More AGE-Breaker Research

The world works in strange ways; as soon as I mention twice the paucity of AGE-breaker and AGE-inhibitor work, more research groups start to come to my attention. Before diving into the example below, you might want to first refresh your memory on the buildup of advanced glycation endproducts (AGEs) and their contribution to aging.

Unfortunately, past evidence suggests that excitement over work in rodents should be muted at best - the history of ALT-711 or alagebrium demonstrates that different types of AGEs are important in shorter-lived mammals versus humans. So far, promising work in mice and rats has translated poorly into human therapies - in most cases, through trying to address the wrong AGEs.

You'll noticed that this group, as for a number of others, is focused on diabetes. This is very much the way of the world in medical research. Regulation - both directly by decree and indirectly through raising costs of development - forces researchers down the road of focusing upon specific common diseases. You can't raise significant funds through the normal channels for work aimed at addressing an aspect of aging itself so long as major regulatory bodies will not approve the end result of your work for use. So, for example, most AGE research aims at diabetes because diabetic metabolism generates - and suffers due to - AGEs at an accelerated rate, but more pertinently because funds can be raised.

So it is that a range of the most promising potential research into addressing aging, not just AGE-breakers, is happening by stealth, in groups whose officially declared purposes span the known diseases of aging. Progress towards the more interesting goal of repairing age-related damage in our bodies proceeds at a fraction of the pace it might, because there is little freedom in medical research and development these days. It's a tragedy; unless this state of affairs is overturned, it will ensure age-related suffering and death comes for us much sooner than would otherwise be possible.

The Key to Parkinson's Disease?

An exciting discovery via ScienceDaily: researchers "have discovered the key brain chemical that causes Parkinson's disease ... Parkinson's disease occurs when some nerve cells in a part of the brain called the substantia nigra die or become impaired. Normally, these cells produce dopamine - a vital chemical that allows smooth, coordinated function of the body's muscles and movements. Scientists have long known that a key protein called alpha-synuclein plays a role in the development of Parkinson's disease. Alpha-synuclein is found throughout the brain - but in some people, the protein clumps together. This causes the death of the dopamine-producing cells, which in turn causes Parkinson's to develop. ... researchers discovered that dopamine itself actually plays a role in destroying the cells that produce it. In the process that leads to Parkinson's disease, dopamine is converted into a highly toxic chemical called DOPAL. Using test-tube, cell-culture and animal models, the researchers found that it is DOPAL that causes alpha-synuclein protein in the brain to clump together, which in turn triggers the death of dopamine-producing cells and leads to Parkinson's." It should go without saying that finding a key mechanism in this day and age will quickly lead into the design of therapies.


Washington Post Interview With Aubrey de Grey

The Washington Post interviews biomedical gerontologist Aubrey de Grey on healthy life extension research: "Aging consists of seven critical kinds of damage, according to de Grey. For example, unwholesome goo accumulates in our cells. Our bodies have not evolved means quickly to clean up "intracellular aggregates such as lipofuscin." However, outside our bodies, microorganisms have eagerly and rapidly evolved to turn this toxic waste into compost. (De Grey made this connection because he knew two things: Lipofuscin is fluorescent and graveyards don't glow in the dark.) By taking soil samples from an ancient mass grave, de Grey's colleagues in short order found the bacteria that digest lipofuscin as easily as enzymes in our stomachs digest a steak. The trick now is getting those lipofuscin-digesting enzymes into our bodies. That has not yet been done. But, de Grey says, comparable fundamental biotechnology is already in clinical use fighting diseases such as Tay-Sachs. So he sees it as merely an engineering problem. Examples like this make up the 262 pages at the center of 'Ending Aging.'"


Stem Cells, Telomeres, DNA Damage, Cancer and Aging

Everything is connected to everything else: our biochemistry is a web of tightly interacting processes, systems and feedback loops. You can't consider any one process in isolation of the whole if you'd like to learn more about how we work. This level of interaction is one reason why it is likely easier to learn to repair damage to our metabolism - the damage that causes aging - than to significantly change our metabolic systems to generate damage more slowly, and thus age more slowly.

With that in mind, I thought I'd point out a selection of papers that illustrate some of the more obvious linkages between stem cells, cancer, DNA damage, telomeres and aging - all a big ball of intricately knotted string. As cells - especially stem cells - become damaged, multiple sentinal processes try to destroy or place them into a quiescent state in order to avoid the runaway replication and mutation of cancer. But removing cells from active service reduces the effectiveness of the body, and is one cause of aging. This is an evolutionary balance of multiple competing and co-operating processes, degeneration with age on the one hand and avoidance of cancer on the other.

DNA repair in stem cell maintenance and conversion to cancer stem cells:

Genomic stability is essential for cell and organism longevity. Without genomic stability, replication errors and external stress as well as direct forms of DNA damage can induce mutations, which decrease cell survival, cause altered gene expression, and can lead to cellular transformation. All represent the antithesis of maintenance of normal stem cell function. We argue here that genomic stability is essential for stem cell maintenance and longevity. This concept is supported by human diseases associated with premature aging and animal models of DNA damage repair abnormalities all of which lead to abnormalities of stem cell survival.


Thus one origin of the cancer stem cell phenotype is the inability to maintain genomic stability among the stem cell population leading to mutational alterations and transformation. Capturing stem cells at this transition point represents an exciting field of discovery possibly leading to early detection and therapeutic interventions.

Two faces of p53: aging and tumor suppression:

The p53 tumor suppressor protein, often termed guardian of the genome, integrates diverse physiological signals in mammalian cells. In response to stress signals, perhaps the best studied of which is the response to DNA damage, p53 becomes functionally active and triggers either a transient cell cycle arrest, cell death (apoptosis) or permanent cell cycle arrest (cellular senescence). Both apoptosis and cellular senescence are potent tumor suppressor mechanisms that irreversibly prevent damaged cells from undergoing neoplastic transformation.

However, both processes can also deplete renewable tissues of proliferation-competent progenitor or stem cells. Such depletion, in turn, can compromise the structure and function of tissues, which is a hallmark of aging. Moreover, whereas apoptotic cells are by definition eliminated from tissues, senescent cells can persist, acquire altered functions, and thus alter tissue microenvironments in ways that can promote both cancer and aging phenotypes. Recent evidence suggests that increased p53 activity can, at least under some circumstances, promote organismal aging.

Telomeres, senescence, and hematopoietic stem cells:

The replicative lifespan of normal somatic cells is restricted by the erosion of telomeres, which are protective caps at the ends of linear chromosomes. The loss of telomeres induces antiproliferative signals that eventually lead to cellular senescence. The enzyme complex telomerase can maintain telomeres, but its expression is confined to highly proliferative cells such as stem cells and tumor cells.

The immense regenerative capacity of the hematopoietic system is provided by a distinct type of adult stem cell: hematopoietic stem cells (HSCs). Although blood cells have to be produced continuously throughout life, the HSC pool seems not to be spared by aging processes. Indeed, limited expression of telomerase is not sufficient to prevent telomere shortening in these cells, which is thought ultimately to limit their proliferative capacity.

Calorie Restriction and Mitochondrial Function

One way in which calorie restriction resists age-related issues with mitochondrial function in your cells is likely to be by encouraging autophagy, the process of recycling damaged cellular components - such as mitochondria, the power plants of your cells. Here, researchers note that one component of mitochondrial function, the malate-aspartate shuttle, declines with age, but is restored by calorie restriction: "Dietary restriction (DR) influences several physiological processes, retards the incidences and severity of various age-related diseases and extends lifespan of various animal species. The effect of DR on the activities of malate-aspartate shuttle enzymes [was] investigated in the liver and kidney of adult (5-months) and old (21-months) male mice. The results show that the activity [of the enzymes] is decreased significantly in the liver and kidney of old mice compared to adult ones. However, DR in old mice reverses significantly the enzyme activities to a level closer to adult animals. ... our results suggest that the late onset of DR in older mice reverses decline in malate-aspartate shuttle enzymes and that it may allow a better metabolic regulation in older animals." More evidence that it's never to late to start on calorie restriction - there are benefits to be had even if you are already aged.


Austad and Olshansky's Bet

Best Life Online looks at the well-known bet made between researchers Steven Austad and S. Jay Olshansky: "Olshansky didn’t think anyone was going to live to 150 anytime soon. But Austad was quite serious, and so the two men made a wager. They each put up $150, which Olshansky invested in a fund. The winnings will be handed out in the year 2150. If there is a 150-year-old alive on earth - someone of sound mind and body - Austad's descendants will get the pot, which Olshansky has calculated will grow to $1 billion thanks to his shrewd, but secret, investments. ... In the years since the bet, the two scientists have closely monitored new evidence, and, somewhat remarkably, neither has seen any reason to budge on the bet. ... In one corner, Austad, the swashbuckling adventurer and optimist, points to the accelerating pace of discoveries about aging: Scientists have identified the genes that prolong the lives of animals and discovered ways to switch those genes on, and researchers are launching pharmaceutical start-ups to create the first real antiaging drugs that could slow the cellular damage. In the other corner, Olshansky, the number-crunching realist, sees too many hurdles in the way. ... Despite their diverging perspectives on life expectancy, both men share a belief that science is finally catching up with aging, and this has ramifications for us all."


Ageless Animals, Clam Edition

It wasn't so long that we were talking about the uncertain longevity of lobsters, but for today it's the turn of the humble clam:

A British scientific team discovered the 405-year-old clam, named after the Chinese dynasty and not the former Liberal Democrat leader, at the bottom of the ocean, and hope its longevity will reveal the secrets of ageing.


The record-breaking shellfish, 31 years older than the previous oldest animal, another clam, was caught last year when scientists from the Bangor University School of Ocean Sciences were dredging the seabed north of Iceland.


Richard Faragher, a gerontologist at Brighton University working with the Bangor team, said: "Most of what we know about the ocean quahog is what it tastes like. We need to find out how it retains muscle strength, remains cancer-free and keeps its nervous system intact over such a long period of time."

As for the lobster (and the bowhead whale, for that matter) this is a good illustration of the limits of present knowledge, for all that the biotechnology revolution is well underway. There are a great many trees in this forest.

Another potentially useful consequence of scientific examination of species of extreme longevity is an increase in public understanding of the range of life spans in the animal world. As scientists demonstrate specific biochemical reasons for differences in longevity between species, that work helps to generate support for medical engineering research aimed at increasing the healthy life span of our own species.

Stepping Towards a Cancer Vaccine

Researchers continue to work at developing a safe way to provoke the immune system into destroying cancer cells: "The discovery in the 1970s of unique sugars on cancer cells set scientists in search of a way to get the immune system to recognize and attack cells that express these cancer-associated sugars. Until now, however, the results have been less than spectacular. ... early cancer vaccines were created by linking the tumor-associated carbohydrate with a foreign protein. The immune system, perhaps not surprisingly, attacked the protein and the linker molecules, but generally left the carbohydrate alone. ... We needed to come up with a vaccine that does not give our immune system a chance to go after anything else but the tumor-associated carbohydrate ... When we tested our best vaccine we got really, really fabulous antibody levels that have never been seen before ... The vaccine has been successful in creating an antibody response that can kill cultured epithelial cells - those commonly involved in most solid tumors, such as breast and colorectal cancer - derived from mice and in stimulating an immune response in healthy mice. The researchers are currently testing the vaccine in mice with cancer, and [hope] to start phase I clinical trials in humans within a year." If medicine often looks like engineering, that's because it is.


An Interview With Aubrey de Grey

Machines Like Us interviews biomedical gerontologist Aubrey de Grey: "It'll almost certainly be a very long time indeed - many decades, possibly centuries - before we can completely repair everything that qualifies as 'damage' [and] therefore totally prevent aging. But luckily, we don't need to reach perfection in order to maintain our youth indefinitely, because a certain amount of damage - the sort of amount we have in early adulthood - is harmless, not causing any disease or debilitation. If we can develop reasonably comprehensive repair and maintenance therapies, that will buy time to develop even more comprehensive ones, thus buying more time to improve the therapies even more, and so on indefinitely, even if the therapies never achieve absolute perfection. "Longevity escape velocity" is the name I've given to the rate at which we would need to maintain this improvement of the therapies, following the initial breakthrough that gives middle-aged people maybe 30 extra years of healthy life."


One of the Ways in Which AGEs Contribute to Aging

Advanced glycation end-products, AGEs, are a wide variety of inconvenient biochemical waste products produced by the operation of your metabolism (and, to a much lesser degree, eaten as a part of your diet). AGEs gum up important biomolecular machinery and disable essential macromolecules by glueing them together. Some AGEs can be broken down by your cells, but accumulate faster than they can be removed. Others cannot be broken down at all, and the slow accumulation renders vital functions in your cells ever more hampered and faulty.

