical exercise, at a level that would make a person breathless, has been shown to increase both the speed and sharpness of thought in people with or without signs of Alzheimer's disease or dementia. Furthermore, exercise has also been shown to improve the volume of brain tissue and the way in which the brain functions ... These results suggest that regular aerobic exercise [can] reliably reverse age-related cognitive decline ... many questions remain unanswered [about] the effect of exercise on the brain. However, [we] can safely argue that an active lifestyle with moderate amounts of aerobic activity will likely improve cognitive and brain function, and reverse the neural decay frequently observed in older adults."

Link: http://www.redorbit.com/news/health/1590207/aerobic_exercise_may_slow_reverse_agerelated_brain_decline/

Thoughts on Death
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From Depressed Metabolism: "The idea that death gives meaning to life is widespread but does not reflect careful reasoning, and is often a desperate rationalization of human mortality. As a consequence, life extensionists have not been at great pains to defeat 'pro-death' arguments. A (secular) philosophical position that is harder to refute is that we should not fear death because we cannot experience it. This is the classical argument of the ancient Greek philosopher Epicurus ... the position of Epicurus on death is often misunderstood. Epicurus did not argue that we should not fear the process of dying or the prospect of dying. One can prefer life over death without committing to the view that death is bad for a person. Although our survival instinct usually prevents us from looking at it in such a way, in real life we have an ongoing 'choice' between life or death. Although death cannot be experienced as being bad, we generally have good reason to prefer life over death, provided life is experienced as positive or has the potential to become positive. Although life extensionists would prefer to have stronger arguments against the Epicurean view on death, a preference for good experience over no experience can do the work just fine."

Link: http://www.depressedmetabolism.com/2008/10/19/death-is-nothing-to-us/

Induced Pluripotency Research is Moving Rapidly
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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.
On Aging and Myelin
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Researchers have found an intriguing association: they "compared how quickly a group of males ranging in age from 23 to 80 could perform a motor task and then correlated their performances to their brains' myelin integrity. The researchers found a striking correlation between the speed of the task and the integrity of myelination over the range of ages. Put another way, after middle age, we start to lose the battle to repair the myelin in our brain, and our motor and cognitive functions begin a long, slow downhill slide. ... speed of a movement increases with the frequency of neuronal action potential (AP) bursts in the brain ... Fast movements require high-frequency AP bursts that depend on excellent myelin integrity over the entire axon network involved in controlling that movement ... the research suggests that the myelin breakdown process should also reduce all other brain functions for which performance speed is dependent on higher AP frequencies, including memory; it also supports the suggestion that myelin breakdown is a biological process of aging underlying the erosion of physical skills and cognitive decline." The question now becomes "why exactly does this decline in myelin happen, and what can be done to reverse it?"

Link: http://www.eurekalert.org/pub_releases/2008-10/uoc--pdc101708.php

Aubrey de Grey in H+ Magazine
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The first issue of the transhumanist H+ magazine includes piece on radical life extension by Michael Anissimov and an interview with biomedical gerontologist Aubrey de Grey: "The three hardest aspects of SENS (at present - this could of course change!) are: the relocation of mitochondrial DNA to the nucleus to make mutations in the original mitochondrial DNA harmless; the introduction of microbial (or other foreign) enzymes into our cells to destroy molecules that accumulate in them; and the elimination of our cells' ability to prevent the ends of the chromosomes from shortening with each cell division, combined with stem cell therapies to address the side effects that this will cause. Research is proceeding healthily in all these areas, largely funded by the Methuselah Foundation. ... I'm actually not mainly driven by a desire to live a long time ... what drives me is to put myself (with luck) and others (lots and lots of others) in a position to make that choice, rather than having the choice progressively ripped away from me or them by declining health. Whether the choice to live longer is actually made is not the point for me."

Link: http://www.hplusmagazine.com/

A Null Result For Some Mitochondrial Differences and Longevity
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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.

