Fight Aging!

The Immortality Institute is running a creative writing contest over the next few months, with a submission deadline in March: "Throughout the history of the Immortality Institute a high priority has been placed on communication. The use of various media including graphic arts, film, and prose has always been a powerful means of disseminating ideas and the idea of life extension is no exception. This focus has led to the creation of the world's first comprehensive tome on modern scientific efforts and philosophy of immortality – The Scientific Conquest of Death, and the documentary film Exploring Life Extension (both available free online). The Immortality Institute has also sponsored writing contests. Read about the most recent non-fiction essay contest here. Winning entries here and here. It is 2010 and time again for forward-thinking individuals to put their best pen forward to communicate the ideals, vagaries, possibilities, and dreams of radical life extension, human enhancement, and immortality. Unlock your imagination and submit a story today!"

Link: http://www.imminst.org/archive/articles/writing-contest

Via ScienceDaily: "Eliminating cancer stem cells (CSCs) within a tumor could hold the key to successful treatments for ovarian cancer ... Ovarian cancer has been challenging to treat because it tends to recur frequently and develop resistance to treatment. ... This recurrence and drug resistance may be due to the presence of CSCs within the tumors that have the capacity to reproduce and to differentiate into non-CSC tumor cells that repopulate the tumor mass. Eliminating these CSCs may be key to successful treatments. ... While in the process of studying the functions of stem cell proteins in human embryonic stem cells, [researchers] unexpectedly discovered that a sub-population of ovarian cancer cells express stem cell proteins Lin28 and Oct4, [both of which are known markers of embryonic or embryonic-like stem cells]. They also found that the two proteins appear to act together in ovarian cancer tissue cells to produce more advanced tumors. Inhibiting their combined expression led to a significant decrease in the growth and survival of cancer cells. A larger-scale ovarian cancer study is currently underway to confirm the significance of the findings."

Link: http://www.sciencedaily.com/releases/2010/01/100127152502.htm

Here is a short editorial recently posted to the Gerontology Research Group mailing list by coordinator Stephen Coles:

According to Homo sapiens DNA sequences, the "overall design" of the human body hasn't changed much over the last 200,000 years, when we first started out as active hunter/gatherers. Prior to the invention of agriculture, however, some 10,000 years ago, our bodies were well adapted by Darwinian evolution to our peripatetic ecological niche, even though our species almost experienced extinction several times.

As little as 100 years ago, that barely mattered. But today it does matter! US life expectancy jumped by more than 25 years - from ~50 to 75+ - over the course of the last century, largely due to public health measures, antibiotics, obstetrical techniques for C-Sections during difficult child births, and so forth. Therefore, on average, we're living much further past our "evolutionary design expectations." Nevertheless, we're not only living longer in modern societies, we're also staying healthier, as measured by a number of biomarkers. Fortunately for us, that means we have the time to enjoy the leisure and freedom we've earned. But it also means that we're almost certain to face very different health problems during our lifetimes, especially at the very end of life - problems that our ancestors never had the opportunity to experience, and for which evolution never prepared us. Therefore, we need to take the evolutionary legacy of our DNA into our own hands: we must read and understand this curious 3.1 GigaBasePair sequence, and then edit it or add the new code that will be needed to rejuvenate our frail bodies.

The good news is that if we can manage to live for another 20 years or so, when new developments in stem-cell therapies and synthetic chromosomes now on the horizon lead to commonplace therapeutic interventions, there should be no reason to compromise our independence or restrict our activities in later years of life. At least not if you are prepared to exploit new DNA/stem-cell technologies by staying abreast of the latest therapies, therapies that will be described in the future pages of this GRG Discussion Group.

Cole's bias is towards some types of therapies that I might not see as favorable roads ahead (such as editing our DNA to change the operation of our metabolism), but the general point being made here is true and important. Progress in science today is very rapid, and this is something new and unusual in the history of humanity. We stand on the cusp of great and sudden advances in biotechnology and medical science; two decades of additional life will make a very large difference in the medical technology you have access to in later life.

The Gerontology Research Group, you might recall, is something of a watering hole for the gerontology community - which is still a comparatively small gathering in comparison to the wider field of human life science research. You'll find that representatives and leaders from most of the present factions and research groups show up on the GRG mailing list from time to time. The core list community is associated with research into supercentenarians, however: as the Supercentenarian Research Foundation, volunteers establish and validate records, and more recently have made inroads into understanding thereasons why supercentarians ultimately die.

"The superseniors deviate from the norm not just in how long they live but in how they die," says Coles, who arranges autopsies of the oldest old as part of his work with the recently established Supercentenarian Research Foundation. ... Coles argues, based on these autopsies, that supers aren't perishing from the typical scourges of old age, such as cancer, heart disease, stroke, and Alzheimer's Disease. What kills most of them, he says, is a condition, extremely rare among younger people, called senile cardiac TTR Amyloidosis. TTR is a protein that cradles the thyroid hormone thyroxine and whisks it around the body. In TTR Amyloidosis, the protein amasses in and clogs blood vessels, forcing the heart to work harder and eventually fail. "The same thing that happens in the pipes of an old house happens in your blood vessels," says Coles.

Alzheimer's research is a field in constant flux; no unifying theory of Alzheimer's biochemistry goes unchallenged, there are a great many such theories coming and going, and much remains to be discovered or proven. Conversely, so much money flows into Alzheimer's science that new results are constantly emerging to sway the picture in one direction or another. This is science at its messiest, which is usually also where it is most interesting, and most likely to soon deliver a firm, defensible theory.