So far, there's nothing radical that can be done about this process - no working, sort-the-problem-out AGE-breaker therapies for humans. The best advice is to try and avoid metabolic disease - exercise, keep fit, eat a calorie restriction diet and don't pack on the fat, in other words - because that condition and the diabetes that follows ramps up the rate of AGE accumulation.

Here's a closer look at some of the details.

Cross-link breakers as a new therapeutic approach to cardiovascular disease:

Fibrillar proteins, such as collagens type I and III, and elastin are components of the extracellular matrix. They form an intricate widespread network that provides a basis for maintaining the physical structure of the heart and vessels and also play an important role in determining cardiovascular function.

Physiologically, collagen and elastin fibres are enzymatically cross-linked to form [the] matrix. In addition to these enzymatically formed cross-links, collagen fibres may be linked non-enzymatically, most notably by formation of AGEs (advanced glycation end-products). AGEs are formed by a reaction between reducing sugars and body proteins; they are formed increasingly in diabetes mellitus and hypertension and they accumulate with aging.

There are several mechanisms whereby AGEs may affect cardiovascular structure and function. These include increased myocardial and vascular stiffness and (upon reaction with their receptors) inflammatory reactions, release of growth factors and cytokines, and increased oxidative stress. Therefore breaking AGEs appears as a promising tool in the therapy of cardiovascular injury related to diabetes, hypertension and aging.

Nothing radical to be done at present: that's a pretty grim picture, considering the widespread suffering caused by AGE buildup. Work is presently underway on AGE-breaker and AGE inhibitor drugs, but it's a small, slow-moving field in comparison to regenerative medicine or other well-funded initiatives.

New Technology For Artificial Retinas

The ability to interface circuitry to cells seems to be keeping pace with the rest of the biotechnology revolution. Here, researchers are uncovering new data with the technology that will be used to build the next generation of artificial retinas: "This has been a fantastic journey through high-energy physics, neurobiology, technology, and human health ... We started out developing instruments to look for fundamental particles such as the top quark and the Higgs boson. Then we realized we could apply some of those technological concepts to studying neural systems. Now we are using the new technology for experiments that will help guide the design of future retinal prosthetic devices ... The device crammed 512 electrodes into an area of 1.7 square millimeters (about the size of a pinhead). Each of the team's experiments [recorded] the electrical activity of more than 250 cells simultaneously ... The high density and large number of the electrodes gave us the ability to pick out individual neurons and at the same time examine a whole collection of cells. If you had only a few electrodes, you might detect a single cell with unusual properties, but you wouldn't know what to do with it - it might just be a sick cell. ... We're working on many other cell types. This is just the tip of the iceberg."


Longevity Medicine Is (and Will Be) Basic Healthcare

From Anne C.: "Treatment of hypertension, for example, is treatment to slow down the aging of your cardiovascular system, so you can live longer and stay physiologically younger. You don't hear anyone saying that treating hypertension is wrong, because we should just let people develop cardiac failure or have a stroke naturally. ... I like this comment because it tidily makes what ought to be a fairly obvious point: which is that we already have longevity medicine to some extent. If a person has hypertension and manages to get it properly treated, it is quite likely that he or she will remain in better health longer than otherwise, because his or her body will not be experiencing as much in the way of accumulated damage. If testing for (and treating) treating hypertension is basic health care for people in middle-age and beyond, there should be nothing too difficult about imagining eventually testing for (and treating) issues pertaining to cancer vulnerability, critical cell loss and atrophy, mitochondrial mutation, etc."


More Engineered Viral Cancer Killers

The defeat of cancer is an important part of any comprehensive approach to repair the damage of aging. Ultimately, we'd all like perfect cancer prevention, but it may be that comprehensive and effective cancer cures will be enough to sustain the first few additional decades of the longevity revolution. That would put us at around 2040, entering "sky's the limit" territory with biomedicine and molecular nanotechnology. Cancer will go the way of smallpox shortly after that.

With regard to cancer cures, two of the most interesting lines of research at present involve engineered viruses and dendrimer-based therapies, both of which I've noted in past months:

Forced to pick the most promising technology base, I would have chosen dendrimers - they offer comparative efficiency in the process of producing new therapies because many components can be attached to a single dendrimer. Complex theraputic concepts - such as seeker molecules or two-stage toxins triggered by biochemicals specific to cancer cells - can be developed in isolation by specialists and the end results combined or built upon by other groups.

A virus doesn't have to be a one-trick pony, however. Engineered viruses that can do more than one job are examined in a recent Wired article:

Researchers at Stanford University and Jennerex Biotherapeutics have tweaked the cancer-killing vaccinia virus JX-963 so that it also stimulates the body to generate cancer-fighting white blood cells. The company intends to take the virus into clinical trials based on a promising animal study.


Scientists claim to have made recent progress targeting cancer cells with modded cold, herpes and smallpox viruses. These viruses infect and kill cancer cells while leaving healthy cells alone.

With the new JX-963 therapy, the virus doesn't have to do the work alone -- it elicits the body's own defenses to mop up cancer cells. The chemical that the virus secretes, granulocyte-macrophage colony-stimulating factor, or GM-CSF, is a protein that stimulates the production of white blood cells.

Interesting stuff. In theory, a virus could be altered to produce a range of useful proteins once it has access to the cellular environment - that might be good enough to give dendrimer therapies a run for their money if widely used engineered virus platforms emerge in the near future.

The existence of multiple competing technologies is one of the most promising signs of progress in any field. Competition turns the wheel, and it's good to see it here - that cancer with your name on it isn't getting any further away in time.

We Can Help Advance Research To Repair Aging

As Michael Graham Richard reminds us, we can can all help to advance LysoSENS research. LysoSENS is bioremediation, the search for bacterial enzymes capable of safely breaking down damaging byproducts of metabolism that are one of the causes of aging and age-related disease. This search needs samples: "The key to the success of this project is microbial diversity. Not all soil microbes are amenable to our screening methods, not all enzymes we discover will work in the human physiological environment, some will have deleterious side-effects, and so on. That's why we need as many different genetic sequences as possible to begin with. ... You can help by sending us environmental samples from biodiverse habitats in your area, or from places that you think are likely to contain microbes capable of degrading age-related aggregates (e.g. because the target substance gets degraded there naturally). The more microbial diversity we can put into these experiments, the better will be our chances of sustained success." So get out there and get digging!


Calorie Restriction Boosts Dopamine Receptors

Continuing the long litany of specific improvements in molecular biochemistry produced by calorie restriction, ScienceDaily notes this research: "scientists found that genetically obese rats had lower levels of dopamine D2 receptors than lean rats. They also demonstrated that restricting food intake can increase the number of D2 receptors, partially attenuating a normal decline associated with aging." It seems that the definition of "normal" is up for grabs if you can do better by better managing your diet. The article is very focused on obesity, but there is a little more on calorie restriction: "The finding that food restriction can attenuate the effects of aging on the brain's ability to respond to dopamine may also help explain why food restriction slows down other changes associated with aging, such as declines in locomotor activity and sensitivity to reward. ... Another main finding was that D2 receptor availability - that is, the number of receptors available for binding dopamine - was greater at adulthood in the obese rats compared to the lean rats. This suggests that perhaps the release of dopamine had significantly decreased with age in the obese unrestricted animals more than in the restricted ones or the lean rats. The possibility of lower release of dopamine in obese subjects is presently being examined."


More on Solar Radiation and Life Expectancy

If you have a long memory, you'll recall I discussed work claiming a link between solar radiation and human longevity at the end of last year:

The assumed general mechanism in biology is good, whatever you might think of the rest of the theory; it's essentially covered by the reliability theory of aging - biochemical damage, caused by radiation or otherwise, lowers remaining life expectancy by reducing or destroying the functionality of component parts in the machine that is you.


Some interesting studies are quoted in the article on solar radiation, but it looks very much like a case of having a hammer and seeing nails in everything. It is logical to suppose that demonstrated variations in human longevity and disease by location of birth date in solar and seasonal cycles have something to do with the sun at root - but that certainly doesn't mean that the sun is the direct cause of the biochemical damage that leads to such variations. It might be solar radiation, or it might be one or more differences in other systems caused by variations in solar radiation - diet, weather, hormonal changes, behaviors ... just to rattle off a few. There are certainly many more.

I noticed a new paper from the same researchers today, and I thought I'd point your attention in that direction.

The light of life: Evidence that the sun modulates human lifespan:

This paper reinforces the findings of others regarding the seasonality of various diseases and that there are factors occurring early in utero that increase susceptibility to diseases later in life. The authors use the vital statistics of 320,247 Maine citizens over a 29-year period to show that those born in 3-year peaks of 11-year solar cycles live an average of 1.5 years (CL 1.3-1.7) less than those born in non-peak years. Males are more sensitive than females to this phenomenon, which is statistically demonstrable well into adult life, showing the effect of probable UVR on the early human embryo despite superimposed adult lifetime hazards.


This study also supports the reliability theory of aging which suggests that events affecting the genome early after conception are important in the expression of adult diseases.

Nice to see them giving the nod to reliability theory in this latest work, but it doesn't look like the authors are any closer to demonstrating likelihood of any one mechanism over another.

And This Is If We Largely Fail

Watch the actuaries - or indeed anyone with a great deal of money on the line - if you'd like a higher class of prognostication on the future of life expectancy. From IFAonline: "As many as 50% of 30 year-olds could live to age 100, according to Paternoster, the insurance company that takes on responsibility for defined benefit (DB) scheme risks. Paternoster based its findings on DB scheme members' data and its study follows research from The Office of National Statistics, which shows a 90-fold increase in the number of people living to age 100." Given that this is based upon present trends, this extrapolation is also based on the assumption that we fail. By which I mean that the biotechnology revolution withers on the vine, producing no great leaps forward, that the prospects for regenerative medicine turn out to be false, that we never get SENS underway, that the cancer research community falters. In short, that trillions invested in research and development infrastructure, presently moving at a very fast rate in a hundred different directions, fails to deliver in any meaningful way. I find that outcome to be highly implausible.


More Research on Calorie Restriction Benefits

From the University at Buffalo: "Severely restricting calories leads to a longer life, scientists have proved. ... such a diet also can maintain physical fitness into advanced age, slowing the seemingly inevitable progression to physical disability and loss of independence. The study, using a rat model of life-time caloric restriction, showed that the diet reduces the amount of visceral fat, which expresses inflammatory factors that in humans cause chronic disease and a decline in physical performance and vitality across the lifespan. ... This is the first study to report that caloric restriction reduced production in visceral fat of the inflammatory cytokine IL-6 and enhanced performance on overall physical function assessments ... In addition, rats that ate a normal diet lost a significant amount of lean muscle mass and acquired more fat, while calorie-restricted rats maintained lean muscle mass as they aged." You'll find more about fat, inflammation and the damage that causes aging in the Fight Aging! archives. Remember that the human practice of CR should properly be called "calorie restriction with optimal nutrition" - it's not just cutting calories, but rather eating optimally. You can find out all about the nuts and bolts of practicing CR at the Calorie Restriction Society.


The Dreaded PI3K-PTEN-Akt-TOR Pathway

Scientists are not in the business of assigning names that make life easy for the rest of us, as illustrated by the PI3K-PTEN-Akt-TOR pathway. But you should read about it anyway, for the same reasons you read about research into calorie restriction and other aspects of metabolism and aging. It's good to know how we work, and gain an appreciation of how close scientists are to safely manipulating the core mechanisms on which a mammal is built:

Cancer, diabetes, and aging are related by their use of the PI3K-PTEN-Akt-TOR signaling pathway. This pathway controls how cells grow when nutrients are available and plays a role in how caloric restriction is able to extend lifespan. If parts of the pathway malfunction due to somatic or genetic mutations, cancer or diabetes can result. Thus, the pathway presents an exciting new frontier in medicine as researchers discover how to treat diseases by stopping the propagation of harmful signals and promoting the transmission of beneficial ones.


When nutrients are plentiful, growth factors spur the pathway to direct the cell toward growth and proliferation. If the pathway becomes overactive, however, cancerous growth results. Persistent activation by excess nutrients can lead to insulin resistance and diabetes. The pathway also appears to be involved in cellular senescence and aging in flies and worms and quite possibly in humans as well. Designing therapies to treat cancer, diabetes, and the aging process will be a challenge given the ubiquitous nature of this signaling pathway.