Mechanisms of Cancer Versus Aging
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Researchers continue to uncover the mechanisms underlying the balance between aging and cancer. Many aspects of our biology have evolved to shut down as damage accumulates, suppressing cancer but causing loss of function: "Four genes that suppress tumor formation also regulate the ability of adult stem cells to replace worn-out tissues, as well as the shutdown of stem cells during aging. The genes switch on and off in a coordinated fashion as cells age to reduce the risk of cancer. In the process, they also shut down stem-cell function in aging tissues, reducing their capacity to regenerate. ... The four genes examined in the study were Ink4a, Arf, Hmga2 and let-7b. ... Ink4a, well known for its role as a tumor suppressor, becomes increasingly active with age and shuts down stem-cell replication in older mice. Flicking that genetic switch likely serves as a defense against cancer-causing genetic mutations, which accumulate as cells repeatedly divide. ... Ink4a's activity in mouse neural stem cells is regulated by Hmga2, which in turn is controlled by let-7b. The same relationship is likely at work in humans, who possess the same four genes."

Link: http://www.wwj.com/UM-Researchers-Find-New-Links-Between-Stem-Cells--/3150041

Gene Therapy Versus Retinal Degeneration
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Via EurekAlert: "Researchers have used gene therapy to restore useful vision to mice with degeneration of the light-sensing retinal rods and cones, a common cause of human blindness. ... This is a proof of principle that someday we may be able to repair blindness in people with conditions like retinitis pigmentosa and macular degeneration. There are several limitations we need to overcome before we can begin clinical trials, but I'm optimistic that this work may someday make a big difference for people who otherwise would have no vision at all. ... The study was designed to investigate the effect of expressing the light-sensitive protein melanopsin in retinal ganglion cells. These specialized neurons receive light signals from the rods and cones and carry those signals into the brain via the optic nerve, which is formed from the cells' axons. Melanopsin is usually produced in a subset of cells that are involved with establishing circadian rhythms but not with vision. The [researchers] used the standard viral vector adeno-associated virus to deliver the gene encoding melanopsin throughout the retinas of mice whose rod and cone photoreceptors had degenerated from lack of a crucial protein."

Link: http://www.eurekalert.org/pub_releases/2008-10/mgh-gtr101608.php

More Ways For Aging Stem Cells To Go Awry
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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.

Sirtuins Increased By Human Calorie Restriction
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Here's a study confirming that sirtuins are indeed overexpressed during the practice of calorie restriction in humans. That should please the resveratrol brigade: "Sirtuins may provide novel targets for treating some diseases associated with oxidative stress, such as obesity and its comorbidities. However, there are a few in vivo studies in humans about the potential role of sirtuins as therapeutic targets among obese patients undergoing caloric restriction. ... Gene expression of two sirtuins (SIRT1 and SIRT2) [of] obese subjects [before] and following an 8-week hypocaloric diet was investigated. ... The intervention up-regulated the expression of both sirtuins ... SIRT1 and SIRT2 may serve as key regulators for some obesity comorbidities related to antioxidant status." The more interesting question is whether these effects occur for people of a more reasonable weight range.

Link: http://www.ncbi.nlm.nih.gov/pubmed/18837744

More Cell Transfer Immunotherapy
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A strategy analogous to early stage stem cell therapies is showing promise for immunotherapy. From the Telegraph: "Cancer patients could have immune cells removed and cultivated in piglets before being injected back into them to boost the body's natural defences ... The new stem cells, which would then be implanted back into the patient, could even be modified in the piglet so as to boost their disease fighting powers, experts believe. They said the new system could mark a major breakthrough in the process which is known as cell transfer immunotherapy or T-cell treatment. ... Immunotherapy is thought to work because usually there are too few of the cells naturally in a patient's body to fight cancer effectively but by boosting them, it boosts natural defences. In its most successful use to date one American patient suffering from advanced skin cancer even made a full recovery following the treatment. This was even though the disease had already spread to the lymph nodes and lungs." The use of pigs solves a problem of cost: culturing immune cells is still very challenging, and thus expensive and even impossible for some patients.

Link: http://www.telegraph.co.uk/earth/main.jhtml?view=DETAILS&grid=&xml=/earth/2008/10/15/scipigs115.xml

Direct Results of Mitochondrial DNA Damage
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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.

Thoughts on Tissue Engineering
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From the Tartan: "As for regrowing whole limbs, Badylak is unsure of when technology will be advanced enough for such a feat. 'That's an impossible question really to answer. I do think that we will be able to stimulate the regrowth of at least digits. The only way we will be able to do that is by understanding the signaling mechanisms that occur in the fetus, when these sorts of structures are normally developed. In a fetus if you amputate these structures at an early enough stage, the fetus will regrow a limb. Yet we lose that ability as we develop into a newborn.' The hardest obstacle of regenerative medicine lies within the cellular communication system. Badylak explained that to regrow a tissue, the cell requires the right kind of signal to start, so that it can in turn stimulate the right cells. The biggest challenge is finding the master switch, a molecular signal which will tell the injured tissue to respond with the means to regrow instead of just heal, and afterward, finding out how activate it. These switches are genes that need to be activated. When activated, the genes can then express proteins that can trigger a cell regeneration cascade."