A large fraction of the Alzheimer's research community focuses in some way on forms of amyloid or other aggregates that build up in the brain: why is it there, what is the mechanism by which it causes harm, how can we get rid of it safely, is it a cause or secondary marker of other harmful mechanisms, and so forth. On that topic, I noticed an interesting article from earlier this month that places Alzheimer's in a spectrum with other, similar neurodegenerative conditions:

Studies demonstrate link among Alzheimer's disease, Down syndrome and atherosclerosis

all Alzheimer's disease patients harbor some cells with three copies of chromosome 21, known as trisomy 21, instead of the usual two. Trisomy 21 is a characteristic shared by all the cells in people with the birth defect Down syndrome as well. This earlier work demonstrated that Alzheimer's disease could be considered a late onset form of Down syndrome.

By age 30 to 40, all people with Down syndrome develop the same brain pathology seen in Alzheimer's disease, including a nerve-killing buildup of sticky amyloid protein clumps.

...

Dr. Potter and his colleagues now show that the Alzheimer's-associated amyloid protein is the culprit that interferes with the microtubule transport system inside cells. The microtubules are responsible for segregating newly duplicated chromosomes as cells divide. ... When the microtubule network is disrupted, chromosomes can be incorrectly transported as cells divide and the result is new cells with the wrong number of chromosomes and an abnormal assortment of genes.

If you read the rest of the article, you'll see that researchers can draw links between other common age-related conditions known to accompany Alzheimer's and damage to the microtubule network. This network is involved in transporting all sorts of important biochemicals around the cell - not just chromosomes. This implies that its widespread disruption in the body might be capable of causing all sorts of issues. But that theorizing needs more supporting science, such as a viable way to interfere in this process of microtubule damage, and then a demonstration that such a therapy in fact improves matters.

A competing theory for linking together the risk of suffering Alzheimer's and other common diseases of aging relates to fat, insulin metabolism, and lack of exercise. There, Alzheimer's is viewed as a form of diabetes, yet another of the many unpleasant consequences of metabolic dysfunction brought on by being overweight and sedentary for many years:

Insulin disappears early and dramatically in Alzheimer's disease. And many of the unexplained features of Alzheimer's, such as cell death and tangles in the brain, appear to be linked to abnormalities in insulin signaling. This demonstrates that the disease is most likely a neuroendocrine disorder, or another type of diabetes.

The microtubule version of a theory to explain the known association between risk of diabetes and risk of Alzheimer's involves problems in the transport of required biochemicals in the insulin signaling network:

key proteins - including insulin receptors and receptors for brain signaling molecules - are also likely locked inside cells when the [microtubule] transport system is damaged by amyloid or other factors. "The insulin receptors are needed to get blood sugar inside the cell where it can be used for energy. The nerve cell signaling receptors help promote memory and learning," Dr. Potter said. "So, if these receptors are unable to function properly, it may lead to diabetes and problems with learning and memory."

Hopefully this gives you a small taste of what almost all areas of Alzheimer's research look like at this time: a great deal of evidence and change, a great many ideas and competing viewpoints.

Granic A, Padmanabhan J, Norden M, & Potter H (2009). Alzheimer A{beta} Peptide Induces Chromosome Mis-Segregation and Aneuploidy, Including Trisomy 21; Requirement for Tau and APP. Molecular biology of the cell PMID: 20032300

At It's Rainmaking Time, you'll find an audio interview with Ben Best on the topic of cryonics: "Many of us would choose to live another 100 years or more, if we only knew how. Enter cryonics: an exciting, fascinating, and highly misunderstood scientific field. We have invited Ben Best, the president of The Cryonics Institute, to help us understand cryonics, where the paradigm is gaining traction, and the logistics involved. Join us for an illuminating discussion." Best, like many of the movers and shakers in the pro-longevity community, is a writer. You should take the time to look through the work at his personal website, especially the essays on cryonics and engineered longevity. For example, the Mechanisms of Aging essay is a fairly detailed overview is what is presently known and debated in the scientific community, whilst Why Life Extension? examines the motivations of those who want to live longer in good health and those who claim not to.

Link: http://itsrainmakingtime.com/2010/cryonics/

From EurekAlert!: researchers "have succeeded in the ultimate switch: transforming mouse skin cells in a laboratory dish directly into functional nerve cells with the application of just three genes. The cells make the change without first becoming a pluripotent type of stem cell - a step long thought to be required for cells to acquire new identities. ... Until recently, it's been thought that cellular specialization, or differentiation, was a one-way path: pluripotent embryonic stem cells give rise to all the cell types in the body, but as the daughter cells become more specialized, they also become more biologically isolated. Like a tree trunk splitting first into branches and then into individual leaves, the cells were believed to be consigned to one developmental fate ... The research suggests that the pluripotent stage, rather than being a required touchstone for identity-shifting cells, may simply be another possible cellular state. ... finding the right combination of cell-fate-specific genes may trigger a domino effect in the recipient cell, wiping away restrictive DNA modifications and imprinting a new developmental fate on the genomic landscape. ... It may be hard to prove. but I no longer think that [induced pluripotency] is a reversal of development. It's probably more of a direct conversion like what we're seeing here, from one cell type to another that just happens to be more embryonic-like. This tips our ideas about epigenetic regulation upside down."

Link: http://www.eurekalert.org/pub_releases/2010-01/sumc-srd012110.php

Why do stem cell populations in the body become less effective with age? The resulting decline in the generation of replacement cells is one of the contributing factors to age-related degeneration, leading to tissues and organs that are damaged, weaker, or dysfunctional. But does this happen because the stem cells themselves are becoming damaged, or fewer in number, or is it because they are responding to changes in the cellular environment and simply doing less work? For example, we might theorize that reduced stem cell activity in response to the biochemical signs of aging is an evolutionary adaptation intended to reduce the risk of cancer. To date, the pendulum of scientific evidence and debate has been swinging more towards theories that involve the cellular environment. You might recall that least some varieties of old stem cell act more like young stem cells if placed in a young cellular environment:

Rando and his colleagues studied muscle stem cells called satellite cells, which in young mice and humans induce repair when injury strikes. Rando found in previous work that satellite cells exist in older muscle, but they don't respond to a muscle's cry for help after injury. In the new study, the presence of younger blood helped the satellite cells work more like they do in young mice.

