Fight Aging!

Thoughts and a couple of charts at BoingBoing, bringing a few of the ideas of engineered longevity a little closer to the masses. Every little bit of advocacy helps in the long run:

Charts: 1

The bad news is that despite all our advances in medicine, sanitation, and other relevant factors, the chart still tapers off around age 100. Average lifespan has increased, but maximum lifespan has not changed significantly.

One reason may be that research to prolong maximum lifespan receives minuscule funding, especially compared with popular endeavors such as cancer research. Many people seem to feel that extending maximum lifespan would be "wrong" (even at a time of rapidly declining birth rates in many nations) or "unnatural" (even though our average life expectancy used to be around 40, and has improved through totally unnatural means such as antibiotics).

As you may infer from the quotation marks, I disagree. Of course, I realize that these are controversial issues.

One of the most effective special-interest groups seeking funding for longevity research is www.methuselahfoundation.org.

Charts: 2

We can feel happy that people today are surviving more tenaciously than anyone expected half a century ago. How will our current prediction turn out fifty years from now? Presumably the answer depends on our priorities. If lives are worth saving, perhaps it will make sense to fund more research into the aging process.

This is an interesting paper. I would be almost inclined to think that the life extension effect has to do with the link between telomerase and mitochondrial damage, but that's very speculative at this point. For all we know, the treatment of mice might have led to accidental calorie restriction and extended life span by that method: "Telomeres become shorter after each cell division, which is one of the mechanisms of gradual ageing. Telomerase is the reverse transcriptase responsible for the extension of telomere length. It is well known that activation of telomerase in the most types of organism's cells is not enough for telomere length stabilization. The reason may be in the telomere 'caps', which cover telomere ends from telomerase action. This experiment shows that telomeres were elongated by the combination of hypoxia activated telomerase and a newly developed pharmacological method removing the telomere cap ... Rats from the control group died at the age 1 year 7 month - 1 year 8 month, which is typical for the Wistar rats from our sub-line. Rats from the experimental group died at the age 2 year 4 month."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19145831

Scientists can reboot a human immune system by destroying it and then transplanting new stem cells. This is a promising line of research given what happens to the immune system with aging, but the present focus is curing autoimmune disease: researchers "appear to have reversed the neurological dysfunction of early-stage multiple sclerosis patients by transplanting their own immune stem cells into their bodies and thereby 'resetting' their immune systems. ... [researchers] treated patients with chemotherapy to destroy their immune system. They then injected the patients with their own immune stem cells, obtained from the patients' blood before the chemotherapy, to create a new immune system. ... We focus on destroying only the immune component of the bone marrow and then regenerate the immune component, which makes the procedure much safer and less toxic than traditional chemotherapy for cancer ... After the transplantation, the patient's new lymphocytes or immune cells are self-tolerant and do not attack the immune system. ... In MS the immune system is attacking your brain. After the procedure, it doesn't do that anymore."

Link: http://www.eurekalert.org/pub_releases/2009-01/nu-sct012909.php

Researchers are expanding the array of methods demonstrated to repair spinal cord injuries: "transplantation of stem cells from the lining of the spinal cord, called ependymal stem cells, reverses paralysis associated with spinal cord injuries in laboratory tests. The findings show that the population of these cells after spinal cord injury was many times greater than comparable cells from healthy animal subjects. The results open a new window on spinal cord regenerative strategies. ... The transplanted cells were found to proliferate after spinal cord injury and were recruited by the specific injured area. When these cells were transplanted into animals with spinal cord injury, they regenerated ten times faster while in the transplant subject than similar cells derived from healthy control animals. ... the presence of these stem cells in the adult human spinal cords suggests that stem cell-associated mechanisms might be exploited to repair human spinal cord injuries."

Link: http://wwwjp.blackwellpublishing.com/bw/press/pressitem.asp?ref=2061

Via EurekAlert!: "Originally conceived as a means of treating genetic diseases, such as cystic fibrosis and hemophilia, gene therapy involves implanting a normal gene to compensate for a defective gene in the patient. ... This study helps extend gene therapy research to nongenetic, nonlethal diseases. Rheumatoid arthritis [RA] is an extremely painful condition affecting multiple joints throughout the body. Arthritis is a good target for this treatment because the joint is a closed space into which we can inject genes ... Evans has spent many years studying the molecules responsible for the breakdown of cartilage in patients with arthritis, identifying interleukin-1 as a good target. But, he adds, once he had this answer, another question was not far behind: How could he effectively reach the joints to block the actions of this protein? Gene therapy provided the answer. By implanting a gene in the affected joint, he was able to stimulate production of a human interleukin-1 receptor antagonist protein, which serves to block actions of the interleukin-1 protein. ... The idea is that by remaining in place, the new gene can continuously block the action of the interleukin-1 within the joints. In essence, the gene becomes its own little factory, continuously working to alleviate pain and swelling."

Link: http://www.eurekalert.org/pub_releases/2009-01/bidm-gtd012609.php

Over at Ouroboros, a look at the enhancement debate and how it impacts advocacy for engineered longevity:

I suspect that the structure of arguments about cognitive enhancement will mirror those of future debates regarding lifespan extension.

Both fields involve treatments that promise to improve or increase a parameter of human performance - one that varies to some extent within the natural population, but that seems fixed for a given individual. In both cases, human beings are 'fine' without the intervention - that is, we live comfortably (and, for the most part, happily) knowing that there is nothing much we can do to make ourselves smarter, and looking forward to our allotted threescore years and ten.

Beginning from the premise that what isn’t broken ought not be fixed, or that the 'natural order' of things ought not be meddled with, critics of both cognitive enhancement and lifespan extension may argue that neither sort of intervention in Normal Human Lives(tm) is warranted.

Pro-death advocates like Leon Kass have already argued extensively for forcing people to age, suffer, and die on just this sort of "natural order" argument. Which they apply selectively, of course, by not arguing that we should go back to living in caves, catching food with our teeth, and abandoning all that we have made.

To my mind, that there are any people at all who argue against future human enhancement through technology (while eagerly availing themselves of present human enhancement through technology) implies that this has much more to do with fear of change than anything else.

Some people would rather embrace any present horror than even the most positive change. This is not one of the better traits we humans seem to have hardwired in our evolutionary heritage.

A great many people grow up with what they know - having things far better than their parents, despite the efforts of past luddites who strived to block advancements - and then spend the rest of their lives fighting against visionaries who are trying to make things even better.

It is strange, but the argument for greater support of longevity science as a way to avoid staggering ongoing rates of disability and death doesn't carry a great deal of weight with most people.

Let's look at the dimensions of the human holocaust that we call "natural death."

The death toll in the Year 2001 was worst in India. Almost 9 million casualties. The bodies were piled nearly as high in China. The United States fell in third, with 2.4 million fatalities. 21 nations lost over half a million lives, each. These 21 countries represented all cultures, races, creeds, and continents. The human death toll in the Year 2001 from all 227 nations on Earth was nearly 55 million people, of which about 52 million were not directly caused by human action, that is, not accidents, or suicides, or war. They were "natural" deaths.

If this argument worked, we'd be done already. But people will accept any terrible situation if it's all they have ever known. Sad but true. On that note, I notice that bioethicist Colin Farrelley is hitting on the argument by megadeaths in a couple of recent posts:

Whether it be the "Black Plague", small pox, malaria, cancer or heart disease, human populations are susceptible to a diverse array of chronic and infectious diseases that threaten both the lives of individuals and the prosperity of nations. And so it is imperative that we think rationally about how we can best respond to these diverse threats to our health and survival. We need accurate data concerning the probable risks of disease facing the world's populations this century and an open mind about the potential strategies for dealing with these threats.

The greatest threat facing the world's existing 6.7+ billion population are the chronic diseases associated with aging. In the year 2005, approximately 55 million people died. Of that number, 35 million died of chronic disease. That number is twice the number of deaths due to infectious diseases (including HIV/AIDS, tuberculosis and malaria), maternal and perinatal conditions, and nutritional deficiencies combined. 35 million deaths a year dwarf the estimated deaths caused by climate change - approximately 150 000 deaths.

...

The diseases associated with aging are not, contrary to popular perception, only a problem for people living in the developed world. Indeed, being vulnerable to disability and frailty is a much greater disadvantage if one lives in a poor society with no decent health care or pension, as the link between income and "ability to work" is much more direct. So the chronic diseases associated with aging are a problem for all societies, not only the richest countries in the world.

One last point to make to illustrate the magnitude of the problem of chronic disease. It is estimated that between the mid-14th century and mid-17th century, the "Black Death" plague killed approximately 25 million people. This means that the current deaths caused by chronic disease in just one year outnumber the deaths caused by 3 centuries of the "Black Death" plague. This clearly illustrates why the imperative to combat chronic disease is one of the greatest imperatives ever facing humanity. And since aging is the major cause of these afflictions, one of the greatest moral imperatives facing humanity today is to tackle aging itself so that we can avoid the unprecedented rise in chronic disease that is expected to befall the world's populations this century.

All true: yet how to proceed armed with these obvious facts to which people are willfully oblivious?

Another study confirms the link between diabetes and Alzheimer's risk, suggesting one again that Alzheimer's is a lifestyle condition for many, brought on by being overweight and not exercising over the years: "Diabetics have a significantly greater risk of dementia, both Alzheimer's disease - the most common form of dementia - and other dementia, reveals important new data from an ongoing study of twins. The risk of dementia is especially strong if the onset of diabetes occurs in middle age ... Our results [highlighted] the need to maintain a healthy lifestyle during adulthood in order to reduce the risk of dementia late in life ... the chances of a diabetic developing Alzheimer's disease may be even greater in real life than in the study, the researchers write. They identify several factors that might have led them to underestimate the risk of dementia and Alzheimer's among those who develop diabetes before the age of 65. Diabetes usually appears at a younger age than dementia does, the researchers note. Diabetes is also associated with a higher mortality rate, which may reduce the size of the sample of older adults. In addition, approximately 30 percent of older adults with diabetes have not been diagnosed. The results of the study implicate adult choices such as exercise, diet and smoking, as well as glycemic control in patients with diabetes, in affecting risk for Alzheimer's disease."