Link: http://thetartan.org/2008/10/13/scitech/stemcells

Hourglass IV Blog Carnival on Aging Science
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Houseglass IV is over at Existence is Wonderful: "In putting together this Carnival, something never far from my mind was the notion of that point at which something ceases to be considered monstrous or strange and is assimilated into the realm of the ordinary, or acceptable, or even welcome. I can only imagine how odd and disturbing the idea of transplanting organs must have seemed prior to it actually being done -- and yet nowadays, if you tell someone you're planning on donating a kidney to your sick cousin, you're likely to be told, 'Oh, how nice!' as opposed to, 'Ugh! What is wrong with you?' ... Similarly, speculations about impressive longevity gains or other boundary-pushing advances seem to intrigue some while frightening others -- which is understandable considering that nobody knows what is ultimately going to be possible when it comes to altering, maintaining, and fine-tuning bodies over time, nor what the implications of any of this will be."

Link: http://www.existenceiswonderful.com/2008/10/hourglass-iv-longevity-blog-carnival.html

SENS4 Conference Set For September 2009
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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.

Looking at BioTime
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From Depressed Metabolism: "Unless you are a long-time cryonicist or a surgeon, you may not have heard of BioTime before. This company, recently profiled for its innovative stem cell research in Life Extension Magazine, is best known for producing the blood-volume expander Hextend, which was initially developed by Trans Time, an early cryonics company performing ultra-profound hypothermia research. ... things are changing at BioTime. Under the direction of CEO Dr. Michael West, and capitalizing on the highly successful sales of Hextend and related products, the company is now heading in a new direction: regenerative medicine. ... Dr. West's mission [is] to understand how to make somatic (i.e., body) cells immortal and then apply this technology to the treatment of aging and aging-related diseases. BioTime is now driven by the potential for stem cell therapy to repair and regenerate organs and tissues and, if possible, to radically extend human lives."

Link: http://www.depressedmetabolism.com/2008/10/12/biotimes-quest-to-defeat-aging/

On Replacement Parts
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Existence is Wonderful looks at the prospects for replacement organs - while we wait for therapies capable of reversing the biochemical damage that makes it necessary to replace organs: "What is needed next, along with wider recognition of the lack of an expiration date on an individual person's value, is a means to replace worn-out parts that doesn't require nearly so many dead donors, and that doesn't pose so much danger to the recipient in terms of infection and immune issues. ... Bioartificial parts are essentially the products of the emerging science of tissue engineering ... applications of tissue engineering will benefit people of all ages (bioengineered bladders have already been successfully implanted in several children), but the growing elderly population stands to benefit tremendously from anything that makes effective replacement parts safer and more readily available. Bioartificial parts could potentially take innumerable forms, but given the organs people really depend most on for [survival], it is definitely good to see that laboratory results (and in some cases, clinical/experimental trials) have been obtained for bioartificial arteries, hearts, livers, and kidneys."

Link: http://www.existenceiswonderful.com/2008/10/livers-and-kidneys-and-hearts-oh-my.html

The Way People Think About Aging
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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.

Update on Viruses Versus Cancer
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A number of groups are presently working on ways to use viruses to precisely target and kill cancer cells. Here's an update on one of them from ScienceDaily: "The Senecavirus [is] harmless to normal human cells, but could infect certain solid tumors, such as small cell lung cancer, the most common form of lung cancer. ... Scientists at Neotropix say that, in laboratory and animal studies, the virus demonstrates cancer-killing specificity that is 10,000 times higher than that seen in traditional chemotherapeutics, with no overt toxicity. The company has developed the 'oncolytic' virus as an anti-cancer agent and is already conducting early phase clinical trials in patients with lung cancer. ... researchers went on to identify several areas on the viral protein coat that they think might hook onto receptors on cancer cells in the process of infecting them. ... It will be critically important to find out what region of its structure the virus is using to bind to tumor cells, and what those cancer cell receptors are. Then we can, hopefully, improve Senecavirus enough to become a potent agent that can be used with many different cancers."