A more recent report is much the same:

In virtually every part of the body, stem cells stand ready to replenish mature cells lost to wounds, disease, and everyday wear and tear. But like other cells, stem cells eventually lose their normal functions as they age, leaving the body less able to repair itself.

Surprisingly, this age-related decline in stem cell potency may be somewhat reversible. A team of Howard Hughes Medical Institute (HHMI) researchers has found that in old mice, a several-week exposure to the blood of young mice causes their bone marrow stem cells to act "young" again.

...

The researchers have not yet isolated the blood-borne factors that can switch old stem cells back to a more youthful state, but their results are consistent with other recent studies that show stem-cell aging may be reversible. Together those results suggest that it might one day be possible to boost the practical lifespan of stem cells, and thereby increase the body's resistance to disease and age-related degeneration.

As cancer therapies are expected to become far more effective, there may well be no real downside to medical technologies that reverse the age-related decline of stem cell populations. People who have been suffering this effect of aging may be able to have it reversed through a drug-like treatment, once the controlling biochemistry is identified.

While we all pay attention to end results in our own field of interest, the general infrastructure biotechnologies that enable those end results are progressing rapidly. This article illustrates just how fast one of the benchmark technologies - DNA sequencing - is moving: "Although Complete Genomics is now slated to sequence an incredible 5,000 human genomes in 2010, this is nothing compared to what the company has in store for the years ahead. ... the company is now hoping to sequence 50,000 genomes in 2011 and a whopping 1 million genomes by 2014. Considering that by the end of 2009 only about 100 or so human genomes had ever been sequenced, most of them by - you guessed it - Complete Genomics, this represents an enormous shift in the industry. ... In November of last year Complete Genomics announced that they had sequenced 3 human genomes at an average cost of materials below $5000 apiece, shattering all previous records by nearly a factor of ten! Last year Complete Genomics was charging its customers $20,000 per genome and this year they will be charging $10,000 or less. We can expect the company’s costs and the prices it charges its customers to continue to drop dramatically in the next few years. The $1,000 genome is indeed within sight."

Link: http://singularityhub.com/2010/01/26/exclusive-complete-genomics-to-sequence-1-million-genomes-interview-with-ceo/

Another good article from h+ Magazine is illustrative of the present state of the art in the DIY Bio scene: "In September 2007, I gave a short talk at Aubrey de Grey's SENS conference in Cambridge outlining my intention to found an open source biotech company that would make customized therapies for breast cancer. The response to the presentation was predictable: many had concerns whether regulators would allow such a drug to be used in a human trial. I had no idea, but I knew the only way to truly find out would be to try. It took almost two years of discussion and feeling my way around, but this company now exists. It‘s called the Pink Army Cooperative. ... Breast cancer is the first target, but ultimately the cooperative's goal is to open a path from diagnostics to the clinic for individualized medicines - to make effective cancer treatments as fast as diagnostic data can be translated into designs, manufactured, tested in the lab, and approved for use on a single person. Using open source synthetic biology, each of these steps can be automated, and each should get cheaper over time. ... Pink Army, then, is the first DIY drug company. It's a container that allows people interested in tackling cancer to connect and focus their passion, skills, and other resources."

Link: http://hplusmagazine.com/articles/bio/why-diy-bio

Last week, I posted on the topic of calorie restriction mimetics, with a focus on enhancement of autophagy and the operation of heat shock proteins as a path to extended longevity - or at least some repair of age-related cellular damage. Both autophagy and heat shock proteins contribute to cleaning up damage and dysfunctional molecular machinery in our cells, and are strongly implicated in the benefits to health and longevity provided by exercise and calorie restriction. As an addendum to that post, let me point out another example of early stage research into enhanced heat shock protein activity. This is an open access paper:

Modulation of Heat Shock Transcription Factor 1 as a Therapeutic Target for Small Molecule Intervention in Neurodegenerative Disease:

The misfolding of proteins into a toxic state contributes to a variety of neurodegenerative diseases such as Huntington, Alzheimer, and Parkinson disease. Although no known cure exists for these afflictions, many studies have shown that increasing the levels of protein chaperones [such as heat shock proteins], proteins that assist in the correct folding of other proteins, can suppress the neurotoxicity of the misfolded proteins. As such, increasing the cellular concentration of protein chaperones might serve as a powerful therapeutic approach in treating protein misfolding diseases.

Because the levels of protein chaperones in the cell are primarily controlled by the heat shock transcription factor 1 [HSF1], we have designed and implemented a pharmacological screen to identify small molecules that can promote human HSF1 activation and increase the expression of protein chaperones. Through these studies, we have identified HSF1A, a molecule capable of activating human HSF1, increasing the levels of protein chaperones and alleviating the toxicity of misfolded proteins in both cell culture as well as fruit fly models of neurodegenerative disease.

As a reminder, the FDA does not recognize aging as a disease and so will not approve therapies aimed at reversing biological consequences of aging that are present in everyone - such as the accumulation of aggregated metabolic byproducts and damaged proteins that could be (at least somewhat) attacked through boosted heat shock protein levels. Simple economics thus constrains research along these lines to treating the named diseases of aging or genetic diseases. The powerhouses of funding require profit at the end of the day, and there is no profit in therapies that are forbidden by regulators.

A wide range of scientific work that is presently constrained to development for late-stage named diseases might have some broader application for people suffering the effects of "normal aging" - but unless the present oppressive regulatory environment is overturned, the research and development required to explore that possibility will never happen.

