Fight Aging!

A little while back, I pointed out the Immortality Institute's present fundraising program for modestly sized research projects. The Institute volunteers solicit proposals from life science researchers, showcase the most worthy, and match donations with funds from from the Institute coffers. The latest project will run in a Singaporean research laboratory and investigate mitochondrial uncoupling.

I believe that this model for fundraising represents the future of research funding: a very transparent process, in which donors can educate themselves about the science, pick and choose exactly the projects they are willing to fund, and engage with the researchers in dialog and feedback. Many small projects compete for funding in place of one large umbrella grant, adding an additional layer of incentives to competition, frugality, and ingenuity. Over time I expect to see the big grant model diminish in size and many competing philanthropic and for-profit venture funding marketplaces for small life science research projects grow energetically.

This transformation of the funding environment is exactly what happened in many other fields - such as, say, software development - as the cost of equipment, development, and investigation fell. When it costs less that $10,000 to accomplish something useful, there will be a great many more people interested in trying than when it cost $100,000, and the way in which people organize themselves to raise funds will be very different.

Biotechnology is entering this new era of low costs and new participants now, and I think it's important to encourage the new fundraising models - and greater transparency in research - wherever possible. Hence I donated to the Institute to help fund this research project, and encouraged everyone else to do likewise.

We absolutely want to see many, many more grassroots organizations adopt this sort of fundraising operation: pick good projects that get the most out of modest donations, and make the most of new technology and established facilities.

I'm pleased to note that a number of folk followed through, and the fundraising target has been met. Thank you all. You can follow the research as it takes place and ask questions of the researchers over in the Immortality Institute forums - take advantage of the opportunity. This is the way in which research will progress in the future, with a great deal more dialog and openness.

One consequence of the success of calorie restriction research is that scientists are now more closely investigating the biochemistry of exercise - and its potential to slow aging. For example: "Brain aging is a period of decreasing functional capacity and increasing vulnerability, which reflect a reduction in morphological organization and perhaps degeneration. Since life is ultimately dependent upon the ability to maintain cellular organization through metabolism, this review explores evidence for a decline in neural metabolic support during aging, which includes a reduction in whole brain cerebral blood flow, and cellular metabolic capacity. Capillary density may also decrease with age, although the results are less clear. Exercise may be a highly effective intervention for brain aging, because it improves the cardiovascular system as a whole, and increases regional capillary density and neuronal metabolic capacity. Although the evidence is strongest for motor regions, more work may yield additional evidence for exercise-related improvement in metabolic support in non-motor regions. The protective effects of exercise may be specific to brain region and the type of insult. For example, exercise protects striatal cells from ischemia, but it produces mixed results after hippocampal seizures. Exercise can improve metabolic support and bioenergetic capacity in adult animals, but it remains to be determined whether it has similar effects in aging animals. What is clear is that exercise can influence the multiple levels of support necessary for maintaining optimal neuronal function."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20802804

An example of the next generation of targeted cancer therapies: "Since last April, 19 cancer patients whose liver tumors hadn't responded to chemotherapy have taken an experimental drug. Within weeks of the first dose, it appeared to work, by preventing tumors from making proteins they need to survive. The results are preliminary yet encouraging. With a slight redesign, the drug might work for hundreds of diseases, fulfilling the promise that wonder cures like stem cells and gene therapy have failed to deliver. ... We can turn off any one of 20,000 genes with RNAi. The challenge has been to get a drug into only the desired cells and not harm others. ... Researchers have worried that a drug might disrupt normal protein production in a healthy cell, or that the immune system will destroy the drug before it reaches its target. [Scientists] overcame both concerns by packaging the drug in a fatty envelope that is absorbed primarily by the liver. This allowed doctors to administer the drug through the blood, rather than by an injection to one spot, which improves results by ensuring that the entire liver receives an even dose. The technique's ability to attack single genes could lead to drugs for the 75 percent of cancer genes that lack any specific treatment, as well as for other illnesses. [Researchers are] already testing RNAi therapy for Huntington's disease and high cholesterol in cell cultures; other researchers are tackling macular degeneration, muscular dystrophy and HIV. The potential has driven nearly every major pharmaceutical company to start an RNAi program."

Link: http://www.popsci.com/science/article/2010-07/rx-every-disease

There is good reason to believe that levels of thyroid hormones, and the changes in thyroid function they represent, influence human longevity. These are amongst a number of hormones in the human body that touch on almost everything you would expect to influence life span over time: metabolic rate, cell growth, use and processing of food, and so forth. You might recall studies on the thyroid hormone triiodothyronine, or T3, for example:

The hypothalamo-pituitary-thyroid axis has been widely implicated in modulating the aging process. Life extension effects associated with low thyroid hormone levels have been reported in multiple animal models. In human populations, an association was observed between low thyroid function and longevity at old age ... These findings suggest that the favorable role of low thyroid hormone metabolism on health and longevity in model organism is applicable to humans as well.

Here is another, more recent study of a human population that pulls in more confirming data:

The objective of the study was to test whether low thyroid activity associated with extreme longevity constitutes a heritable phenotype, which could contribute to the familial longevity observed in the Leiden Longevity Study. ... Eight hundred fifty-nine nonagenarian siblings (median age 92.9 yr) from 421 long-lived families participated in the study. Families were recruited from the entire Dutch population if at least two long-lived siblings were alive and fulfilled the age criterion of age of 89 yr or older for males and 91 yr or older for females.

...

We found that a lower family mortality history score (less mortality) of the parents of nonagenarian siblings was associated with higher serum TSH levels (P = 0.005) and lower free T4 levels (P = 0.002) as well as lower free T3 levels (P = 0.034) in the nonagenarian siblings. ... Our findings support the previous observation that low thyroid activity in humans constitutes a heritable phenotype that contributes to exceptional familial longevity observed in the Leiden Longevity Study.

This matter of thyroid hormones is largely an inherited factor in your biochemistry, but it is worth noting that the practice of calorie restriction (CR) is shown to reduce T3 levels - and there is every reason to expect this to be beneficial:

Long-term CR with adequate protein and micronutrient intake in lean and weight-stable healthy humans is associated with a sustained reduction in serum T3 concentration, similar to that found in CR rodents and monkeys. This effect is likely due to CR itself, rather than to a decrease in body fat mass, and could be involved in slowing the rate of aging.

Rozing MP, Houwing-Duistermaat JJ, Slagboom PE, Beekman M, Frölich M, de Craen AJ, Westendorp RG, & van Heemst D (2010). Familial Longevity Is Associated with Decreased Thyroid Function. The Journal of clinical endocrinology and metabolism PMID: 20739380

From The Week: "In 20 years, we will have stem cell banks like pharmacies. You will get a specific diagnosis and take a specific type of stem cell. ... Meantime, scientists are using cells to produce pig hearts, rat livers, and mice teeth that grow independently in a lab. Anthony Atala, director of the Wake Forest Institute for Regenerative Medicine, grows human bladders, and has implanted more than two dozen of them in human patients since 2006. ... Hollow organs are easier to create than solid ones, but researchers have recently made strides with livers, hearts, and even lungs. Major challenges remain. But sometime in the future, scientists hope, humans will be able to mimic the processes that enable other animals to regenerate body parts. When a salamander loses a leg, it sprouts a new one. A zebra fish can even regenerate a portion of its heart. Humans can regenerate bones and skin, but like other higher species, lost the capacity to regrow limbs and organs during the process of evolution. By manipulating specific genes, scientists may turn this miraculous power back on. ... In a world in which aging or diseased people can swap a damaged heart, liver, or other organ for a new one created from their own DNA, a majority of children alive today might live to 100 or beyond. It's hard to know how far-reaching the effects might be because we're still only at the dawning of the biological revolution. But true believers have seen enough to predict changes of historical import. ... We're beginning to understand how life is coded and how life makes things. How we make things, where we make things, is going to change on a scale similar to that of the Industrial Revolution. It's already happening."

Link: http://theweek.com/article/index/206480/building-a-better-human

Broadly, we might think that there are two types of degeneration that accompany aging: the forms that are largely preventable via lifestyle choices, and the forms that you can only slow down, even with the best tools presently available. Insulin resistance is an example of the former, and mitochondrial damage is an example of the latter. From a recent review paper: "This review addresses the question whether insulin sensitivity and mitochondrial oxidative capacity are independently affected during aging and type 2 diabetes. ... Humans with or at risk of type 2 diabetes frequently exhibit insulin resistance along with structural and functional abnormalities of muscular mitochondria. Low mitochondrial oxidative capacity causes muscular fat accumulation, which impedes insulin signaling via lipid intermediates, in turn affecting oxidative capacity. However, insulin sensitivity is not generally reduced with age, when groups are carefully matched for physical activity and body fatness. Moreover, lifestyle intervention studies revealed discordant responses of mitochondrial oxidative capacity and insulin sensitivity. ... In the elderly, low mitochondrial oxidative capacity likely results from age-related effects acquired during life span. Insulin resistance occurs independently of age mostly due to unhealthy lifestyle on top of genetic predisposition. Thus, insulin sensitivity and mitochondrial function may not be causally related, but mutually amplify each other during aging."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20798481

Demographic researchers Leonid Gavrilov and Natalia Gavrilova pointed me to a powerpoint of their latest presentation, titled How Long Will We Live in the 21st Century?:

We are pleased to share with you the power-point-presentation of our keynote lecture made recently at the international conference in Bermuda, which may be interesting to you.

The presentation is a good overview of presently established trends and viewpoints held in the mainstream of medical research. In essence, present trends lead to only modest gains in human life span if extrapolated - but extrapolation, always a dangerous undertaking, is particularly foolhardy in these early years of the biotechnology revolution. The oldest and most extensive demographic data is next to useless now:

Mortality trends before the 1950s are useless or even misleading for current forecasts because all the 'rules of the game' has been changed.

Further, the technologies that may lead to radical extension of the healthy human life span - such as realization of the Strategies for Engineered Negligible Senescence - are the most uncertain in terms of timing. The present pace of research is both rapid and unpredictable, and so is the time it will take for new paradigms of longevity science to become dominant in large research communities. The story of longevity in the 21st century is one of great unpredictability - but the flip side of that pronouncement is that the future is open to change. The more we do now to accelerate research and advocate longevity science, the sooner we'll see results.

From Nature: "A model published this week questions a popular theory dubbed the 'grandmother hypothesis', which says that human females, unlike those of the other great apes, survive well past their reproductive prime because of the benefits that post-menopausal women offer to their grandchildren. ... Chimps almost never live into their forties in the wild, but most humans, if they're lucky enough to make it to adulthood, live beyond the childbearing years. ... Despite its anecdotal support and intuitive appeal, the grandmother hypothesis lacked much quantitative proof showing that it was possible for longevity to evolve from grandmothering ... [Researchers] ran a mathematical simulation to test the theory's plausibility. Their agent-based model, which simulates the actions and interactions of individuals, begins with a population of 1,000 people whose lifespans and reproductive windows are an inherited trait that mutates over time. ... After about 500 generations, the model demonstrated that the assistance of a grandmother during infancy shortened the interval between the times their daughters give birth, and led to shorter reproductive windows. However, compared with simulations in which grandmothers did not help out, the benefits never result in a change in longevity. ... In hindsight [the] result isn't as surprising at it might seem. Natural selection is strongest early in life, and its influence on a trait wanes as an organism ages. Therefore, the benefits of grandmothering would have to be enormous to extend human lifespan."

Link: http://www.nature.com/news/2010/100824/full/news.2010.430.html

A post on autophagy at Metamodern: "I’d like to say a few words about one of the hottest and, in my view, most important areas in biomedicine: autophagy, a process crucial to health, disease, and aging. Autophagy research is expanding rapidly. In autophagy ('self eating'), cells engulf and digest their own macromolecules and organelles. Autophagy serves two functions: providing critical nutrients in times of scarcity, and recycling damaged cellular structures. ... It seems that lab animals and human beings fed ad-libitum do too little autophagic recycling. The resulting accumulation of damaged machinery causes a wide range of functional deficits, and accumulation of damaged mitochondria, in particular, increases the production of reactive oxygen species, accelerating further damage. In a range of organisms, dietary restriction both induces autophagy and results in wide-ranging health benefits, including the extension of healthy lifespans. Blocking autophagy blocks the most important of these effects. Rapamycin induces autophagy and extends lifespan, as does sirtuin-1. Autophagy again appears to be central to these effects. A recent review article examines genetic interventions that indicate 'tight connections between autophagy, health span and aging'."

Link: http://metamodern.com/2010/07/24/autophagy-why-you-should-eat-yourself/

If you're of the opinion that there's something interesting to be found in understanding the biology of queen bee longevity, then you might want to take a look at what's going on in the world of ant research of late:

Some ants live longer than others - way longer. And the mapping of the first full genome sequences of ants helps to reveal how two ants from the same colony, and with much the same genetic material, can have such different life histories.

...

The sequences provide clues that explain why queen ants can live as much as 10 times as long as female worker ants, and researchers are keen to figure out what factors go into determining this extreme longevity. When a queen from an H. saltator colony dies, female worker ants fight to decide who will take over. Once a new queen is selected, her form and function change. She shifts from workaday laborer to fertile egg layer, adjusting body and life history in the process.

The researchers found that in the ants, expression of telomerase, enzymes that help to protect the genetic information at the end of chromosomes, changed along gamergate queens went from worker to egg layer. "That gamergate queen, she starts expressing higher level of telomerase," and her life span increases from that of an average worker ant, Berger explains. She and her colleagues are interested in finding the "aspects of longevity that correlate with this genetic switch."