Link: http://www.sciencedaily.com/releases/2008/10/081008151320.htm

Cuervo On Autophagy
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A piece from earlier this year at InfoAging: "Aging is characterized primarily by the decline of function in various cellular and molecular systems in the body. These changes are influenced by three factors: genetics, metabolism, and the environment. The focus in Dr. Cuervo's lab is the metabolic changes and resulting damage from these changes that are experienced with age, specifically damage to proteins. Every person experiences this damage to some degree, regardless of their age, but when it comes to repairing or removing the damage, the difference between young and old is clear. In younger people, the damaged or misfolded proteins can be repaired by what are known as chaperone proteins. Yet, like an old car, proteins that have undergone too much repair are not worth maintaining and so they are transported by the chaperone to the lysosome as 'trash' where they bind to a receptor and undergo autophagy (literally, self-eating) inside the organelle. Dr. Cuervo's research focuses on this pathway and how a major decline in its functionality is seen in older organisms." The piece goes on to describe how researchers restored this functionality to youthful levels in aged mice.

Link: http://websites.afar.org/site/PageServer?pagename=IA_spotlight_main

A Good Example of a Cell Signaling Application
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An important field resulting from stem cell research is the discovery and application of biochemical signals to direct existing stem cells in the body - they can be made to repair damage where they would ordinarily remain inactive. Only where stem cells themselves are damaged would new cells be needed: in most situations, greater control over the cells you have is good enough. Via Xconomy: "Provasculon is tackling one of the bigger ideas in regenerative medicine - how to stimulate growth of new blood vessels after they've been damaged by a heart attack. ... in rat studies that a novel protein was able to stimulate a certain type of stem cells (better known to scientists as endothelial progenitor cells) to migrate to damaged heart tissue, promote growth of new blood vessels, and ultimately help the heart pump better after a heart attack. The trick here is that Provasculon is trying to make a genetically engineered form of the key protein, SDF-1, that is able to avoid certain enzymes in the body that would like to chop the protein up and render it useless."

Link: http://www.xconomy.com/boston/2008/10/09/provasculon-a-biogen-backed-startup-testing-regenerative-medicine-on-hearts/

The Hardwired Certainty of Immortality
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Scientific American takes a look at one of the reasons it's hard to convince people to give an appropriate level of support to longevity research: "the only real mystery is why we're so convinced that when it comes to where we're going 'when the whole thing’s done,' we're dealing with a mystery at all. After all, the brain is like any other organ: a part of our physical body. And the mind is what the brain does - it's more a verb than it is a noun. Why do we wonder where our mind goes when the body is dead? Shouldn’t it be obvious that the mind is dead, too? And yet people in every culture believe in an afterlife of some kind or, at the very least, are unsure about what happens to the mind at death. My psychological research has led me to believe that these irrational beliefs, rather than resulting from religion or serving to protect us from the terror of inexistence, are an inevitable by-product of self-consciousness. Because we have never experienced a lack of consciousness, we cannot imagine what it will feel like to be dead. In fact, it won't feel like anything - and therein lies the problem. ... our ancestors suffered the unshakable illusion that their minds were immortal, and it's this hiccup of gross irrationality that we have unmistakably inherited from them. Individual human beings, by virtue of their evolved cognitive architecture, had trouble conceptualizing their own psychological inexistence from the start."

Link: http://www.sciam.com/article.cfm?id=never-say-die&print=true

The Difference Made by iPS Cells
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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

...

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.

Imminst Folding@Home Prize Update - 3rd Quarter Contest Begins
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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.

...

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?

All Problems Are a Matter of Atoms
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The ultimate goal of medicine is to be able to reliably and precisely manipulate any the molecules in our bodies: all disease, all aging, is a matter of the wrong molecules being in the wrong place at the wrong time. From Accelerating Future: "It's important to realize the obvious: that every human problem, every malady, every concern, every evil, is at root simply a suboptimal arrangement of atoms and molecules. If this sounds quasi-spiritual, it's because it is - for millennia, pre-scientific humans have attributed all ills to various agents - the gods, magicians, and other humans. This is because these ills demand an explanation, and we didn't have a plausible one, so we made it up. Now, at least in the abstract, we have a concrete, very likely correct answer: suboptimal atomic arrangements. This realization is neither trivial nor too broad to be useless. If your problems are caused by the gods (that some people sadly still believe in...), then to solve them, you either need to give up, on engage in rituals [that] have an empirical impact of precisely zero." There is a simple criteria by which to judge whether new technologies will enable better medicine: do they give us the ability to more precisely and easily move atoms around? Modern biotechnology and the molecular manufacturing that will follow are both good examples.