Neef, D., Turski, M., & Thiele, D. (2010). Modulation of Heat Shock Transcription Factor 1 as a Therapeutic Target for Small Molecule Intervention in Neurodegenerative Disease PLoS Biology, 8 (1) DOI: 10.1371/journal.pbio.1000291

Researchers are investigating a range of ways to restore aspects of the aged immune system to youthful levels. Here is one: "By comparing the immune responses of both, young and old mice, to bacterial infection they found that the number of macrophages, one of the major cell populations involved in the elimination of infecting bacteria, decreases rapidly in aged mice. This decline in the number of fighters and the associated weakness of the immune defense may be responsible for the age-associated increase in susceptibility to infections. [Researchers] have succeeded to enhance the resistance to an infection in aged mice by treating them with a macrophage-specific growth factor. This treatment increases the amount of macrophages in aged mice and improves their capacity to fight the infection. ... The treatment made aged mice much more resistant and they could fight much better the infection. The results of our study indicate that repeated prophylactic administration of this growth factor can help to maintain the macrophage compartment in the elderly and the fitness of the immune system."

Link: http://www.eurekalert.org/pub_releases/2010-01/haog-rto012610.php

Here's a report on a presentation given by biomedical gerontologist and engineered longevity advocate Aubrey de Grey in Finland: "All in all, I found the presentation very understandable, concise and even entertaining. Everything except maybe the part about the seven types of aging damage was understandable even for the layperson. If you have doubts about whether ending aging is desirable or possible, I very much recommend watching some of his lectures online. They're also very useful if you want to convince others that the fight against aging is an important one. One thing I noticed Aubrey does well (and I don't) is to counter arguments by people whose life philosophy is, in my opinion, grounded on bad logic. For example, he gave a good response to the religious objection that life extension is a sin, arguing that it's essentially the other way around, because not doing anything to aging is the same thing as allowing suffering, which must be wrong. ... Another important point is that unlike what people imagine their own death to be like - quick and painless - for the overwhelming majority of the world's population it is nothing of the sort. What it is is a slow decline in physical and mental capabilities followed by a complete collapse and, ultimately, death. It is a process of slow deterioration that goes on for decades, with each decade being progressively worse in terms of biological functions than the previous one. To wish such a fate upon yourself is irrational, and to wish it upon others is just evil."

Link: http://inhumanexperiment.blogspot.com/2010/01/aubrey-de-grey-in-helsinki-finland.html

Once you start digging into a topic, it becomes all too easy to lose sight of your previous state of knowledge, and the opinions you held before you learned more. What were your thoughts on aging research and engineered longevity before you became interested enough to start reading this blog on a regular basis? When we talk about advocacy and fundraising for projects like the Strategies for Engineered Negligible Senescence, we are really talking about convincing people who are presently where you used to be: they are potentially interested, but not in the loop, and not seeing the whole picture. If you lose sight of how these folk think - which is the same way that you used to think - then you will find it harder to persuade and educate.

The opening paragraphs of a recent book review manage, I think, to capture the present state of mind of the educated layperson. He knows that something interesting is going on, dismisses most of what is said about aging and longevity beyond the scientific community, and is ignorant of specific research initiatives most likely to show promise.

There is a paradox at the heart of the debate on aging. All the recipes for averting the effects of senescence - the anti-wrinkle oils, the vitamin supplements, the testosterone shots, the strict dieting regimens - are plainly little better than snake oil. And yet something is obviously working: People are living longer and longer, and are getting healthier and healthier in old age. Experts have been predicting for decades that average life expectancy will level out, but it stubbornly keeps rising. Others have predicted a growing burden of ill health among the elderly. Yet old people are healthier than ever, much of their illness compressed into shorter periods at the end of life.

Average life expectancy across the world has roughly doubled in the past century. In the U.S., the passing of every day marks another five hours added to people's lives; the number of Americans who are 100 or older has doubled since 2000. The chief cause of this remarkably benign trend is the defeat of serious infectious disease, but there are other elements as well: Heart disease is killing fewer, and stroke is striking later.

The science of age is equally paradoxical. It abounds in empirical facts about what causes aging, yet the science still lacks any convincing, unifying theory. Eating dramatically less food - caloric restriction - makes mice live longer; just two genetic mutations can double the life span of a worm; breeding from the oldest flies in a test tube can double the life span of flies in a few generations; bats and birds, tortoises and rougheye rockfish live for decades while opossums are senile two years after birth. Naked mole rats live five times as long as their size implies they should.

It is the large number of people who hold these views and this level of knowledge that we must educate and persuade to help out if we are to see significant progress in the repair of aging in our lifetimes. What they know now is a jumbled collection of facts that have not been assembled into a coherent whole - but until that assembly happens there is no apparent motivation to learn more or pitch in and help. It is the responsibility of advocates to help move as many people as possible from "this is all very interesting, but..." to "ah, now I see the potential."

An open access paper: "The notion that autophagy increases longevity is well illustrated by experiments in which the massive induction of autophagy by either pharmacological methods (such as the administration of rapamycin [Rapa] or spermidine) or genetic manipulations (like the knockdown the autophagy inhibitor p53) improves organismal survival and hence reduces age-associated mortality. Caloric restriction (which is the most physiological inducer of autophagy), Rapa (which is the best characterized pharmacological inducer of autophagy), or knockdown of the p53 ortholog cep-1, all extend the lifespan of the nematode Caenorhabditis elegans only when the autophagic machinery is intact. Thus, knockdown of AuTophaGy-related (atg) genes annihilates the longevity-enhancing effect of caloric restriction, Rapa, and p53 depletion. ... Similarly, it has been found that the lifespan-extending properties of the natural polyamine spermidine strictly rely on the activation of the autophagic program in several model organisms including yeast, nematodes, and flies."