Ants provide "a natural system where there's a lifespan difference," Smith explains. "We can see where nature has leveraged these [epigenetic] pathways" to extend life.

In addition to questions of longevity, the genetic and epigenetic profiles of ants can provide interesting insights about metabolism. "Queens and workers have very different energy usage profiles," Smith notes. Ants' fat reserves seem to help determine behavior, he explains. "Worker ants don't have much to run on, so they run off to find more food." And because ants have insulin signaling pathways similar to those of humans, researchers might also be able to study crucial health issues such as metabolic syndrome and calorie use.

Ants and bees, (much like naked mole rats, who are also a eusocial species with long-lived queens), stand as extreme examples of what epigenetic can contribute to structure, life span, and metabolism. Radically different animals can result from the same genes, and the difference lies in the way in which those genes are translated into the machinery of biology.

Obviously, this provides researchers who focus on metabolic manipulation with the hope that potential longevity-inducing alterations can be brought to higher mammals, such as we humans. If effective genetic mutations for longevity aren't found, then perhaps other layers of our biological foundation can be altered beneficially. If not the genes, then the way the genes are used.

As always, I think this is the wrong road to engineering longevity for those of us alive today. It most likely won't result in meaningful progress rapidly enough to help us. It can only slow aging, and we will be old already by the time the first useful therapies emerge. The focus should instead be on repairing and reversing damage to the metabolism we already - the Strategies for Engineered Negligible Senescence or similar projects that are actually capable of producing rejuvenation therapies.

Work on artificial replacements for damaged corneas is showing promise: "A new study from researchers in Canada and Sweden has shown that biosynthetic corneas can help regenerate and repair damaged eye tissue and improve vision in humans. ... Globally, diseases that lead to clouding of the cornea represent the most common cause of blindness. More than a decade ago, [researchers] began developing biosynthetic corneas in Ottawa, Canada, using collagen produced in the laboratory and moulded into the shape of a cornea. ... Together, they initiated a clinical trial in 10 Swedish patients with advanced keratoconus or central corneal scarring. Each patient underwent surgery on one eye to remove damaged corneal tissue and replace it with the biosynthetic cornea, made from synthetically cross-linked recombinant human collagen. Over two years of follow-up, the researchers observed that cells and nerves from the patients' own corneas had grown into the implant, resulting in a 'regenerated' cornea that resembled normal, healthy tissue. Patients did not experience any rejection reaction or require long-term immune suppression, which are serious side effects associated with the use of human donor tissue. The biosynthetic corneas also became sensitive to touch and began producing normal tears to keep the eye oxygenated. Vision improved in six of the ten patients, and after contact lens fitting, vision was comparable to conventional corneal transplantation with human donor tissue."

Link: http://www.medicaldaily.com/news/20100826/1457/seeing-the-world-with-new-eyes-biosynthetic-corneas-restore-vision-in-humans.htm

Cellular reprogramming progresses: "Because liver cells (hepatocytes) cannot be grown in the laboratory, researching liver disorders is extremely difficult. However, today's new research [demonstrates] how to create diseased liver-like cells from patients suffering from a variety of liver disorders. By replicating the organ's cells, researchers can not only investigate exactly what is happening in a diseased cell, they can also test the effectiveness of new therapies to treat these conditions. It is hoped that their discovery will lead to tailored treatments for specific individuals and eventually cell-based therapy - when cells from patients with genetic diseases are 'cured' and transplanted back. Additionally, as the process could be used to model cells from other parts of the body, their findings could have implications for conditions affecting other organs. ... the scientists took skin biopsies from seven patients who suffered from a variety of inherited liver diseases and three healthy individuals (the control group). They then reprogrammed cells from the skin samples back into stem cells. These stem cells were then used to generate liver cells which mimicked a broad range of liver diseases - the first time patient-specific liver diseases have been modelled using stem cells - and to create 'healthy' liver cells from the control group. Importantly, the three diseases the scientists modelled covered a diverse range of pathological mechanisms, thereby demonstrating the potential application of their research on a wide variety of disorders."

Link: http://www.eurekalert.org/pub_releases/2010-08/uoc-lcc082410.php

Cryonics isn't a service you can just sign up for and forget, hoping it works out if you need it. That cryonics requires preparation, thought, and a modest ongoing investment of time in order to work out well - more so than an insurance contract - is one of the few concrete reasons we can point to for its comparative unpopularity. If buying the product involves work, fewer people will buy the product: simple and true. Cryonics providers are becoming better at helping their customers with these preparations, but like all serious medical procedures, there's a core set of arrangements and due diligence that no provider can take out of your hands. If you want it to work, you have to put in the effort.

Along these lines, here's a recent post from Michael Anissimov at Accelerating Future:

it’s easy to fantasize that if I happen to be hit and killed by a truck tomorrow, someone will quickly notice my cryonics necklace, call up Alcor, a heroic field technician will give me a heparin injection (to prevent clotting), quickly whisk me away to a hospital, where I am pronounced dead, packed with ice, and shipped to Scottsdale for an effective cryonic suspension. However, such a suspension would probably be considered seriously suboptimal. My blood would be clotted and my tissue would be swollen.

He goes on to discuss Alcor's standby program, one of the service-oriented improvements Alcor employs to encourage and ensure a good outcome for end of life arrangements. It can't help if you're hit by a truck when young and healthy, but there's no reason for an elderly and dying customer to suffer just as poor a cryosuspension when they could be attended by a standby team at the time of death:

Standby is the process in which cryonics personnel are deployed and waiting near the bedside of a patient at serious risk of death. The purpose of Standby and a Standby Team is to take prompt action to restore blood circulation, administer protective medications, and start rapid cooling when the heart stops beating. This is critically important to achieve a good cryopreservation.

Signing up for cryonic suspension at the present time is less like buying an invitation to an event, and more like agreeing to help organize an event. As time goes on and cryonics organizations grow and mature, I imagine this will change - but still, as I said above, does anyone go into a major medical procedure in this day and age assuming they will bring nothing to the table in terms of planning? It's just the same for cryosuspension. Ultimately, making it work for you comes down to your input to the process.

Mitochondria are an important determinant of life span, demonstrated by some beneficial mutations and comparison between species. Researchers continue to investigate longevity mutations to better understand the underlying mechanisms: "The [known] Caenorhabditis elegans mitochondrial (Mit) mutants have disrupted mitochondrial electron transport chain (ETC) functionality, yet, surprisingly, they are long lived. We have previously proposed that Mit mutants supplement their energy needs by exploiting alternate energy production pathways normally used by wild-type animals only when exposed to hypoxic conditions. We have also proposed that longevity in the Mit mutants arises as a property of their new metabolic state. If longevity does arise as a function of metabolic state, we would expect to find a common metabolic signature among these animals. ... we show that long-lived clk-1(qm30) and isp-1(qm150) Mit mutants have a common metabolic profile that is distinct from that of aerobically cultured wild-type animals and, unexpectedly, wild-type animals cultured under severe oxygen deprivation. Moreover, we show that 2 short-lived mitochondrial ETC mutants, mev-1(kn1) and ucr-2.3(pk732), also share a common metabolic signature that is unique. ... Our study suggests long-lived, genetically specified Mit mutants employ a novel metabolism and that life span may well arise as a function of metabolic state."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20732954

A press release from InnoCentive and the SENS Foundation announces a short-term incentive program "seeking innovative ideas to biologically reverse one of the causes of aging and age-related diseases believed to be attributed to glucosepane, a protein crosslink that reduces elasticity throughout the body. This is a Theoretical Challenge, so Solvers need to submit a detailed and thorough description of their solution. The Challenge runs for 60 days and one Solver will receive $20,000 if their solution is chosen. ... Finding an innovative solution to breaking down glucosepane, or what we call 'public enemy number one,' is our Foundation's top priority in the category of protein crosslinks, as it is the most abundant protein crosslink in aged humans. We believe there are several radical possibilities to solving this Challenge - things we haven't even thought of - and will keep an open mind to solutions we receive. Our goal is to discover solutions that can be implemented and reverse stiffening, therefore restoring youthful health and vigor to the world's population. ... Evidence suggests that glucosepane may play a role in osteoporosis, cardiovascular diseases like hypertension, inflammation and diabetes. Scientists have studied the accumulation of glucosepane for 30 years with little success, so SENS Foundation is reaching out to InnoCentive's 200,000+ Solvers for innovative solutions to find a way to break the formation of glucosepane." This seems like a good way to draw attention to aspects of the SENS program that are not greatly studied - very few groups are working seriously on crosslink breakers at the present time.

Link: http://www.marketwire.com/press-release/InnoCentive-SENS-Foundation-Seek-Innovative-Ideas-Help-Reverse-Age-Related-Illnesses-1308936.htm

The latest issue of Rejuvenation Research is available online for those of you who like to keep up with the scientific journals. In the opening commentary, Aubrey de Grey points to the recent position paper issued by noteworthy biogerontologists and folk from the Lifestar Institute. In his view, it is a sign of noteworthy progress in the long struggle to turn the institutions of life science research towards a more productive approach to human aging:

Most nonbiologists, and even quite a few biologists, are spectacularly hazy on the topic of how aging relates to the diseases of old age. The prevailing biogerontological approach has long been that aging is not a disease, or at best that it predisposes to disease. Regular readers will know I'm not going to agree with that, and that I view it as axiomatic that aging is the set, progressive early stages of the various age-related diseases, without which they simply could not be age-related. But whatever one's view, it should be clear that maintenance of that traditional rhetoric will continue to limit the amount of public funding that will be spent on productive aging research, and to completely scupper the argument that some of the money spent on those diseases could very profitable be spent on postponing aging by repairing the progressive early stages of disease.

It remains unclear when, and how, the transition to a simple and compelling description of biomedical gerontology - as, for example, "preventative geriatrics" - will finally occur, but it certainly has not occurred yet, and the result is that the potential for intervention in aging to address the diseases and disabilities of old age remains vastly underrecognized in the funding policies of the nations that lead biomedical research.

You might look back at a previous Fight Aging! post on the topic of whether to declare aging a disease, which could be considered a part of the same battle. One the one hand you have to win the debate within the scientific community over strategy for future work, and on the other hand you have to convince the large funding entities to pay for research and development according to that strategy. This sort of change proceeds incrementally as a rule. Looking back over the past five to ten years, progress is certainly being made in bringing the rest of the world around to our point of view on aging and longevity science, but we'd all like this process to be faster.

From the SENS Foundation: "A comprehensive suite of rejuvenation biotechnologies must include the removal of extracellular aggregates from aging cells and tissues. The most clinically-advanced such biotechnology is immunotherapy against aggregated beta-amyloid protein (Abeta), a characteristic neuropathological lesion that accumulates in the brain in Alzheimer's disease (AD) patients and as part of "normal" brain aging. ... The promise of active and passive Abeta-targeting vaccines is high, but experimental and clinical testing of such therapies have revealed some of their limitations. Immunotherapeutics currently in clinical development rely in different ways on the mobilization of the patient's immune processes. ... Therapeutic efficacy thus depends on the patient's immune response to vaccination, which notoriously declines with aging. ... An ideal Abeta immunotherapy would thus not depend on the patient's immune system for effectiveness or safety, but would have an "intrinsic" mechanism of action ... [researchers] have made significant progress with a promising novel approach to Abeta immunotherapy that promises to deliver on all of these fronts. They have identified, purified, and characterized [antibodies] with direct hydrolytic activity against these pathological aggregates." Antibodies are the weapons used by immune cells to mark and destroy their targets - but if you can regularly infuse antibodies into the body, then you don't necessarily need the immune cells to take action.

Link: http://www.sens.org/research/research-blog/optimizing-abeta-clearance-catalytic-immunoglobulins

Cancer chemotherapy is harrowing is because it is indiscriminate. But all of the old chemotherapies can be made much better and safer when used as the payload in one of the new cell targeting nanotechnologies: researchers "have developed a nano-sized vehicle with the ability to deliver chemotherapy drugs directly into cancer cells while avoiding interaction with healthy cells, increasing the efficiency of chemotherapeutic treatment while reducing its side effects. ... Inside the nano-vehicle itself are tiny particles of chemotherapy drugs. When the delivery vehicle comes into contact with cancer cells, it releases the chemotherapeutic payload directly into the cell. ... the nanomedical device can be used to treat many different types of cancer, including lung, blood, colon, breast, ovarian, pancreatic, and even several types of brain cancers. ... The key to the drug delivery platform is the molecule used to create the outer coating of this cluster nano-vehicle, a sugar recognized by receptors on many types of cancer cells. ... When the nano-vehicle interacts with the receptor on the cancerous cell, the receptor undergoes a structural change and the chemotherapy payload is released directly into the cancer cell. [This] leads to more focused chemotherapeutic treatment against the diseased cells. ... clinical trials [should] begin in two years or less."

Link: http://www.sciencedaily.com/releases/2010/08/100823131739.htm

Mitochondria are the power plants of our cells, tiny organelles churning away to turn food into ATP, the molecule used to transport energy used in cellular processes. Mitochondria were once symbiotic bacteria, way back in the dim and distant evolutionary past, and one remnant of that origin is that they contain their own DNA, separate from the DNA within the cellular nucleus. Unfortunately for us - and all other species that depend upon mitochondria - the operating processes of these organelles gradually damages their DNA, which in turn leads to a chain of consequences and further cellular damage, spreading and accelerating over the years to produce a large faction of what we know as degenerative aging.

Aging is nothing more than accumulated biochemical damage, and our mitochondria produce more than their fair share of that damage.