Link: http://www.sciencedaily.com/releases/2009/01/090127152835.htm

Ouroboros weighs in on SkQ1 research: "Mitochondria produce rreactive oxygen species (ROS) as a byproduct of metabolism. These ROS are implicated in the mitochondrial free radical theory of aging (MFRTA) as the major cause of aging phenotypes. If the MFRTA is true, one could delay aging by removing these mitochondrially-produced ROS with enzymes or antioxidants. Although many antioxidant therapies for cancer and other age-related diseases have proved fruitless, these studies did not specifically target antioxidants to the mitochondria. One group recently did just that in mice with catalase, an antioxidant enzyme normally found in peroxisomes. By translocating catalase to the mitochondria, the scientists expanded the lifespan of the animals by five months. Such genetic manipulations such as these are not in the cards when it comes to preventing human aging. Therefore, other mitochondrial targeting strategies must be employed. Accordingly, Vladamir Skulachev's group synthesized an antioxidant attached to a positively charged ion, which they call SkQ1. This compound can readily pass through the cell membrane and travel to the mitochondrial intermembrane space, the only negatively charged region in the cell. There, SkQ1 will soak up any ROS formed by the electron transport chain. SkQ1 works similarly to the popular MitoQ, but does not have the pro-oxidant properties MitoQ is known to have at higher concentrations. SkQ1 is also better than MitoQ at inhibiting apoptosis induced by hydrogen peroxide."

Link: http://ouroboros.wordpress.com/2009/01/28/skq1-a-mitochondrially-targeted-antioxidant-that-extends-lifespan/

As a followup to de Wolf's post on the self-sabotaging misconceptions that lead people away from successfully arranging cryopreservation upon death, you'll find an unfortunate and cautionary tale over at Depressed Metabolism. Even with the best of intentions and good preparation, life - and especially the actions of other people who think they know best - can still sabotage your efforts to take advantage of cryonics and thereby ensure a chance at future restoration:

I have been informed that Marcelon (Marce) Johnson died on 01/21/2009, was cremated, and not cryopreserved.

I understand this information may come as a surprise and as a disturbing shock to many people, especially those who loved and knew Marce, as I did. I thus feel an obligation to explain how this happened and to provide some closure to this story for the many people who helped, or tried to help, avert this catastrophe.

While Marce was alive I was unable to share the full story of what was happening. Now that she is dead and gone I believe it important and the responsible thing to do to relate the story as best I know it.

Read the whole thing, learn from it, and amend your own plans as appropriate.

Another metric by which to measure the more rapid impacts of calorie restriction upon health: "The participants [underwent] memory tests before and after going on the diet. At the end of three months, the calorie-restricted group increased its scores by about 20 percent, while the performance in the other groups did not change. ... in addition to showing a boost in memory, the study also suggests that the same underlying mechanisms uncovered in animals could be at work in humans too. The researchers found that people who cut calories had improvements in several indicators of metabolic health, such as blood levels of insulin and C-reactive protein, a marker of inflammation. In fact, the rise in cognitive test scores correlated with lower insulin levels. In animal studies, high insulin levels and low-grade inflammation - products of being overweight and of high calorie intake - have been shown to hamper cognitive function. ... limiting calories in mice boosts a molecule in the brain called BDNF, which has a key role in memory. Regular exercise, along with calorie restriction, also boosts the growth of new brain cells in mice. ... the current results [suggest] that those pathways from animal studies might also work in humans."

Link: http://www.technologyreview.com/printer_friendly_article.aspx?id=22023

A lengthy post at Existence is Wonderful looks at the intersection of modern pessimism in the transhumanist community and advocacy for radical life extension: "sometimes I feel like I'm caught in the middle between, on the one hand, well-meaning folks (who might very well be contributing plenty from a scientific and fundraising standpoint to longevity research) who nonetheless see superlativity critique as pessimistic or irrelevant, and other folks (such as Jones and Carrico) who in my assessment seem to have very astutely identified particular problems in public technology discourse (including that surrounding biogerontology) as it presently stands." It has become somewhat fashionable for the transhumanist mainstream to be more concerned with existential risk than with progress these days and to disparage visionary viewpoints as "superlativity" or similar. In that the community reflects the spirit of the times - it's environmentalism's shadow cast large, an infection of the mind brought over from the vast number of people who deeply fear change or wish a return to an imagined idyllic past. I can't see this ending well, given that the change of progress is exactly what transhumanism is all about.

Link: http://www.existenceiswonderful.com/2009/01/thanks-but-ill-take-test-tubes-of.html

A good example of the very diluted, delayed way in which news of progress in aging research makes its way into the mainstream from CBS News: "Dr. Westphal says we all may soon be taking a drug that just might beat the clock, a simple pill that could delay the inevitable. 'Our goal is to prevent and forestall many of the diseases that strike us as we reach 50, 60, and 70. All with one pill.' Asked if he's suggesting that it's some kind of a rejuvenation drug that would turn a 70-year-old into a 35-year-old, Westphal tells Safer, 'That might be pretty hard to do. But I think if we're on a train heading one direction, we can slow down that train. I think we can slow down these genes that control the aging process.' That quest to put death on hold began in 2003 when Westphal met David Sinclair, a biochemist at Harvard who was studying the genetic components of aging. 'Five years ago I met David. And he had shown that you could extend life span in yeast. That's pretty exciting,' Westphal recalls. Yeasts are one thing. Human beings are more complicated. So Sinclair focused on a gene present in almost all life forms: the sirtuin gene. It's normally inactive, but when it is active, Sinclair believes it triggers a survival mechanism that extends life. Convinced that something in nature could activate that gene, Sinclair randomly tested thousands of compounds and got a hit: resveratrol."

Link: http://www.cbsnews.com/stories/2009/01/25/60minutes/printable4752082.shtml

Via EurekAlert!: "We still have a very poor understanding of the mechanisms behind cell aging. It has been known for some time that the gene expression profile of an aging cell changes and somehow is linked to age-related diseases, but no one really knows why. Our work could provide an explanation for why we observe age-dependent defects in cells ... Like guards controlling access to a gated community, nuclear pore complexes are communication channels that regulate the passage of proteins and RNA to and from a cell's nucleus ... Do they turn over in nondividing cells, or do they remain in place for the life of the cell? Because most of the cells in our body are not actively dividing, the answer would have implications for aging and age-related diseases. ... Many of the neurons in the cortex area of the brain are as old as we are; they are nondividing for a very long time. ... What they found was that in aging cells, one of the proteins composing the scaffold structure becomes damaged, and the permeability barrier deteriorates; molecules that should be restricted to the cytoplasm invade the nucleus. ... Because some cells live for a long time, the accumulation of damage in the long-lived nuclear pore complexes can impair their function and have important consequences for cell homeostasis and survival. It may also play a significant role in the aging process."

Link: http://www.eurekalert.org/pub_releases/2009-01/si-tbo012009.php

One should always read the science press with a skeptical eye: scientists are just like the rest of us in that they sometimes get things wrong and often don't know everything of interest in a field. That latter point is especially true as most fields of research in the life sciences have expanded far beyond the awareness capacity of a single busy professional. So it's very helpful to have some background knowledge yourself, to help sort out the relevant from the potentially flawed.

Take this recent work on calorie restriction for example, which is announced as a potential proof that calorie restriction is not going to be useful in healthy humans:

"Our study questions the paradigm that caloric restriction is universally beneficial," Sohal said. "Contrary to what is widely believed, caloric restriction does not extend (the) life span of all strains of mice."

By measuring the animals' metabolic rate, Sohal and his colleagues came to a deceptively simple conclusion: Caloric restriction is only useful when, as in the case of the obese mice, an animal eats more than it can burn off.

"Your energy expenditure and your energy intake should be in balance," Sohal said. "It's as simple as that. And how do you know that? By gain or loss of weight.

"The whole thing is very commonsensical."

For humans of normal weight, Sohal strongly cautions against caloric restriction. In a 2003 study, he and Forster found that caloric restriction begun in older mice - both in DBA and leaner C57 individuals - actually shortened life span.

Given the very large number of studies showing strong positive effects on health and longevity in individuals of normal weight through calorie restriction, one should immediately be cautious in looking at this sort of claim in a single paper. Over at the Immortality Institute, calorie restriction expert Michael Rae dives in to take it apart in more detail:

These guys have really made some extremely unreasonable leaps of reasoning.

First, yes, it's true that DBA/2 mice are resistant to the effects of CR on lifespan -- that's been shown repeatedly, since at least the early 80s, and not just by Sohal; and (per this study) yes, they apparently have some aesthetically happy genetic perk, that allows them to eat ad libitum without gaining any weight, while other mice gain weight as one would expect.

But so what? First, as Anthony noted, while they have demonstrated these two facts, they haven't done anything to prove that this resistance to weight gain in response to an AL diet is what *causes* their resistance to the age-retarding effects of CR in this strain.

Second, as Matt notes, these are sickly mice

...

in [their prior referenced 2003] study, they violated almost every rule of adult-onset CR in the book: they administered CR as shock therapy instead of stepwise to allow for gradual adaptation, and they didn't boost the %protein in the diet to ensure that they got the full rodent 'RDA' of the AL mice. Weindruch and Walford's big 1982 breakthru', showing that you COULD actually make CR work in adults, was based precisely on not making those mistakes - and it's been repeated numerous times since.

...

the current study doesn't come anywhere close to proving what Sohal is evidently asserting about it.

For those of us without this level of background knowledge, the weight of science test is the best way to go: only start to pay serious attention to a claim when it has a cluster of papers backing it. One paper standing in opposition to dozens or hundreds of others is either wrong or the first sign of a change of viewpoint - for an observer outside the scientific community there's no harm done in dismissing it in either case. If change is underway, there will be more papers and studies to support the new viewpoint in due course.

Back in full flow for 2009, you'll find a brace of posts on aging research from the past few days over at Ouroboros.

Telomere length and psychological stress:

it should come as no surprise to learn that chronic psychological stress has been associated with accelerated telomere shortening in circulating white blood cells. The problem arises in trying to provide a biological mechanism that links this form of stress to increased telomere loss.

Links between accelerated aging and extended longevity:

I’m sitting in an auditorium listening to a seminar by Laura Niedernhoefer from U. Pittsburgh. She’s telling us that Ercc1-/- mice, which are deficient in nucleotide excision repair, show transcriptional changes that mirror those found in old wildtype or unusually long-lived mutant animals. Her data is strongly reminiscent of recent findings that progeroid DNA repair mutants exhibit transcriptional similarities to aging calorie-restricted and dwarf animals.

Old cells and organ transplants:

Because senescent cells accumulate with age, senescence has been considered a biomarker of aging - that is to say, a measurable feature of a tissue that would allow us to calculate its "biological" or "physiological" age without necessarily knowing the chronological age of the donor. This makes abundant sense: tissues with more senescent cells would have lower proliferative capacity and higher levels of deleterious secreted factors; given two samples of the same chronological age, one could argue that the one containing more senescent cells was "older" in some meaningful way. This idea is central to a recent paper demonstrating that senescence correlates negatively with the efficacy of a transplanted tissue.