Link: http://www.nature.com/cddis/journal/v1/n1/full/cddis20098a.html

Biotechnology will follow the path of software: it will become a low-cost open source garage industry, and thus highly innovative and competitive. Here, h+ Magazine looks at the transhumanist side of the DIY Bio movement: "Hardware hacking has a rich history, filled with geek heroes, and these skills are being turned towards the creation of biotech equipment. On the bleeding edge of it all, some DIYbiologists are applying their skills to h+ technologies. SENS researchers John Schloendorn, Tim Webb, and Kent Kemmish are conducting life-extension research for the SENS Foundation, building equipment for longevity research, saving thousands of dollars doing it themselves. The DIY SENS lab is headed by PhD candidate John Schloendorn. John is a last- year PhD student at Arizona State University. He volunteers full time for the SENS Foundation. Entering his lab was a mind-blowing experience. The ceilings were high, the lab itself was spacious and well-lit. It smelled of sawdust, the product of constructing the furniture on site. The equipment was handmade, but brilliantly so. Elegance and function were clear priorities. When a panel could be replaced with a tinted membrane, it was. When metal could be replaced by sanded wood, it was. The on-site laser was modified from a tattoo-removal system. Costs were down, but the technical skill involved in manufacturing was top notch."

Link: http://hplusmagazine.com/articles/bio/diy-bio-growing-movement-takes-aging

Could a drug introduced in the 2010s be able to induce rejuvenation, the repair of age-related damage? To a very limited degree, yes. We would expect some types of drug, early and poor examples of which are presently undergoing investigation in the laboratory, to be able to stimulate the aged body to repair certain types of cellular damage and aggregate buildup that it would otherwise be unable to deal with - in other words to rejuvenate some aspects of cellular biology to their youthful states of operation. One line of research to this end is based on what has been learned from the study of the biochemistry of calorie restriction and exercise.

A calorie restriction mimetic drug is one that replicates some of the biochemical changes in gene expression and cellular processes caused by calorie restriction - and hopefully thereby also produce noteworthy benefits to health and longevity. No existing medical technology even comes close to what calorie restriction can achieve in humans and other mammals, a fact also true of exercise. The traditional drug industry is sinking vast sums of money into discovering and developing pharmaceutical methods to capture the benefits of calorie restriction and exercise - things that most people won't do for themselves, but will happily pay for in the form of a pill.

Both calorie restriction and exercise share some mechanisms in common, such as improving the operation of heat shock proteins:

Heat shock proteins are molecular chaperones, and their activities in the body are boosted by exercise and calorie restriction, two line items known to extend healthy life in laboratory animals and produce impressive health benefits in humans. Put simply: molecular chaperones detect proteins that are misfolded, and have the ability to refold those proteins into the appropriate, non-toxic shape. Additionally, if the protein is so badly misfolded that it cannot be repaired, the molecular chaperones can also recruit other proteins that have the ability to "tag" the toxic protein for destruction by the cell.

Heat shock proteins are one aspect of the process of autophagy, wherein damaged materials and cellular components are recycled. Calorie restriction may operate largely through boosting autophagy:

the weight of evidence points to more and better autophagy as beneficial overall, most likely because it leads to fewer lingering damaged components inside a cell. Repeated throughout all your cells, this should result in better functioning tissue, fewer errant biological systems, and a longer life - remember that aging itself is nothing more than accumulated damage and the thrashing of systems trying to adapt to that damage.

But it is also hard to discount benefits of calorie restriction that occur due to nothing more than avoiding large amounts of of visceral fat, which greatly reduces chronic inflammation caused by fat deposits.

Not to hammer on the point too much, but excess body fat held over the years causes chronic inflammation, which enrages your immune system, which leads to atherosclerosis, which tends to kill you abruptly and without warning. All very avoidable.

If being charitable, we might think of any drug that boosts autophagy, the operation of heat shock proteins, or one of the other biochemical changes brought on by calorie restriction as a form of calorie restriction mimetic. Researchers are investigating quite a few such drugs these days; I noticed a couple of recent research papers that are illustrative of the sort of work taking place at the moment, and the level of knowledge in the field:

Metformin Induces a Dietary Restriction–Like State and the Oxidative Stress Response to Extend C. elegans Healthspan via AMPK, LKB1, and SKN-1

Metformin, a biguanide drug commonly used to treat type-2 diabetes, has been noted to extend healthspan of nondiabetic mice, but this outcome, and the molecular mechanisms that underlie it, have received relatively little experimental attention. To develop a genetic model for study of biguanide effects on healthspan, we investigated metformin impact on aging Caenorhabditis elegans. We found that metformin increases nematode healthspan, slowing lipofuscin accumulation, extending median lifespan, and prolonging youthful locomotory ability in a dose-dependent manner. Genetic data suggest that metformin acts through a mechanism similar to that operative in eating-impaired dietary restriction (DR) mutants, but independent of the insulin signaling pathway.

17-AAG induces cytoplasmic alpha-synuclein aggregate clearance by induction of autophagy

The accumulation and aggregation of alpha-synuclein in nerve cells and glia are characteristic features of a number of neurodegenerative diseases [such as Parkinson's disease, for example]. alpha-Synuclein is a highly soluble protein which in a nucleation dependent process is capable of self-aggregation. The causes underlying aggregate formation are not yet understood, impairment of the proteolytic degradation systems might be involved.

...

Our data demonstrate that [the drug] 17-AAG attenuated the formation of alpha-synuclein aggregates by stimulating macroautophagy. ... Our data demonstrate for the first time that 17-AAG not only causes the upregulation of heat shock proteins, but also is an effective inducer of the autophagic pathway by which alpha-synuclein can be removed. Hence [this or similar drugs] may provide a means to modulate autophagy in neural cells, thereby ameliorating pathogenic aggregate formation and protecting the cells during disease and aging.

Resveratrol and rapamycin: are they anti-aging drugs?

Studies of the basic biology of aging have advanced to the point where anti-aging interventions, identified from experiments in model organisms, are beginning to be tested in people. Resveratrol and rapamycin, two compounds that target conserved longevity pathways and may mimic some aspects of dietary restriction, represent the first such interventions. Both compounds have been reported to slow aging in yeast and invertebrate species, and rapamycin has also recently been found to increase life span in rodents. In addition, both compounds also show impressive effects in rodent models of age-associated diseases. Clinical trials are underway to assess whether resveratrol is useful as an anti-cancer treatment, and rapamycin is already approved for use in human patients. Compounds such as these, identified from longevity studies in model organisms, hold great promise as therapies to target multiple age-related diseases by modulating the molecular causes of aging.