You will recall that DNA is essentially a blueprint for proteins, and that the proteins produced from these blueprints through the process of gene expression are components in biological machinery vital to the operation of a cell - or of a mitochondrion. If a section of mitochondrial DNA is knocked out by damage, then that mitochondrion is no longer capable of full functionality. It can no longer produce one or more of the proteins it needs, a state of affairs which causes all sorts of issues.

If, however, scientists could employ modern biotechnology to repair or work around mitochondrial DNA damage and the consequent loss of important proteins, then the medical community could build a therapy to completely alleviate this aspect of aging. We know that it takes a few decades of life for the effects of accumulated mitochondrial DNA damage to even start to become significant (given that most thirty year olds are in good shape), so a repair therapy for mitochondria would only have to be applied once every twenty or thirty years at worst.

How are researchers approaching the development of a fix for mitochondrial DNA damage, however? Over at the SENS Foundation, Michael Rae summarizes the options:

A number of credible proposals have been advanced for rejuvenation biotechnology to restore youthful mitochondrial function [to cells overtaken by damaged mitochondria]. The lead candidate approach, first proposed by SENS Foundation Chief Scientific Officer de Grey, is the placement of functioning "backup copies" of the protein-coding mtDNA genes in the cell nucleus ("allotopic expression" (AE)). There has been substantial progress in this area since then, and in recent years SENS Foundation has prioritized funding of AE research beginning with early work by Mark Hamalainen in Ian Holt's lab at Cambridge, and later in both the SENS Foundation Research Center and in the lab of Dr. Marisol Corral-Debrinski at the Institut de la Vision at Pierre and Marie Curie University, Paris. Active investigation of AE is soon to resume in the latter two centers.

But other potential routes to mitochondrial rejuvenation do exist and should also be developed, including the wholescale intraorganellar replacement of mtDNA using "protofection" and the delivery of allotopic RNA to the organelle. The latter possibility was highlighted by work targeting tRNA human cell mitochondria with the transgenic use of the transfer RNA import complex adapted from the parasitic protozoon Leishmania tropica. Working with Newcastle University's Dr. Robert Lightowlers and others, UCLA's Carla Koehler and Michael Teitella have now identified and begun to characterize a mammalian-specific mitochondrial system for the import of nuclear-encoded RNA, which could well be exploited to meet this biomedical challenge.

...

And of course, in principle there is no exclusivity between AE of protein and AE of mRNA: provided that at minimum the mitochondrial tRNAs can be allotopically expressed and imported, regenerative engineers could deliver some fully-translated AE proteins and some mRNA precursors, depending on the facility and efficiency of either approach for a given protein, and on the burden on the relevant import machinery.

Delivering RNA is an option because the process of gene expression - of turning the DNA blueprint into the protein end result - uses RNA as an intermediate stage. Genetic transcription is the first step in gene expression, wherein RNA is formed from the DNA blueprint. So if you can deliver the right RNA to the right place in a cell, you don't need the original DNA: it could be damaged or missing, and the desired protein would still be produced.

That there are at least three options under serious consideration for mitochondrial rejuvenation is a good sign for the future of this field. Competition is the lifeblood of progress, and the more of it the better.

Researchers continue to produce improvements to infrastructure technologies needed for stem cell research and development: "Human pluripotent stem cells, which can become any other kind of body cell, hold great potential to treat a wide range of ailments, including Parkinson's disease, multiple sclerosis and spinal cord injuries. However, scientists who work with such cells have had trouble growing large enough quantities to perform experiments - in particular, to be used in human studies. Furthermore, most materials now used to grow human stem cells include cells or proteins that come from mice embryos, which help stimulate stem-cell growth but would likely cause an immune reaction if injected into a human patient. To overcome those issues, MIT chemical engineers, materials scientists and biologists have devised a synthetic surface that includes no foreign animal material and allows stem cells to stay alive and continue reproducing themselves for at least three months. It's also the first synthetic material that allows single cells to form colonies of identical cells, which is necessary to identify cells with desired traits and has been difficult to achieve with existing materials."

Link: http://www.sciencedaily.com/releases/2010/08/100822150643.htm

From the Mayo Clinic: "researchers found that healthy young people who put on as little as 9 pounds of fat, specifically in the abdomen, are at risk for developing endothelial cell dysfunction. Endothelial cells line the blood vessels and control the ability of the vessels to expand and contract. ... [researchers] recruited 43 healthy Mayo Clinic volunteers with a mean age of 29 years. They were tested for endothelial dysfunction by measuring the blood flow through their arm arteries. The volunteers were assigned to either gain weight or maintain their weight for eight weeks, and their blood flow was tested. The weight-gainers then lost the weight and were tested again. ... Endothelial dysfunction has long been associated with an increased risk for coronary artery disease and cardiovascular events. Gaining a few pounds in college, on a cruise, or over the holidays is considered harmless, but it can have cardiovascular implications, especially if the weight is gained in the abdomen. ... Among those who gained weight in their abdomens (known as visceral fat), even though their blood pressure remained healthy, researchers found that the regulation of blood flow through their arm arteries was impaired due to endothelial dysfunction. Once the volunteers lost the weight, the blood flow recovered. Blood flow regulation was unchanged in the weight-maintainers and was less affected among those who gained weight evenly throughout their bodies."

Link: http://www.mayoclinic.org/news2010-rst/5919.html

As you might recall, the Immortality Institute started their search for a new research project to fund earlier this year. This is a follow-on to raising funds for laser ablation of lipofuscin last year. I am hopeful that the Institute can make this a regular yearly feature, and not least because establishing reliable methods for crowdsourcing life science funding is an important development for the future of research.

The Institute has settled on the project to be funded, which is an investigation of the phenomenon of mitochondrial uncoupling:

Scientific research is the only way to conquer the blight of involuntary death. The ImmInst.org community isn't rich, so we pick our priorities quite carefully. The mitochondroial uncoupling project ticks all the important boxes:

• it investigates a crucial mechanism of how and why we age
• it may show the path towards practical interventions in the aging process
• it is small enough that your donation, every cent of which will be matched by ImmInst, *will* make a real difference
• it is led by a reputable scientist who will respond to community questions and update us periodically on the progress of the research

Any donation, of any amount is appreciated. We need at least $6000 to get going, with the matched funding in place that means at least $3000 from donors like you. Any surplus would go into the next scientific research initiative that is already in the pipeline.

You can read the project proposal for the work that will take place in a research laboratory in Singapore at the Institute website, and discuss fundraising and prospects in the forums - even direct questions and suggestions to the researchers. This sort of transparency in fundraising and the research process is something that will become increasingly important as costs of life science research continue to fall:

Using C. elegans, we propose to answer the following questions:

1) Can chemical uncoupling be used to significantly reduce mitochondrial ROS production in vivo? At what dose of uncoupler is this effect maximal?

2) Does reduction of mitochondrial ROS production result in decreased mtDNA damage, preserved mitochondrial function and protection of mtDNA integrity?

3) Does (1) lead to lifespan extension and, if so, can this extension be plausibly explained by (2)?

...

We are in an ideal position to carry out this investigation because we have already established the relevant assays, including novel mtDNA related assays, as part of ongoing investigations in our laboratory. The proposed project would be embedded into these ongoing investigations with full support from the [primary investigator] and would take advantage of the specialized nematode facilities, standard lab equipment and reagents available in the Centre. A recently graduated student with more than two years of nematode specific laboratory experience could be recruited for 6 months to carry out the work proposed. For this we require budget sufficient to hire one recent graduate for a period of 6 months. Assuming a 45h week, we would therefore require no more than $6000 to carry out the entire project.

I think this is a worthwhile effort, and encourage you to donate. We absolutely want to see many, many more grassroots organizations adopt this sort of fundraising operation: pick good projects that get the most out of modest donations, and make the most of new technology and established facilities. As is always the case, I'm not asking you to do anything I haven't done myself: I donated $1000 to the project today, and consider it money well spent.

This is one of several techniques shown to restore function in spinal injury using transplanted stem cells: "A UC Irvine study is the first to demonstrate that human neural stem cells can restore mobility in cases of chronic spinal cord injury, suggesting the prospect of treating a much broader population of patients. Previous breakthrough stem cell studies have focused on the acute, or early, phase of spinal cord injury, a period of up to a few weeks after the initial trauma when drug treatments can lead to some functional recovery. The UCI study [is] significant because the therapy can restore mobility during the later chronic phase, the period after spinal cord injury in which inflammation has stabilized and recovery has reached a plateau. There are no drug treatments to help restore function in such cases. ... The [team] transplanted human neural stem cells into mice 30 days after a spinal cord injury caused hind-limb paralysis. The cells then differentiated into neural tissue cells, such as oligodendrocytes and early neurons, and migrated to spinal cord injury sites. Three months after initial treatment, the mice demonstrated significant and persistent recovery of walking ability in two separate tests of motor function when compared to control groups."

Link: http://www.sciencedaily.com/releases/2010/08/100819144440.htm

Via PhysOrg.com: "A team of University of Michigan scientists has found that suppressing a newly discovered gene lengthens the lifespan of roundworms. Scientists who study aging have long known that significantly restricting food intake makes animals live longer. But the goal is to find less drastic ways to achieve the same effect in humans someday. ... scientists found that a gene, drr-2, is an important component in a key cellular pathway, the TOR nutrient-sensing pathway, where many scientists are looking for potential drug targets. The U-M scientists then found that when they caused the drr-2 gene to be under- or over-expressed, they could lengthen or shorten lifespan in C. elegans, a worm widely used in research. Manipulating the drr-2 gene's action produced the same effects as reducing or increasing caloric intake. ... The study also found that drr-2 appears analogous to a human gene, eIF4H, that controls similar cell functions. ... Many genes identified in C. elegans to control the speed of aging turned out to be evolutionarily conserved, meaning that you can find them in other animals, too. And many are very similar to those found in humans. ... When calories or certain nutrients are restricted, scientists detect less oxidative damage in animal cells and a slower decline in DNA repair, a decline that normally occurs with age. It's thought that limiting oxidative damage and slowing the decline in DNA repair could help postpone or avoid many age-related diseases."

Link: http://www.physorg.com/news201367360.html

I noticed a paper on longevity in turtles today that speculates on a link between species life span and tolerance of low-oxygen environments. It seems to be as interesting a line of research as any opened up by the comparison of differences in biochemistry and longevity between species. Why are long-lived species long-lived, and can we expect the answers to translate, as for calorie restriction research, into potential benefits for human health?

Forever young: mechanisms of natural anoxia tolerance and potential links to longevity

While mammals cannot survive oxygen deprivation for more than a few minutes without sustaining severe organ damage, some animals have mastered anaerobic life. Freshwater turtles belonging to the Trachemys and Chrysemys genera are the champion facultative anaerobes of the vertebrate world, often surviving without oxygen for many weeks at a time. The physiological and biochemical mechanisms that underlie anoxia tolerance in turtles include profound metabolic rate depression, post-translational modification of proteins, strong antioxidant defenses, activation of specific stress-responsive transcription factors, and enhanced expression of cytoprotective proteins. Turtles are also known for their incredible longevity and display characteristics of "negligible senescence".

We propose that the robust stress-tolerance mechanisms that permit long term anaerobiosis by turtles may also support the longevity of these animals. Many of the mechanisms involved in natural anoxia tolerance, such as hypometabolism or the induction of various protective proteins/pathways, have been shown to play important roles in mammalian oxygen-related diseases and improved understanding of how cells survive without oxygen could aid in the understanding and treatment of various pathological conditions that involve hypoxia or oxidative stress.

When reading this my first thought was of another unusually long-lived species that has a high tolerance for low-oxygen life: the naked mole-rat. As researchers noted in past years:

Here we report that brain tissue from naked mole-rats, rodents that live in a chronically low-oxygen environment, is remarkably resistant to hypoxia: naked mole-rat neurons maintain synaptic transmission much longer than mouse neurons and can recover from periods of anoxia exceeding 30 min.

It is possibly a coincidence that some whale species are also very long-lived; consider their exposure to anoxia during feeding dives. On the whole, and if considered from the perspective of researchers interested in metabolic manipulation to slow aging, the anoxia angle seems well worth pursuing.

Krivoruchko A, & Storey KB (2010). Forever young: mechanisms of natural anoxia tolerance and potential links to longevity. Oxidative medicine and cellular longevity, 3 (3), 186-98 PMID: 20716943

An author returns to an old topic: "About seven years ago, I reported regularly on the science of longevity, and the prospect of human life extension, for a site called Sage Crossroads. And then I stopped - pretty much dropping the topic for a while and going on to other things. So when I attended the Techonomy session yesterday entitled 'The Longevity Dividend,' it was a perfect chance to hear just how far scientists think their field has come since I last reported on it closely. And I have to say, I was struck by the difference in tone. Seven years ago, scientists who study aging - so-called biogerontologists - already thought it was possible or even likely that at some point in the future, we would find a way to retard its rate in humans. After all, there were already numerous studies showing that genetic interventions could lengthen the lifespan of other species, particularly mice and roundworms. ... So there were reasons to think that human life extension was coming - and more specifically, that a means of slowing the rate of human aging would be possible. But most mainstream scientists weren't so bullish then. So optimistic. In particular, they were very worried about giving false hope, and encouraging anti-aging quackery. I detected a different tone yesterday. S. Jay Olshansky, an aging expert at the University of Chicago, put it plainly. He thinks we can get an average 7 year extension of the human life span by finding a pill that tweaks the right gene pathway - perhaps mimicking the special genetics of those among us who are (or are fated to become) centenarians. 'I'm suggesting, and we are suggesting, that the time has arrived for us to go after the biggest prize of all,' said Olshansky. 'Let's alter our own biology. Let’s alter humanity.'"