A challenge if you're of the school that believes the only way to tackle aging is to slow it down somewhat by redesigning metabolism, a hugely complex task that produces results of very limited benefit to those who are already old.

There is an alternate way forward, however: learn to repair the metabolism we have, and that we have invested so much time in understanding. Reversing or fixing the known biochemical changes that are the root of aging is arguably no harder - and arguably very much easier - than changing our metabolism. Yet progress along this path would greatly benefit those already old by producing therapies capable of rejuvenation rather than just a slowing of aging.

Work that leads to a greater understanding of our biochemistry will never be a waste - but it is very possible for the research community to head down a path that will never produce rejuvenation therapies in time to help those of us reading this now. Our job is to do our best to avoid that outcome.

Calorie Restriction Enhances DNA Repair

The full text is freely available for this recent review paper: "Caloric restriction (CR) reduces the incidence and progression of spontaneous and induced tumors in laboratory rodents while increasing mean and maximum life spans. It has been suggested that CR extends longevity and reduces age-related pathologies by reducing the levels of DNA damage and mutations that accumulate with age. This hypothesis is attractive because the integrity of the genome is essential to a cell/organism and because it is supported by observations that both cancer and immunological defects, which increase significantly with age and are delayed by CR, are associated with changes in DNA damage and/or DNA repair. Over the last three decades, numerous laboratories have examined the effects of CR on the integrity of the genome and the ability of cells to repair DNA. The majority of studies performed indicate that the age-related increase in oxidative damage to DNA is significantly reduced by CR. Early studies suggest that CR reduces DNA damage by enhancing DNA repair. With the advent of genomic technology and our increased understanding of specific repair pathways, CR has been shown to have a significant effect on major DNA repair pathways, such as NER, BER and double-strand break repair."


Cryonics and the Unexpected

Via Accelerating Future: "Anyone not signed up for cryonics has now lost the right to make fun of Paris Hilton, because no matter what else she does wrong, and what else you do right, all of it together can't outweigh the life consequences of that one little decision. Congratulations, Paris. I look forward to meeting you someday. ... I totally agree. You can make fun of Ms. Hilton all you want, but if in 100 years you're rotting in the ground, and she has her frozen cells repaired and remetabolized by nanomedicine, guess who's laughing now? ... Whether she's serious or not, I don't know, but signing up for cryonics isn't the sort of PR stunt to do for popular support - so it was obviously her personal decision. I myself associate signing up with cryonics with long-term thinking about the future of humanity, but maybe some see it as selfishness. Your mileage may vary." All publicity for cryonics is good; an industry that aims to give people with no other options a shot at additional years of life in the future should garner more attention and support than it does at present. I suspect that this latest news is one of those unexpected events that illustrates more about the rest of us - in our varied responses - than it does about Hilton.


Calorie Restriction Improves Stem Cell Function With Age

Evidence of specific age-related declines in our biochemistry that are put off, avoided, reduced or otherwise slowed by the practice of calorie restriction - known as "dietary restriction" in some scientific circles - should no longer be a surprise. Here's another piece of welcome research for those who like to cut out the empty calories:

Effects of dietary restriction on hematopoietic stem cell aging are genetically regulated:

Diminished stem cell functions with age may be a major cause of anemias and other defects. Unfortunately, treatments that increase stem cell function can also increase the incidence of cancers. Lifelong dietary restriction (DR) is known to decrease spontaneous cancers and lengthen lifespan. This study examines the effect of DR on the ability of bone marrow cells to repopulate irradiated recipients and produce erythrocytes and lymphocytes.


Hematopoietic stem cell (HSC) numbers are highly variable in aged BALB mice, however, the observed loss of marrow function is due to a major loss in repopulating ability per HSC. DR greatly ameliorates this loss of function with age. In contrast, function per HSC in B6 mice is neither affected by age nor by DR.

Thus, DR increases or maintains increased marrow repopulating ability with age in the 3 different genotypes tested, but effects on function per HSC depend on genotype. The fact that DR increases or maintains stem cell function with age, while decreasing cancer, has far-reaching health implications.

Good news all round.

You'll recall that age-related decline in the capacity of stem cells to repair and generate new tissue likely has as much to do with the aging of their cellular support environment as any inherent change in the cell population. Are the stem cells becoming damaged, are they ramping down as a part of an evolutionary program to avoid cancer, or is the cellular environment controlling it all? A great deal of work is presently focused on answering these questions, and then doing something about it.

A Thoughtful Ending Aging Review

Infidel753 reviews "Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime": "Can the human aging process be stopped and even reversed, allowing the human lifespan to be extended indefinitely -- to centuries or even millennia? In this book, just published in September, Aubrey de Grey makes the case not only that is this possible, but that the necessary technology is much closer to being within our grasp than most would imagine. ... In every case, de Grey's proposed treatment is based on well-established current knowledge; in most cases, the treatment he describes or something quite similar is actually already being developed or even at the animal or human testing stage, even if the intent of the work is to address some more specific problem than combating aging in general. Of course, even when the full SENS program is available for use on humans, it will not work perfectly, but it won't have to; extending the vigorous lifespan by even a few decades would allow people to benefit from further refinements and new technology which would be developed during those decades, thus extending their lives still further, and so on."


Another Type of Long-Lived Dwarf Mice

The Guardian reports on another breed of gene-engineered mice with increased longevity: "Experiments in male mice showed that those without a gene called IRS-1 lived 20% longer and had much healthier lives. Female mice without the gene had even better longevity, living 30% longer on average. In addition to longer lives, the mice without IRS-1 were much healthier than normal mice as they aged - they had brighter eyes, better immune function and healthier skin and bones. ... IRS-1 is involved in regulating the function of insulin, a hormone that controls the amount of sugar in the blood. [The results] add to a growing body of scientific work which points to a link between the genes that regulate insulin and how an animal ages. Similar genes in fruit flies and worms have already been linked to extended lifespan." Insulin regulation is becoming one of the more studied areas of metabolic manipulation - but building true repair technologies still beats out any tweak that lengthens life by reducing the wear on the system.


Letter on a Recent CBC Longevity Science Documentary

Some of you might have seen a recent documentary on longevity science on Canadian TV, and noticed some of the less enthused resulting press. So did Kevin Perrott, organizer of the Edmonton Aging Symposium and Methuselah Foundation volunteer, and sent in this letter to the Globe and Mail:

As a participant in the documentary "Living Forever: The Longevity Revolution" on David Suzuki's "The Nature of Things" on the CBC network, it was with great interest that I read a review on the program by your Arts columnist, Kate Taylor.

To be sure, given the content of the program and where the concept of 'aging' sits in the heart of western civilization, I am unsurprised at the negative impression she received from the program, but I find it personally gratifying that nothing of what she wrote was of much substance and really simply indicated her own bias. Still, our culture and society hold progress in high esteem and in the name of such forward motion I feel compelled to describe a different perspective than that written in the thoughts of Ms Taylor.

To start, Ms Taylor seems at a loss as to why anyone would want to live past 100. I'm not sure about Ms Taylor, but 100 years isn't enough for me to accomplish everything I want to do or see. For certain, just the little pleasures in life would be enough for me to wake up and be 100 years-old-and-a-day. There is always another book to read, embrace with a loved one, sunset to see, piano to play, planet to explore and belly laugh to share amongst innumerable other moments and precious activities that make life worth living. I'm surprised that as an accomplished writer this simple answer is opaque to Ms Taylor.

Ms Taylor muses how society would cope with the massive demographic shift of having many more people living a century or more. Firstly, as these therapies would effectively cure many age-related diseases, turning them from expensive chronic conditions to acute and preventative syndromes, the 80% of our health care dollar spent dealing with the degenerative diseases of old age would be dramatically reduced, freeing billions of dollars of capital. I would refer Ms Taylor to some serious, high-profile gerontologists in the U.S. who have proposed a "Longevity Dividend" (S. Jay Olshansky et al.) who are urging congress to allocate funds to slow aging showing that even a tiny decrease in the rate of aging would result in tremendous economic shifts to the good. Secondly, there are of course many sociological consequences of having healthy supercentenarians in our midst. Many more grandparents would live to be great-grandparents which would obviously bolster the sense of family continuity. Many more healthy consumers would bolster the economy. Many more healthy individuals, who have lived through the hormone-ridden decisions of youth to arrive at the 'been there done that' period of senior citizenship, would find themselves able to offer their experience to mentor upcoming generations from the perspective of hale and hearty bodies rather than the invisibility of cowering in the shadows of the institutions they currently inhabit.

How indeed would society cope with a generation of individuals who have lived a century or more? Perhaps our world may achieve a more 'mature' perspective and many perennial problems which have escaped solution may be approached from a different direction with the attitudes of altruism and cooperation we find more prevalent at advanced ages. For a small taste of what one might expect in spades from healthy supercentenarians, have a look at CivicVentures.Org. Ms Taylor and perhaps you might envision a different world than one where the elderly simply take up space.

Given that Ms Taylor is not a scientist, nor does her bio list any training in science, it is perhaps understandable that her treatment of the facts and feasibility behind the technologies discussed in the program is superficial at best. The disinterest and lack of understanding of the subject matter is exemplified when she asks the question "Where will all these kidneys come from?" with reference to the segment of the program dealing with cryobiology. She doesn't even bother to mention his name when she refers to Dr. Greg Fahy where he describes the technology for freezing organs for use in later life as they are required. Her question as to where the 'kidneys' would come from indicates that she never heard/understood a word of most of his interview. Dr. Fahy clearly says that such organs would be tissue-engineered from a patient's own cells, something which has already seen success in Anthony Atala's work at the University of Pittsburgh Medical Center where he grew the first organ, a bladder, outside the body and transplanted it to help a child lead a more normal life. There are plenty more well publicized examples of promising tissue-engineering technology. It is likely that many have not heard of the rapid progress in the use of printing technology to actually 'print' solid organs, but a look at the work of Gabor Forgacs of the University of Missouri in 'bioprinting' with 'bioink' might be an interesting read. (New Scientist, April 13, 2006)

Ms Taylor does bring up one very important point; that of the potential disparity in the availability of these therapies. However, is such potential disparity in availability really an argument against development? Is the fact that we can't share with the Third World a reason to forgo the development of valuable medical technologies for people suffering today? It would seem that the problems are not related in the least. I don't think distribution problems have much to do with ethical questions of developing technologies that will eventually benefit billions of people. If we followed the logic that therapies should not be available to any unless they are available to all, therapies would never be developed. Restricting the development and availability of therapies will result in exactly the effect that Ms Taylor fears, the wealthy will access such technologies in countries that do not have such issues through medical tourism while the situation for the poor remains unchanged at home or is worse. Developing the therapies at home and making them accessible as quickly as possible to as many as possible is what we should be shooting for, not restricting access and forgoing development.

I was somewhat taken aback by Ms Taylor referring to the program as an example of "immature journalism" when actually her own story exemplifies a remarkable lack of interest in wanting to delve any deeper into the background than is needed to satisfy her own closed-minded preconceptions of what the value of the elderly is. She ultimately willfully blinds herself to the fact that old people suffering from age-related disease in need of therapies are PEOPLE, loving and beloved, parents and grandparents, individuals who have contributed to her well-being and the world. Off-hand remarks such as "What is it all those extra centenarians are going to do, other than consume more fossil fuels?" indicate that she has obviously not thought things through, or about how abysmally unethical it is to talk about PEOPLE as if they have nothing to offer when they reach old age. Such a viewpoint is sadly endemic in our society, and changing such a viewpoint is one welcome consequence that would result from having many healthy oldsters around a century or more.

Finally, Ms Taylor berates Dr. Suzuki for featuring a program where more people suffer less and live longer than previous generations, intimating that the focus of environmentalism would be ill-served by having yet more healthy elderly people on the planet. She completely ignores the fact that the elderly are the ones whose perspective is most valuable in the preservation of the environment as they have seen the changes wrought by years of empire building by the relatively young. If people knew they would live to be centuries old, perhaps they may think twice about making decisions which foist onto future generations the environmental fallout from their greed and poor stewardship. Dr. Suzuki is right on the money in suspecting that older individuals would care substantively more than those who we know from past experience care little.

Sadly, the attitude expressed by Ms Taylor is all too prevalent in a society that glorifies youth and denigrates the elderly. As is the case however, the young soon enough grow old and will experience the motivation necessary to work for changes that will create a world where getting older is truly something that enriches, rather than diminishes, the individual and society. If we all work together, we will avoid the worst pitfalls and bring about such a day all the sooner.