The resveratrol results in mice are being challenged, however, and were never actually all that impressive in the first place, when considered in comparison to other calorie restriction mimetic candidates. Drugs engineered to boost or repair failing autophagic processes in the old are, to my eyes, the most promising potential outcome of this wide-ranging field of research. Improved autophagy in the old can clear out intracellular aggregates and the buildup of cellular damage, which is exactly a form of rejuvenation - restoring an aspect of the aging cellular environment to youthful levels. Therapies built upon such drugs would be limited to reversing only those forms of age-related damage that autophagy can clean up, but it is nonetheless a form of rejuvenation.

Onken, B., & Driscoll, M. (2010). Metformin Induces a Dietary Restriction–Like State and the Oxidative Stress Response to Extend C. elegans Healthspan via AMPK, LKB1, and SKN-1 PLoS ONE, 5 (1) DOI: 10.1371/journal.pone.0008758

Stroke is another cause of death wherein risk is significantly increased by obesity: "Analyzing the ARIC Study database in which subjects' BMI, waist circumference and waist-to-hip ratio were measured at the study's start, [researchers] followed 13,549 middle-aged black and white men and women in four U.S. communities from 1987 through 2005. Participants started the study free of cancer and cardiovascular disease. During the follow-up period of about 19 years, 598 ischemic strokes occurred. The researchers calculated incidence rate - the number of new cases per 1,000 people per year - according to groups representing different degrees of obesity, using each obesity measure ... the correlation between increasing stroke incidence and increasing degree of obesity was apparent in both races and genders ... Individuals in the highest BMI category had 1.43 to 2.12 times higher risk of stroke. When waist circumference was used as a measure of obesity instead of BMI, those risk ratios ranged from 1.65 to 3.19; and 1.69 to 2.55 when waist-to-hip ratio was used. Thus, for any obesity measure, individuals in the highest category had approximately two times higher risk of stroke compared to the lowest category in each race-sex group."

Link: http://americanheart.mediaroom.com/index.php?s=43&item=930

Via EurekAlert!, another of the many ways in which excess fat tissue hurts you: "Obesity comes with plenty of health risks, but there's one that's perhaps not so well known: an increased risk of developing cancer, and especially certain types of cancer like liver cancer. Now, a group of researchers [have] confirmed in mice that obesity does indeed act as a 'bona fide tumor promoter.' They also have good evidence to explain how that happens. ... liver cancer is fostered by the chronic inflammatory state that goes with obesity, and two well known inflammatory factors in particular. The findings suggest that anti-inflammatory drugs that have already been taken by millions of people for diseases including rheumatoid arthritis and Crohn's disease may also reduce the risk of cancer in those at high risk due to obesity and perhaps other factors as well ... [Researchers were] able to trace the source of obesity's tumor-promoting effect to a rise in two inflammatory factors known as IL-6 and TNF. Obese mice lacking either the TNF receptor or IL-6 don't show the same rise in liver cancer. Those treatments also led the mice to accumulate less fat in their livers, he said. ... They still get fat, but the distribution of the fat is different. The fat goes to other places, but not to the liver."

Link: http://www.eurekalert.org/pub_releases/2010-01/cp-ouc011910.php

You might recall that p66(Shc) mice are long-lived for reasons that are still open for debate - they are a good illustration of the sheer complexity of attempting to safely extend life through metabolic manipulation, and the time taken to understand what is going on. Here is more on the subject: "Evidence is mounting that reactive oxygen species (ROS) produced because of stressful challenges could interfere with the proper functioning of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in greater vulnerability to aging and neurodegeneration. Here we tested the hypothesis that p66(Shc-/-) mice, which have been described to have an extended life span and a high resistance to oxidative stress, might be less susceptible to the effects of inflammatory insults at adulthood. ... Overall, the greater resilience to inflammation-induced changes in the p66(Shc-/-) mutants might underlie the better health status and the greater longevity characterizing these mice." Chronic inflammation that increases with age - due to putting on visceral fat, or increasing disorder in the immune system - is a big issue. Protection against it is similarly important.

Link: http://pmid/20085805

It is the common wisdom that people who practice calorie restriction don't tend to manifest minor illnesses like colds and the like - but I'm not aware of any study to back up that claim. A while back, research linked hunger hormone ghrelin with increased immune function, and here is another study on the topic of fewer calories leading to a more aggressive immune system: "researchers have discovered an elementary mechanism which regulates vital immune functions in healthy people. In situations of hunger which mean stress for the body's cells, the body releases more antimicrobial peptides in order to protect itself. ... his natural immune defence system is linked directly to the metabolic status via the insulin signalling pathway. ... If we have not eaten for a while or have to climb many stairs, the energy level of our cells drops and with it the level of insulin. The researchers from Bonn have now discovered that in the case of a low insulin level the FOXO transcription factor is activated. A transcription factor can switch genes on and off. FOXO switches genes for immune defence proteins on when energy is needed. These antimicrobial peptides (AMP) - not to be confused with antibodies - are subsequently jettisoned by the body's cells. They destroy possible pathogens by dissolving their cell walls." One would expect calorie restricted people to have more of this going on in their bodies.

Link: http://www.eurekalert.org/pub_releases/2010-01/uob-hig011910.php

Cryonics is the science and business of the low-temperature preservation of the body and brain upon clinical death. By preserving the fine structure of the brain, you preserve the data stored within - the mind itself. Cryopreserved individuals can then wait for as long as needed for technologies to advance to the point at which they can be restored to active life. Typically, this is envisaged to involve molecular manufacturing and medical nanorobots capable of cellular repair - none of which is impossible under our present understanding of the laws of physics.