Link: http://techonomy.typepad.com/blog/2010/08/bullish-on-longevity.html

Via EurekAlert!: "Scientists have reprogrammed stem cells from a key organ in the immune system in a development that could have implications for tissue regeneration. Their research shows that it is possible to convert one stem type to another without the need for genetic modification. Researchers, who used rat models, grew stem cells from the thymus - an organ important for our immune systems - in the laboratory using conditions for growing hair follicle skin stem cells. When the cells were transplanted into developing skin, they were able to maintain skin and hair for more than a year. The transplanted follicles outperformed naturally-produced hair follicle stem cells, which are only able to heal and repair skin for three weeks. Once they were transplanted, the genetic markers of the cells changed to be more similar to those of hair follicle stem cells. When an animal develops, embryos form three cellular or germ layers - ectoderm, endoderm and mesoderm – which then go on to form the body's organs and tissues. Ectoderm becomes skin and nerves, endoderm becomes the gut and organs such as the liver, pancreas and thymus, and mesoderm becomes muscle, bones and blood. Until now it was believed that germ layer boundaries could not be crossed - that cells originating in one germ layer could not develop into cells associated with one of the others."

Link: http://www.eurekalert.org/pub_releases/2010-08/uoe-scv081810.php

Not so long ago, the SENS Foundation folk kicked off efforts to organize a Los Angeles chapter of supporters. The Foundation has a great many supporters and some significant donors in the Bay Area, so it seems only fair that the other half of California has a chance to show their worth.

The second chapter meeting will be held later this month; if you're in the area, you should drop by:

On behalf of SENS Foundation I am excited to write to you to invite you to join us for our 2nd SENS Foundation L.A. Chapter meeting to be held on Friday, August 27th, at the Westwood Brewing Company (1097 Glendon Avenue, Los Angeles, CA 90024-2907) from 6PM until we have had enough fun.

In this second meeting we will be joined by the fabulous Dr. Sarah Marr (SENS Foundation Vice President)... and, of course, me! ;-) Sarah is going to take this opportunity to tell you a little more about SENS Foundation's Mission, and the ways in which it is working to communicate that mission. Our hope is that we'll be able to empower all the members of the chapter to work with us in promoting the Foundation effectively.

We will also talk about generalized outreach, the Foundation's structure, volunteering, fund raising and more, giving you the chance to connect more closely to us. Also, we'll discuss our plans for future chapter meetings -- making them relate to both the Foundation and the wider research environment in which it works -- and our ideas for bringing in outside speakers.

All of this in a visually interesting, fun and accessible way, and we will of course again have a full bar available for general networking, schmoozing, chit-chatting, gossiping, confabulating, and all of the above. The idea of these local gatherings is to create a local initiative to promote the Foundation's interests and mission by engaging a network of enthusiasts, field professionals, potential donors, sponsors, collaborators, students, etc. Also, to promote educational efforts in the area, and to reach out to the Hollywood community and gain their support.

Please RSVP.

We hope you will come and join us! And as Aubrey says, "Cheers!"

Maria Entraigues
SENSF Volunteer Coordinator
maria.entraigues@sens.org

You can find out more about volunteer opportunities at the Foundation website. Many hands make light work, and there's certainly a lot left to accomplish between here and the advent of real, working rejuvenation medicine based on the Strategies for Engineered Negligible Senescence research and development outline.

One of the challenges in developing autologous stem cell therapies for age-related conditions is that old people have damaged stem cells and damaged stem cell niches. This research demonstrates a technology platform that might eventually encompass all sorts of repair and support for cells to ensure that the age of the donor and recipient can be made irrelevant: "Therapeutic cells, such as those implanted in the body to battle cancer or replenish devastated populations of stem cells, may someday be able to carry their own life-support packets. New research [shows] how transplanted cells can be loaded with minuscule particles, or nanoparticles, which contain substances that help the therapeutic cells survive and flourish. These tiny packets of drugs may provide more effective support for the therapeutic cells, and cause less harm overall, because doctors might be able to achieve therapeutic effects with smaller doses of medicine. ... [During one immune therapy test] researchers found they could load about 100 nanoparticles on each T cell without interfering with the cells' division, or with their ability to migrate through tissue, find targets in the bloodstream, and kill tumor cells. ... Both the T cells and stem cells could keep the nanoparticles sitting on their surface - with dividing cells actually splitting up the cargo - an intriguing finding."

Link: http://www.hhmi.org/news/irvine20100815.html

Hormetic effects, in which a little damage improves health by activating defense and repair systems, are important in the relationship between exercise, calorie restriction, and longevity. Here, researchers suggest that therapies based on manipulating hormetic mechanisms will have to be tailored to the individual: "Hormesis, the beneficial effect of a mild stress, has been proposed as a means to prolong the period of healthy ageing as it can increase the average lifespan of a cohort. However, if we want to use hormesis therapeutically it is important that the treatment is beneficial on the individual level and not just on average at the population level. Long lived lines have been shown not to benefit from [hormesis, while] in many experiments hormesis has been reported to occur in one sex only, usually males but not in females. Here we investigated the interaction between the hormetic response and genetic background, sex and duration of a mild heat stress in D. melanogaster, using three replicate lines that have been selected for increased longevity and their respective control lines. We found that genetic background influences the position of the hormetic zone. The implication of this result could be that in a genetically diverse populations a treatment that is life prolonging in one individual could be life shortening in other individuals. However, we did find a hormetic response in all combinations of line and sex in at least one of the experiments which suggests that if it is possible to identify the optimal hormetic dose individually hormesis might become a therapeutic treatment."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20711813

This year's Singularity Summit was held in San Francisco a few days ago, and generated a fair amount of coverage. The event was largely focused on artificial intelligence and other topics not directly related to engineering greater human longevity, but there were nevertheless one or two interesting presentations that touched on related science. Here is a small selection of links for those who didn't manage to make it to the event:

Singularity Summit 2010 - Optimism, Intelligence, and the Future - Oh My

The Singularity Summit is a weird beast. Part science lectures, part networking, part philosophical discussion it comes off as an enthusiastic collection of people who aren’t afraid to think well outside the box. ... [Ben] Goertzel shared his recent collaborations with Genescient using AI to examine the genomes of fruit flies bred for incredible longevity (five times the normal). He thinks AI biologists are the key to understanding human genes and extending human life spans.

Singularity Summit Promises to Stimulate Your Brain

The idea over time is to improve people’s thinking about the future and increasing public awareness of radical technologies under development today and of the transformative implications of such technologies as part of a larger process.

Reverse-Engineering of Human Brain Likely by 2030, Expert Predicts

Reverse-engineering the human brain so we can simulate it using computers may be just two decades away, says Ray Kurzweil, artificial intelligence expert and author of the best-selling book The Singularity is Near.

The Singularity Is Coming; or No It Isn't; or Wait Maybe It Is!

I came here pretty skeptical about it. When you look at what has actually been achieved so far on the AI front, it's all pretty primitive. But I can't deny that my skepticism is being, if not assuaged, at least chipped away at and complicated. ... And you talk to a guy who's been breeding fruit flies for longevity for 30 years and studying the changes in their genome and figuring out how we could manipulate the human genome in similar ways ... well, it's good to know somebody's working on that.

You'll find a whole bunch of archived liveblogging from the Summit at the Speculist:

• Singularity Summit 10 Morning
• Singularity Summit 10 Mid-Day
• Singularity Summit 10 Afternoon
• Singularity Summit 10 Evening
• FastForward Radio -- Live from Singularity Summit 2010
• Singularity Summit Day 2 Morning
• Singularity Summit Day 2 Mid-Day
• Singularity Summit Day 2 Afternoon
• Singularity Summit Day 2 Evening
• What Next?

The Singularity Summit was an exciting two days. I had a great time meeting up with old friends and making new ones. I hope I was able to convey a little of the energy and give a glimpse of some of the amazing ideas that were covered.

Now if we could just arrange matters such that the engineered longevity conferences generate this much discussion, light, and noise. This is not a trivial task, of course. Behind the chatter lies a great deal of careful arrangement, networking, and years of groundwork by the Summit organizers - making a splash doesn't just happen. This is something that the longevity science community isn't good at yet, sad to say: it must be added to the list of critical areas to work on.

Thoughts on the impact of better technology on free radical theory: "The role of oxidative stress in aging proposed by the free radical theory has been the focus of investigations for more than fifty years. The results of a large number of these investigations provide support for this theory. However, numerous recent findings point to the existence of unexpected complexity in the relationships between oxidative stress and aging. This complexity is highlighted by the discovery [that] a key element of oxidative stress defenses in the model organism budding yeast, shortens lifespan in concert with enhanced resistance to oxidative stress. In addition to the implications of this finding for understanding aging, identification of this mutation by massively parallel sequencing of whole genomes emphasizes the enormous utility of next-generation sequencing technologies as investigative tools that will likely revolutionize genetics. ... In some cases, the apparent disconnect between experimental results and predictions of the free radical theory regarding connections between oxidative stress and lifespan is related to hormesis effects that elevate oxidative and other stress defenses in response to low levels of oxidative stress. ... The more transparently clear lesson here is that not all forms of oxidative stress are equivalent in their effects on aging. This isn't surprising in the context of the multitude of pathways that respond to different forms of oxidative stress and the numerous mechanisms by which oxidants can modify different macromolecular targets. Whatever the explanation, [research findings] emphasize the enormous complexity of relationships between oxidative stress and aging."

Link: http://www.impactaging.com/papers/v2/n8/full/100188.html

From the New York Times: "In the 100 years since the first moose swam into Lake Superior and set up shop on an island, they have mostly minded their moosely business, munching balsam fir and trying to evade hungry gray wolves. But now the moose of Isle Royale have something to say - well, their bones do. Many of the moose, it turns out, have arthritis. And scientists believe their condition's origin can help explain human osteoarthritis - by far the most common type of arthritis, affecting one of every seven adults 25 and older and becoming increasingly prevalent. The arthritic Bullwinkles got that way because of poor nutrition early in life, an extraordinary 50-year research project has discovered. That could mean, scientists say, that some people's arthritis can be linked in part to nutritional deficits, in the womb and possibly throughout childhood. The moose conclusion bolsters a small but growing body of research connecting early development to chronic conditions like osteoarthritis. ... Nutrients, experts say, might influence composition or shape of bones, joints or cartilage. Nutrition might also affect hormones, the likelihood of later inflammation or oxidative stress, even how a genetic predisposition for arthritis is expressed or suppressed."

Link: http://www.nytimes.com/2010/08/17/health/research/17moose.html

Induced pluripotent stem cells - cells reprogrammed to exhibit self-renewal and the ability to differentiate into any type cell - are beginning to look like good replacements for embryonic stem cells in regenerative medicine. If this pans out, it will result in large cost reductions in sourcing cells for use. Any skin cell sample from a patient can be reprogrammed to be pluripotent via present methods, meaning it can in theory be used as the foundation to build new tissue and replacement cell populations that have no risk of immune rejection.

Here is another recent demonstration to show that induced pluripotent cells might be all they are hoped to be:

Researchers at the Buck Institute for Age Research have successfully used human induced pluripotent stem cells (iPSCs) to treat rodents afflicted with Parkinson's Disease (PD). The research, which validates a scalable protocol that the same group had previously developed, can be used to manufacture the type of neurons needed to treat the disease and paves the way for the use of iPSCs in various biomedical applications.

...

Researchers in the Zeng lab used human iPSCs that were derived from skin and blood cells and coaxed them to become dopamine-producing neurons. Dopamine is a neurotransmitter produced in the mid-brain which facilitates many critical functions, including motor skills. Patients with PD lack sufficient dopamine; the disease is a progressive, incurable neurodegenerative disorder that affects 1.5 million Americans and results in tremor, slowness of movement and rigidity.

Researchers transplanted the iPSC-derived neurons into rats that had mid-brain injury similar to that found in human PD. The cells became functional and the rats showed improvement in their motor skills. Zeng said this is the first time iPSC-derived cells have been shown to engraft and ameliorate behavioral deficits in animals with PD. Dopamine-producing neurons derived from hESCs have been demonstrated to survive and correct behavioral deficits in PD in the past. "Both our functional studies and genomic analyses suggest that overall iPSCs are largely similar to hESCs," said Zeng.

Which is good news. The cost of research and later the cost of producing therapies is a large factor in determining the pace of progress. Cheaper means faster.

From the Korea Times: "Stem cells, or early-stage cells that retain the potential to turn into other specialized types of cells, are intriguing for their immense potential in treating a wide range of difficult diseases and conditions. And holding an important key to such innovations would be adult stem cells, which are taken from mature tissue, as they could theoretically be taken from patients, grown in culture and transplanted back into the patient without the fear of provoking an immune response. ... The downside of adult stem cells, however, is that they age much faster than embryonic cells, which has limited their usefulness in transplants. ... It has been presumed that the decreasing regenerative capacity of adult stem cells, which is linked to their aging, is a result of inborn genetic variations. But [researchers suggest] that the process isn't dictated by heritable events, such as DNA damage, but rather determined by an 'epigenetic' regulation of gene expression. ... There weren't many studies on finding micro-RNAs related to the aging of cells and learn how they affect stem cells, but this area could be important in developing a way to have adult stem cells retain their normal ability for a longer time."