Kevin Perrott PhD Student
Department of Biochemistry
University of Alberta

I should have mentioned that Perrott isn't content with organizing impressive conferences on the repair of aging and improving the lot of the Methuselah Foundation, but has also gone back to the grindstone of earning a doctorate. He is changing careers to become a molecular biologist for aging research, and thereby help to get the job done in person. Now there is dedication to the cause, ladies and gentlemen - he's an example for all of us.

Tissue Engineering Nerves

ScienceDaily notes an advance in tissue engineering: researchers have "isolated the stem cells from the fat tissue of adult animals and differentiated them into nerve cells to be used for repair and regeneration of injured nerves. They are now about to start a trial extracting stem cells from fat tissue of volunteer adult patients, in order to compare in the laboratory human and animal stem cells. Following that, they will develop an artificial nerve constructed from a biodegradable polymer to transplant the differentiated stem cells. The biomaterial will be rolled up into a tube-like structure and inserted between the two ends of the cut nerve so that the regrowing nerve fibre can go through it from one end to the other. This 'bionic' nerve could also be used in people who have suffered trauma injuries to their limbs or organs, cancer patients whose tumour surgery has affected a nearby nerve trunk and people who have had organ transplants. With a clinical trial on the biomaterial about to be completed, the researchers hope the treatment could be ready for use in four or five years."


An Update on Myostatin Science

The Technology Review looks at progress towards the safe manipulation of myostatin: "Over the past few years, pharmaceutical companies have been racing to develop ways to mimic myostatin gene mutations in the hope of treating everything from the muscle loss that accompanies muscular dystrophy, cancer, and aging to obesity and other metabolic disorders. Pharmaceutical giants Wyeth and Amgen are expected to release clinical-trial results of myostatin inhibitors for muscle-wasting diseases within the next few months. A smaller company, Acceleron Pharma, [says] that its more broadly acting drug could bring more brawn than can drugs targeting myostatin alone. ... There's been a huge amount of interest for human therapeutics. If you could increase or maintain muscle strength as people age, you could have a tremendous impact on health and well-being. ... There is [presently] no effective agent to prevent the accelerated loss of muscle associated with disease, infection, or illness, such as cancer, heart failure, and kidney disease and dialysis. As treatments of disease like cancer and heart failure become more effective, the issue becomes more prominent."


A Few Thoughts on the Funding of Aging Research

Yesterday I stumbled onto a press release on the topic of funding from the Ellison Medical Foundation and the American Federation for Aging Research. I am very struck by the tone of the piece:

The Ellison Medical Foundation has awarded AFAR more than $2.8 million to support 45 postdoctoral fellows (both MDs and PhDs at any level of postdoctoral training) over the next three years in the fundamental mechanisms of aging. With this new commitment, the Ellison Medical Foundation/AFAR partnership has increased five-fold the number of researchers it will support.


There are so many promising scientists yet we are only able to fund eight percent of the applicants who seek grants. There's a potential to lose a tremendous brain trust of future leaders in aging research. The Ellison Medical Foundation has taken a lead role in helping the next generation of researchers establish careers and an aging society will benefit


In the face of this opportunity we currently see declining federal support for scientists. Those just beginning their careers are especially vulnerable as support dries up. Our hope is that this decline is temporary, yet even a temporary reduction in support for scientists just beginning their careers, or those deciding whether to stay in science or build a career elsewhere, could result in the loss of most of a whole generation of scientists.


"While AFAR-supported grant programs have traditionally focused on early-career scientists, it is also important to sustain that investment in our scientists at all stages of their careers," said Stephanie Lederman. This generous grant can make all the difference in allowing years of painstaking research to continue."

"Mid-career scientists, with newly acquired tenure, are at a unique career stage. Freed from worry about getting tenure and job stability, they have more intellectual freedom than they have ever had before. We hope to empower them to try riskier research with great potential pay-off, for themselves and for an aging society."

This might as well be language lifted from a mythical government release on the Full Employment Act for Gerontologists. It's all so grey and tired - rescue the scientists, pay the scientists, help the scientists. Note the utter absence of any sort of discussion of goals or results. What are these scientists actually doing? What is the value of it? Where are they going? When will they get there? What does it mean to me?

This sort of thing is exactly why there is little public support for or understanding of mainstream aging research. I've long said that basic research is no different from any other human endeavor. It isn't magic, immune to planning - you can set goals, plans and schedules. You can invest in research in exactly the same way as commercial companies invest in research day in and day out. Those who claim that you can't set goals, timelines, explain matters to the public, create excitement and make real fireworks fly in an area of fundamental research are generally much more interested in the steady flow of dollars or their own particular hobby than in actually getting something meaningful accomplished.

The drift of mainstream American science into government dependency has drained it of vigor and accountability to produce real progress. There's a reason why most of the interesting, productive scientists largely work outside that system, in the market or philanthropic ventures.

Another thought: the languishing of aging science - in comparison to, say, regenerative medicine, tissue engineering or cancer research - makes $2.8 million a big deal. $10 million from the Glenn Foundation to establish the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging was a big splash in the pond.

With those numbers for comparison, note that the Methuselah Foundation has $4.8 million pledged to Strategies for Engineered Negligible Senescence (SENS) research. I will venture to say that the Foundation has succeeded in building up to that level of funding by being everything that the Full Employment Act for Gerontologists is not. There is a plan, there are goals, there are timelines, there is accountability for failing to deliver - and a real effort to explain what all this work and funding really means to folk like you and I.

Stem Cells, Tissue Environments, Aging

From Ouroboros: "These papers add to the growing body of evidence that stem cells don't fare well in aged niches. In other words, the stable introduction of stem cells into patients will become more difficult as a function of the recipients' age; since it's a question of capacity rather than efficiency, the problem can't be solved by adding more stem cells. Clinically, this means that [we] may need to engineer the niche itself in order to cajole aged tissues into accepting a new batch of stem cells - and this will be very hard. We are much better at manipulating cells outside the body and re-introducing them than we are at making genetic changes to particular cells inside a specific tissue architecture while they remain inside the body - and by 'much better' I mean that at present we can do the former sometimes and the latter not at all. Perhaps a better approach would be to make the stem cells less sensitive to the cues they receive from the niche? Yes, that would be nice: immortal cells, freed from requirements for context-specific pro-growth and anti-apoptotic factors, free in the body to do as they pleased ... oh, wait." There's an evolutionary reason for many of the declines of aging - it's called cancer. The body is a finely tuned device; fixing problem A is often going to require fixing problems B and C as well. This is one of the reasons a general strategy of repairing all age-related changes is needed.


More On the Cost of Obesity

Via the LEF News, another look at the costs of excess fat: "While smoking reduces life by an average of ten years, the research says being seriously overweight can cut life expectancy by as much as 13 years. ... If current trends continue, by 2050 about 60 per cent of men, 50 per cent of women and 25 per cent of children in the UK will be clinically obese - so fat that their health is in danger. At present around a quarter of adults are obese. The effects of this on the nation's health will be devastating. The report expects type 2 diabetes to rise by 70 per cent, strokes to go up by 30 per cent and a 20 per cent rise in coronary disease. The rates of certain cancers will also go up. The associated chronic health problems will cost an extra Pounds 45.5 billion a year, more than half the amount of money that goes into the entire NHS at the moment. ... the majority of adults are already overweight and that being overweight is now seen as 'normal'." Trends are trends, but insofar as your own health goes, you have all the choice in the world. Altering the trajectory of your own healthy life span by a decade or two could make the difference between living to see the first working rejuvenation therapies - or missing the boat by just a few years.


On Replacing the Wetware

We humans like to look ahead to step two as a distraction from the labors of step one. Here, Al Fin discusses options for replacing the biological basis of the mind with whatever nanotechnology can build a better neuron - versus a strategy of repairing the neurons we have, that is. He is, correctly I think, pessimistic about progress on rapid time frames for the nanotechnology option, and more optimistic about repair initiatives like the Strategies for Engineeered Negligible Senescence. First things first, I say. We will see the first brain prosthetics become widely available within the next decade, judging by the state of present research, but they will be dedicated devices, large compared to a neuron, aimed at specific errant brain components. It's quite a way from there to replacement of your fallible tissue, cell by cell, with more study artifical components. It will become possible sometime later this century, and we'll all be the better for having that choice, but it's far more useful now to focus on repairing the biology we have today, given that our expiration date approaches all too rapidly.


Regenerative Powers of the Sea Cucumber

Scientists are already hard at work on the biochemistry of salamanders and zebrafish, deer antlers and MRL mice, to see if the ability to regenerate organs can be ported to humans. The sea cucumber is another target of research, as noted by EurekAlert!: "Sea cucumbers should be viewed as the tissue regeneration equivalent of the squid for our knowledge of nerves and Drosophila for genes and the genome. They can help us learn to fix ourselves. Many people, including scientists, regard sea cucumbers and other echinoderms like star fish and brittle stars as bizarre, exceptional outcasts because of their regenerative abilities. But we've shown that they use the same 'ordinary' mechanisms and processes to both regenerate and heal wounds. ... There must be some unusual properties of the healing processes found in animals capable of organ regeneration. So it remains to be seen at a molecular level what limits healing processes being used for regeneration by all animals in all tissue. ... Many of these regenerative mechanisms are the same as those being used by other animals to heal and repair - this includes us humans. Sea cucumbers will probably provide us with the key to deciphering how to regenerate our tissues, or at least find out what is needed to do this."


Charles Platt on the Alcor Conference, Cryonics, and Related Topics

Charles Platt, who presently works with Suspended Animation, Inc., has a long history with the cryonics community. Over at CryoNet, you'll find a three part report on the recent Alcor conference:

There might be a touch too much insight into the sausage-making process for some folk. Small communities of passionate people tend to produce the sort of history, disagreements and debates worthy of a writeup - and that might not appear too noble at first glance, or from certain angles. There's no such thing as too much transparency or constructive criticism, however - for any service, never mind one upon which you are relying for a chance at life. It seems to me that Alcor is more transparent than many organizations seeded by a small, motivated community.

The cryonics industry, small and still very dependent on passion and volunteerism, suffers from all of the problems you normally find in those circumstances. Resources are tight, bad apples can have a disproportionate effect, and so forth. That the industry has sustained itself and even managed some growth and professionalization over a number of decades speaks well of those folk who stepped up and got the job done when a crisis loomed. But that's no way to run for the long term; one day, through accident or decline, there will be no-one there capable of saving the day.

This is why the cryonics industry needs publicity, economic offshoots, spin-off technologies, demonstrated progress in research related to the core ideal of cryopreservation and restoration, and other means of becoming larger and more viable. The goal must be more eggs in more baskets, such that there will always be resources on tap to handle the unexpected.

The Prospects for Enhancing Autophagy to Combat Age-Related Degeneration

You'll find a rather interesting paper (abstract and full PDF are available) at the Annals of the New York Academy of Sciences on the topic of manipulating autophagy to repair some classes of age-related damage to cells and cellular components.

Aging denotes a post-maturational deterioration of cells and organisms with the passage of time, an increased vulnerability to challenges and prevalence of age-associated diseases, and a decreased ability to survive. Causes may be found in an enhanced production of reactive oxygen species (ROS) and oxidative damage and not completed housekeeping.

Caloric restriction is the most robust anti-aging intervention known so far. Similar beneficial effects on median and maximum life-span were obtained by feeding animals a 40% reduced diet or by every-other-day ad libitum feeding. In both instances, animals are forced to spend a great part of their time in a state of fasting and activated autophagy.

Autophagy is a highly conserved process in eukaryotes, in which the cytoplasm, including excess or aberrant organelles, is sequestered into double-membrane vesicles and delivered to the lysosome/vacuole, for breakdown and eventual recycling of the resulting macromolecules.

This process has an essential role in adaptation to fasting and changing environmental conditions, cellular remodeling during development, accumulation of altered ROS-hypergenerating organelles in older cells. Several pieces of evidence show that autophagy is involved in aging and is an essential part in the anti-aging mechanism of caloric restriction.

As an application, intensification of autophagy, by the administration of antilipolytic drug, rescued older cells from accumulation of altered [mitochondrial] DNA in less than 6 hours. It is concluded that the pharmacological intensification of autophagy [has] anti-aging effects and might prove to be a big step towards retardation of aging and prevention of age-associated diseases in humans.

Autophagy is a form of maintenance, the first step in the process of replacing damaged components with newly built components. It is promising that even today there are tools that could be applied to enhancing that process, or more likely serve as a starting point for the development of better, safer tools in the years to come.