Link: http://www.acceleratingfuture.com/michael/blog/2008/10/physical-basis-for-problems/

Pondering Aging Stem Cells in the Gut
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From Science News: "Old age can hit animals in the gut. That's where elderly fruit flies experience a signaling imbalance that disrupts renewal of the gut wall, new research shows. The discovery could help scientists understand why the body's organs malfunction in old age, and why intestinal cancer is so common among older people. ... Normally, 'adult' stem cells in the intestinal wall churn out a steady stream of new cells to replenish the lining [but] in older animals, this balance seems to be breaking down ... The imbalance appears to be triggered by stress - not psychological stress, but the chemical stresses put on cells by free radicals or by chronic inflammation, both of which get worse as an animal ages. Cells in the gut lining respond to this stress by activating a protective gene [which] is part of a signaling pathway that spurs intestinal stem cells to grow and divide. In response, another signaling pathway - called the Delta/Notch pathway - ramps up to try to keep that growth in check. But too much Delta/Notch can also derail the natural conversion of these stem cells into mature gut cells, causing an abnormal accumulation of halfway converted cells. ... [This] malfunctioning of adult stem cells in old age [is] very similar to what happens in certain human stem cell populations."

Link: http://www.sciencenews.org/view/generic/id/37382/title/Old_age_causes_problems_for_gut_cells

Your Longevity and the Composition of Your Mitochondria
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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

...

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.

Death Versus Destruction
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From Depressed Metabolism: "the author argues that 'the continuing fact of death renders all talk of liberty ultimately futile.' The author further argues that our concern for the future will diminish as we approach death. But instead of facing the enemy, we devise all kinds of defensive strategies. Life extensionists often speak disparagingly of such coping mechanisms. But [one] can hardly blame people for trying to live in peace with the inevitable. Raging at the prospect of death, if no rational means can be imagined to overcome or delay it during our lifetime is foolish and unproductive. But as Herbert Marcuse said, there is a difference between accepting death and elevating it to something that gives meaning to life. ... Historically, the delay between the technical ability to place a person in low subzero temperatures to avoid decomposition and its actual implementation was not excessive at all. Perhaps the biggest technical obstacle to broader acceptance of cryonics is that most people still believe that the inability of the human body to sustain itself as an integrated organism must necessarily mean the end of the person as well." Which isn't the case, even now. Death is not destruction - at least not until the fine structures of the brain decay. That is why cryonics has a good chance of success: there is all the time in the world to wait in low temperature storage for medical science to become capable of restoring a damaged but intact person to life.

Link: http://www.depressedmetabolism.com/2008/10/06/liberty-and-oblivion/

Attacking Macrophages in Fat
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You might recall that the reason excess fat tissue is so damaging seems to be due to roaming macrophages that release inflammatory biochemicals. Via EurekAlert!, a demonstration that reinforces this point: "Over the past decade, it has become quite clear that obesity gives rise to a state of chronic, low-grade inflammation that contributes to insulin resistance and type 2 diabetes ... [researchers] recently found that a specific subset of macrophages invades obese fat and muscle tissue. Although little was known about them, those macrophages are defined by a CD11c marker expressed on their surfaces. They also produce high levels of proinflammatory chemicals that are linked to the development of obesity-associated insulin resistance. ... We used a genetic 'trick' that allowed us to rapidly kill these macrophages. The treatment killed these cells within hours, and insulin resistance simply reversed itself. It argues strongly that macrophages are causative for the inflammation that leads to diabetes [in those who are obese]. ... The most interesting thing is that this reversal occurs very rapidly. Twenty-four hours later the animals' insulin response had completely normalized. They were still obese, but no longer insulin resistant."

Link: http://www.eurekalert.org/pub_releases/2008-10/cp-ki093008.php

A Little Mathematics and Modeling
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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.

...

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.