More on old cells and transplants:

Another group, working in a mouse model, has shown that older donor tissues express higher levels of the senescence marker p16, which is negatively correlated with proliferative capacity. But the old material doesn’t just start from behind, but also gets worse more rapidly: p16 levels rise dramatically in old grafts following transplantation, much faster than in young grafts, indicating that older cells are more sensitive to the stresses of undergoing transplantation and that they respond to this stress by undergoing senescence.

All organs equal before oxidative damage:

What causes organ failure during aging? Is it stochastic, with individual organ systems deteriorating and failing more or less independently - or is it more like a chain of dominoes, with a primary organ failure in one tissue putting pressure on other tissues and accelerating their decline?

Mitochondrial uncoupling protein extends lifespan:

The most surprising result is that [mutants lacking uncoupling protein] have shorter lives, implying that mitochondrial uncoupling is a key mechanism for controlling oxidative stress throughout the lifespan.

Another longevity mutation is shown to work by reducing the all-important emmission of free radicals from the mitochondria: "first discovered in 2000 [a] mutation in the Indy ('I'm Not Dead Yet') gene [extends] the life span of fruit flies .. Subsequent studies of the Indy flies have led to the new finding that a mechanism in those genetically altered fruit flies appears to reduce significantly the production of free radicals, a cellular byproduct that can contribute to the aging process. This intervention takes place with few or no side effects on the quality of life for the fruit fly. The discovery could lead to the development of new anti-aging treatments. ... There are very few, if any, interventions that are known to dramatically extend healthy lifespan. Understanding how [the] Indy mutation alters the metabolic state of the fruit fly would allow someone to come up with pharmacological interventions that could mimic it and give you the benefit of genetic manipulation without having to do genetics."

Link: http://news.brown.edu/pressreleases/2009/01/aging

As the New York Times reports, Geron's embryonic stem cell therapy for spinal injuries is soon entering phase I human trials. Make what you will of timing, and consider that in the absence of the FDA this would already be in clinics: "The clearance of the clinical trial - of a treatment for spinal cord injury - is to be announced Friday ... Geron's trial will involve 8 to 10 people with severe spinal cord injuries. The cells will be injected into the spinal cord at the injury site 7 to 14 days after the injury occurs, because there is evidence the therapy will not work for much older injuries. ... Geron's therapy involves using various growth factors to turn embryonic stem cells into precursors of neural support cells called oligodendrocytes, which are then injected into the spinal cord at the site of the injury. The hope is that the injected cells will help repair the insulation, known as myelin, around nerve cells, restoring the ability of some nerve cells to carry signals. There is also some hope that growth factors produced by the injected cells will spur damaged nerve cells to regenerate." By way of a reminder, we should all be interested in technologies for myelin repair, given the evidence for a general decline in myelin during aging.

Link: http://www.nytimes.com/2009/01/23/business/23stem.html

A study on correlations between air quality and life expectancy is doing the rounds in a science press at the moment. The bottom line from their statistical analysis:

average life expectancy in 51 U.S. cities increased nearly three years over recent decades, and approximately five months of that increase came thanks to cleaner air.

Which doesn't seem unreasonable on the face of it: there's plenty of supporting evidence for the general thesis that air quality and longevity have some correlation. My caveat would be that any single study showing an effect of less than a year on human longevity should be taken with a grain of salt. Firstly that's certainly small enough to be either an artifact or due to some other, related correlation, and secondly it doesn't much matter in the grand scheme of things.

You can probably push your life expectancy a decade or more in either direction - 20 times as long as the variation in the paper - just by changing what you eat and the level of exercise in your life. Beyond that, progress in medical science has the potential to increase your healthy life span by a far greater number of years.

We don't have all the time in the world to make our future better, healthier, and longer. It's best to focus on what will have the greatest impact: everything else is a distraction.

An article from headway looks at some of the work presently taking place in the field of regenerative medicine: "Understanding the regeneration of damaged nerves - and eventually controlling where and when it occurs - could have a large impact on the kind of recovery trauma patients achieve. Walking may be the ultimate goal, but for many patients, regaining bladder function or abolishing neuropathic pain is an immediate priority. To this end, [a team] is identifying the genes responsible for regenerating the nerve's long, branch-like body. Their work begins in organisms like Caenorhabditis elegans and Drosophila melanogaster - tiny worms and fruit flies that are hugely valuable to genetics research. Once a gene has been identified in a fruit fly or worm, scientists can search a database to find its vertebrate homologue, and then test it and manipulate it in a mouse or other animal. ... Once we have used genetics to identify genes that control nerve regeneration, we can develop animal models to find drugs that will mimic the genes in the pathway, or up-regulate their expression."

Link: http://www.mcgill.ca/headway/winter2008-09/indepth1/

From the Technology Review: "Researchers working on tissue engineering hope to eventually be able to use a patient's own cells to grow replacement tissue for damaged hearts, livers, and nerves. But mimicking the structure and function of the body's tissue has proved difficult. Matrices of supportive, fibrous proteins sustain the cells of the heart, lungs, and other tissues in the body. These scaffolds provide both structural support and chemical signals that enable an organ or nerve tissue to function properly. ... Viruses that mimic supportive nerve tissue may someday help regenerate injured spinal cords. While other tissue-engineering materials must be synthesized and shaped in the lab, genetically engineered viruses have the advantage of being self-replicating and self-assembling. They can be designed to express cell-friendly proteins on their surfaces and, with a little coaxing, be made into complex tissuelike structures. Preliminary studies show that scaffolds made using a type of virus called a bacteriophage (or phage) that infects bacteria but cannot invade animal cells can support the growth and organization of nerve cells."

Link: http://www.technologyreview.com/biomedicine/21991/

Alcor does a good job at their website clearing up the major myths and answering questions about cryonics, the practice of low-temperature, ice-free storage of the body and brain after clinical death. After you die, the structure of your brain remains intact - if stored, plausible future technology could one day restore you to life. The important thing, the core of what is you, is the data represented by the preserved structure of your brain.

But if you want to benefit from cryonics, you have a little work to do. Like most forms of insurance, it has to be set up in advance and preparations kept up to date if you want to benefit. Over at cryonics blog Depressed Metabolism, Aschwin de Wolf looks at some of the self-sabotaging assumptions that get in the way:

Unfortunately, advances in the science of cryopreservation will not automatically translate into better patient care. Other factors, such as the delay between time of "death" and start of procedures, and the protocols, equipment and personnel of the responding cryonics organizations, matter as well. For example, if a cryonics standby team is not able to get to a patient before 24 hours after cardiac arrest, pumps him full of air during remote blood washout, and ships him back to the cryonics organization at subzero temperatures, that patient will not benefit from advances in human cryopreservation such as rapid induction of hypothermia, neuroprotection and vitrification.

...

Both critics and supporters have made specific probability estimates about how likely cryonics is to work. In its worst form such probability assessments convey nothing more than putting a number on overall feelings of pessimism or optimism.

...

At the time a person really needs cryonics, he may no longer be able to communicate those desires, lack funding to make arrangements, or encounter hostile relatives. A more subtle variant concerns the person who expects that aging will be solved before cryonics will be necessary. This person may or may not be right, but such optimism may not make him more immune to accidents than other people. This mindset is often observed among young "transhumanists" and practicing life extensionists.

Researchers are starting to build targeted therapies for what are believed to be characteristic cancer stem cell populations. From EurekAlert!: "After identifying an apparent population of cancer stem cells for neuroblastoma, researchers successfully used a reprogrammed herpes virus to block tumor formation in mice by targeting and killing the cells. ... the study [adds] to a growing body of evidence suggesting early stage cancer precursor cells with stem-cell-like properties may explain how some cancers form, are treatment resistant and prone to relapse. The study also underscores the increasing potential of targeted biological therapies ... The main finding of our study is that pediatric neuroblastomas seem to have a population of cells with stem-cell characteristics that we may need to target for therapy ... In the next research phase, the team will try to verify results in the current study by seeing if they can detect the presence of cancer stem cells in primary neuroblastoma tumor cells from patients."

Link: http://www.eurekalert.org/pub_releases/2009-01/cchm-evt011309.php

A fascinating article: "stem cells are an imprecise physiological system to directly communicate to cellular networks of a host organism. The future of stem cell research will not necessarily be in the transplantation of stem cells to a specific pathogenic tissue region, but rather in reeducating or reprogramming that particular cellular network. Each organism has an exacting molecular blue print, which as a function of epigenetics, is either enhanced or mollified through its interfacement with a particular environmental milieu. ... stem cell transplantation is not a precise strategy for amelioratively reprogramming cellular networks, which are compromised. In most instances, the stem cells, which have been transplanted are only inducing a minimum benefit in terms of their medicinal efficacy. ... stem cell transplantation is not a therapeutic pantheon, but rather a way to comprehend how to modify a tissue's proteomics or physiological processes. Clinical medicine in the future will not involve providing imprecise cellular substrates, which vaguely impact genetic transcription and translation or millions of stem cells to a pathophysiologic tissue. ... medical therapies will [instead] be a precise utilization of peptides which can ardently reprogram an overall cellular system."

Link: http://www.agemed.org/default.asp?page=ShaneLaskyBeyondStemCellsJan09

Avoid chronic inflammation like the plague:

Chronic inflammation is a pathological condition characterized by continued active inflammation response and tissue destruction. ... chronic inflammation can be a major cause of cancers and express aging processes.

Moreover, many studies suggest that chronic inflammation could have a serious role in wide variety of age-related diseases including diabetes, cardiovascular and autoimmune diseases. The inflammatory process induces oxidative stress and reduces cellular antioxidant capacity. Overproduced free radicals react with cell membrane fatty acids and proteins impairing their function permanently. In addition, free radicals can lead to mutation and DNA damage that can be a predisposing factor for cancer and age-related disorders.