You'll find more on autophagy as a process and its relationship to aging, mitochondria and calorie restriction back in the Fight Aging! archives:

Work on AGE Inhibitors

For the same reason that repair is better than good maintenance, AGE-breakers should be better than AGE inhibitors when it comes to reducing the contribution of AGE buildup to aging. Few groups are effectively working on either, however, so I am always pleased to see more published research on the topic: "The reno- and cardiovascular-protective effects of angiotensin II receptor blockers (ARBs), have been ascribed, at least in part, to their ability to inhibit the formation of advanced glycation end products (AGEs), independently of their effect on blood pressure. They act through decreased oxidative stress, unlike previously reported AGE inhibitors which entrap reactive carbonyl (RCOs) precursors of AGEs. The hypotensive effects of ARBs', however, may limit their use. In the present study, we report the synthesis of a new AGE inhibitor, TM2002, and its effects in vitro and in vivo. ... In vivo, TM2002, given acutely or for 8 weeks, has no adverse effects. In four different rat models of renal injury [and cardiovascular injury] TM2002 improves renal and cardiovascular lesions without modification of blood pressure." Inhibitors may be useful for the class of AGEs that are in fact broken down in the body, just more slowly than they accumulate. Unfortunately, animal studies have proven to be misleading for AGE-breakers in the past; the types of AGEs important in other mammals turn out to be much less important in humans.


Probing the Aging-Cancer Link

(From ScienceDaily). There is plenty of evidence for the proposition that the balance between cancer and aging is a tradeoff; when tinkering with the settings in mammalian biochemistry, you can pick one of those two unpleasant choices to improve. As researchers dig deeper in the mechanisms of life, they are finding that other options may be on the table: "A person is 100 times more likely to get cancer at age 65 than at age 35. But new research [identifies] naturally occurring processes that allow many genes to both slow aging and protect against cancer in the much-studied C. elegans roundworm. Many of the worm genes have counterparts in humans, suggesting that new drugs may some day ensure a long, cancer-free life. ... This is very exciting. There is a widely held view that any mechanism that slows aging would probably stimulate tumor growth. But we found many genes that increase lifespan, but slow tumor growth. Humans have versions of many of these genes, so this work may lead to treatments that keep us youthful and cancer-free much longer than normal."


No Shortage of Theories

Modern biotechnology is capable of churning out information somewhat faster than the research community can presently make sense of it. Like armor and weapons, the technologies of organization, synthesis and management seem to be perpetually a generation behind the technologies of investigation and exploration. Along those lines, it's easier to run an experiment than to write a really good theory - but there's no shortage of theories when it comes to aging. Now that the biochemistry of metabolism as it pertains to aging is becoming clearer, the related theories are becoming more detailed, specific, localized and provable. This is a good thing.

Energy metabolism, altered proteins, sirtuins and ageing: converging mechanisms?

The predominant molecular symptom of ageing is the accumulation of altered gene products. Nutritional studies show that ageing in animals can be significantly influenced by dietary restriction. Genetics has revealed that ageing may be controlled by changes in intracellular NAD/NADH ratio regulating sirtuin activity. Physiological and other approaches indicate that mitochondria may also regulate ageing. A mechanism is proposed which links diet, exercise and mitochondria-dependent changes in NAD/NADH ratio to intracellular generation of altered proteins.

It is suggested that ad libitum feeding conditions decrease NAD availability which also decreases metabolism of the triose phosphate glycolytic intermediates [which] can spontaneously decompose into methylglyoxal (MG).

MG is a highly toxic glycating agent and a major source of protein advanced-glycosylation end-products (AGEs). MG and AGEs can induce mitochondrial dysfunction and formation of reactive oxygen species (ROS), as well as affect gene expression and intracellular signalling. In dietary restriction-induced fasting, NADH would be oxidised and NAD regenerated via mitochondrial action. This would not only activate sirtuins and extend lifespan but also suppress MG formation. This proposal can also explain the apparent paradox whereby increased aerobic activity suppresses formation of glycoxidized proteins and extends lifespan. Variation in mitochondrial DNA composition and consequent mutation rate, arising from dietary-controlled differences in DNA precursor ratios, could also contribute to tissue differences in age-related mitochondrial dysfunction.

You'll actually find most of what you need to know to understand the scientese above by reading up on introductions to calorie restriction, the contribution of mitochondrial damage to aging, and AGEs - it's nowhere near as complex a set of ideas as it might at first appear:

It is gratifying to see attempts to tie many threads of aging research together into one synthesis, and to see that synthesis be testable at many easy, specific points. That's a sign of progress.

Cryonics and Unhelpful Legislation, Attitudes

As pointed out at TechNewsWorld, organizing the cryopreservation of someone who will not survive to benefit from near-future healthy life extension medicine faces all sorts of hurdles from third parties who would, in a just world, have no ability to interfere: "In 2003, a daughter of Ted Williams attempted to stop the cryonic suspension of the Hall of Fame baseball player. Williams had signed a 'family pact' asking to be preserved, but delays and a media circus ensued. He is not the only one that Alcor, the nation's leading cryonics organization, has had to fight to preserve. ... Even with clear legal documentation, hospitals around the country are wary of giving up bodies for cryopreservation. In at least one state, Arizona, legislators have considered making it nearly impossible for individuals to choose to be cryonically suspended. This brings up the universal question of individual self-determination as well as the proper role of government. ... Government should have no role in deciding one's fate after death so long as the individual's choice isn't harming anyone. ... Few people thought it would ever be possible to launch airborne a large piece of machinery or to send a person to the moon. Despite this, the Wright brothers and the U.S. Apollo 11 mission succeeded. Perhaps one day a nanotechnologist and cryobiologist will join that list. ... Meddlesome government types should leave them alone."


The Meaning That Immortality Gives to Life

Eliezer Yudkowsky pens another great post on radical life extension over at the Singularity Institute blog: "Philosophers have put forth a mighty effort to find nice things to say about death. But this is scant reason to fear lifespan extension, when philosophers have not put forth an equally motivated effort to say nice things about immortality. Such is human nature, that if we were all hit on the head with a baseball bat once a week, philosophers would soon discover many amazing benefits of being hit on the head with a baseball bat: It toughens us, renders us less fearful of lesser pains, makes bat-free days all the sweeter. But if people are not currently being hit with baseball bats, they will not volunteer for it. Modern literature about immortality is written primarily by authors who expect to die, and their grapes are accordingly sour. ... In truth, I suspect that if people were immortal, they would not think overmuch about the meaning that immortality gives to life. People in the Deaf subculture may ponder the implications of deafness; some Deaf parents even want to ensure that they have deaf children. Yet I rarely find myself pondering the meaning of hearing - perhaps I should! Only clouds must be searched for silver linings." Immortality here meaning agelessness - the result of working technologies capable of repairing and reversing the aging process.


On Supporting Cryonics

The folk of the People Database Project have transcribed Aubrey de Grey's presentation from the 7th Alcor conference: "the idea that a biologist can go out and just assert ex cathedra that [cryopreservation] for most organs is a wonderful thing to be researching, and doing it for the brain is simply outrageous, it's just so exceptionally not true. But you have to ask, how you can get away with it. And the answer is of course, he's relying on the public's yuck factor. What it means is that publicly funded scientists, you can't trust what they say in fora that may influence their subsequent funding. If they say, at the moment that cryonics is reasonable because it's reasonable for other organs, then they know they're going to be in trouble the next time they try to get a grant application funded. I don't want to be too dismissive. In a real sense it's not their fault. So, we have to take the lead and point these things out, and essentially help these people out of the trap that they find themselves in. ... you should not treat the battles that you fight, in terms of controversy, as being independent from each other. Expediency, the attempt to sound reasonable but to pull the wool over people's eyes, that tends to get spotted these days." When the rest of the world is wrong, you're not going to become a better person or achieve great things by bowing down to the crowd. Remember that and you'll do well in life.


On The Drive For Radical Life Extension

A little Canadian TV from CBC: "Scientists from around the world are racing to answer one of humanity's chief questions: can we turn back the human clock? Hitch a ride on this controversial roller-coaster with charismatic gerontologist Michael Rose as he leads us to where the cutting-edge science in life extension is happening: biotechnology, genetic research, therapeutic cloning and stem-cell research – fields which have moved to the outer reaches of our wildest imagination. ... Just to be clear, Living Forever is not a documentary about 60-year-olds who want to look like young and sexy 25-year-olds. This is a film about stopping, slowing down - even reversing - human aging. It is about the modern quest to create a longer, healthier old age, or - the Holy Grail - eliminating old age altogether. So, what happens if humans are able to live for another 100 or 500 years? Should we create a race of immortals, just because we have the know-how? At what evolutionary cost? What about the ethical issues? Given humanity's trajectory thus far, it's likely that most people will say ethics be damned: let The Longevity Revolution begin." We can hope they do more than just talk about getting the job done.


Aging Biochemistry and the Comparison of Rodents

Researchers are beginning to develop a more detailed understanding as to why different species of a similar size and taxonomy can have widely varying rates of aging. You might recall that in the case of the renowned and long-lived naked mole rat, there are noteworthy differences in the biochemicals making up some of the cellular machine most vulnerable to oxidative damage. That oxidative damage is a part of the many types of damage to living machinery that cause aging - it can't hurt to suffer less of it, or so present science strongly suggests. Along those lines, here's a couple of more recent papers:

Vascular superoxide and hydrogen peroxide production and oxidative stress resistance in two closely related rodent species with disparate longevity:

Vascular aging is characterized by increased oxidative stress, impaired nitric oxide (NO) bioavailability and enhanced apoptotic cell death. The oxidative stress hypothesis of aging predicts that vascular cells of long-lived species exhibit lower production of reactive oxygen species (ROS) and/or superior resistance to oxidative stress. We tested this hypothesis using two taxonomically related rodents, the white-footed mouse (Peromyscus leucopus) and the house mouse (Mus musculus), that show a more than twofold difference in maximum lifespan potential (MLSP = 8 and 3.5 years, respectively).


increased lifespan potential in P. leucopus is associated with a decreased cellular ROS generation and increased oxidative stress resistance, which accords with the prediction of the oxidative stress hypothesis of aging.

Life and death: metabolic rate, membrane composition, and life span of animals:

Maximum life span differences among animal species exceed life span variation achieved by experimental manipulation by orders of magnitude. The differences in the characteristic maximum life span of species was initially proposed to be due to variation in mass-specific rate of metabolism. This is called the rate-of-living theory of aging and lies at the base of the oxidative-stress theory of aging, currently the most generally accepted explanation of aging.

However, the rate-of-living theory of aging while helpful is not completely adequate in explaining the maximum life span. Recently, it has been discovered that the fatty acid composition of cell membranes varies systematically between species, and this underlies the variation in their metabolic rate. When combined with the fact that 1) the products of lipid peroxidation are powerful reactive molecular species, and 2) that fatty acids differ dramatically in their susceptibility to peroxidation, membrane fatty acid composition provides a mechanistic explanation of the variation in maximum life span among animal species.

When the connection between metabolic rate and life span was first proposed a century ago, it was not known that membrane composition varies between species. Many of the exceptions to the rate-of-living theory appear explicable when the particular membrane fatty acid composition is considered for each case. Here we review the links between metabolic rate and maximum life span of mammals and birds as well as the linking role of membrane fatty acid composition in determining the maximum life span.

If a somewhat more resistant cellular composition - building block molecules that are harder to damage with those dangerous free radicals churned out by your metabolism - can explain such wide variations in life span, think how much better we can do by repairing the damage at regular intervals. There is plenty of evidence to suggest that manipulating the rate of oxidative damage in precise ways in mammals can have meaningful effects on healthy life span, after all.

Ever More Stem Cell Therapy Trials

The first generation stem cell therapy trials aimed at regenerating damaged hearts continue to roll out - here's an example via ScienceDaily: "The technique begins with the extraction of myoblast cells, by means of a biopsy of muscular tissue from the leg of the patient, a procedure carried out under local anaesthetic. From the tissue fragment obtained, the researchers isolate the adult muscle stem cells. These cellular units must be cultured for a month in order to obtain sufficient numbers of cells to carry out the transplant. ... the cells obtained are injected into the heart of the patient [using] a special injection catheter. The cells are implanted in and around the damaged areas of cardiac muscle. ... In order to implant myoblasts it is necessary to generate an anatomical reproduction of the left ventricle, which is the zone to be treated. ... This technique manages to reconstruct the left ventricle in a three-dimensional form, a system that enables the location and analyses of low-voltage areas. ... It is these zones without electrical activity that anatomically correspond to the heart attack. ... The procedure is undertaken using local anaesthetic, with the patient being conscious, and lasts three or four hours. To date 14 patients have undergone the trials, all with satisfactory results."