Link: http://www.koreatimes.co.kr/www/news/tech/2010/08/133_71494.html

In a nutshell: "Adipose tissue accounts for approximately 20% (lean) to [more than] 50% (in extreme obesity) of body mass and is biologically active through its secretion of numerous peptides and release and storage of nutrients such as free fatty acids. Studies in rodents and humans have revealed that body fat distribution, including visceral fat (VF), subcutaneous (SC) fat and ectopic fat are critical for determining the risk posed by obesity. Specific depletion or expansion of the VF depot using genetic or surgical strategies in animal models has proven to have direct effects on metabolic characteristics and disease risk. In humans, there is compelling evidence that abdominal obesity most strongly predicts mortality risk, while in rats, surgical removal of VF improves mean and maximum life span. There is also growing evidence that fat deposition in ectopic depots such as skeletal muscle and liver can cause lipotoxicity and impair insulin action. Conversely, expansion of SC adipose tissue may confer protection from metabolic derangements by serving as a 'metabolic sink' to limit both systemic lipids and the accrual of visceral and ectopic fat. Treatments targeting the prevention of fat accrual in these harmful depots should be considered as a primary target for improving human health span and longevity."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20703052

Advocacy for longevity research is a balancing act informed by ongoing developments in raising funds, actual progress in the fields of interest, and the growth of the community of supporters. In an ideal world, these three factors will all advance steadily: an upward curve of success. In practice things are never that easy. A supportive community of a given size will only contribute so much in the way of resources: are those resources assigned to research, which tends to produce newsworthy results at irregular intervals in addition to actual progress, or to outreach and education? What will best grow the community so as to grow the resource pool of donations, and in turn help to achieve research goals more rapidly?

Life science research is an unreliable beast by its very nature: progress is unexpected and unpredictable, never as fast the news cycles these days, and costly. But the end goal of new medical technologies is the whole point of the exercise, and research is the only path to that goal. Without a steady flow of signs of incremental progress resulting from funded research, the community becomes discouraged, which in turn makes it harder to raise funds and bring in new faces. When a field is young and the research community comparatively small, a steady flow of signs of progress isn't a realistic expectation, however.

No-one said the early stages were going to be easy, of course. You have to lug the rocks uphill before you roll them back down to create the avalanche.

At the present time, meaningful longevity research (meaning anything based on the Strategies for Engineered Negligible Senescence, or taking place in the community connected to the SENS Foundation and Methuselah Foundation) is in an awkward stage of its growth. The comparatively small, enthusiastic community that helped these organizations launch and raise more than $10 million for prizes and research is more or less maxed out in terms of the resources its members will contribute on an ongoing basis. Meanwhile, the research is proceeding at the normal pace for modestly funded work - which is to say very slowly for people acclimatized to the short attention span of the modern news cycle.

Thus at present, it is more important than ever to grow the community. That way lies increased funding, which in turn can speed the advent of new research results that encourage support for the cause. All of the organizations involved in advocacy for longevity research are engaged in efforts to grow the community of supporters in one way or another. The SENS Foundation, to pick one example, is laying the groundwork for the next generation of the research community itself via the Academic Initiative. Aubrey de Grey meanwhile is a tireless presenter and persuader, who has for years taken the message that longevity science is achievable to movers and shakers around the world. This is old fashioned persuasion at its best: make sure as many people as possible have the chance to think over what you have to say, and encourage those who want to join in and help.

More of the old fashioned persuasion of movers and shakers is in evidence at the LifeStar Institute, whose founders are engaged in the process of pulling together a global initiative to pour funds into longevity science. This is the path of conferences, presentations, position papers, and a great deal of networking. So the thinking goes, bringing a great many people around to your view of the world is best accomplished by persuading the nodes in the social network: the thought leaders and other influential folk. They in turn will help you spread the message and gather new supporters.

The Methuselah Foundation is trying a more directly populist path at present in conjunction with the recently launched New Organ Prize. The aim here appears two-fold: firstly regenerative medicine and tissue engineering enjoys widespread public support and comprehension. By establishing itself as a leader in the tissue engineering space through a research prize - just as it has for the aging research space via the Mprize - the Foundation can ensure that a great many people come to see that regenerative medicine and organ engineering are just one part of a larger technological battle against degenerative aging. Some will step up and do their part to help.

Secondly, the Methuselah Foundation is supporting the growth of broad patient support and advocacy groups via My Bridge 4 Life, a social network startup which focuses on helping people fight and survive life-threatening diseases. For example, the New Organ Network is a My Bridge 4 Life-enabled social network for folk who need organ transplants, their supporters, and their friends. The community is geared towards encouraging the growth of the NewOrgan Prize and participation in accelerating progress towards the goal of organs built to order through tissue engineering.

Very few people think about their own mortality and what to do about it. But if you're suffering from a potentially fatal condition, it's hard to avoid all those considerations - your future just became very compressed, and you're forced to deal with it right here and right now, with no fuzzy thinking or head stuck in the sand. With the help of a will to live, modern technology, and support communities, many people put in this unenviable position survive - and it is possible that their perspectives on life may be turned to the fact that they have won one battle, but are still threatened by aging, the root of all the waiting age-related conditions that lie ahead. Teaching cancer survivors, organ recipients, and other survivors that this next fight against aging awaits - and that it it will be hard, but it there is a way to win it - is a plausible path to finding many more supporters of longevity science.

Low-level chronic inflammation is produced by the aging immune system and causes many further problems: "Osteoarthritis (OA) is the most common cause of chronic disability in older adults. Although classically considered a 'wear and tear' degenerative condition of articular joints, recent studies have demonstrated an inflammatory component to OA that includes increased activity of several cytokines and chemokines in joint tissues that drive production of matrix-degrading enzymes. Rather than directly causing OA, aging changes in the musculoskeletal system contribute to the development of OA by making the joint more susceptible to the effects of other OA risk factors that include abnormal biomechanics, joint injury, genetics, and obesity. Age-related sarcopenia and increased bone turnover may also contribute to the development of OA. Understanding the basic mechanisms by which aging affects joint tissues should provide new targets for slowing or preventing the development of OA."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20699160

The differences in a nutshell: "Calorie restriction (CR) is the only paradigm that has consistently increased lifespan in a wide variety of model organisms. Many hypotheses have been proposed as the underlying mechanism, including a reduction in body size and adiposity, which is commonly observed in calorie-restricted animals. This has led to investigations as to whether similar changes in body composition produced by increasing energy expenditure via exercise can replace or enhance the benefits of reducing energy intake. ... In rodents, the data clearly show that exercise, regardless of body weight changes, can improve health and survival, but unlike CR, fails to extend lifespan. In humans, short-term weight loss studies show that exercise and CR produce similar improvements in disease risk factors and biomarkers of aging, while some parameters clearly benefit more with exercise. Epidemiologic evidence in humans supports exercise as a strategy to reduce the risk of morbidity and mortality, but not to extend lifespan. It is unknown whether CR can extend human lifespan, but the metabolic profile of humans engaged in long-term CR shares many similarities with calorie restricted rodents and nonhuman primates. In conclusion, like CR, exercise can limit weight gain and adiposity, but only CR can extend lifespan. Therefore, in rodents, the ability of CR to slow aging is apparently more dependent on decreasing nutrient flux, rather than changes in energy balance and body composition."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20703061

A recent h+ Magazine article by Ben Goertzel provides a good outline of a point of view that is quite common in the healthy life extension community. There's a fair overlap between transhumanist groups, advocates for engineered longevity, advocates for the development of strong artificial intelligence, and the people who are in fact working on making progress rather than talking about the need for progress. Many of these AI advocates and researchers are strongly in favor of radical life extension efforts - so much so in some cases that it begs the question as to why they're primarily working on AI. The reasoning provided by Goertzel is essentially utilitarian: he believes that the ultimate goal of repairing and reversing aging will be achieved more rapidly if preceded by the advent of strong artificial intelligence.

AIs, Superflies, and the Path to Immortality:

Death and disease are such basic aspects of current and historical human life, that to envision a world without them requires considerable effort. And yet, as technology advances, it becomes increasingly clear that they’re solvable problems.

...

Some researchers believe we can massively reduce death and disease via "patching up" the various problems that arise in the body, without fully understanding the mechanisms underlying these problems. Others believe that the key is going to be a full understanding of the biological organism and - once we know how the body works - we’ll be able to systematically figure out how to improve its health and extend its healthspan. Both approaches are being avidly pursued by serious scientists, and, in my view, eventual success is almost certain. But the big question is when. There are many obstacles between here and there, including funding for research and limitations of current experimental technology. However, I’m increasingly convinced the most severe limitation constraining the quest for improved health and extended healthspan is the human mind itself.

If you find the article interesting, you should probably also read Goertzel's paper on the subject, AI Against Aging, Accelerating the Quest for Longevity via Intelligent Software. For my part, while I agree with some of the assumptions - in particular that strong AI will lead to a revolution in technology and productivity that will make everything we've achieved as a species to date look small - I don't think the utilitarian math quite adds up here.

Yes, we want better tools applied to the tasks and vast complexity of biotechnology, and as soon as possible. But an examination of the Strategies for Engineered Negligible Senescence - and the technologies needed to repair specific forms of cellular damage that cause aging - suggests that money is the real issue, not technology. All the necessary technologies to repair the damage of aging can be developed as logical extensions of the biotechnology of today; no radical new developments are needed, and if the research programs were fully funded, we could expect meaningful therapies in twenty to thirty years. This is no different from the projected path of progress for regenerative medicine - the medical students of today will be directing the processes of growing organs to order and replacing almost any cell population safely and accurately by the 2030s. That will happen even if AI research makes no progress.

But outside regenerative medicine, there is no great initiative or enthusiasm for medical research into repairing the fundamental biochemical damage of aging. No large-scale funding, no massive research community. Yet. This absence of research infrastructure and resources is the cause of slow progress and uncertainty, not the quality of tools that are presently available. Strong AI will make research and development both faster and better. But the timescale for its development is also a few decades from now, assuming things go well and the funding pool grows larger. So under the best case scenarios the first rejuvenation medicine will be contemporary with the first AIs worthy of the name.

While the FDA tries to block commercial application of stem cell therapies in the US, veterinary practices continue to demonstrate that the technology is ready and potentially useful: "A Golden Retriever, plagued with arthritis, recently underwent a stem cell extraction and implant to help with mobility. ... From the sounds of things, you would never suspect McIntyre was a frail and feeble dog. And these days, he's moving around pretty well, thanks to anti-inflammatory medicines, physical therapy and a new experimental surgery involving stem cells. ... like family, she wanted McIntrye to feel better and have a better quality of life. Cells were taken from his belly fat and shipped to California. Stem cells were extracted and then implanted back into his joints by a vet in Alpharetta. ... He'll never be like a puppy as far as agility but it will just give him a quality of life where he doesn't hurt and suffer." Meanwhile, the actions of unaccountable, unelected bureaucrats at the FDA mean that US residents must travel overseas to find the same treatment offered to humans. More importantly, what might already be a wildly successful and growing field is slowed down to a comparative crawl. When you're forbidden to sell a product, few organization will invest in development.

Link: http://www.walb.com/Global/story.asp?S=12964756

Via ScienceDaily, an example of the sometimes indirect way in which stem cell transplants can cause benefits: "Acute lung injury is brought on by a number of conditions, such as pneumonia and sepsis, also known as blood poisoning. In some cases, acute lung injury develops into a more serious condition, known as acute respiratory distress syndrome, and results in insufficient oxygenation of blood and eventual organ failure. ... inflammation due to injury or infection can make the border of epithelial cells become more porous than it should be. The increased permeability allows an often-deadly mix of substances, such as fluid and cells, to seep into and accumulate in the alveoli. ... The team decided to re-create the unhealthy lung conditions in the lab - by culturing human alveolar cells and then chemically causing inflammation - and to observe how the presence of bone marrow stem cells would change things. ... We then introduced mesenchymal stem cells without direct cell contact, and they churned out a lot of protein, called angiopoietin-1, which prevented the increase in lung epithelial permeability after the inflammatory injury ... [researchers] hope clinical trials will prove the therapy is a viable one for preventing respiratory failure in critically ill patients."

Link: http://www.sciencedaily.com/releases/2010/08/100811162352.htm

We all grow up indoctrinated; bathed in the common views and short-cut truths of the society in which we were raised. The early rebellious years don't tend to change this state of indoctrination all that much. For every obvious thing to rebel against, there are a hundred viewpoints layered deep - opinions and teachings left unexamined for so long that they become axioms. Those are the chains and walls that matter: the things that nearly everyone takes for granted, that place bounds upon how you view the world. But people tend to rebel against the color of the wallpaper - whilst taking it as read, just like their parents and peers, that the wall must exist and must be made of bricks.

Unless you are particularly willful, it can take a lifetime to escape the formative shaping of your mind. It is the slow labor of decades to examine the axioms you've been dealt by the random chance of your birth culture and conclude for yourself, by your own reasoning, that they are right or wrong. Or irrelevant, or subtly misleading, or any number of other dangerous attributes.

Few people look beyond the walls, however. That's just the way of life; human nature at work. The visionaries, the disaffected, and the other unreasonable folk - those who persist in examining and rejecting what is taken for granted by everyone else - are a tiny fraction of the population. This is one of the reasons why sweeping change is usually slow, even when it could in theory be rapid.

If you are one of the few people in the world to think seriously about engineered longevity, about greatly extended life spans, and about how to make it happen before you are too old to benefit, then you have escaped one of the more insidious axioms of our time. We are brought up to see that aging simply is - like rain or grass or bad-mannered people. That tens of millions of deaths every year and pervasive pain and suffering are unavoidable. That aging is graven in stone forevermore.

It isn't, of course. But that fact didn't stop us from spending year after year accepting, not questioning, not even thinking much about how things might be different.