As I've noted in the past, the best short term way of evading chronic inflammation, and thereby increasing your chances to living more healthy years, is to avoid carrying excess visceral fat. But that only gets you so far: eventually even the healthiest immune system in the healthiest body starts to fall into a permanent condition of chronic inflammation called inflammaging. Evolution didn't produce a system that can be used for as long as we modern humans would like:

Inflammation is necessary to cope with damaging agents and is crucial for survival, particularly to cope with acute inflammation during our reproductive years. But chronic exposure to a variety of antigens, especially to some viruses such as cytomegalovirus, for a period much longer than that predicted by evolution, induces a chronic low-grade inflammatory status that contributes to age-associated morbidity and mortality. This condition carries the proposed name "inflammaging". Centenarians are unique in that, despite high levels of pro-inflammatory markers, they also exhibit anti-inflammatory markers that may delay disease onset. The key to successful aging and longevity is to decrease chronic inflammation without compromising an acute response when exposed to pathogens.

So when I say "avoid chronic inflammation" I'm not really talking about sane lifestyle choices, although that's very necessary as well. I really mean "do what you can to help advance medical research into repairing our aged immune systems." As time goes by, you'll find that the greatest determinant of your health and longevity is medical technology that can repair the damage of aging. While we're healthy and active, we should do what we can to advance that medical research; it'll pay off later.

As some of you know, you can use a Javascript include to show the Longevity Meme news on your website - as is done at Fight Aging!, for example. The implementation sorely needed updating, however, as has been the case for the past five years or so. We're on the ball here, as you can tell. On those odd occasions when the the Longevity Meme host was down (no-one provides 100% uptime), a page with the Javascript included would hang as the browser tried to download it and failed. I've (finally) updated the script to work in a somewhat more friendly manner using a div and innerHTML manipulation. It will still work the old way for those with an existing placement, but take a look at the instructions for the new methodology, assuming you'd like to move up a little from the paleolithic era of Javascript design patterns.

Link: http://www.longevitymeme.org/news/syndication.cfm

The latest Hourglass blog carnival is up, another look at the biology of aging: "Alex Palazzo over at The Daily Transcript gives us a very interesting introduction into the cell polarity theory of aging. With all the current interest in stem cells this theory could get plenty of attention and research, which will help provide additional information regarding this theory. .... Chris Patil from Ouroboros informs us about the interesting bridge between calorie restriction, DNA damage, and transcriptional deregulation in aging. It is an intriguing story about how Sirt1 (which increases with calorie restriction), among its many other jobs, both depresses transcription and also when required goes off to repair broken DNA. ... Mo at Neurophilosophy (great blog name) posts about a subject matter which I think will garner a great deal of attention in the coming years - aging and myelin. The traditional theory of brain aging usually concentrates on the loss of neurons as we age. However, Mo post concentrates of the loss of myelin and how it correlates with the behavioural decline in a number of cognitive measurements. By reading his post you will find out what correlates best with the cognitive decline observed with age - loss of neurons or loss of myelin."

Link: http://brainhealthhacks.com/2009/01/20/hourglass-vii-biology-of-aging-blog-carnival/

My attention was drawn today to an article I missed from the latest FUTURIST magazine, the author painting Silicon Valley as the hub for modern transhumanism, including advocates for engineered longevity. Insofar as transhumanism has a geographic hub, I'd say Silicon Valley is as good a guess at it as any:

Aubrey de Grey, an English biologist with a doctorate from Cambridge University, is head of the Methuselah Foundation and one of the world's foremost antiaging champions. With high-profile partners like Arizona State University's new Biodesign Institute, the Methuselah Foundation is trying to reverse degenerative cell damage. Little in the way of usable research has been produced, but the unabashed ambition of his work (and his creeping mainstream acceptance) has made de Grey something of a guru to the transhumanists of Silicon Valley. He visits the Bay Area every couple of months, often speaking at the offices of Yahoo and Google.

On an unseasonably warm winter's day, de Grey was at Brickhouse, the product-innovation division that Salim Ismail runs for Yahoo. De Grey had come to promote his new book, Ending Aging. Wiry and fidgety, de Grey spoke in a distinct English accent, avoiding eye contact. A rust-colored beard hung nearly to his waist, and his hair was pulled back in a long ponytail. De Grey set up a projector and screen as 50 employees gathered around during lunch break and started munching on catered gourmet sandwiches.

The lights came down, and de Grey began a talk titled "Prospects for Extending Healthy Life--A Lot." While the audience idly chewed away, de Grey told them, "I think that many people in this room have a good chance of living to one thousand." That got the Yahoo workers' attention. Several in the audience put down their focaccia and took out notepads. De Grey launched into a sermon about the inhumane effects of aging.

It's a neutral piece, as you might be able to tell - the author is clearly one of those who remain to be convinced that change is afoot, healthy longevity is good, and the biotechnology revolution will take us all to far places. The movement for engineered longevity is, however, a movement, and it's steadily growing. That growth means an increase in advocacy, fundraising, funded research, and other metrics of success.

The BBC looks at a clinical trial for Reneuron's foetal-derived stem cell line: "A Glasgow team is to launch a major trial to assess whether stem cells can be used to treat stroke patients ... If it works, as it has done in animal model systems, it may allow new nerve cells to grow or regeneration of existing cells and actual recovery of function in patients who would not otherwise be able to regain function. .... For the high proportion of patients who make an incomplete recovery [you] can reorganise the brain, you can help that reorganisation with physiotherapy but you cannot cause new nerve cells to grow. The hope with stem cell therapy is that by putting in new cells and new tissue that you can further improve on that recovery. ... We have only taken one donation of tissue to make this product. We have a technology that is able to scale up an individual cell into all of the cells that are required to treat thousands of patients. We think this is a major plus in the technology we have and really negates the ethical concerns about the original use of foetal tissue."

Link: http://news.bbc.co.uk/2/hi/health/7795586.stm

An interview with the Osiris Therapeutics president is as revealing of the way in which the FDA constrains progress as it is of the work being done. Broadly promising scientific applications are held back for years and squashed down to minor, narrowly approved uses - and everyone involved has to speak as though this is wonderful and the best of all possible worlds lest they are targeted for retribution. It's a sorry state of affairs. From the interview: mesenchymal stem cells or MSCs "do three things: They downregulate inflammation, they work to regenerate the damaged connective tissue, and they prevent scarring or fibrosis. That's the Holy Trinity of the mesenchymal stem cell. It's the natural progression or sequence of how we respond to injury. When we're young, that process works well. Children heal in miraculous ways. Conversely, an elderly person will die of something like a fractured hip. This is because children have 1,000-fold more MSC in their body than adults do. What happens is an adult ends up with a very exaggerated inflammatory response, a weak regenerative response, and a lot of scarring. We can reverse that trend by administering MSC. Because MSCs naturally have a broad range of things they can respond to, our job is to package them as something that will satisfy the FDA."

Link: http://pharmexec.findpharma.com/pharmexec/ArticleStandard/Article/detail/575911?contextCategoryId=47505

Amongst plenty of other evidence, I think that the effectiveness of the targeted mitochondrial antioxidant SkQ1 demonstrates handily that the reactive oxygen species generated by your mitochondria are killing you slowly. The damage they cause is a significant portion of aging itself, and targeting mitochondria has become a matter of great interesting to a variety of research groups. The more varied the scientists producing technologies aimed at mitochondria, to more rapidly we are likely to see a good result rapidly. Competition and diversity are real signs of progress soon to come.

I noticed today that the radiology and cancer research community might also have cause to develop means of delivering drugs to mitochondria to alter the output of reactive oxygen species:

Adverse effects of ionizing radiation are mediated through reactive oxygen and nitrogen species. Mitochondria are the principal source of these species in the cell and play an important role in irradiation-induced apoptosis. The use of free radical scavengers and nitric oxide synthase inhibitors has proven to protect normal tissues and, in some cases, to sensitize tumor tissues to radiation damage. Dual molecules that combine radical-scavenging and NOS-inhibitory functions may be particularly effective. Drugging strategies that target mitochondria can enhance the effectiveness of such agents, in comparison to systemic administration, and circumvent side effects.

Which is a good thing. The more the merrier. Still, throwing antioxidants at our mitochondria can only slow down the process of damage. A much better approach is to repair mitochondria that become damaged due to the reactive oxygen species they emit, or change our cells such that the most common forms of mitochondrial damage no longer matter. Both of these are very plausible lines of research, and advances along this road have been demonstrated in the laboratory in recent years:

• Slightly Insider Info: Mitochondrial Protofection Works
• SENS 2 Report: Moving Mitochondria

A proposed theory: "Centenarians are exceptionally long living individuals who escaped the most common age-related diseases. In particular they appear to be effectively protected from cancers. The mechanisms that underlie this protection are quite complex and still largely unclear. ... Centenarians appear to be characterised by low IGF-1-mediated responses and high levels of anti-inflammatory cytokines such as IL-10 and TGF-beta, a condition that results in protection from cancer. Both inflammation and IGF-1 pathway converge on the tumour suppressor p53. Accordingly, some studies indicate that genetic variants of p53 are associated with human longevity by providing protection from cancer mortality. ... The available data let us to hypothesise that among other possible mechanisms, well-preserved p53-mediated responses are likely a key factor contributing to protection from cancer in centenarians." You might recall research from 2007 demonstrating that suitable tinkering with p53 expression both protects from cancer and extends life in mice.

Link: http://www.ncbi.nlm.nih.gov/pubmed/19139887

Studies show that a range of strategies to reduce the level of reactive oxygen species produced by mitochondria extend life in lesser mammals - pointing to the operation of mitochondria as an important determinant of aging. One of these strategies is to increase uncoupling protein 2 (UCP2) expression, which causes mitochondria to generate more heat rather than packaged chemical energy for use in the cell. "The long-term effects of uncoupled mitochondrial respiration by uncoupling protein 2 (UCP2) in mammalian physiology remains controversial. Here we show that increased mitochondrial uncoupling activity of different tissues predicts longer lifespan of rats compared to mice. UCP2 reduces reactive oxygen species (ROS) production and oxidative stress throughout the aging process in different tissues in mice. The absence of UCP2 shortens life span in wild type mice ... Thus, UCP2 has a beneficial influence on cell and tissue function leading to increased lifespan."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19141680

I pointed out the LifeStar Project website yesterday at the Longevity Meme. This is the brand under which the Millard Foundation will invest in advancing the development of practical, working longevity medicine. The Foundation is a wealthy family concern under the control of a few people with a demonstrated interest in longevity science, and with the resources to get things done.

In short, this is another of the beneficial signs we advocates have been hoping would emerge sooner rather than later. A philanthropic organization drawing upon existing fair-sized resources and possessed of the will to use them in advancing the cause of human longevity through the most direct methods possible. From their website:

therapies are rapidly being developed, in labs all over the world, which, in combination, will be able to actually prevent age-related diseases and loss of functionality. The governments of the world are unprepared to answer this challenge, but potentially could be.