Ouroboros on Hormesis and Oxidative Stress

From Ouroboros: "A counter-intuitive proposal for a mechanism of lifespan extension comes from Schulz et al., who contend that glucose restriction extends worm lifespan by increasing mitochondrial respiration and thereby the production of reactive oxygen species (ROS). Wait, you thought that ROS were deleterious? Welcome to the topsy-turvy world of hormesis, the biological equivalent of Was mich nicht umbringt, macht mich starker, in which a little bit of a bad thing is actually a very good thing. ... Usually, however, hormesis comes from acute exposure to stress: even if it's repeated, there's a chance for the cells (or the body) to recover before the next challenge. What I'm having a tough time wrapping my head around is how a chronic stress (i.e., elevated ROS levels resulting from lifelong glucose deprivation) could protect the body from another chronic stress that is essentially identical (i.e., elevated ROS levels pursuant to aging). For the model to hold true, it seems that either the system must be exquisitely tuned and the authors were lucky to hit a very narrow 'sweet spot', or ROS production must be increasing resistance to other stresses that are more relevant to C. elegans lifespan than oxidation."


New Scientist on Death and Healthy Life Extension

The New Scientist is running a batch of articles on death, science, life extension and related topics in their latest issue. Here is the first of the two articles you'll probably find most interesting, although both are behind their subscription wall:

The problems of living longer:

From an ethical point of view, two scenarios offer themselves in connection with the future of death. One relates to a situation in which the average human lifespan grows ever longer, but without major solutions to ageing and its many attendant diseases and disabilities. The other relates to the simultaneous conquering both of death and the current downsides of ageing, so that people live healthy well-functioning lives for 150 or 200 years or even beyond.

In the first case there will have to be a debate about the moral legitimacy and manner of elective death - both suicide and euthanasia - and the medical provision for them. In the latter case there will have to be questions about restricting conception, pregnancy and birth, to avoid a global population catastrophe.

Standard Malthusian boilerplate, in other words, mixed in with the Tithonus Error - all utterly wrong, but very familiar. It's rather sad, but to be expected, I suppose. Malthusianism and the Tithonus Error will continue for a while to represent the point of conflicting views at which advocates for the choice of healthy longevity educate those folk still ignorant of the true picture. It's not hard to describe reality - that any successful attempt to lengthen life span must reduce age-related damage and thereby extend healthy life span as well, and that overpopulation is a myth - but it is a challenge to convince people who have lived and breathed false perspectives since childhood, and who must break from the views of their peers in the process of coming to a true picture of the world.

That it is a challenge simply means we owe it to all those who will suffer and die from aging to try harder, of course.

The second piece is more useful, being an interview with biomedical gerontology Aubrey de Grey and transhumanist thinkers Anders Sandberg and Nick Bostrom. The latter penned the excellent Fable of the Dragon-Tyrant, you might recall.

The plan for eternal life:

New Scientist talks to Aubrey de Grey, Nick Bostrom and Anders Sandberg about how we could become immortal.

"Immortal" in the modern press sense of physical immortality - agelessness, in other words, or at least to have your biology repaired well enough and often enough to remain in a youthful, healthy state for as long as you please. Fortunately, video of the interviews is up on YouTube. Take a look and see what you think - and if you haven't yet read Bostrom's fable on the fight to cure aging, go and read it now. You won't be disappointed.

SENS3 Conference Report For Non-SENS Scientists

Researcher Attila Chordash shares a conference report originally intended for journal publication: "Missions in science and technology are no other than macro problems that need to be solved, beyond the 'publish or perish' horizon. One such mission is to find an all pervasive cancer therapy and probably the oldest mission is to understand aging in order to increase healthy lifespan. As we know more and more about how deeply aging and cancer are interrelated, it might turn out that those old missions are really the two sides of the same coin. The convergence of different science motivations can eventually lead to a yet unseen multifaceted scientific co-operation and amplify the efforts of extending our healthy human lifespan. In a wider sense, a well-funded life extension community might finally revise the notion of the basic human right for life. On the SENS3 conference, the emphasis was not on the big non-ideological mission (that was taken for granted), but on the scientific-technical and cultural details, which is a sign of maturity."


Stem Cell Decline and Aging Niches

ScienceDaily notes progress in our understanding of why stem cell function declines with age: "A stem cells' immediate neighborhood, a specialized environment also known as the stem cell niche, provides crucial support needed for stem cell maintenance. ... During the aging process, the level of support drops off, diminishing the stem cells' ability to replenish themselves (self-renew) indefinitely. ... in older flies a steep decline in the growth factor unpaired (upd), which is necessary to maintain stem cells, results in fewer stem cells in the testis of the fruit fly Drosophila. Identifying the reasons for reduced upd expression could reveal how aging leads to changes in stem cell behavior, and counteracting these changes may slow the loss of adult stem cells during aging. ... Taken together, our results suggest that over time the niche is changing to the point where you start losing self-renewing stem cells." Understanding these mechanisms is a step on the path to doing something about the loss of regenerative capacity with age.


Enter the Conspiracy Theorists

The strange - and far too large - world of people who believe in all-powerful "elites," conspiracies, suppression of new technologies, and carry a delightful range of other cultural baggage seems to have stumbled over the healthy life extension community of late. So, of course, it was only a matter of time before someone was up there misinterpreting us to suit whatever paid sermon is presently underway.

The development of successful life-extension technologies will be a reality within 30 years, but the application of such stunning advances will be tightly restricted by a ruling elite, and eventually may be used as a justification to completely wipe out humanity, according to some of the scientific community’s leading pioneers.

A recent article carried by the Methuselah Foundation, an organization that advocates the development of life extension and nanomachinery technology, concludes that life-extension technology and “(greatly) augmenting our biology with nanomachinery” will have arrived by the 2030’s, but that “The new bio- and nanotechnologies of the 2040s will be massive overkill for the “simple” task of repairing the damage of aging.”

The report concludes that the greatest obstacle in the field is not the development but the application of such technology, suggesting that living for hundreds of years is inevitable only for the wealthy elite.

Pressure groups pushing for more widespread funding of life-extension technology research seem to be constantly frustrated by the fact that major global scientific institutions seek to contain progress within very selective parameters and are very reticent to encourage more open access to the field.

Um, no. Not according to "the scientific community’s leading pioneers." According to you, guy writing at TruthNews, picking over content for pieces to support the pre-fabricated conclusion and tout a film project.

But really, how silly is all this? Start out by presenting Fight Aging! as an "organization" that issues "reports" and build up to fantastical cold war-styled sci-fi predictions of new overlords and oppressed masses. Along the way, blame the present lack of research infrastructure for longevity medicine on the ever-present "elites," and generally otherwise see planning and hidden controllers where there are none. It's all very melodramatic, and no doubt helps sell products to people who get a kick out of that memetic space.

I wouldn't normally comment on this sort of thing, but those are my words up there being cut up for use as stage props.

So I'll say this, for what it's worth: stop being foolish. Get a grip. Take off the blinders. I'm just a person, Fight Aging! is just a blog. The world is made of people, and people talk and get things done. There are no shadowy organizations, no nefarious controlling "elites," no plans for the future that are any different in nature than the plans you make for your own life and the organizations you support. Want a say in the future? Stand up and wave your arms, speak up, accomplish tasks. It's easy - I'm doing it, and there's nothing special about me.

As I've said before, there are plenty of folk out there who'd like to be the nefarious "elites." The disreputable types who infest the political arena spring to mind, fighting one another for more power to line their own nests. But they're people too; just as dumb, smart, lucky, hardworking, lazy and unfortunate as the rest of us. The same goes for all those people in the world who happen to have more power and influence than you do right at this moment in time. These folk aren't magical, and nor are they really any different from the rest of us. They are no less uncertain, fallible, confused, impotent and ignorant. A belief in magically efficient organizations and secret controllers of society is a comfort myth for some people, but that's all it is.

Make no mistake, there are factions in our centralized, over-regulated, over-governed societies that aspire to call themselves "elites," enriching themselves at cost to the rest of us, parasites warring to leverage the mechanisms of the state to force their agendas. But you'll note that these "elites" - whomever you might think they are - have no greater access to medical technologies than any average fellow who takes care of his finances. This is the way the world actually works: new technologies move from dream to expensive, clunky reality to cheap and effective product in a fraction of a lifetime. So it was - and continues to be - for heart surgery, so it will be for gene therapy, and so it will be for the first true longevity therapies capable of repairing age-related cellular and biomolecular damage.

I've done my share of talking about the dangers of centralization of power in the past. That's pragmatism and reality, not conspiracy theories. There are fallible human beings out there trying their best to live off your hard work, reduce your freedoms, and otherwise make your life shorter and more miserable. Some of them are even doing it intentionally - access to power corrupts at all levels, from the power of possessing a pretty face to the power to direct taxed dollars. But corruption doesn't turn people into competent, shadowy elites. It just makes them reprehensible.

There are very definitely battles to be fought: against centralized power; against the destruction of medicine through socialism and regulation; to persuade and fund into existence a vast research culture for longevity science; to raise popular support and understanding for healthy life extension; to dispense with harmful myths and beliefs about the way the world works. But fight the right battles, not the dumb, made-up, unreal battles.

Towards Artificial Corneas

Prosthetics research continues to threaten to give tissue engineering a run for its money over the next decade or two. Here, CORDIS looks at building artificial components for the eye: researchers "have developed an artificial cornea that may be tested on humans as early as the beginning of 2008. ... So far it has proven difficult to produce suitable artificial corneas due to [conflicting requirements]: While the implant has to grow firmly into the natural tissue, the centre has to remain clear of cells, so as such cell growth would impair vision. ... Our artificial corneas are based on a commercially available polymer which absorbs no water and allows no cells to grow on it ... Once the polymers have been shaped, the edge of the cornea is coated with a special protein, which the cells of the natural cornea can latch onto. ... The new artificial cornea has already been tested in the laboratory, being implanted in rabbits. Those tests have produced promising results ... [other research groups are] trying to reconstruct a human cornea in vitro, using tissue engineering. Such a development would transform eye surgery and dramatically cut the number of experiments conducted on animals."


Much Needed Irreverence

This punchy YouTube short entitled "How to Cope With Death" is not the normal sort of thing I point out, but it caught my attention. What I see as the right attitude towards death by aging is so sorely lacking in this culture of ours that positive thinking - and positive art, for that matter - stands out without even trying. So here is a little irreverence for the day, in the hope that we see many more fists shaken in the face of death in the years ahead. It's that attitude that leads to setting forth to do something about age-related degeneration - a great and now plausible goal in this age of accelerating biotechnology. Those who set out afresh upon this road soon find there are many traveling companions. Who wants to suffer and degenerate, really, when it comes down to it? Who wants oblivion? How much better it is to contribute towards the end of aging, to work towards the elimination of the greatest source of suffering and death in the world. To hell with death and aging - we can do better!


The Mortality Tariff

A nice turn of phrase spun here:

According to the Milken Institute, "It's been estimated that $2.6 T was added to the U.S. every year, just due to the extension of life in the past century. Solving cancer today is worth $46.5 T to the U.S., and adds $125 T to the world economy" (queue up the 53:30 minute mark).

The way I presently see it, the flip side of the Longevity Dividend, is the Mortality Tariff. As a society, we pay huge unrecoverable costs as a penalty for living short, disease-ravaged, frail lives. Counter to conventional so-called wisdom that might view super longevity as some kind of starry-eyed whimsical pursuit, I would argue that the costs of mortality to society are so high that inaction to contain these costs is fiscally irresponsible. Of course, in recent years one of the most active and articulate champions for the cause of putting realistic costs upon the impacts of aging is Dr. Aubrey de Grey.

Some people respond more readily to the repair of the broken window in front of them than a call to general renovation; there is merit to this sort of argument. The costs of age-related degeneration and death are so high that one has to argue the same sort of blindness and acceptance of aging as seen elsewhere are at work - otherwise, would we not pouring every last spare cent into this great work? If people can look ahead to save for the future, they can look ahead to fund longevity research.