So you have escaped a portion of your deep programming: a cause for celebration. But don't forget to dig around some more while you're there; there are no doubt many, many more axioms yet to be examined and tested.

We'd like to see the research community persuaded to work on the Strategies for Engineered Negligible Senescence rather than focusing on merely slowing aging via traditional drug development. So persuasion is important. Equally, the time frame is long, so another viable path is to guide the next generation of researchers in the right direction. This second approach is the purpose of the SENS Foundation's Academic Initiative (SENSFAI) program, which has been running for a few years now. Here's one of the young researchers to benefit from it: "Kamil Pabis is in his second year of university and has been working with the SENSFAI since 2009. He is currently studying biology at the University of Vienna. After completing his degree, Kamil plans to pursue his PhD and eventually a career in Molecular Biology or Biogerontology. ... I research vascular (and in part general) calcification and their relation to aging and age-related tissue decline. The impact of calcification could be major and under-appreciated, but unfortunately we do not have definitive data. This basic research lays the ground work for future projects. A relatively thorough understanding is required to distinguish the most promising therapies for actual reversal of the pathology. Eventually I plan to help facilitate and do research under a 'regression first' paradigm."

Link: http://www.sens.org/ai/blog/featured-student-2010-august

Via EurekAlert! a reminder that we can think of most age-related conditions as resulting from one or more forms of damage that everyone suffers to some degree - but has progressed further in those who have the condition: "In many neurodegenerative diseases, such as Alzheimer's and Huntington's, clumps of proteins known as aggregates appear in the patients' brains as the degeneration progresses. Those clumps contain some proteins that are unique to the specific disease (such as Abeta in Alzheimer's), intertwined with many others that are common in healthy individuals. For years, those common proteins were thought to be accidental inclusions in the aggregates ... In fact, they may not be innocent bystanders at all, but instead their presence may influence the course of neurodegenerative disease. ... in the presence of proteins specific to Huntington's disease, these aggregators actually sped up the course of the disease, indicating that they could be fundamental to its progression. These findings indicate that widespread protein insolubility and aggregation is an inherent part of aging and that it may influence both lifespan and neurodegenerative disease. The presence of insoluble protein aggregates has long been a hallmark of protein aggregation diseases such as Alzheimer's, Huntington's and amyotrophic lateral sclerosis (ALS) disease. The team [asked] a simple question that had never been asked before: do normal proteins form insoluble clumps when normal, healthy individuals age?" Those "normal, health individuals" are on their way to the same end destination of neurodegeneration, just not as fast.

Link: http://www.eurekalert.org/pub_releases/2010-08/plos-np080610.php

Exercise correlates with a reduced risk of suffering dementia in later life, just as excess visceral fat is correlated with an increased risk of later developing dementia. The underlying mechanisms are somewhat different, but they both boil down to the quality of the blood vessels in your brain. Impaired blood vessels mean a lower blood flow or the breakages and lesions of vascular dementia - neither of which is good for you in the long term.

Another issue to consider in this context is the ongoing impact of atherosclerosis, the build-up of fatty material on blood vessel walls. This can result in sudden death due to blockage and rupture of larger deposits, but the condition harms your brain across the years leading up to that point:

Atherosclerosis, dementia, and Alzheimer disease in the Baltimore Longitudinal Study of aging cohort

We examined the relationship between systemic atherosclerosis, Alzheimer type pathology, and dementia in autopsies from 200 participants in the Baltimore Longitudinal Study of Aging, a prospective study of the effect of aging on cognition, 175 of whom had complete body autopsies. ... we found that the presence of intracranial but not coronary or aortic atherosclerosis significantly increased the odds of dementia.

Just as for the other forms of damage to blood vessels in the brain mentioned above, atherosclerosis is largely something that you do to yourself as a result of your lifestyle. Being fat and sedentary will get you there. Unfortunately, the characteristic mitochondrial damage of aging also spurs the onset of atherosclerosis - so a solution will be required one way or another even for those folk in perfect health. But the time left before you will be in pressing need of that solution is up to you, which is at least something.

Repairing mitochondrial damage is one of the long term solutions. Thirty-year-olds don't have atherosclerosis, so a comprehensive repair of your mitochondria is something that would only have to be done every few decades. For those people already suffering the build-up of material in their blood-vessels, forms of immune therapy or biomedical remediation are promising lines of research - the search for methods to safely break down unwanted chemicals and aggregates that build up with age.

The availability of these foreseeable forms of therapy still lies in the near future, however. In the here and now, the smart thing to do is take care of your health, rather than burning your candle at both ends while hoping that medical science progresses rapidly enough to save you from yourself.

Dolan H, Crain B, Troncoso J, Resnick SM, Zonderman AB, & Obrien RJ (2010). Atherosclerosis, dementia, and Alzheimer disease in the Baltimore Longitudinal Study of aging cohort. Annals of neurology, 68 (2), 231-40 PMID: 20695015

Don't become fat: "Individuals with a large waist circumference appear to have a greater risk of dying from any cause over a nine-year period ... Having a large waist circumference has previously been associated with inflammation, insulin resistance, type 2 diabetes, abnormal cholesterol levels and heart disease ... This may be because waist circumference is strongly correlated with fat tissue in the viscera - surrounding the organs in the abdomen - which is thought to be more dangerous than fat tissue under the skin. ... [researchers] examined the association between waist circumference and risk of death among 48,500 men and 56,343 women age 50 and older (median or midpoint age, 69 years in men and 67 years in women). All had participated in the Cancer Prevention Study II Nutrition Cohort, for which they completed a mailed questionnaire about demographic, medical and behavioral factors in 1992 or 1993 and provided information about weight and waist circumference in 1997. Deaths and their causes were tracked through the National Death Index until Dec. 31, 2006; a total of 9,315 men and 5,332 women died during this timeframe. ... After adjusting for body mass index (BMI) and other risk factors, very large waists (120 centimeters or 47 inches or larger in men, and 110 centimeters or 42 inches or larger in women) were associated with approximately twice the risk of death during the study period. A larger waist was associated with higher risk of death across all categories of BMI, including normal weight, overweight and obese."

Link: http://www.eurekalert.org/pub_releases/2010-08/jaaj-lwa080510.php

A conference on general health tactics that are likely to maximize your remaining life expectancy will be held in October in San Francisco: "Advances are being made daily on what each of us can do NOW to slow the aging process to a minimum, and to delay or prevent the diseases of aging. Life extension news comes out faster than any one of us can evaluate it on our own. Let's get together and determine how to take personal action." Many of the folk involved in the longevity advocacy or research communities are also tinkerers who go beyond simply practicing calorie restriction and exercise, and taking a sensibly modest set of vitamins. My suspicion has always been that this is a dangerous path: there is nothing presently available to the public that is proven to do more for long-term health than calorie restriction and exercise. When you spend time tinkering and optimizing in the absence of solid data, you're not spending time helping to bring forward the advent new medical technologies. The recent history of the pro-longevity community is rife with people who have become distracted from the future and who end up behaving no differently than the pill-sellers and potion-hawkers of the "anti-aging" marketplace. Beware this fate.

Link: http://lifeextensionconference.com

A few years ago, I pointed out some speculative work on environmental radiation during embryonic development and its possible effects on later longevity:

• Speculation on Solar Radiation and Longevity
• More on Solar Radiation and Life Expectancy

The amount of [solar] radiation varies according to where you are in the world, what time of year it is and cyclic changes in the sun’s behaviour. The Equator generally gets the most radiation, and in the northern hemisphere, the usual radiation peaks will be in June and July, but there will be variations from year to year according to "solar cycles." Every 11 years the Sun goes through a cycle when the magnetic field changes and the number of sunspots grows and dwindles. This affects the amounts of radiation produced. The Maine researchers suggest that high radiation levels either stress the immune system of embryos and foetuses or cause small mutations in their DNA, which can either predispose or protect from disease, mould brain characteristics and influence length of life.

The reliability theory of aging and longevity models complex organisms such as humans as an array of systems composed of many redundant component parts. It suggests that we are all born with a certain level of preexisting damage, and this early life damage load goes some way towards determining life expectancy. More damage at the outset means a greater likelihood of a shorter life.

I recently noticed a paper that takes the natural next step in this consideration of radiation, which is to look at the way in which cosmic radiation varies over time, and whether that might be correlated with damage to developing embryos. The level of cosmic radiation we experience at the Earth's surface is tied to the solar cycle, amongst other influences: the solar cycle is essentially an electromagnetic phenomenon, and the sun's electromagnetic fields shield against cosmic radiation to a level dependent on their current strength and configuration.

In this article, the author proposes to consider a link between infant mortality rate (IMR) and galactic cosmic radiation (CR) density. The periodical increase in solar activity increases the effect of the magnetic field of the sun, and therefore weakens galactic cosmic rays hitting the Earth's surface. As a result, embryos in their early stages of development may be less exposed to high-energy ionizing cosmic rays when the solar activity peaks. In the study discussed here, cosmic ray density data were correlated with the U.S. infant mortality rate in the following year. Statistical analysis shows that in the past 30 years, Pearson correlation between the change in galactic CR flux and IMR decrease in the following year was -0.36 (p < .05)

So not terribly correlated then - much like the prior studies on solar radiation, this suggests there might be a cause and effect in there somewhere, but it's small compared to other influences, and the data is noisy. Still, this is a good approach to identifying potential developmental factors that impact later longevity: when considered from the reliability theory point of view, any environmental condition that raises infant mortality rates should also reduce life expectancy for the survivors.

Shamir L (2010). Does cosmic weather affect infant mortality rate? Journal of environmental health, 73 (1), 20-3 PMID: 20687328

The FDA is the only reason that we don't see dozens of different serious commercial efforts to treat people using early-stage stem cell therapies within the US. One of the few groups to try is presently under pressure, as this press release notes: "Regenerative Sciences, Inc., a Colorado medical practice that specializes in the use of a person's own stem cells to help patients avoid more invasive orthopedic surgery, announced today that the US Food and Drug Administration (FDA) is seeking to enjoin the clinic physicians from practicing medicine using patients' own stem cells. The lawsuit will allow Regenerative Sciences to question the FDA's policy that adult stem cells can be classified as drugs when used as part of a medical practice. ... The FDA will finally answer our questions, in court, about their claims and jurisdiction as opposed to doing everything in their power to avoid the issue that we are not a drug manufacturer, but simply a medical practice." The FDA has a long history of abuse and overreach, and this is simply more of the same - exactly what we should expect of bureaucrats left largely unaccountable for their actions. Progress and discovery becomes entirely secondary to the urge to power. When everything that is not explicitly permitted is forbidden, there is no innovation, no progress. This age of biotechnology could be far further advanced if not for the short-sighted fools who write and enact medical regulations.

Link: http://www.prnewswire.com/news-releases/colorado-medical-clinic-welcomes-opportunity-to-fight-fda-in-court-100247969.html

Via EurekAlert!: "Researchers for the first time have induced robust regeneration of nerve connections that control voluntary movement after spinal cord injury, showing the potential for new therapeutic approaches to paralysis and other motor function impairments. ... They did this by deleting an enzyme called PTEN (a phosphatase and tensin homolog), which controls a molecular pathway called mTOR that is a key regulator of cell growth. PTEN activity is low early during development, allowing cell proliferation. PTEN then turns on when growth is completed, inhibiting mTOR and precluding any ability to regenerate. ... Until now, such robust nerve regeneration has been impossible in the spinal cord. ... An injury the size of a grape can lead to complete loss of function below the level of injury. For example, an injury to the neck can cause paralysis of arms and legs ... These devastating consequences occur even though the spinal cord below the level of injury is intact. All these lost functions could be restored if we could find a way to regenerate the connections that were damaged. ... are now studying whether the PTEN-deletion treatment leads to actual restoration of motor function in mice with spinal cord injury."

Link: http://www.eurekalert.org/pub_releases/2010-08/uoc--ibn080510.php

Yesterday, a commenter wrote:

If you only had 20 minutes, what would you do to convince an intelligent (college educated or professional) audience of the significance of life extension beyond 120 years? Assume they do not commit the tithonus error and are rational enough to understand that probably do want to live indefinitely so long as the quality of life meets their own standard. The problem then becomes convincing others that it is indeed possible to live very very long lives. However, how can you convince someone that extreme life extension is scientificially valid research? It seems like some persons will dismiss the possibility because their is no such empirical example, just as planets outside our solar system were not outright denied, but ignored.