Behind the Scenes of Aging Research
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This article looks at an aging research lab typical of the community presently working to better understand aging and metabolism: "Aging is not just a simple fact of life. Scientists see life span as a complex process in which genetics and environmental stresses interact involving the whole animal. Regulating the genes - switching them on or off - that control aging may increase healthy, active life spans dramatically. Why is it, ask scientists, that animals have dramatic differences in life spans? Size does not explain the difference. A canary lives only a few years while a bat can live as many as 50 years, yet both are similar in size. And even animals vastly different in size have similar factors and pathways that control life span. ... Dong and his colleagues focused on the master factor DAF-16, which some scientists call the 'Fountain of Youth' gene. They identified a co-factor that, when deactivated, can prolong C. elegan's life span by 40 percent and improve the worm's resistance to damage to its DNA and proteins. So far, researchers have identified several hundred genes in C. elegans that may affect life span. ... Dong's laboratory is collecting the research results, identifying individual genes and grouping them by their link to environmental stresses."

Link: http://www.clemson.edu/newsroom/articles/2008/october/Life_span_research.php5

The Mixed Op-Eds Are Becoming More Positive
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Across the years, I've seen many mixed op-ed columns holding forth on the subject of engineered longevity. There's a particular style to this sort of thing, usually involving disclaimers of any personal interest in living a longer, healthier life - because that is the Done Thing - but I think that on the whole they are trending towards a more positive outlook: "The (at present very remote) prospect of having your conscious mind uploaded on to a computer may not be so enticing, but who wouldn't choose to extend flesh and blood life by the fruits of biomedical science? We do so already, of course, taking the life-sustaining gifts of modern medicine for granted. Given the chance of a little more life, and yet a little more, most of us would take it, eking out our lives indefinitely. We'd keep on keeping on. And radically increased longevity is no longer a fantasy. Quite likely, as the present century unfolds, advances in genetic engineering, nanotechnology and regenerative medicine will deliver on their life-extending promise. ... Life is infinitely rich. The possibilities for new knowledge and experience are endless. So I don't buy the boredom argument. As the philosopher John Harris put it, only the terminally boring are in danger of becoming terminally bored."

Link: http://women.timesonline.co.uk/tol/life_and_style/women/the_way_we_live/article4876758.ece

Reliably Taking Care of Your Health Matters in the Long Term
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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.

...

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.

...

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.

Biomaterials to Stimulate Regeneration
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Many branches of medicine are concerned with manipulating tissue and its environment so as to generate the right biochemical signals for increased regeneration - strategies that we hope will become obsolete as researchers learn to create those signals directly. Here is one example: "ChonDux consists of a hydrogel made of polyethylene glycol - a polymer commonly used in a variety of medical products - and a bioadhesive to keep the hydrogel in place after injection. First, the surgeon coats the inside of the cavity where the cartilage is missing with the bioadhesive and then, as in microfracture [surgery], drills tiny holes into the bone next to the cavity. Then the surgeon fills the empty space with the hydrogel and shines UVA light on the material, which causes the polymer to harden from a viscous liquid into a gel. The blood clot that forms from the microfracture then gets trapped in the hydrogel. ... more cells from the bone marrow get trapped in the blood clot when the hydrogel is present, compared with microfracture conducted without the gel. The researchers also noted that the defects fill faster with the biomaterial than without, and that the newly formed tissue more closely resembles true cartilage."

Link: http://www.technologyreview.com/printer_friendly_article.aspx?id=21448

More on Comparative Longevity
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Researchers continue to try to learn from differences in longevity and metabolism between species: "Haussmann studied cacti and turtles before zeroing in on a small, marine bird that contradicts traditional assumptions about aging. ... Leach's storm-petrels should die young but live a long life and break the conventional rules. First of all, they're small, and there tends to be a relationship between body size and life span. Elephants live longer than humans. Humans live longer than mice. So this bird shouldn't live long, but it does. ... His studies of storm-petrels have shown that certain characteristics of DNA - specifically lengths of the protective telomeres at the tips of DNA - are associated with species that live longer lives and possibly with how susceptible they are to cancer-causing tumors. ... [Bird species] with shorter life spans, such as zebra finches, lost their protective telomere caps quickly over time. Species such as the common tern, which lives to be about 30 years old, had less shortening over time." The petrels apparently produce more antioxidants as well - which may tie into the evidence suggesting that mitochondrial damage is the cause of shortened telomeres. Antioxidants slow the rate of that damage. The question remains as to where telomere length sits in the spectrum of cause and effect.

Link: http://www.bucknell.edu/x45446.xml

Reactive Oxygen Species and Stem Cell Decline
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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.

...

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.