This first decade of the 21st century forms a tipping point for public support of scientific research to extend healthy life and repair aging. We've come very far in just the past few years, with the rise of comparatively well supported new organizations and research groups, growth in the community and much more publicity. A handful more years of this and we'll start to meet the young people who have no idea why supporting healthy life extension is such a big deal. It'll be obvious to them, and obvious to all who were once ignorant or unsure. This is the way of progress; nothing unusual here, and getting from where we were to where we need to be is "just" a matter of hard work and good organization.

Dwarf Mice and the New Biotechnology

Given a longevity mutation, the logical thing to ask is "how does it work?" This is especially true in the case where the mutants suffer undesirable characteristics, as in the case of dwarf mice - we'd like to see if there's something to be salvaged. The rapid advance in biotechnology takes us ever close to answers; more can be done in a year by a single small group now than by the entire research establishment of 1980. "Long-lived strains of dwarf mice carry mutations that suppress growth hormone (GH) and insulin-like growth factor I (IGF-I) signaling. The downstream effects of these endocrine abnormalities, however, are not well understood and it is unclear how these processes interact with aging mechanisms. ... Comparative analysis of microarray datasets can identify patterns and consistencies not discernable from any one dataset individually. ... In this context, 43 longevity-associated genes are identified and individual genes with the highest level of support among all microarray experiments are highlighted. These results provide promising targets for future experimental investigation as well as potential clues for understanding the functional basis of lifespan extension in mammalian systems." This would be life extension through manipulating the system rather than by repairing it however; I see building a better metabolism as the less promising way forward.


More On Microglia and Alzheimer's

You might recall research suggesting that more or different microglia could be used to attack amyloid plaque in Alzheimer's. Here is a different slant on this branch of inquiry from Ouroboros: "Why do amyloid plaques cause Alzheimer's disease? While it would seem to be self-evident that neurons would prefer not to be surrounded by tangled forest of malfolded, insoluble protein deposits, the mechanism by which these plaques cause neuronal death remains an active subject of inquiry. ... What if the primary action of amyloid plaques is on another type of cell entirely - such as the ubiquitous, essential, yet still poorly understood neuronal support cell, the microglia? Flanary et al. argue that the presence of amyloid plaques accelerates the process of microglial senescence. ... The authors do not demonstrate a direct connection to Alzheimer's pathology, but it's easy to build a model in which senescent microglia contribute to cell death." As noted in the post, a connection between Alzheimer's and senescent cells would boost research aimed at the targeted destruction of those cells - which is one strand of the Strategies for Engineered Negligible Senescence.


7th Alcor Conference Converage

The 7th Alcor conference wrapped up yesterday: a conference at the intersection of the healthy life extension, cryonics, advanced nanotechnology and transhumanist communities. You'll find ample coverage from the Alcor blog; some snippets below:

7th Alcor Conference, Friday Morning sessions:

Alcor policy specialist Barry Aarons gave an introductory speech summarizing the recent progress of Alcor's status as a research entitity in Arizona. Indeed, within only four years, Alcor has progressed from being existentially threatened by the state government, to being perceived as an accepted research and technology institute furthering the public good. We are all grateful to Barry and the Alcor leadership for their excellent public relations work that made this possible. The next step should be to strengthen Alcor's relations to other leading Biotech institutions in Arizona, and begin collaborations with efforts like the Biodesign Institute in Tempe, or the Bio5 in Tucson. In the long term, this should establish Alcor as an indispensible part of Arizona's sprawling academic and Industrial Biotech network.

7th Alcor Conference, Friday Afternoon Sessions:

The afternoon session featured several illustrious speakers from the fields of molecular, cell and tissue repair, which would seem indispensable for successful resuscitation from cryonic suspension. We began with an introduction to molecular nanotechnology from Ralph Merkle, PhD, which may one day allow us to rebuild damaged structures molecule by molecule. The next higher level of repair, cell repair, was the topic of Mike West, PhD. West’s Advanced Stem Cell Technology may one day allow us to reassemble lost human tissues and organs cell by cell.


Sunday began with a bioethics panel discussion on the ethics of life and death, and in particular definitions of death, which have of course profound implications for the cryonicist’s legal situation. The panelists were care physician David Crippen, Alcor COO Tanya Jones and bioethicist Leslie Whetstine. Next, Steven Harris, MD introduced his fluorocarbon-based rapid body cooling system for resuscitation and cryonics applications. Calvin Mercer, PhD continued to address possible relations between people of religious faith and cryonicists or more broadly life-extensionists. Christine Petersen finally provided a survey of allegedly existing life-extension technologies.

On the spot conference converage can also be found at the Frontier Channel - just keep scrolling.

Stephen Van Sickle, Ralph Merkle, Michael R. Seidl, and Brian Wowk of the Alcor Board of Directors answered questions from the audience for the last session of the day. The Board addressed questions about the current state of Alcor finances. Alcor is financially stable, with the following sources of income:

1/3 membership dues
1/3 bequests and estates
1/3 grants and donations

At the current number of members (approximately 800) Alcor cannot support all the efforts it needs to support. Employees must wear many hats to cover all the administrative and technical tasks required. Better fund-raising was a popular suggestion for improvement by Board members.

“Alcor will aways muddle through,” said Van Sickle, stressing that this was both a strength and a weakness.

Maintenance costs are expected to remain stable over the next few decades, but operations costs are generally less stable. With more members, Alcor could see economies of scale, but exactly how does Alcor gain new membership?

The cryonics industry has been in the classic bootstrap phase for longer than I've known it existed; the stable provision of service continues on the strength of dedicated, hardworking volunteers and visionaries. Progress towards technological advancement and top to bottom professionalization of cryonics organizations has been solid but painfully slow; the same can be said of growth in capacity and provision of services. This is the state of affairs that young companies overcome with venture funding, something that the cryonics community has seen comparatively little of - though there are promising signs of late in that regard.

The cryonics industry should be supported in its efforts to reach mainstream size and success for the same reason that we support advocacy for healthy life extension research: far too few people even realize they have a choice beyond the grave and certain oblivion, and real progress is all about offering that choice. There's a long way to go, but that just makes the first steps easier, right?

Not Sure What To Make of This One

I am unable to tell whether this Huffington Post op-ed on biomedical gerontologist Aubrey de Grey and the Strategies for Engineered Negligible Senescence (SENS) is pure snark or not. The author clearly grasps the idea and the scientific backing of SENS, yet omits any mention of de Grey's role in editing a high impact factor scientific journal, organizing a respected conference series attended by the best and brightest of biotechnology and medical research, and pushing forward ongoing research into developing the nuts and bolts of SENS technology. I can't help but feel that if the topic to hand was anything other than the plausible case for a path to radical life extension through biotechnology, this would not be the case - none so blind, and all that. See what you think, and I will content myself with noting that there truly is no such thing as bad publicity for facts, truths and success in the making. As SENS is brought to the attention of more people, more people will decide that it's the better way forward for longevity science.


Biomechanisms of Type 2 Diabetes

ABC News reports on an advance in understanding of type 2, age-related diabetes: "The team has identified an enzyme in diabetics as the active agent that blocks the production of insulin, which is a hormone that helps the pancreas convert blood-sugar into energy. Current treatments try to control insulin levels but do not address the reasons why insulin production is failing. ... the next step will be to work with pharmaceutical companies to develop a drug to block the enzyme, known as PKCepsilon, allowing cells in the pancreas to function normally. ... What we've identified is a target that we can now latch onto to get therapy, but the journey from target to tablet of course is a long one ... It's probably going to take another 10 years at least to get something that's effective in humans. ... In their study, the researchers used genetically modified mice to observe the link between an oversupply of fat and type 2 diabetes. They found mice without the enzyme did not develop diabetes, despite gaining weight on a high-fat diet." It's worth remembering that diabetes is a lifestyle condition and very avoidable for most of us. It's just not smart to expect or rely on future medical science to rescue us from the consequences of health negligence - the cavalry only arrives on time in the movies, while the world helps those who help themselves.


Autophagy Required For Calorie Restriction Benefits?

Today, I noticed a new paper on the relationship between the demonstrated health benefits of calorie restriction and autophagy, the process by which cells recycle damaged organelles (such as the increasingly important mitochondria) and other components. More efficient autophagy is generally considered to be a good thing for all the obvious quality control reasons - newly created, functional cellular components are better than old, malfunctioning cellular components.

Autophagy is Required for Dietary Restriction-Mediated Life Span Extension in C. elegans:

Dietary restriction extends life span in diverse species including Caenorhabditis elegans. However, the downstream cellular targets regulated by dietary restriction are largely unknown. Autophagy, an evolutionary conserved lysosomal degradation pathway, is induced under starvation conditions and regulates life span in insulin signaling C. elegans mutants. We now report that two essential autophagy genes (bec-1 and Ce-atg7) are required for the longevity phenotype of the C. elegans dietary restriction mutant (eat-2(ad1113) animals. Thus, we propose that autophagy mediates the effect, not only of insulin signaling, but also of dietary restriction on the regulation of C. elegans life span. Since autophagy and longevity control are highly conserved from C. elegans to mammals, a similar role for autophagy in dietary restriction-mediated life span extension may also exist in mammals.

The work is in nematodes rather than people, but most interesting. If you look back into the Longevity Meme archives, you'll see a few references to calorie restriction and autophagy in mammals. The focus there was to understand to what degree increased autophagy causes the health and longevity benefits of calorie restriction - such as by culling the numbers of damaged mitochondria and thus reducing their deleterious effect on the rest of the body:

I believe this is the first I've seen of the suggestion that autophagy is strictly necessary for the benefits of calorie restriction in any way. One can speculate as to whether that raises the profile of the role of mitochondrial damage in age-related disease and degeneration - but there's a lot more research yet to be done here.

Fortunately, research groups around the world are converging on the biochemistry of calorie restriction from all sorts of directions: autophagy; sirtuins; other likely pathways; the immune system; studies in worms, flies, mice, monkeys and people. Today's mysteries won't last much past 2012, I'd wager - a lot of money is flowing into this field.

More Telomere Complexity

As a companion to recent posts on telomere science, here's an example of yet more complexity in the engines inside our cells: "At the end of [chromosomes] are telomeres, zones of repeated chains of DNA that are often compared to the plastic tips on shoelaces because they prevent chromosomes from fraying, and thus genetic information from getting scrambled when cells divide. The telomere is like a cellular clock, because every time a cell divides, the telomere shortens. After a cell has grown and divided a few dozen times, the telomeres turn on an alarm system that prevents further division. If this clock doesn't function right, cells either end up with damaged chromosomes or they become 'immortal' and continue dividing endlessly - either way it's bad news and leads to cancer or disease. Understanding how telomeres function, and how this function can potentially be manipulated, is thus extremely important. ... It was thought that telomeres were 'silent' - that their DNA was not transcribed into strands of RNA. The researchers have turned this theory on its head by discovering telomeric RNA and showing that this RNA is transcribed from DNA on the telomere." All new understanding of how to manipulate telomere length will be eagerly applied by those groups working on telomere-based therapies for age-related conditions.


The Longevity of Naked Mole Rats

Here's a good popular science piece on research into the longevity of naked mole rats: "Some of the 'hottest' research on naked mole rats today concerns senescence, or aging. Naked mole rats in the lab have reached up to 28 years of age. And it's not just the controlled environments of their captivity that are doing this. Braude has observed mole rats in the wild that are 17 years and older. ... For a rodent of this size, they are ridiculously long-lived ... A key component in the aging of any species is oxidative damage, where the cells accrue damage from poisons, environmental toxins and other effects throughout life. In such a long-lived rodent, it was thought that naked mole rats had a very efficient way of repairing oxidative damage. This wasn't the case, however, and current theory points to the strange metabolism of this hairless wonder. Naked mole rats appear to deal with oxidative stress in pulses, largely due to their ability to essentially shut down their metabolism when there are hardships, such as lack of food. In this way, mole rats may be able to rid their body of harmful reducing agents and poisons more easily during these metabolic pulses. ... Another way to think of it is, their gross life span might be 28 years, but their metabolism is going in these short bursts so maybe the net damage is only 3 or 4 years of net use. They're living their life in pulses."


The Cost of Aging, Illustrated

A fairly sweeping set of data compiled by the Milken Institute (also the force behind the interesting but probably irrelevant FasterCures initiative) caught my eye today. It catalogues the cost of chronic disease, but in doing so it is really establishing the cost of aging.

In its groundbreaking study, "An Unhealthy America: The Economic Impact of Chronic Disease," the Milken Institute details the enormous financial impact of chronic disease on the U.S. economy - not only in treatment costs, but lost worker productivity - today and in the decades ahead. It also describes the huge savings if a serious effort were made to improve Americans’ health.