Given twenty minutes, it is really only possible to set forth an outline of a position, and show people where to look for the supporting evidence. But an outline might look something like this:

• Consider that there is a very wide range of life spans between even very similar species. Take the naked mole rat, a mammal that lives for nine times as long as similarly sized rat species. Or the larger whales, mammals that can live for nearly two centuries. Very long-lived mammals are possible at any body size, and their longevity is a matter of their particular evolved genome and metabolism. More esoteric species are even more long-lived: four centuries for some clams, for example, and no-one knows how long lobsters and some urchins can live because they appear to be essentially ageless.
• But evolution has clearly not selected for extended healthy life in many species, a broad range of mammals included. This is demonstrated by the fact that there are now something like twenty different ways of extending mouse life span by 10% to 60%. Many of these are modest genetic engineering projects: a single gene, or few genes altered, well within what we'd expect evolution to accomplish on its own.
• We should not expect primates, humans included, to be exceptional in this regard. While we are long-lived in comparison to many mammals, we are far outclassed by a good many other species.
• An animal such as a mammal is a complex system built of many interacting subsystems, which are in turn built out of many redundant parts. The general behavior of systems of this nature is well described by reliability theory: mean time to failure grows small as a system ages because it accumulates damage that knocks out its redundant components. Aging and all that comes with it - frailty, disease, organ failure, and ultimately death - is the result of accumulated damage and the flailing of damaged systems.
• At the lowest level, we are machines: our cells are finely turned, reactive, programmable, self-repairing machinery. The nuts, bolts, cogs, and pistons are proteins built according to the patterns encoded in our genes. Over time cells build up damage in the form of broken, malformed, or unwanted proteins, some of which can be repaired or removed, and some of which cannot. This damage is a natural consequence of the operation of our metabolism: it is accumulating slowly within everyone's body right now. Everything that happens to us in aging ultimately stems from a build-up of broken, worn, misplaced, and errant parts of our biological machinery.
• All means of extending longevity demonstrated to date in mammals in the laboratory are essentially forms of damage reduction. They reduce the rate at which damage accumulates over time: by creating greater damage resistance, attenuating the effects of damaging processes in our metabolism, or spurring cells and the immune system to greater natural vigilance, repair, and recycling efforts. Less damage per unit time is exactly a slowing of aging.
• But if slowing down the build-up of damage is good, how much better will it be to repair and remove that damage completely? Consider that the only differences between a young body and an old body are (a) levels of damage and (b) the disarray of biological systems and organs reacting to that damage. Complete repair of damage is one and the same with rejuvenation.
• There is a fortunate confluence of purpose between research to repair the biochemical damage of aging and research into therapies for age-related diseases. These diseases are caused by the varying forms of biochemical damage that create the condition that we see as aging; a therapy that repaired a specific form of damage would be beneficial for everyone who suffered from the diseases it causes. It would lift some of the burden of aging, restoring a body some way towards its youthful state, and this would be beneficial for everyone who is old.
• But we do not have to be hypothetical when talking about the forms of biological damage that cause aging, or ways to approach the development of therapies that can remove that damage. The damages of aging are in fact well documented in many of the varied life science and medical fields, and are summarized in the Strategies for Engineered Negligible Senescence:

Some tissues lose cells with advancing age, like the heart and areas of the brain. Stem cell research and regenerative medicine are already providing very promising answers to degeneration through cell loss.

We must eliminate the telomere-related mechanisms that lead to cancer. de Grey suggests selectively modifying our telomere elongation genes by tissue type using targeted gene therapies.

Mitochondrial DNA is outside the cellular nucleus and accumulates damage with age that impairs its critical functions. de Grey suggests using gene therapy to copy mitochondrial DNA into the cellular nucleus. Other strategies for manipulating and repairing damaged mitochondrial DNA in situ were demonstrated for the first time in 2005.

Some of the proteins outside our cells, such as those vital to artery walls and skin elasticity, are created early in our life and never recycled or recycled very slowly. These long-lived proteins are susceptible to chemical reactions that degrade their effectiveness. Scientists can search for suitable enzymes or compounds to break down problem proteins that the body cannot handle.

Certain classes of senescent cell accumulate where they are not wanted, such as in the joints. We could in principle use immune therapies to tailor our immune systems to destroy cells as they become senescent and thus prevent any related problems.

As we age, junk material known as amyloid accumulates outside cells. Immune therapies (vaccines) are currently under development for Alzheimer's, a condition featuring prominent amyloid plaques, and similar efforts could be applied to other classes of extracellular junk material.

Junk material builds up within non-dividing, long-life span cells, impairing functions and causing damage. The biochemistry of this junk is fairly well understood; the problem lies in developing a therapy to break down the unwanted material. de Grey suggests searching for suitable non-toxic microbial enzymes in soil bacteria that could be safely introduced into human cells.

• It is not so hard for people nowadays to visualize the transformative power of regenerative medicine. This is a field in full swing, to the accompaniment of large-scale publicity and public support. There is the ability to renew aging cells, such as nerve cells in the retina that are never naturally replaced and slowly give way to cause age-related blindness - a way to give a renewed life span to small but vital bodily systems. Or the ability to grow and transplant completely new organs to replace age-worn hearts, kidneys, livers, or lungs - but this just scratches the surface of what will soon be possible.
• Yet regenerative medicine is one field of seven in the list above. Each of the others has the potential to be just as transformative to health and longevity. By removing the damage that degrades a range of bodily systems, a body can be moved closer to the state it was in when young. Systems that were flailing and causing problems of their own can be restored to a healthy state, and return to contributing to health rather than damaging it.
• You don't have to take my word for it, of course. Regenerative medicine and organ building is a thriving growth field, populated by thousands of highly skilled researchers who are well aware of the benefits their work will bring to the elderly and the damaged. In labs around the world, and to a lesser degree, work is slowly proceeding on each of the other other six fields above.
• Within the broad life science research community it is now taken as a given that extending healthy longevity is serious, meaningful science. Billions of dollars have already been invested into research and development for early stage longevity science. The arguments are over how it will be accomplished, and what is possible to achieve within our lifetimes.

That seems to be a decent first pass at the topic. It needs refinement, but you're all welcome to have a go at it.

From the Telegraph: "In as little as five years, researchers hope to be able to coax the heart into regenerating itself, repairing the damage caused by cardiac arrests and old age. ... It works in a similar way to stem cells but instead of the new cells being grown outside the body and then injected back in, the technique simply makes the cells [transform] at the point where they are needed. ... The main problem is that when beating muscles cells - known as cardiomyocytes - die during an attack there is no way to reactivate them and the surrounding connective tissue - known as fibroblasts - cannot take over their role.
Now [researchers] have discovered a way of reprogramming fibroblasts into cardiomyocytes. ... We first have to test if the same factors can convert human fibroblasts to beating heart muscle and then find ways to safely introduce these factors, or small molecules that mimic these factors, into the coronary circulation so they can reprogram the existing fibroblasts in the heart. I envision such factors being loaded into a stent that is placed in the coronary artery and can elute (allow to emerge) the reprogramming factors over 1-2 weeks. ... The team found that they needed a combination of just three substance - Gata4, Mef2c, and Tbx5 - to efficiently convert fibroblasts into cells that could beat like cardiomyocytes."

Link: http://www.telegraph.co.uk/health/healthnews/7928426/Damaged-heart-could-be-coaxed-into-mending-itself-claim-scientists.html

These researchers argue that embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are most likely the same in any aspect that matters: "the pluripotency of ES cells fueled excitement over their use in regenerative medicine. While ethical hurdles associated with the clinical application of human ES cells appeared to have been overcome with the development of methods to create iPS cells, some recent research has suggested that ES and iPS cells have substantial differences in which sets of genes they express. These findings [argue] to the contrary, rekindling hopes that, under the proper circumstances, iPS cells may indeed hold the clinical promise ascribed to them earlier. ... iPS cells are made by introducing three key genes into adult cells. These reprogramming factors push the cells from a mature state to a more flexible embryonic stem cell-like state. Like ES cells, iPS cells can then, in theory, be coaxed to mature into almost any type of cell in the body. Unlike ES cells, iPS cells taken from a patient are not likely to be rejected by that patient's immune system. This difference overcomes a major hurdle in regenerative medicine. ... At this stage, we can't yet prove that they are absolutely identical, but the available technology doesn't reveal differences. ... Some earlier studies have indicated that iPS and ES cells are dissimilar enough to be classified as different cell types. [The researchers] concluded that the differences noted in other studies were not consistent between different laboratories and thus were not likely to be a result of fundamental differences between the cell types."

Link: http://www.eurekalert.org/pub_releases/2010-08/wifb-hes080510.php

Parallels can be drawn and biochemical similarities pointed out between (a) limb and organ regeneration in lower animals like newts and salamanders, (b) embryonic growth in all species, and (c) cancer. Regeneration of lost limbs is a controlled replication of the processes of embryonic development, while cancer stems from those same processes unleashed and run wild. Nothing is quite as simple as that, of course, but it is a framework for thinking about how these fields of life science research overlap and inform one another.

This is well illustrated by a recent advance from one of the research groups studying newt biochemistry with an eye to replicating it in mammals - or at least understanding the crucial differences. We should not be surprised to see that cancer-suppressing genes are at the heart of the puzzle:

Although there's been a lot of discussion about using adult or embryonic stem cells to repair or revitalize tissues throughout the body, in this case the researchers weren't studying stem cells. Instead they were investigating whether myocytes, run-of-the mill muscle cells that normally don't divide, can be induced to re-enter the cell cycle and begin proliferating. This is important because most specialized, or differentiated, cells in mammals are locked into a steady state that does not allow cell division. And without cell division, it is not possible to get regeneration. In contrast, the cells of some types of amphibians are able to replace lost or damaged tissue by entering the cell cycle to give rise to more muscle cells. While doing so, the cells maintain their muscle identity, which prevents them from straying from the beaten path and becoming other, less useful cell types.

Previous research had shown that a tumor suppressor called retinoblastoma, or Rb, plays an important role in preventing many types of specialized mammalian cells, including those found in muscle, from dividing willy-nilly. But the effect of blocking the expression of Rb in mammalian cells has been inconsistent: In some cases it has allowed the cells to hop back into the cell cycle; in others, it hasn't. The researchers employed some evolutionary detective work to figure out that another tumor suppressor called ARF might be involved. Like Rb, ARF works to throw the brakes on the cell cycle in response to internal signals. An examination of the evolutionary tree provided a key clue. They saw that ARF first arose in chickens. It is found in other birds and mammals, but not in animals like salamanders nestled on the lower branches. Tellingly, it's also missing in cell lines that begin cycling when Rb is lost, and it is expressed at lower-than-normal levels in mammalian livers - the only organ that we humans can regenerate.

Based on previous investigators' work with newts, Blau said it "seemed to us that they don't have the same limitations on growth. We hypothesized that maybe, during evolution, humans gained a tumor suppressor not present in lower animals at the expense of regeneration."

Sure enough, Pajcini and Pomerantz found that blocking the expression of both Rb and ARF allowed individual myocytes isolated from mouse muscle to dedifferentiate and begin dividing. When they put the cells back into the mice, they were able to merge with existing muscle fibers - as long as Rb expression was restored. Without Rb the transplanted cells proliferated excessively and disrupted the structure of the original muscle.

This is a modest step towards being able to carefully spur regeneration in mice; one might envisage researchers switching gene expression of Rb and ARF on and off in tissues during the regenerative process so as to obtain the desired result of controlled regrowth while avoiding cancer. But I can't imagine that will be a straightforward process.

On this topic you might recall that at least one breed of laboratory mouse - the MRL breed - is in fact able to regenerate unusually well for a mammal, and earlier this year that capability was pinned down to removal of the p21 gene:

p21, a cell cycle regulator, was consistently inactive in cells from the MRL mouse ear. P21 expression is tightly controlled by the tumor suppressor p53, another regulator of cell division and a known factor in many forms of cancer. The ultimate experiment was to show that a mouse lacking p21 would demonstrate a regenerative response similar to that seen in the MRL mouse. And this indeed was the case.

Surprise, surprise, another connection to cell division and cancer suppression. So far it looks like making mammals regenerate like amphibians is a realistic undertaking for modern medicine, but will require great care in its implementation so as to avoid the risk of cancer.

LysoSENS is a project of the SENS Foundation aimed at developing a means to safely remove harmful metabolic byproducts (such as 7KC) that accumulate in lysosomes with age. That buildup degrades the lysosomal ability to clear cells of unwanted junk, which in turn leads to what is known as the garbage catastrophe in aging. At the moment, LysoSENS work focuses on discovering bacterial enzymes that can break down the most important forms of unwanted junk in the lysosome. Here is a progress report from one of the researchers: "The 7KC-degrading bacterium I've been studying, Rhodococcus jostii RHA1, has two large gene clusters that are up-regulated by 7KC, but not cholesterol. In these two gene clusters lie a number of enzymes we believe are involved in 7KC degradation, including an enzyme that could reduce the 7-keto group to a hydroxyl. What makes this interesting to us is that while 7KC is highly cytotoxic, 7alpha-hydroxycholesterol (7alphaOH) is relatively harmless. So I am now methodically going through suspected candidates, searching for reductase activity against 7KC. Currently I am looking at nine different enzymes, and am in various stages of cloning the genes into expression vectors and assaying their products for activity. While I've uncovered some interesting findings, so far I haven’t found the reductase I'm looking for. This could be for several reasons, the first being that I haven't assayed all the enzymes I need to. As I still have the majority remaining, this is a likely scenario. However, one possibility is that the normal substrate for the enzyme is not 7KC, but some downstream metabolite."

Link: http://www.sens.org/node/1261

Chemical and Engineering News surveys work aimed at replicating the ability of lower animals to regenerate whole limbs and organs: "complicating the attempt to unravel regeneration is the fact that these capabilities change over the lifetime of a single organism. A tadpole, for example, can generally replace a missing tail or limb but loses this ability after its metamorphosis into a frog. Likewise, higher vertebrates such as mammals can regenerate much better during their embryonic and fetal stages than after they have become adults. ... Levin and his collaborator David Kap­lan [are] now testing whether a replicated amniotic environment can promote regeneration in adult mammals. Kaplan has already developed a small, cylindrical 'regenerative sleeve' that can be filled with an aqueous solution and fastened onto the stump of a rat's amputated limb. The sleeve is fitted with a variety of ports and electrical connections so the researchers can sample and alter the container's chemical contents ... the researchers hope to create a regenerative current at the stump's surface by adjusting the ionic composition of the solution inside the sleeve and by adding drugs that open or close ion channels in the membranes of the cells at the wound site. The sleeve will offer some additional benefits. The aqueous environment it provides will prevent the scarring that normally develops in a mammalian wound exposed to air. The researchers might also use it to bathe the wound with scar-reducing compounds, immune-modulating drugs, and more traditional growth factors."