Submissions Wanted for the Next Hourglass Carnival
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The next Hourglass blog carnival on the biology of aging will be held at Existence is Wonderful on the 14th. Don't forget to send in your blog posts for consideration ahead of time: "Eligible submissions can cover any aspect of longevity science: biogerontology, current and ongoing research into aging, emerging longevity medicine, research into specific conditions, brain aging, cardiovascular aging, etc. Also encouraged are posts discussing socio-cultural, ethical, philosophical, and economic issues surrounding longevity and longevity research. And as a reminder, you don't need to be a biogerontologist to participate - aging affects 100% of us! If you're interested in participating, please email a link to your submission to hourglass.host @ gmail.com by Monday, October 13, 2008. The Carnival will be posted the following day. I look forward to seeing your posts!"

Link: http://www.existenceiswonderful.com/2008/10/reminder-submit-your-october-hourglass.html

Assessing Calorie Restriction Effects
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Ouroboros casts a skeptical eye on research I mentioned a little while ago at Fight Aging!: culturing cells using blood serum from calorie restriction (CR) and alternate day fasting (ADF) volunteers before and after the program to examine the differences. "we used sera collected from those studies to culture human hepatoma cells and assessed the effects on growth, stress resistance and gene expression. ... I was concerned by the lack of phenotypic benefits in cells treated with CR sera, as compared to cells treated with ADF sera: The CR-treated cells exhibited no increase in heat-shock resistance, no decrease in cell proliferation, and no correlation of Sirt1 expression to reduced triglyceride levels. In interpreting this finding, the authors suggest that the increased effects seen in the ADF participant serum could be due to the 'short, regular intervals of complete caloric deprivation,' which might provide a more potent serum profile capable of producing the observed in vitro changes. ... Alternatively, I think that these data could be a result of the cell type used in this assay (a tumor line); it would be interesting to see this experiment repeated on primary cells or a non-cancerous transformed cell line."

Link: http://ouroboros.wordpress.com/2008/10/02/feast-and-famine-in-vitro-techniques-to-assess-longevity-diets/

New SAGE Crossroads Podcasts on the Evolution of Aging
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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:

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.

Delaying the Degenerative Disease of Aging
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Another Aging 2008 presentation from the "work to slow aging rather than repair it" contingent: "All of life is trade-offs [and] that is an inevitable byproduct of living. Nature is better than most engineers - it is 98 or 99% efficient, but as you get older the mitochondria are putting out more oxidants. It is like an old car engine that has less efficiency and more black smoke. ... The argument is that throughout all of evolution, animals were running out of one micronutrient or another ... Animals are running out of magnesium or iron. What does nature want to do when you are running out of magnesium? It cuts out any metabolism that is long-term. DNA damage shows up as cancer five years down the road? The hell with it. Your adaptive immunity leads to dying of a more severe infection five years down the road? The hell with it. ... Basically you are paring down to what is vital so you can reproduce a little bit. That's what nature cares about. That is the argument: I call it triage [and] we are in the middle of trying to test it in people. The pathology is all insidious - it is the very things that happen with aging. DNA damage goes up with aging, your adaptive immunity goes out with aging, your mitochondria put out more oxygen radicals with aging, and that is what is accelerated by micronutrient deficiency."

Link: http://www.acceleratingfuture.com/people-blog/?p=2368

The Novel Paradigm of Longevity Science
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Over at Future Current, one of the presentations from Aging 2008: "What can each of us do to advance a new paradigm for health promotion and disease prevention in the 21st century that makes as its central tenet the slowing of aging? Recently, the board of directors of [the Alliance for Aging Research] committed to an aggressive effort to speak out for longevity science, which I think is a more elegant way of saying biogerontology, in order to hasten the social benefits extending healthy aging, a goal that we have referred to as 'pursuing the longevity dividend.' Now, the members of my board are not naive. They know very well that longevity science continues to be a tough sell. Let's face it, call it by any name, the quest for significantly extended lifespan has an image problem. ... Most established scientific leaders have been brought up to believe that aging is not only unchangeable, but not even very interesting. Now let's move to lay people. Most of them think there is not anything you can do about aging. ... They believe that even if you could, it would be a social and an economic catastrophe. Too many sick, old people sitting around, not pulling their weight. Even if people believed there could be some scientific breakthrough that would make it possible to extend the healthy years of life, many will set themselves up in opposition because it sounds unnatural or upsetting to social norms or religious beliefs. ... What will it take to overcome negative assumptions among the public?"

Link: http://www.acceleratingfuture.com/people-blog/?p=2366