What is needed - and does not yet exist - is a concerted, focused, competent, and fully-funded effort to catalyze the coalescing of this work into the complete set of therapies and protocols that will prevent the occurence of these diseases.

The LifeStar World Health Initiative has been created to respond to this need. With the right approach, we believe this result can be produced within the next 10-15 years.

The Millard Foundation principals, and by extension the LifeStar Project, differ from other large Foundations interested in aging and longevity - such as the Glenn Foundation and the Ellison Foundation - by virtue of their strong support for the "repair the damage" viewpoint that informs the Strategies for Engineered Negligible Senescence. Aging is exactly the results of an accumulation of biochemical damage acquired over time: we should be trying to directly repair that damage, not just slow down its accumulation by tinkering with genes and metabolism.

The resources backing the "repair the damage" viewpoint are growing steadily year by year in a variety of different ways. The successful fundraising of the Methuselah Foundation is one visible form of that growth, and convincing folk like the Millard family to direct their resources to this grand project is another. I'm sure we'll be hearing much more from the LifeStar Foundation in the years ahead.

Here's a paper published last month that contains more information on the research behind mitochondrial antioxidant SkQ1: "Antioxidants specifically addressed to mitochondria have been studied to determine if they can decelerate senescence of organisms. For this purpose, a project has been established with participation of several research groups from Russia and some other countries. This paper summarizes the first results of the project. A new type of compounds (SkQs) [has] been synthesized. ... In the fungus Podospora anserina, the crustacean Ceriodaphnia affinis, drosophila, and mice, SkQ1 prolonged lifespan, being especially effective at early and middle stages of aging. In mammals, the effect of SkQs on aging was accompanied by inhibition of development of such age-related diseases and traits as cataract, retinopathy, glaucoma, balding, [graying hair], osteoporosis, involution of the thymus, hypothermia, torpor, peroxidation of lipids and proteins, etc. SkQ1 manifested a strong therapeutic action on some already pronounced retinopathies, in particular, congenital retinal dysplasia. With drops containing [SkQ1], vision was restored to 67 of 89 animals (dogs, cats, and horses) that became blind because of a retinopathy. Instillation of SkQ1-containing drops prevented the loss of sight in rabbits with experimental uveitis and restored vision to animals that had already become blind. A favorable effect of the same drops was also achieved in experimental glaucoma in rabbits. ... Thus, SkQs look promising as potential tools for treatment of senescence and age-related diseases."

Link: http://dx.doi.org/10.1016/j.bbabio.2008.12.008

Via EurekAlert!: "Researchers have unraveled crucial details of how aging causes broken bones to heal slowly, or not at all, [and] also successfully conducted preclinical tests on a potential new class of treatments designed to 'rescue' healing capability lost to aging. ... COX-2 levels drop dramatically with age, and that the drop most explains why stem cells no longer turn into cartilage as efficiently, an early step in the chain reaction of healing. While a role for COX-2 in bone repair had been detailed prior to the current study, the cell populations responsible for the supply of COX-2 to the fracture callus, the layer of pre-cartilage cells (cartilage progenitors) that form first around a fracture to guide bone building, had not. The team also confirmed for the first time that healing ability lost with age can be rescued by manipulating the COX-2 pathway with existing, experimental drugs. The study was in mice, but is especially relevant to human medicine because of the similarity between human and mouse COX-2 gene."

Link: http://www.eurekalert.org/pub_releases/2009-01/uorm-rdh011509.php

The Glenn Foundation continues to expand its funding for mainstream aging research, largely aimed at slowing down aging through metabolic and genetic manipulation. Via the Gerontology Research Group website, we learn:

Breaking news was announced at the very start of the [Processes of Aging Conference at the Salk Institute] by Marc Collins that The Paul Glenn Foundation will fund the Salk Institute for aging studies at the rate of $1 million per year for the next five years, along with the prior MIT and Harvard Glenn Centers.

As noted, that's three research centers now being funded by Paul Glenn. The prior two:

Paul F. Glenn Laboratories at Harvard

The Paul F. Glenn Laboratories are dedicated to finding the molecular causes of aging so we can understand the mechanisms of normal aging and develop interventions to delay its onset and progression, thereby extending the healthful years of human life.

Glenn Laboratories for the Science of Aging

Why do living things age? What genes influence longevity? Is it possible to extend youthfulness by means of genetic manipulation? Our research analyzes these tantalizing questions and others in molecular detail.

I hope that the years ahead see more visionary funding sources, such as the Millard Foundation, depart the "slowing aging" mindset and start to more seriously fund the very plausible research aimed at repairing the damage of aging, thus reversing aging itself. Now that more philanthropists are becoming involved in supporting aging research, I think that this is a good goal to aim for: convincing philanthropists that the presently minor voice in the aging research community is in fact the best path ahead.

Time is creeping up on the year's first Hourglass blog carnival. Get your submissions ready: "Topics of posts should have something to do with the biology of aging, broadly speaking - including fundamental research in biogerontology, age-related disease, ideas about life extension technologies, your personal experience with calorie restriction, maybe even something about the sociological implications of increased longevity. Opinions expressed are not necessarily those of the management, so feel free to subvert the dominant paradigm. If in doubt, submit anyway. Submissions should be emailed to [hourglass.host][at][gmail][dot][com]. ... By the way, if you’d like to volunteer to host, please email me directly - basically all of 2009 is wide open. If you've already hosted before, don't let that hold you back; while the carnival is young, some repeat hosting is going to be par for the course."

Link: http://ouroboros.wordpress.com/2009/01/13/hourglass-vii-call-for-submissions/

The LifeStar Project is a new initiative from the Millard Foundation, folk who are very interested in longevity science and the Strategies for Engineered Negligible Senescence view of research in particular: potential longevity therapies "are rapidly being developed, in labs all over the world, which, in combination, will be able to actually prevent age-related diseases and loss of functionality. The governments of the world are unprepared to answer this challenge, but potentially could be. What is needed - and does not yet exist - is a concerted, focused, competent, and fully-funded effort to catalyze the coalescing of this work into the complete set of therapies and protocols that will prevent the occurence of these diseases. The LifeStar World Health Initiative has been created to respond to this need. With the right approach, we believe this result can be produced within the next 10-15 years." The mission statement: "To do or cause to be done whatever is necessary to develop and make available to all human beings repeatable clinical protocols which repair, reverse, and reduce the accumulations of damage and changes which interfere with the human body's innate ability to defend itself from disease and loss of functionality as soon as humanly possible."

Link: http://www.lifestarproject.org

Oxidative damage to cells and important molecules is generally considered an important root cause of aging, though there's certainly a great deal of ongoing debate in the scientific community over exactly how and why this is the case. I noticed an open access review paper today that makes an effort to tie inconsistencies in the observed behavior of antioxidants - sometimes demonstrated to prolong healthy life and otherwise improve matters, and more often shown to do very little - with the presence of iron. The main foundation for this theory is that:

in some circumstances (especially the presence of poorly liganded iron) molecules that are nominally antioxidants can actually act as pro-oxidants. The reduction of redox stress thus requires suitable levels of both antioxidants and effective iron chelators.

An iron chelator is a substance that can bind iron and remove it from ongoing reactions with other molecules - such as the way iron turns mild oxidants into very damaging oxidants.

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular 'reactive oxygen species' (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation.

Also of interest: iron has been implicated in a different area of aging biochemistry, the buildup of chemical junk called lipofuscin in lysosomes within our cells that prevents the normal processes of cellular recycling and generally makes a mess of things. For example, when cells can't deal with iron correctly, lipofuscin becomes an even bigger problem:

Further experiments confirmed that when TRPML1 is defective, iron becomes trapped in the lysosome. One result of the buildup is formation of a brownish waste material, lipofuscin, known as the "aging pigment." In skin cells, lipofuscin is the culprit responsible for the dreaded liver spots that appear with increasing age, but in nerve, muscle and other cells, its accumulation has more serious consequences.

Precisely targeted chelation - aimed at the lysosomes though gene engineering or other sophisticated strategies, which won't happen using anything you can buy in the store - has been proposed as a way to deal with lipofuscin accumulation. This is analogous to the way in which antioxidants precisely targeted to the mitochondria, oxidative damage central in your cells, have a good track record of extending healthy life in experiments with mice and lesser animals.

So back to the original paper I mentioned, which concludes:

Overall we argue, by synthesising a widely dispersed literature, that the role of poorly liganded iron has been rather underappreciated in the past, and that in combination with peroxide and superoxide its activity underpins the behaviour of a great many physiological processes that degrade over time.

Which may be the case. I'm still sold on the idea that where you target antioxidants in the cell is the dominant explanation for experimental observations to date, however. Targeted to the mitochondria, we see a balance of experiments showing extended healthy life. Targeted elsewhere, the balance of experiments show no significant effect. When we consider that the cell is a highly specialized grouping of components, each serving a very different purpose, this sort of result makes a lot of sense.

Future Current provides a transcript for an interesting presentation from a few years back: "To be practically useful, the measurement of aging rate (by monitoring the decline of a global index of functional capacity, expressed as a rate function) must be relatively easy and inexpensive. Measured aging rate should enable empirical testing of purported anti-aging interventions in relatively short-term human clinical trials. ... The reason people don't make it to a hundred is because we don't age in our own bodies uniformly. You have different processes that are declining at different paces. In this case, this gentleman's cardiovascular system declined prematurely (this happens quite often) and hit the threshold for the viability of his cardiovascular system with a heart attack and died at age 65. He might have had perfectly good bones and perfectly good muscle, but he is just as dead at 65 and was cheated out of an extra thirty years of lifespan because his weakest link bumped him off early. Traditional medicine identifies those problems late in the game and intervenes in targeted ways to address the symptoms of the disease. If they are successful they can buy a few additional years. What we suggest as a better approach is to identify those degenerative processes as early as possible and use targeted interventions as early as possible to head it off at the pass, offering the individual many more years of healthy life expectancy."

Link: http://www.acceleratingfuture.com/people-blog/?p=2769

Via e! Science News: "loss of the protein HMGB2, found in the surface layer of joint cartilage, leads to the progressive deterioration of the cartilage that is the hallmark of osteoarthritis. ... the protein HMGB2 is uniquely expressed on the surface layer of cartilage in joints, where it supports the survival of chondrocytes, the cells that produce and maintain cartilage. Aging is associated with the loss of HMGB2 and an accompanying reduction or total elimination of chondrocytes in the superficial zone. The scientists provided further links between HMGB2 and osteoarthritis by breeding mice to be genetically deficient in HMGB2; these mice had an earlier and more severe onset of osteoarthritis. ... If small molecules can be found to prevent or stop the loss of HMGB2, or conversely, to stimulate the production of this protein, then it is possible that osteoarthritis may one day either be prevented or reversed ... Because cartilage is unable to heal itself, scientists have been searching for ways to use stem cells to grow replacement cartilage in the lab that could be used to surgically replace damaged or non-existent cartilage. With the discovery of the link between HMGB2 and surface layer protein, scientists now have a clue about how they might be able to engineer the surface layer cartilage."