Link: http://pubs.acs.org/cen/science/88/8831sci1.html

Blood donation will be a thing of the past not so many years from now. Building blood to order is one of the fields of research and development in which entirely artificial alternatives might beat tissue engineering to the broader marketplace. On the one hand several well-funded initiatives presently aim to mass-produce particles that behave like red blood cells - and that might even perform some tasks more effectively than the real thing. On the other hand, tissue engineers are working on reliable methodologies to generate large quantities of blood from stem cells. The most advanced of these efforts have made it to the trial stage.

An example of the second approach can be found over at Singularity Hub:

Two years ago, DARPA awarded a $1.95 million grant to a Cleveland company called Arteriocyte, which was developing technology that could quickly transform stem cells into red blood cells. The idea was to develop a system that could produce an almost limitless amount of universal donor blood (O-negative) in remote areas. And earlier this month, Arteriocyte submitted samples of their artificially produced blood to the Food and Drug Administration (FDA), seeking approval before making the technology available to both the civilian and military sectors.

...

Hematopoietic cells isolated from umbilical cord blood are cultured in an environment that provides them with all the nutrients and molecular signals they need to develop into red blood cells. Currently, it takes about 3 days to generate up to 20 units of transfusion-ready blood from a single unit of umbilical cord blood.

It's a good example of how even early stage products of the growing regenerative medicine industry have the potential to produce large infrastructure changes - reducing cost and improving quality along the way. Looking at the other side of the aisle, an example of fully artificial red blood can be found back in the Fight Aging! archives:

Samir Mitragotri of the University of California and his team got their inspiration from the way real red blood cells acquire their final shape in the body. They start out as spherical cells which then collapse into mature red blood cells following exposure to various substances. Similarly, Mitragotri's team found that if they added small balls made of a polymer called PLGA to a particular solvent, the spheres would collapse into a biconcave shape.

The researchers coated these 7-micrometre across, tyre-shaped particles, in a layer of protein. When they dissolved away the polymer core, a soft biodegradable protein shell was left behind with the same mechanical properties as red blood cells.

One of the reasons researchers work with flies is that it is comparatively cheap to produce mutant breeding lines - even hundreds of different ones. So studies like this can exist: "To identify genes involved in aging, we assessed longevity in a collection of over 1,300 Drosophila lines ... We found 58 mutations in novel loci that increase life span by up to 33%. Most mutations had different effects on male and female life span, and for some the effects were opposite between the sexes. Effects of these mutations on starvation resistance, chill coma recovery, and climbing ability varied, but all had a deleterious effect on at least one other trait. A sample of ten mutations with increased life span formed genetic interaction networks, but the genetic interactions were different, and sometimes in opposite directions, in males and females. ... Whole-genome transcript profiles of seven of the mutant lines and the wild type revealed 4,488 differentially expressed transcripts, 553 of which were common to four or more of the mutant lines, which include genes previously associated with life span and novel genes implicated by this study. Therefore longevity has a large mutational target size; genes affecting life span have variable allelic effects; alleles affecting life span exhibit antagonistic pleiotropy and form epistatic networks; and sex-specific mutational effects are ubiquitous."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2912381/

Some variants of mitochondrial DNA are well correlated with longevity; numerous studies have identified SNPs and haplotypes found far more often in long-lived people. This shouldn't be surprising, given the evidence indicating an important role for mitochondria in determining life span. Here is a Chinese study to add to the others: "OBJECTIVE: To investigate the human mitochondrial DNA (mtDNA) variations associated with longevity in Bama elderly population from Guangxi. METHODS: Mitochondrial genome of 20 individuals over 96 years of age was sequenced, and seven target single nucleotide polymorphism(SNPs) were observed by comparing with the standard rCRS sequence, and two were tested by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) method in a larger population including 208 individuals of 90-113 years old, and 586 unrelated control individuals from Guangxi. RESULTS: The 4824G frequency of the mtDNA4824A/G locus increased with age both in the long-lived elderly and in controls. And it was significantly higher in controls than that in long-lived population. CONCLUSION: The mtDNA4824 A/G is not only an age-related locus, its mutation is also negatively correlated with longevity."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20677150

Your body is an integrated collection of systems, all interacting with one another. When any one system becomes damaged and degraded, that change is felt elsewhere. The degenerations of aging are an accelerating downward spiral precisely because our biology is this way: slow at first, accumulated damage in different locations and biological processes feeds on itself. Degraded performance in each failing system causes more damage elsewhere, a feedback loop that moves ever faster as the years pass until the catastrophic end when a critical organ fails.

The way out of this feedback loop is to understand what the damage is and how to repair it. That is presently something that can be partially achieved in mice - for some forms of damage only - and therefore the same is probably possible in humans. No research group has moved much beyond proof of concept yet, even for mitochondrial repair, which is possibly the most advanced area of interest outside the busy field of regenerative medicine.

In any case, here are a couple of examples of the way in which the little things - accumulating damage of the sort you can damp down by taking better care of your health, rather than the sort you can't do much about with present day medicine - can accelerate the consequences of aging:

New evidence from NYUCD supports link between gum inflammation and Alzheimer's disease

NYU dental researchers have found the first long-term evidence that periodontal (gum) disease may increase the risk of cognitive dysfunction associated with Alzheimer's disease in healthy individuals as well as in those who already are cognitively impaired. The NYU study offers fresh evidence that gum inflammation may contribute to brain inflammation, neurodegeneration, and Alzheimer's disease.

Low Blood Flow Ages Brain Faster

People whose hearts pump blood inefficiently may lose brain volume faster, putting them at risk for dementia, a new study indicates. Researchers examined brain and heart MRI data on 1,504 patients without a history of neurologic disease enrolled in the Framingham Offspring Cohort study. The participants, all between 34 and 84 years of age, half of whom were women, were divided into three groups based on the pumping ability ("cardiac index") of their hearts. Participants whose hearts pumped the least amount of blood showed almost two years more brain aging than those with the healthiest hearts, researchers say.

By now regular readers should know that chronic inflammation is not good over the long term, as it is effectively a source of biochemical and cellular damage. So I shouldn't have to say much on that topic. The second article above points to exercise, to my mind at least. Exercise, blood flow, and brain health all seem to go hand in hand, and the beneficial effects of exercise, like those of calorie restriction, appear in nearly every aspect of aging biology examined to date.

Via KurzweilAI: "researchers have uncovered a mechanism through which caloric restriction and exercise delay some of the debilitating effects of aging by rejuvenating the connections between nerves and the muscles that they control. ... Their research, conducted through laboratory mice genetically engineered so their nerve cells glow in fluorescent colors, shows that some of the debilitation of aging is caused by the deterioration of connections that nerves make with the muscles they control, structures called neuromuscular junctions. These microscopic links are remarkably similar to the synapses that connect neurons to form information-processing circuits in the brain. ... The work showed that mice on a restricted-calorie diet largely avoid that age-related deterioration of their neuromuscular junctions, while those on a one-month exercise regimen when already elderly partially reverse the damage. ... With calorie restriction, we saw reversal of all of these things. With exercise, we saw a reversal of most, but not all. ... Because of the study's structure - mice were on calorie-restricted diets for their whole lives, while those that exercised did so for just the month late in life - [the researchers] cautioned against drawing conclusions about the effectiveness of exercise versus calorie restriction in preventing or reversing synaptic damage. ... longer periods of exercise might have more profound effects."

Link: http://www.kurzweilai.net/how-caloric-restriction-and-exercise-delay-some-effects-of-aging

"Immortality" is a problematic term, and the press insist on using it when talking about efforts to extend healthy life: "As with cryonics, a proposal to extend life substantially is greeted with bizarre concerns about living too long, or the wrong people living longer. Why not apply such complaints to ordinary medical gains? A big part of the problem, I think, is that talk of 'immortality' invokes an extremely far view. But finite increases in lifespan really have little to do with immortality. Immortality means you never die, ever. But forever is a really really long time! In fact, nothing you can imagine is remotely as long. ... A thousand year lifespan would be fantastic, relative to our lifespan. I want it! But it is nothing like immortality. It would have clear stages, and a very real end to anticipate. Anyone with a halfway decent imagination couldn't remotely run out of new interesting things to do, places to visit, people to see, etc. Yes they'd have time for twenty times as many careers, hobbies, marriages, and vacations as we do now, but it should only take a moment's reflection to realize you there are far more than twenty times as many things to do than we manage in our lives. For example, any decent library holds twenty times more books than you've ever read."

Link: http://www.overcomingbias.com/2010/08/immortality-not-on-offer.html

In a typically densely written post over at the SENS Foundation, Michael Rae looks at research into the aging of stem cells, putting it into the context of the SENS view of aging. In short, we know that stem cell populations within the body decline in effectiveness with age, losing their ability to regenerate injuries and maintain tissue in good condition. Researchers are making steady inroads into understanding exactly why this is the case: some of the theories with respectable evidence behind them include damaged signaling mechanisms, damage to the niche cellular environments that support stem cells, an evolutionary adaptation to protect against cancer that might emerge from age-damaged stem cells, or a reduction in the number of active stem cells. These are not all mutually exclusive, of course.

One of the points Rae makes is that only a few types of cellular and biochemical damage observed in aging are fundamental. Almost all observed forms of decline and damage are secondary effects that will to some degree fade away - repaired by our own regenerative capacity - if the primary forms of damage are removed. There is evidence to support the case that stem cell decline is a secondary form of damage, for example, triggered by damage-induced disarray in our biochemistry.

But to return to that SENS Foundation post:

[Recent findings show that] age-related loss of [haematopoietic stem cells (HSC)] function is substantially attributable to derangement of HSC regulation by the aging niche, much of which is secondary to shifts in systemic factors in the aging niche microenvironment rather than to cell-autonomous defects.

...

this latest example of the rejuvenating effect of youthful systemic environment [reinforces] the expectation that the effects of regenerative engineering therapies will not be narrowly confined to restoring the function of their specific target tissues.

As we remove, repair, replace, or render harmless the cellular and molecular damage of aging, the progressive restoration of normal cell and tissue function can be expected to result in a concomitant, progressive normalization of the systemic milieu, as oxidative stress, inflammation, endocrine and paracrine signaling, and other systemic responses to - and sequelae of - the damage of aging are obviated and the body's inherent maintenance capacities are engaged. With this normalization, these studies suggest, the deranging effects of an aged systemic environment will gradually be alleviated, and remote tissues will begin to return to more youthful function; in turn, the renewal of those remote tissues' function then further contribute to the re-establishment of youthful homeostasis in the system as a whole.

As the regenerative process feeds back upon itself, accelerated with each new therapy applied and each additional form of damage repaired, the function of tissues, organs, we may hypothesize that the organism as a whole will re-emerge in unexpected ways and with unanticipated inflection points, until we stand restored to the full health, vigor, and capacity of youth.

The concept of striking at the fundamental forms of damage rather than patching up the tail end consequences of that damage is one of the many reasons to support the SENS approach to aging. Patching symptoms is an endless and expensive process, doomed to failure - but in contrast, every success in removing fundamental damage will bring some of the body's systems back into a state in which they can help to improve health once again.

From the Guardian: "What's so wrong with getting old? It is simply that people get sick when they get older. I don't often meet people who want to suffer cardiovascular disease or whatever, and we get those things as a result of the lifelong accumulation of various types of molecular and cellular damage. This is harmless at low levels but eventually it causes the diseases and disabilities of old age - which most people don't think are any fun. Is this the biggest health crisis facing the world? Absolutely. If we look at the industrialised world, basically 90% of all deaths are caused by ageing. They are deaths from causes that affect older people and don't affect young adults. And if we look at the whole world, then the number of deaths that occur each day is roughly 150,000 and about two-thirds of them are because of ageing. ... People have been trying to claim that we can defeat ageing since the dawn of time, and they haven't been terribly successful; there is a tendency to think there is some sort of inevitability about ageing - it somehow transcends our technological abilities in principle, which is complete nonsense. And when people have made their peace with this ghastly thing that is going to happen to them at some time in the distant future, they tend to be rather reluctant to re-engage the question when someone comes along with a new idea."

Link: http://www.guardian.co.uk/technology/2010/aug/01/aubrey-de-grey-ageing-research

Over at TechCrunch, the resident jester shows himself to be a deathist - though one shouldn't take anything he writes terribly seriously. It's a funhouse mirror reflection of ill-thought and emotional attitudes to engineered longevity that are in fact held by a great many people. They knee-jerk in favor of what is, or against suspected privilege, without thinking about the mass suffering and death that we could work to prevent: "Oh yes, go to any Silicon Valley party right now and you'll find a scrawny huddle in the corner discussing the science of living forever: a topic that's gone from fringe to hot to cliche in - ironically - less time that it takes a tsetse fly to start getting interested in girls. But then why wouldn’t it when the science of ageing touches on so many valley obsessions? For a start, gerontology is a science. But it's also hacking: human bodies aren't supposed to live much beyond 80, and these are people who would gladly spend a weekend hacking a Furby to make it curse, just because it's not supposed to. ... And so the research goes on, millions more dollars are poured in to deathhacking startups by rich-mortal-and-terrified benefactors, dozens more books are published on the subject and every day countless startup founders jump into their Teslas and speed to their 'doctors' to pick up the latest batch of pills that they hope will keep them around until someone figures this shit out. And why not? Here's why not."

Link: http://techcrunch.com/2010/08/01/what-kills-us-makes-us-stronger/