But the vitrified waiting part of the equation requires the cryonics community to continue and expand from generation to generation. From this community are drawn the (presently few) professionals in the cryonics field, financial support for operations, and other necessities for running a cryonics provider as a long-term business. Those older folk who presently support cryonics expect to be cryopreserved, and their legacy protected by younger supporters - which means that all the normal advocacy and community engineering undertaken in any successful field of human endeavor are especially important here.

This noted, I see there are two reports published online in recent days from members of the community who attended a meeting of younger cryonics supporters and advocates, held earlier this month in Florida. That is the home state of the Life Extension Foundation; the founders of that organization have long supported the cryonics community, both financially and otherwise.

Teens and Twenties Cryonicist Event 2010

The event was funded by Bill Faloon and the Life Extension Foundation. Cairn Idun, creator and coordinator of the Asset Preservation Group, created and coordinated this event as well. Although the Asset Preservation Group was created to devise means of protecting the assets of cryonicists during cryostasis, the group has expanded its concerns to many related issues, including nurturing future generations of cryonics activists to replace the current generation of aging cryonics activists.

...

Overall I am very enthusiastic with how the weekend went. I made many valuable connections, as did most (if not all) of the others, I believe. It also lifted my spirits, which I also believe was a common experience. Bill Faloon wants to make this an annual event.

Normal Cryonics

The young cryonicists' travel was subsidized. I suspect this led to a greatly different selection filter than usually prevails at conferences of what Robin Hanson would call "contrarians". At an ordinary conference of transhumanists - or libertarians, or atheists - you get activists who want to meet their own kind, strongly enough to pay conference fees and travel expenses. This conference was just young people who took the action of signing up for cryonics, and who were willing to spend a couple of paid days in Florida meeting older cryonicists.

...

Those young cryonicists weren't heroes. Most of the older cryonicists were heroes, and of course there were a couple of other heroes among us young folk, like a former employee of [Methuselah Foundation] who'd left to try to put together a startup/nonprofit around a bright idea he'd had for curing cancer (note: even I think this is an acceptable excuse). But most of the younger cryonicists weren't there to fight a desperate battle against Death, they were people who'd signed up for cryonics because it was the obvious thing to do.

And it tears my heart out, because I am a hero and this was like seeing a ray of sunlight from a normal world, some alternate Everett branch of humanity where things really were normal instead of crazy all the goddamned time, a world that was everything this world could be and isn't.

...

You know what? I'm going to come out and say it. I've been unsure about saying it, but after attending this event, and talking to the perfectly ordinary parents who signed their kids up for cryonics like the goddamn sane people do, I'm going to come out and say it: If you don't sign up your kids for cryonics then you are a lousy parent.

This sort of event sounds like something worth making an institution in the community. Cryonics has a long way to go to become mainstream, but every step is a step closer. So many, many lives will be lost between now and the advent of working rejuvenation medicine - and the methodology presently exists to save those lives though cryonics. Most people are not aware of it or interested in it, however, and cryonics provision needs to be scaled up to handle the masses. Scaling is a trivial problem compared to convincing people that a viable workaround to death exists; as soon as there is desire for a product, there will be competition and development.

As pointed out above, we do not live in a particularly sane world. We could argue that the fact that cryonics is a fringe movement with a working way to evade death shows that most people don't much care about evading death, and certainly don't much care about helping others to evade death - at the very least during those parts of their lives where they are active and healthy enough to be doing something about it.

One part of the scientific method is concerned with how to sift through research results and theories that are mostly flawed or otherwise wrong in order to extract, further explore, and (where possible) prove the results that have value. Consensus amongst scientists is important to the scientific community because independent replication of results is important to the scientific method. Nothing should be taken at face value, or as more than a possibility, until there is a weight of research from diverse scientific groups to support it.

The scientific community doesn't produce an output of nice, neat tablets of truth, pronouncements come down from the mountain, however. It produces theories that are then backed by varying weights of evidence: a theory with a lot of support stands until deposed by new results. But it's not that neat in practice either. The array of theories presently in the making is a vastly complex and shifting edifice of debate, contradictory research results, and opinion. You might compare the output of the scientific community in this sense with the output of a financial market: a staggeringly varied torrent of data that is confusing and overwhelming to the layperson, but which - when considered in aggregate - more clearly shows the way to someone who has learned to read the ticker tape.

But even consensus itself isn't a clear-cut item. We live in a complex world, and as pointed out over at Depressed Metabolism, some reaches of science can present challenges to the normally safe approach of interpreting the present state of knowledge through scientific consensus:

Scientific consensus seems a reasonable concept. If a great number of individual scientists arrive at a similar opinion this is generally a sufficient reason to have confidence in those views. Skeptics about scientific consensus often use examples of scientific views that started out as a minority view to become the majority view later. Although these examples raise interesting questions about how science evolves as a collective undertaking, they cannot be used to argue against the importance of scientific consensus as such. For every minority view that became a majority view there are a lot more examples of crackpot theories that are still crackpot theories today. Nevertheless, there are a number of situations where the concept of scientific consensus is of limited value.

A good example are fields that are so interdisciplinary that there is no clearly identifiable group of scientists who can be perceived as authorities on the matter. For example, what is the scientific consensus on cryonics? The consensus of biologists? The consensus of cryobiologists? The consensus of neuroscientists? The consensus of experts on nanotechnology? The consensus of those who study cryonics in all its aspects? It is clear that when there is no clearly identifiable group of experts, the concept of scientific consensus becomes problematic.