Take a look a look at the major categories of chronic disease examined in the report website - almost all are age-related conditions. The greatest correlation for suffering chronic disease and associated costs is with age, with the toll of cellular and biochemical damage established across a lifetime of metabolic activity.

But aging is always the elephant in the room when you're looking at the work of those close to the regulators. Obvious, behind all the facts and figures, and absolutely unmentioned. That has to change if progress is to be made.

That said, the report provides another reminder than no plausible level of well-organized and effective investment in longevity research could be too high. The costs of aging are staggering, dwarfing any hard fought socioeconomic cause of today you care to name. Yet we struggle to make it a topic for discussion - and that also must change if progress is to be made.

Continual Discovery of Stem Cell Populations

A few years ago, uncovering another multipotent stem cell population would have been big news. That this one will pass by without much notice is a sign of progress. From ScienceDaily: scientists have "succeeded in finding and manipulating a population of cells that strongly resemble stem cells in the stomachs of mice. They have been able to show that these cells, which they call 'gastric progenitor cells,' can give rise to all the different types (or lineages) of specialized cells needed to form the functional stomach glands that line the lower portion of the stomach. ... The epithelial cells that make up the millions of glands of the stomach are constantly turning over. Most of the mature functioning cells live only 20 to 60 days before being replaced by progeny of dividing resident stem cells. These stem cells are not only a constant source of new cells, but they represent an important reservoir for repair of damage to the stomach caused by injury or inflammation. In addition, since the stem cells are the longest-lived of the gastric cells, it is thought that these are the only cells that live long enough to accumulate the multiple mutations that can cause cancers. For these reasons, the ability to identify and manipulate stomach progenitor cells has been an important goal for decades."


More Progress in Engineered Blood Vessels

WebMD reports on a trial of tissue engineered blood vessels: researchers "gathered cells from the skins and blood vessels of 10 adults with end-stage renal (kidney) disease. Next, the scientists put those cells in test tubes (keeping each patient's cells separate from the other patients' cells) and coaxed those cells to grow into blood vessels. After making sure that the lab-made blood vessels wouldn't burst under expected conditions, the researchers implanted the tailor-made blood vessels into the patients. So far, results are available for the first six patients, who got their tissue-engineered blood vessels more than a year ago. One of those patients died of unrelated causes. The lab-made blood vessel failed in another patient. A third patient used the lab-made blood vessel for more than 13 months until receiving a kidney transplant. The three other patients haven't had any problems with their engineered blood vessels. Those early results show that 'this new approach may be feasible,' write the scientists." The age of reliable, low-cost, on-demand replacements for age-damaged organs comes ever closer.


Complexities of Telomere Biology

Biochemistry is a resource-intensive science - the closer you look, the more detail there is to find. At our present level of understanding, everything is open to closer inspection - biotechnology and medical research could make good use of far more resources than are presently devoted to progress.

Everything is more complex than you think, and more complex than we'd like for rapid progress. Take telomeres, for example: much as we'd like their relationship to aging and cancer to be comparatively straightforward, there is a great deal of complexity going on in there. Telomere length is one part of a dynamic, evolved system churning away in all our bodies - the grand balance between maintaining the ability to heal damage and maintaining the ability to suppress cancer as we age. Take a look at these examples:

Research points towards early cancer detection:

Telomeres control cell division in the body - by gradually becoming shorter they can tell cells when it is time to stop dividing. However when telomeres stop working properly, they can cause the cells to mutate and start dividing uncontrollably, which can lead to the formation of tumours.

The Cardiff study used ground-breaking techniques to study telomeres in human cells. The researchers found the critical length at which telomeres stop working and also that some telomeres can be shortened or deleted at random, without any external cause.


This study threw up a number of significant results. The fact that telomeres can be deleted at random in otherwise normal cells indicates that some of the earliest cancerous changes can be initiated without any obvious extraneous influence. Our long-term aim with this research is to develop a clinical test to pick up these events.

Two wrongs make a right?

In mice, telomerase deficiency results in a segmental progeria that increases in intensity over the generations, as the telomeres grow shorter; in humans, similar mutations can result in the syndrome known as dyskeratosis congenita, whose symptoms include bone marrow failure. Mismatch repair defects results in increased cancer incidence (in humans, especially colon tumors). Both types of mutation dramatically decrease lifespan.

In combination, however, these mutations actually improve longevity.


We’ve seen numerous examples of tradeoffs between tumor prevention and tissue regeneration, usually in situations where increased activity of a tumor suppressor resulted in diminished regenerative capacity. Here, however, we see a case where two different antitumor mechanisms 'cancel each other out' to give both improved tissue regeneration and diminished cancer risk. How many other winning combinations are hiding out there?

A number of companies are forging ahead with the development of telomere-based therapies; a large part of that work today, and a lasting benefit whether these companies succeed or fail commercially, is figuring out just what is going on inside our cells as we age.

ScienceNOW on Stem Cell Heart Therapies

ScienceNOW takes a conservative look at issues in the development of regenerative medicine for heart damage. It is good to take stock of the challenges in any field alongside the breakthroughs: "It's been more than 6 years since the first person was injected with stem cells to rescue a failing heart. Hundreds of patients have since followed the lead of that 46-year-old German man. But experts are still divided on how well the strategy works. ... Clinical trials and animal studies are supplying a wealth of information; so far, the treatment seems safe. But it is not at all clear which stem cells should be given, or by what method - or, most importantly, whether patients who get them are likelier to survive.
Cardiologists seized on cell therapy as a way to prevent decay of heart muscle immediately after a heart attack and restore muscle long after it had died. But three of the four largest clinical trials have failed to accomplish what they set out to do - improve a particular measure of heart function, measured as an increase the amount of blood pumped, the so-called ejection fraction. By other measures of health, however, such as regeneration of heart muscle or preventing heart attacks, the trials may have been a success, argued some of those who conducted them. ... It's sad, but it's life. should we be discouraged? Certainly not."


Another Engineered Calorie Restriction Method

It's been worms all the way down the past few days, and more worm engineering here via ScienceDaily: "worms live to an older age when they are unable to process the simple sugar glucose ... The findings may also cast some doubt on the prevailing treatments for type 2 diabetes, all of which are aimed at lowering blood levels of glucose by increasing the amount of sugar taken up by body tissues ... researchers exposed the nematode Caenorhabditis elegans to a chemical that blocked the worms' ability to process glucose, producing a metabolic state the researchers said resembles that of dietary glucose restriction. That treatment extended the worms' life span up to 20 percent ... Unable to depend on glucose for energy, the long-lived worms ramped up the activity of cellular powerhouses known as mitochondria to fuel their bodies ... That mitochondrial activity led to the increased production of reactive oxygen species, sometimes referred to as free radicals. In turn, the worms' defenses against 'oxidative stress' increased."


Gigabytes of SENS3 Presentation Video

Gigabytes of video presentations in mp4 format are available for download at the website for the third conference on Strategies for Engineered Negligible Senescence (SENS3). Most of the speakers at this conference on longevity science and efforts to repair the biomolecular damage of aging are represented, and you'll find a great deal of very valuable material there.

Thanks to the prodigious efforts of Richard Schueler (who supervised the recordings, provided the camera and edited the files), splendidly assisted by Irvin Bussel and Stuart Calimport (who did most of the actual filming), we are able to provide video recordings of most of the talks at SENS3.

That's a hefty amount of data, weighing in a little under 300 megabytes per presentation - the impatient amongst us can find some streaming versions ready made at Richard Shueler's website, however.

I encourage the community to set to work on recompressing the best of SENS3 for upload to YouTube and Google Video, there to join the many other presentations on healthy life extension science to be found online. Conferences like SENS3 will be made far more worthwhile over the long term through many, many people coming to view just how active the scientific community can be in the quest to repair aging.

We should all thank the volunteers who worked hard to make this happen - these presentations will be bringing new support to longevity research for years to come.

SIRT1 Benefits Demonstrated in Mice

There has been some discussion and back and forth in recent years as to whether manipulation of SIRT1 is really going to trigger calorie-restriction-like benefits in mammals. Researchers have now amply demonstrated that it can in mice: "We generated mice that overexpress the sirtuin, SIRT1. Transgenic mice have been generated by knocking in SIRT1 cDNA into the beta-actin locus. Mice that are hemizygous for this transgene express normal levels of beta-actin and higher levels of SIRT1 protein in several tissues. Transgenic mice display some phenotypes similar to mice on a calorie-restricted diet: they are leaner than littermate controls; are more metabolically active; display reductions in blood cholesterol, adipokines, insulin and fasted glucose; and are more glucose tolerant. Furthermore, transgenic mice perform better on a rotarod challenge and also show a delay in reproduction. Our findings suggest that increased expression of SIRT1 in mice elicits beneficial phenotypes that may be relevant to human health and longevity."


Joining the Dots in CR Biochemistry

While researchers continue to blaze ahead to find new dots in the calorie restriction (CR) puzzle, there's much to be said for the steady work of joining the existing dots and establishing chains of cause and effect. "Dietary restriction (DR) is the most effective environmental intervention to extend lifespan in a wide range of species. However, the molecular mechanisms underlying the benefits of DR on longevity are still poorly characterized. AMP-activated protein kinase (AMPK) is activated by a decrease in energy levels, raising the possibility that AMPK might mediate lifespan extension by DR. ... we find that AMPK is required for this DR method to extend lifespan and delay age-dependent decline. We find that AMPK exerts its effects in part via the FOXO transcription factor DAF-16. FOXO/DAF-16 is necessary for the beneficial effects of this DR method on lifespan. Expression of an active version of AMPK in worms increases stress resistance and extends longevity in a FOXO/DAF-16-dependent manner. Lastly, we find that AMPK activates FOXO/DAF-16-dependent transcription and phosphorylates FOXO/DAF-16 at previously unidentified sites, suggesting a possible direct mechanism of regulation of FOXO/DAF-16 by AMPK."


Mitochondria and Wormish Longevity

It's all worms and mice over at the Longevity Meme today - so worms it will be here too. We should be thankful that evolution has chanced to produce an biosphere in which we are so closely related in structure and biochemistry to creatures that are efficient to study. I can't think of work that shows this is anything but likely, given the way in which evolution works, but for all we know we are very lucky to be in this circumstance. Imagine the slow crawl of longevity research if we could only usefully learn from close relatives like primates.

But back to the worms:

Microscopic worms used for scientific research are living longer despite cellular defects, a discovery that is shedding light on how the human body ages and how doctors could one day limit or reverse genetic mutations that cause inherited diseases ... researchers manipulated the metabolic state of genetically engineered lab worms called C. elegans and discovered a window of high-efficiency cellular processing that enabled the worms to slow their rate of aging.


Rea and his team used RNAi to produce worms with varying levels of mitochondrial dysfunction with the hope of solving a mystery that has baffled scientists for years. They wanted to know why the genetically engineered worms, known as "Mit mutants," lived longer despite cellular defects that would have caused similarly damaged human cells to become diseased or die off in the lab.


The research suggests that the worms' cells receive signals from their nuclei as DNA problems are sensed and not, as previously thought, from their disrupted mitochondrial power sources. The signal-sending nuclei order cells to shut down DNA replication, allowing them time to fix problems and create an environment that copes better with DNA damage and stress, researchers believe.

"It is only in this window that survival is enhanced. Once you move too far outside, then, like human cells, worm cells also die," Rea said. "We think there's a whole shift in the metabolism and the way it protects DNA. We show very clearly in our work that long life is intimately linked with the control of cell division."

The process appears to mimic the "hunker down" survival mode that stressed animals adopt during times of famine and danger. When conditions improve, the animals procreate again to ensure the survival of their species.

In the future, Rea and his collaborators hope to build on these findings with biochemistry and genetics to discover what controls this pro-longevity mode and how humans can reduce oxidative stress that causes cellular damage. "Life extension in humans is around the corner. There is no doubt about it," Rea said.

Very pleasing to see more researchers openly expressing their views on healthy life extension through modern biotechnology in humans. This work is an intriguing way of implementing something that looks like calorie restriction - in worms, in any case. We shall see in time whether it is one of the many commonalities or many differences between humans and nematodes.

This research does present a novel window into methodologies by which metabolism could be improved, to thereby cause less cellular and biomolecular damage over time and increase longevity - but it still doesn't make that path more attractive than the path of sticking with the metabolism we have and learning to repair it really well. You can tweak the efficiency of a system as much as you like, but it's still going to degrade, age and die. The only efficient way to greatly extend longevity is through repair - so why not just direct the lion's share of resources in that direction?