Link: http://esciencenews.com/articles/2009/01/12/scripps.research.scientists.find.cause.cartilage.degeneration.osteoarthritis

Humanity+, formerly the World Transhumanist Association, is positioning itself these days as an unthreatening organization with a middle-of-the-road position on futurism, interested in human growth and welfare. In this era, that means a lot of consideration given to policy, government, control, and the teeming environmentalist masses who are terrified of science and believe the world is ending. The latest iteration of the transhumanist declaration contains a wealth of that sort of thing lurking between the lines. Far more, in fact, than actual thoughts on progress!

This is a way forward, consciously chosen. I like the name change, but I can't say I think the rest of it is a good path ahead - I'm more in favor of suitably outrageous extremes, freedom, and getting things done directly - but the nascent Humanity+ strategy is an appealing choice for many.

Humanity+ is presently electing a new board with voting taking place from today through Thursday:

Humanity+ (WTA) Board members set policy goals and oversee their implementation, contributing with their experience and expertise to the WTA's work. We’ve got a very full agenda for the coming year, setting up our new website, revising the Transhumanist Declaration, fundraising, building our network of chapters and student groups, and publishing our new H+ magazine.

...

Voting will be conducted Monday January 12th to Thursday January 15th, 2009.

...

You can become a voting member here:

http://transhumanism.org/index.php/WTA/joinnow/

The varied candidates have posted their statements online at the Humanity+ site; you might recognize some of the names from the pro-longevity community.

A long piece from the Globe and Mail looks at the folk behind supplement makers Juvenon and TA Sciences. Supplements are not the way forward, are utterly unimportant in the grand scheme of what is possible through scientific research, but somehow attract all the attention: "Once considered a fringe field littered with charlatans and quacks, anti-aging research has entered its prime. Respected scientists are pursuing regenerative medicine through stem cells, searching for clues to longevity in the genes of fruit flies, flat worms and really old men and women. Dozens of legitimate companies are developing anti-aging drugs. ... We have all the tools - we understand genes, metabolism, and these things are much easier [now] to measure and manipulate. I think we can push back all the degenerative diseases of aging. I think we can add a few years to everyone's life." No supplement or drug being sold now can do as much for a healthy person - or has anywhere near the weight of science backing it - as exercise and calorie restriction.

Link: http://www.theglobeandmail.com/servlet/story/RTGAM.20090109.wtelomeres-DONOTPOST/BNStory/specialScienceandHealth/home

One strategy for future immune therapies is to control existing immune cells in the body and direct them to take specific actions. For example: "Implants that sit in the body and reprogram a person's immune cells could be used to treat a range of infectious diseases and even cancer. In a trial on mice with an aggressive melanoma that usually kills within 25 days, the new treatment saved 90% of the group. Because cancer cells originate within the body, the immune system usually leaves them alone. Therapies exist that involve removing immune cells from the body before priming them to attack malignant tissue and injecting them back into a patient. Results are not encouraging, though - more than 90% of re-injected cells die before they can have any effect ... [researchers] have now developed a technique that directs the immune system from within the body - a method that is more efficient and potentially cheaper too. ... The team thinks modified versions of [their work] could be effective against a range of cancers and infectious diseases. These might also help reprogram the immune system to combat autoimmune diseases such as type 1 diabetes, caused by immune cells destroying insulin-producing cells in the pancreas."

Link: http://www.newscientist.com/article/dn16391-implant-raises-cellular-army-to-attack-cancer.html

The third in the series of podcasts on compression of morbidity is up at SAGE Crossroads: the "obvious benefits for society it will have are that it will decrease the number of dollars we will need in order to keep people in good care, medical care. If people are going to live longer and in good health, they will prolong their contribution to society. They are not going to use medical services which can be costly. Not only costly in terms of the number of years but because increasingly, medical services are high technology and therefore costly. We are going to decrease the number of years of ill health, but we are going to prolong the number of years that people can potentially contribute to society. The gain for society is double both in terms of less expenses incurred but also prolonging contribution of people to their societies, and I can't think of any negative effects. This what people individually want. They want to live as long as possible but in good health. Old age and longevity in ill health is an empty price. Societies want people in good health so that they will contribute and not incur expenses." Which is essentially the argument for any form of healthy life extension.

Link: http://www.sagecrossroads.net/sagecast56

Time flies: it doesn't seem as though more than two years have passed since entrepreneur turned fund manager Peter Thiel made a $3 million matching pledge to the Methuselah Foundation. Every two dollars of a donation to Strategies for Engineered Negligible Senescence (SENS) research aimed at repairing the damage of aging and reversing its effects draws an additional dollar from this matching fund.

Over that time, $1.3 million have been drawn from the fund, boosting the $2.6 million raised for research. That leaves another $1.7 million to go - and a little under 12 months until this matching pledge expires. Three years seems an eternity when it's ahead of you, but when you're done you wonder where it went so quickly.

Thanks to solid fundraising over the years of its existence, the Methuselah Foundation has made a real impact on the course of longevity research. First by influencing the debate within the aging community, engaging the public, and helping to change a stagnant research culture in which no-one could talk about engineering additional longevity without risking their funding. Secondly, through funding SENS research aimed at repairing the known biochemical damage that causes aging and age-related disease. Thirdly, and this is a project for the long term, building a community of younger researchers, the gerontologists of tomorrow, who are very interested in the fastest possible path to reversing aging.

If you want something done, it's not enough to agitate for it, and its not enough to have the money. You also need a community of workers. Over a timespan of, say, twenty years, I think we'll see many growing bootstrap efforts like the Methuselah Foundation that merge advocacy, fundraising, and cultivation of a research community. This is how a field of research moves from the ideas of a few people to become a self-sustaining culture that gets the job done.

These are still early days in the grand scheme of things, but that's no reason to let things go at their own pace. Here is a great opportunity to help move things along: push a few dollars in the direction of SENS research and help polish off Peter Thiel's matching fund this year.

The cyborg age is sneaking up on us by way of the tools of tissue engineering and improvements in nanoscale manufacture. Sooner or later most of us will have artificial structures in our bodies - though perhaps not the ones we imagined having when we were young: "With age, the human body wears out. And engineered materials - metals, polymers and ceramics - increasingly help repair or replace injured or destroyed body parts. ... As we become more sophisticated in our ability to design materials, particularly at the nanoscale, we open all kinds of opportunities for repairing damaged body parts. The potential is really unlimited ... Considering the great strides materials engineers are making in developing materials that are readily accepted by the body and that accelerate the process of recovery and healing, the age of the Cyborg seems not so much science fiction as it does science fact - a good thing given the increasing life expectancy and enduring desire to lead active lives."

Link: http://www.publicaffairs.ubc.ca/ubcreports/2009/09jan08/cyborg.html

Continuing investigation into the mechanisms of regeneration is producing a steady stream of minor improvements and practical learnings. For example, the potential for scar-free regeneration of damaged skin by mimicking aspects of the process of embryonic development:

Scarring in the skin after trauma, surgery, burn or sports injury is a major medical problem, often resulting in adverse aesthetics, loss of function, restriction of tissue movement and/or growth and adverse psychological effects. Current treatments are empirical and unpredictable, and there are no prescription drugs for the prevention or treatment of dermal scarring.

We have investigated the cellular and molecular differences between scar-free healing in embryonic wounds and scar-forming healing in adult wounds. We have identified Transforming Growth Factor beta 3 (TGFbeta3) as a key regulator of the scar-free phenotype in embryonic healing. Exogenous addition of TGFbeta3 to cutaneous wounds in pre-clinical (adult) in vivo models reduces early extracellular matrix deposition and these molecules are deposited with a markedly improved architecture in the neodermis, resembling that of normal skin. This improvement of structural organisation in the healing wound is self-propagating and leads to a reduction of subsequent scarring.

TGFbeta3 has completed safety studies and entered human clinical trials. Data from these studies have demonstrated that TGFbeta3 (Juvista) in humans is safe and well tolerated. Acute, local administration of TGFbeta3 (Juvista) significantly reduces dermal scarring in a dose responsive manner resulting in the regeneration of a skin structure that is permanently improved.

Manipulation of skin healing today, and one would hope far more impressive manipulations of internal organ regeneration tomorrow. Small steps on a long road. One potential future for the field of regenerative medicine sees very little in the way of stem cell therapies as we current understand them: instead of transplants, our existing cells are controlled by precise signals, manipulated into working the way we want them to.

From EurekAlert!: "Two previously identified pathways associated with aging in mice are connected ... The finding reinforces what researchers have recently begun to suspect: that the age-related degeneration of tissues [is] an active, deliberate process rather than a gradual failure of tired cells. Derailing or slowing this molecular betrayal, although still far in the future, may enable us to one day tack years onto our lives ... There is a genetic process that has to be on, and enforced, in order for aging to happen. It's possible that those rare individuals who live beyond 100 years have a less-efficient version of this master pathway." I suspect that one reason that theories of programmed aging remain somewhat popular is that the reactions of our cells to a slow stochastic accumulation of biochemical wear and tear do look something like the unfolding of a program. Gene expression steadily changes as the damage mounts. So you see research like this, said to support programmed aging but which could just as well support aging as an accumulation of damage. Researchers are linking changes in gene expression previously noted to be important to aging and longevity, but without evidence of the root cause of these changes, it's premature to declare aging programmed.

Link: http://www.eurekalert.org/pub_releases/2009-01/sumc-sru010509.php

From EurekAlert!: "When a person has a disease or an injury, the bone marrow mobilises different types of stem cells to help repair and regenerate tissue. ... new research [shows] that it may be possible to boost the body's ability to repair itself and speed up repair, by using different new drug combinations to put the bone marrow into a state of 'red alert' and send specific kinds of stem cells into action. In the new study, researchers tricked the bone marrow of healthy mice into releasing two types of adult stem cells - mesenchymal stem cells, which can turn into bone and cartilage and that can also suppress the immune system, and endothelial progenitor cells, which can make blood vessels and therefore have the potential to repair damage in the heart. ... The researchers were able to choose which groups of stem cells the bone marrow released, by using two different therapies. Ultimately, the researchers hope that their new technique could be used to repair and regenerate tissue, for example when a person has heart disease or a sports injury, by mobilising the necessary stem cells. The researchers also hope that they could tackle autoimmune diseases such as rheumatoid arthritis, where the body is attacked by its own immune system, by kicking the mesenchymal stem cells into action."

Link: http://www.eurekalert.org/pub_releases/2009-01/icl-scu010709.php

From the Economist: "tissue engineers have mastered the arts of artificial skin and bladders, and recently they have managed to rig up a windpipe for a patient whose existing one was blocked. But more complicated organs elude them. And simpler ones, too. No one, for instance, has managed to grow bone marrow successfully. At first sight, that is surprising. The soft and squishy marrow inside bones does not look like a highly structured tissue, but apparently it is. That does not matter for transplants. If marrow cells are moved from one bone to another they quickly make themselves at home. But it matters for research. Bone marrow plays an important role in the immune system, and also in bodily rejuvenation. Stem cells that originate within the marrow generate various sorts of infection-fighting blood cells and also help to repair damaged organs. However, many anti-cancer and anti-viral drugs are toxic to marrow. That leaves patients taking them susceptible to disease and premature ageing. Experiments intended to investigate this toxicity using mice have proved unsatisfactory. Nicholas Kotov of the University of Michigan in Ann Arbor and his colleagues have therefore been trying to grow human marrow artificially."

Link: http://www.economist.com/science/tm/displaystory.cfm?story_id=12883495

Researchers continue to rapidly improve the technology of production for induced pluripotent stem (iPS) cells: a "research team has discovered a more efficient way to create [iPS] cells, derived from mouse fibroblasts, by using a single virus vector instead of multiple viruses in the reprogramming process. The result is a powerful laboratory tool and a significant step toward the application of embryonic stem cell-like cells for clinical purposes such as the regeneration of organs damaged by inherited or degenerative diseases ... Prior research studies have required multiple retroviral vectors for reprogramming - steps that depended on four different viruses to transfer genes into the cells' DNA - essentially a separate virus for each reprogramming gene ... Upon activation these genes convert the cells from their adult, differentiated status to what amounts to an embryonic-like state. However, the high number of genomic integrations - 15 to 20 - that typically occurs when multiple viruses are used for reprogramming, poses a safety risk in humans, as some of these genes [can] cause cancer. ... The major milestone [was] combining the four vectors into a single 'stem cell cassette' containing all four genes. The cassette (named STEMCCA) [was] able to generate iPS cells more efficiently - 10 times higher than previously reported studies."

Link: http://www.eurekalert.org/pub_releases/2009-01/bu-cas010709.php

The latest edition of Rejuvenation Research has been up and I've been forgetting to mention the fact. One paper in particular caught my eye, and I think you'll find it interesting.

Engineered Repeated Electromagnetic Field Shock Therapy for Cellular Senescence and Age-Related Diseases:

A new consensus of gerontologists proposes that delay of biological senescence is the most potent public health measure for preventing chronic disease in late life. At the most fundamental level, cellular aging is characterized by a decline in repair and homeostatic systems. Thus, interventions that protect or rejuvenate these cellular systems hold significant promise for preventing or delaying the onset of age-related diseases.

The most likely candidates for delaying senescence are the longevity-linked transcription factors DAF16 and HSF1. If one were to engineer negligible senescence, a key target would be the heat shock protein axis regulated by HSF1. This pathway is the preferred pathway to prevent protein damage or aggregation, whereas DAF-16/FOXO is a backup pathway activated during stress. Reduced HSF1 activity appears to accelerate tissue aging and shortens life span. Conversely, over-expression of HSF1 increases life span and decreases amyloid toxicity in animal models.

This paper describes enhancement of the HSR/HSF1 pathway engineered by repeated electromagnetic field shock (REMFS). In a recent study, we demonstrated that REMFS therapy upregulates the HSR/HSF1 pathway, delays cellular senescence in young cells, and transiently reverses it in senescent cells, thus altering cellular mortality. The technology of applying certain beneficial EMF energy to the human body to stimulate the natural stress response and activate the repair and maintenance systems is a new strategy for engineered negligible senescence. We discuss the exciting clinical implications of REMFS therapy in human aging and disease.

A different approach indeed, leaving aside the standard objections to merely slowing aging by manipulating pathways versus reversing aging by repairing damage. I can see that electromagnetic fields could be thought of as broadly similar to drugs: a tool that can be used to interfere in a particular biochemical reaction while trying to avoid interfering in others. Any such body of work is far behind the drug industry of course, largely due to the past history of technology and available tools, I would imagine. Yet the established radiology and MRI technology base could be starting point for a future branch of medicine that employs careful and extremely precise manipulation of electromagnetic fields. This is not implausible.

CLK-1 - or clock-1 - is a gene that affects lifespan, most likely through its influence on mitochondrial activity. It's the standard story, or at least appears to be: anything that can lower the rate at which mitochondria damage themselves will extend life in flies, mice, and so forth. I noticed a piece today on a drug candidate for neurodegenerative diseases that researchers now think works through manipulation of CLK-1:

Recent animal studies have shown that clioquinol - an 80-year old drug once used to treat diarrhea and other gastrointestinal disorders - can reverse the progression of Alzheimer's, Parkinson's and Huntington's diseases. Scientists, however, had a variety of theories to attempt to explain how a single compound could have such similar effects on three unrelated neurodegenerative disorders.

...

"Clioquinol is a very powerful inhibitor of clock-1," explained Hekimi, McGill's Strathcona Chair of Zoology and Robert Archibald & Catherine Louise Campbell Chair in Developmental Biology. "Because clock-1 affects longevity in invertebrates and mice, and because we're talking about three age-dependent neurodegenerative diseases, we hypothesize that clioquinol affects them by slowing down the rate of aging."

...

Hekimi is optimistic but cautious when asked whether clioquinol could eventually become an anti-aging treatment.

"The drug affects a gene which when inhibited can slow down aging," he said. "The implication is that we can change the rate of aging. This might be why clioquinol is able to work on this diversity of diseases that are all age-dependent."

However, he admits to being concerned about how people may interpret his results.

"The danger is that you can buy a kilogram of this compound at a chemical wholesaler, but we don't want people to start experimenting on themselves. Clioquinol can be a very toxic substance if abused, and far more research is required."

Wait and see is a smart strategy in medicine so long as you have the time for that choice. This is a mechanism for affecting mitochondria that I haven't seen mentioned much in the past, and so a big dive into the unknown. Even if progress is made in manipulating it, I imagine we won't hear much on the development side for some years. Those of you interested in keeping your mitochondria in better shape would most likely be better off exercising and eating less in any case - even the current batch of potential mitochondria-affecting drugs don't do as well as calorie restriction and exercise combined.

Needless to say, the real solution to all this is not to dig up drugs that slow things down, but rather to develop processes that repair or replace damaged mitochondria and thus reverse this aspect of aging. Based on what has been taking place in laboratories over the past few years, this doesn't look to be any harder, and should be a lot more effective.

One of the items I'd like to see reasonably settled soon is whether longevity can be reliably engineered by targeting antioxidant compounds to the mitochondria and thereby slowing the accumulation of damaged mitochondria and their contribution to aging. We have good demonstrations that it can, and good demonstrations that it can't. Something interesting is clearly going on (as indicated by mice living significantly longer than they ordinarily would), but the details are still fuzzy. One of the lines of this research I've been following for a while is the work of Skulachev and colleagues in Russia, who seem to have developed an ingested compound called SkQ1 that can perform the mitochondrial targeting trick without the need for gene engineering of the sort employed by Rabinovitch. Here's the latest paper from that group: "Very low (nano- and subnanomolar) concentrations of 10-(6'-plastoquinonyl) decyltriphenylphosphonium (SkQ1) were found to prolong lifespan of [an] insect (Drosophila melanogaster) and a mammal (mouse). ... The lifespan increase is accompanied by rectangularization of the survival curves (an increase in survival is much larger at early than at late ages) and disappearance of typical traits of senescence or retardation of their development. Data summarized here and in the preceding papers of this series suggest that mitochondria-targeted antioxidant SkQ1 is competent in slowing down execution of an aging program responsible for development of age-related senescence."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19120018

From the Seattle Times: "the real news about the future of dentures is that there isn't much of one. ... It turns out wisdom teeth are prolific sources of adult stem cells needed to grow new teeth for you. From scratch. In your adult life, as you need them. In the near future. ... Regenerating a whole tooth is no less complicated than rebuilding a whole heart ... Not only do you have to create smart tissue (nerves), strong tissue (ligaments) and soft tissue (pulp), you've got to build enamel - by far the hardest structural element in the body. And you have to have openings for blood vessels and nerves. And you have to make the whole thing stick together. And you have to anchor it in bone. And then you have to make the entire arrangement last a lifetime in the juicy stew of bacteria that is your mouth. It's a nuisance, but researchers are closing in on it. They think the tooth probably will be the first complex organ to be completely regenerated from stem cells. In part, this is because teeth are easily accessible. ... Nobody is predicting when the first whole tooth will be grown in a human, although five to 10 years is a common guess."

Link: http://seattletimes.nwsource.com/html/nationworld/2008593860_teeth06.html

Robert Freitas, the nanotechnologist and longevity science advocate, has an article in the current Life Extension Magazine, also available online:

Nanotechnology is the engineering of molecularly precise structures and, ultimately, molecular machines. The prefix 'nano-' refers to the scale of these constructions. A nanometer is one-billionth of a meter, the width of about five carbon atoms nestled side by side. Nanomedicine is the application of nanotechnology to medicine. The ultimate tool of nanomedicine is the medical nanorobot - a robot the size of a bacterium, composed of molecule-size parts somewhat resembling macroscale gears, bearings, and ratchets. Medical nanorobotics holds the greatest promise for curing disease and extending health span. With diligent effort, the first fruits of medical nanorobotics could begin to appear in clinical treatment as early as the 2020s.

...

Right now, medical nanorobots are just theory. To actually build them, we need to create a new technology called molecular manufacturing. Molecular manufacturing is the production of complex atomically precise structures using positionally controlled fabrication and assembly of nanoparts inside a nanofactory.

...

But now it’s time to put our theories to the test. After working closely for three years with Philip Moriarty, one of the leading scanning probe microscopists in the UK, our international colleague is now undertaking direct experiments to build and validate several of our proposed mechanosynthesis tooltips in his laboratory. We are also preparing a research program proposal of our own to solicit additional funding from various US public or private sources to support further mechanosynthesis-related experimental and theory work on a greatly accelerated schedule. We expect these efforts will ultimately lead to the design and manufacture of medical nanorobots for life extension, possibly during the 2020s.

But read the whole article: make machines small enough, and they could interface with our cells to repair damage, replace worn structures, or even replace the function of cells entirely. More effective oxygen-carrying blood cell machines, for example, or hyper-efficient immune cell machines. Cells are just complicated small devices, and we humans are becoming very good at making complicated small devices - it's just a matter of time until we can build better machinery than than the evolved biological devices presently powering our bodies.

A retrospective narrative via PhysOrg.com provides a good look at the recent pace and excitement of stem cell research: "Early in 2008 the 32-year-old postdoctoral student from France joined a biomedical revolution by reprogramming human skin cells back to their embryonic origin, just as James Thomson in Madison and Shinya Yamanaka in Japan did when they made headlines in November 2007. Now Si-Tayeb and his supervisor, Stephen A. Duncan, a Medical College professor, were engaged in the next great race. In 2008, scientists began trying to turn the new reprogrammed cells into all of the building blocks doctors might use to treat a multitude of diseases. Cardiac cells to repair a damaged heart. Insulin-producing cells to help diabetics. Photo receptor cells to restore lost vision. The work would be crucial if stem cells were to fulfill their promise and begin a new wave of medicine."

Link: http://www.physorg.com/news150295895.html

An interesting interview: "I believe humans have always overcome their biological limitations. It is what has brought us out of the caves and onto the moon. We have cured ourselves of diseases, we fly remarkable machines through the air at 500 miles per hour. We communicate instantly and wirelessly across the world. Why is it such a stretch to imagine us re-programming our biochemistry (much like computer software) so that we may alleviate suffering, decay, and death? ... Death is a profound tragedy. Human consciousness is basically a profound (and valuable) pattern of information residing in a complex biological machine. This machine can repair itself for a certain period, but over time it wears out and decays at a faster rate than it can fix itself. This is why we die. Today, however, we are at the verge of correcting this. Death is the loss of everything that matters - It is our memories, our loves, the images and dreams that define us - the songs that moved us and the films that shaped us. Death takes this all away. I argue that in the same way we feel compelled to preserve the works of Shakespeare and other great works of art, why shouldn't we extend this into our physicality?"

Link: http://www.bravenewtraveler.com/2009/01/05/interview-jason-silva-on-how-science-will-make-you-live-forever/

With the evidence backing methionine restriction, researchers are examining various forms of non-calorie restricted diet to see if reduced methionine intake could plausibly produce health benefits: "Recent studies confirm that dietary methionine restriction increases both mean and maximal lifespan in rats and mice, achieving 'aging retardant' effects very similar to those of caloric restriction, including a suppression of mitochondrial superoxide generation. Although voluntary caloric restriction is never likely to gain much popularity as a pro-longevity strategy for humans, it may be more feasible to achieve moderate methionine restriction, in light of the fact that vegan diets tend to be relatively low in this amino acid. Plant proteins - especially those derived from legumes or nuts - tend to be lower in methionine than animal proteins. Furthermore, the total protein content of vegan diets, as a function of calorie content, tends to be lower than that of omnivore diets, and plant protein has somewhat lower bioavailability than animal protein. ... Furthermore, low-fat vegan diets, coupled with exercise training, can be expected to promote longevity by decreasing systemic levels of insulin and free IGF-I; the latter effect would be amplified by methionine restriction - though it is not clear whether IGF-I down-regulation is the sole basis for the impact of low-methionine diets on longevity in rodents."

Link: http://www.ncbi.nlm.nih.gov/pubmed/18789600

Scientists are a cautious lot, and funding is available for careful studies that replace sound assumptions with even more sound established facts. Now that calorie restriction (or dietary restriction, DR) research is attracting so much funding at the development end of R&D, you'll see more studies aimed at firming up the foundations. Take this open access paper for example:

One of the promising advances towards the goal of uncovering the mechanisms by which DR extends life was the discovery that the effect is evolutionarily conserved. However, even with the use of short-lived model organisms for relatively rapid lifespan experiments, the mechanisms remain elusive. This is likely to be largely due to the complexity of physiology involved in determining length of life, but may be also in part due to technical issues in experimental design hampering a clear path of progress.

The ease with which complexity can be introduced into these studies can be illustrated by the large effects on fly lifespan caused by very small changes in nutrition. For example, substituting one source of the dietary yeast Saccharomyces cerevisiae, with another from a different supplier in an otherwise identical diet can have large effects on fly lifespan. Similarly, lifespan differences have been reported due to the use of different bacterial strains as food for Caenorhabditis elegans or by interchanging casein and soy peptone as the source of dietary protein for rodents. In fact, a recent article has proposed that DR itself may have arisen as a by-product of laboratory life as animals are unintentionally subjected to selective breeding in the presence of an artificially rich nutritional environment. Clearly, these issues need to be addressed if we are to uncover the molecular mechanisms of DR.

As might be expected from the weight of existing evidence for calorie restriction to extend healthy longevity, increasing the rigor of the experiments didn't prevent the beneficial effects:

In this study, we have examined the effect of laboratory stock maintenance, genotype differences and microbial infection on the ability of dietary restriction (DR) to extend life in the fruit fly Drosophila melanogaster. None of these factors block the DR effect.

Researchers are further uncovering how Parkinson's disease kills brain cells: "Neurologists have observed for decades that Lewy bodies, clumps of aggregated proteins inside cells, appear in the brains of patients with Parkinson's disease and other neurodegenerative diseases. The presence of Lewy bodies suggests underlying problems in protein recycling and waste disposal, leading to the puzzle: how does disrupting those processes kill brain cells? One possible answer: by breaking a survival circuit called MEF2D. ... MEF2D is sensitive to the main component of Lewy bodies, a protein called alpha-synuclein. In cell cultures and animal models of Parkinson's, an accumulation of alpha-synuclein interferes with the cell's recycling of MEF2D, leading to cell death. MEF2D is especially abundant in the brains of people with Parkinson's. ... MEF2D is a transcription factor, a protein that controls whether several genes are turned on or off. Previous studies have shown MEF2D is needed for proper development and survival of brain cells. To function, MEF2D must be able to bind DNA. ... most of the accumulated MEF2D [in cases of Parkinson's disease] can't bind DNA. This may indicate that the protein is improperly folded or otherwise modified."

Link: http://www.eurekalert.org/pub_releases/2009-01/eu-tmi122908.php

This year's Edge annual question is:

What game-changing scientific ideas and developments do you expect to live to see?

With that lead-in, it's perhaps not surprising to see a range of thoughts on engineered longevity in amongst a range of less relevant but still interesting responses:

Gregory Benford:

Live to 150: I expect to see this happen, because I'll be living longer. Maybe even to 150, about 30 more years than any human is known to have lived. I expect this because I've worked on it, seen the consequences of genomics when applied to the complex problem of our aging.

Emanuel Derman:

The biggest game-changer looming in your future, if not mine, is Life Prolongation. It works for mice and worms, and surely one of these days it'll work for the rest of us.

David Eagleman:

While medicine will advance in the next half century, we are not on a crash-course for achieving immortality by curing all disease. Bodies simply wear down with use. We are on a crash-course, however, with technologies that let us store unthinkable amounts of data and run gargantuan simulations. Therefore, well before we understand how brains work, we will find ourselves able to digitally copy the brain's structure and able to download the conscious mind into a computer.

Bart Kosko:

Society will change when the poor and middle class have easy access to cryonic suspension of their cognitive remains - even if the future technology involved ultimately fails.

Today we almost always either bury dead brains or burn them. Both disposal techniques result in irreversible loss of personhood information because both techniques either slowly or quickly destroy all the brain tissue that houses a person's unique neural-net circuitry. The result is a neural information apocalypse and all the denial and superstition that every culture has evolved to cope with it.

Corey S. Powell:

I have little doubt that progress in fighting disease and patching up our genetic weaknesses will make it possible for people to routinely reach the full human lifespan of about 120. Going far beyond that will require halting or reversing the core aging process, which involves not just genetic triggers but also oxidation and simple wear-and-tear. Engineering someone to have gills is probably a much easier proposition. Still, if we can hit 200 I see no reason why the same techniques couldn't allow people to live to 1,000 or more. Odds: 60 percent.

I can't say as I think any of these folk are exactly on the ball, even Benford, who clearly subscribes to the mainstream view of genetic and metabolic reprogramming to slow aging rather than the damage repair view of the Strategies for Engineered Negligible Senescence. It is promising to see engineered longevity as a prominent topic, but it still looks like a lot of fumbling around in the dark is taking place. That shows that more work is needed on the part of advocates to direct interest and potential support onto the best paths forward.

Being thorough: "The proposition that increased energy expenditure shortens life has a long history. The rate-of-living theory states that life span and average mass-specific metabolic rate are inversely proportional. Originally based on interspecific allometric comparisons between species of mammals, the theory was later rejected on the basis of comparisons between taxa (e.g., birds have higher metabolic rates than mammals of the same size and yet live longer). It has rarely been experimentally tested within species. Here, we investigated the effects of increased energy expenditure, induced by cold exposure, on longevity in mice. Longevity was measured in groups of 60 male mice maintained at either 22 degrees C (WW) or 10 degrees C (CC) throughout adult life. ... we observed no significant differences in median life span among the groups ... [energy expenditure] in CC mice significantly exceeded that of WW mice. This result demonstrates that increased energy expenditure does not shorten life span and adds evidence to the intraspecific refutation of the rate-of-living theory."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19115965

Mainstream research into cryopreservation of tissue will likely provide benefits to the cryonics community: researchers "have developed a new approach for producing more effective medical antifreeze fluids for preserving kidneys, hearts, and other organs donated for transplantation. These next-generation antifreezes can decrease damage to organs caused by ice crystals, and thus prolong the time a donated organ will remain viable prior to transplantation. ... the scientists describe the development of 'hydration index' that can be used to more reliably predict how prospective antifreeze materials will behave. Their index provides a clearer picture of how water molecules interact with the sugar component [and] affect their chemical behavior. This is a key to understanding their ability to resist the formation of ice crystals when chilled." Cryonics researchers have already developed antifreezes in conjunction with vitrification, but a more rigorous way forward to better antifreezes certainly can't hurt.

Link: http://www.sciencedaily.com/releases/2008/12/081222081214.htm