This interdisciplinary issue of consensus and shared information is becoming ever more an issue in the life sciences, and in particular in aging research. Human biology is so complex that entire academic lifetimes can be - and have been, and are - spent on cataloging very tiny parts of the whole. The cutting edge of biology and biotechnology research is conducted at the very tips of the widespread leaves, that are at the end of the widespread twigs, that are at the end of the widespread branches of biology as a field. But many widely separated twigs are still related in the processes of aging - and that is an issue, because there is too little communication and synthesis taking place between these many disparate enclaves of knowledge. Biology as a field needs, and is in fact entering, an era of synthesis, in which drawing together existing knowledge is just as important to progress as generating new knowledge:

Scientific progress goes through cyclic periods of fragmentation followed by synthesis. During fragmentation, many different groups toil away at their own little pieces of the great unknown. Each group generates data that, at first, appears to have little to do with other efforts. As the data piles higher, correlations start to appear - and so do the efforts at synthesis. Gradually, the focus in a field shifts from finding new information to making sense of what is known, pulling it all together such that links, correlations, and chained mechanisms are understood. Then they next great unknown beckons and the process of fragmentation starts once more.

At present the grand study of human biochemistry is moving from fragmentation to synthesis. It is still the case that some different specialties know little of one another's work. Researchers look at the same mechanisms and compounds, giving them different names and assuming different dominant roles in biochemical processes, all the while missing out on the enlightenment that a complete picture can bring.

A little cell biology research in the old school mode for you today: throw in some changes and see what happens. Here, the researchers build a case for the accumulation of advanced glycation endproducts (AGEs) with age (and especially with metabolic syndrome or type 2 diabetes) to interfere with the operation of heat shock proteins (HSPs). These HSPs are a vital component of the recycling and repair machinery that keeps cells operating well, and appear to be the root cause of the hormesis effect, wherein a little adverse stress put upon your biology inspires it to operate more effectively. Both calorie restriction and exercise appear to produce at least some part of their benefits on health and longevity through boosting the operation of HSPs. Here, then, is evidence for AGEs to have the opposite effect: "Nonalcoholic steatohepatitis (NASH) is a feature of metabolic syndrome. Advanced glycation end-products (AGEs) are formed by the Maillard reaction, which contributes to aging and to certain pathological complications of diabetes. A recent study has suggested that glyceraldehyde-derived AGEs (Glycer-AGEs) are elevated in the sera of patients with NASH. ... Among the intracellular Glycer-AGEs that were formed, heat shock cognate 70 (Hsc70) was identified as a GA-modified protein, and its modification reduced the activity of Hsc70."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20084527

From the Los Angeles Times: "The California Institute for Regenerative Medicine recently awarded 14 grants to stem cell-based projects that are close to being ready for clinical trials. Here are some of the projects. ... A team from City of Hope in Duarte plans to genetically modify the blood-forming stem cells of AIDS patients so that they can rebuild their immune systems with new T cells that aren't susceptible to HIV. ... Researchers from USC and UC Santa Barbara are growing human embryonic stem cells into retinal pigment epithelium cells that can replace damaged eye cells in patients with age-related macular degeneration. ... Scientists from UCLA, USC and Stanford are developing drugs to target the harmful stem cells that drive the growth of tumors in brain, colon and ovarian cancer. ... Researchers at Cedars-Sinai Medical Center in Los Angeles plan to inject heart-attack patients with concentrated amounts of their own cardiac stem cells, which naturally repair heart tissue."

Link: http://www.latimes.com/news/nationworld/nation/la-sci-stem-cells-box10-2010jan10,0,1531506.story

One of the more interesting frontiers in research aimed at slowing aging is the search for methods that complement calorie restriction rather simply recapturing a part of its benefits to health and longevity. To date, there have not been much in the way of results on this count, but I think that this will change: the number of ways to extend life in laboratory animals is expanding rapidly, as is the pool of funding for the field.

You might recall last year's research demonstrating rapamycin to extend life in mice, and to a great enough degree to be a contender for the Mprize for longevity science.

Compared with the non-drug-taking group, the lifespans of the mice given rapamycin increased by up to 14%, even though they were middle-aged when treatment began. Their life expectancy at 20 months shot up by 28% for the males and 38% for the females.

On this topic, my attention was caught today by research into rapamycin-related biochemistry in flies:

The target of rapamycin (TOR) pathway is a major nutrient-sensing pathway that, when genetically downregulated, increases life span in evolutionarily diverse organisms including mammals. The central component of this pathway, TOR kinase, is the target of the inhibitory drug rapamycin, a highly specific and well-described drug approved for human use. We show here that feeding rapamycin to adult Drosophila produces the life span extension seen in some TOR mutants. Increase in life span by rapamycin was associated with increased resistance to both starvation and paraquat. Analysis of the underlying mechanisms revealed that rapamycin increased longevity specifically through the TORC1 branch of the TOR pathway, through alterations to both autophagy and translation.

Rapamycin could increase life span of weak insulin/Igf signaling (IIS) pathway mutants and of flies with life span maximized by dietary restriction, indicating additional mechanisms.

That last part is the interesting point, for me at least. Based on the behavior of rapamycin and calorie restriction tested separately in flies and mice, it would be consistent for rapamycin to further extend the life span of calorie restricted mice - and hence other mammals too. Which in turn means, as the authors point out above, that there exist other accessible mechanisms of metabolic determination of longevity that are not triggered by calorie restriction.

If forced to guess - which, frankly is a fool's game in anything to do with biology - I'd say that these additional mechanisms are involved in genetic translation rather than autophagy. We already know that autophagy and calorie restriction are strongly linked; there is a plausible argument that calorie restriction exerts its effects largely through increased autophagy and the consequences thereof.

Autophagy is, broadly speaking, the process by which your cells recycle damaged components. ... more autophagy appears to be a good thing. You don't want damaged organelles running wild in your cells; one only has to look at the mitochondrial free radical theory of aging to see where that can lead - a trick of biochemistry prevents mitochondria from being recycled, and ever more damaged cells spew toxins into your body, causing the degenerations of aging that follow.

Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A, & Partridge L (2010). Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell metabolism, 11 (1), 35-46 PMID: 20074526

Regularly infusing the body with large numbers of T cell immune cells has the potential to help with a range of issues, given that the immune system declines with age: recent research "provides new insights into how our immune system produces T cells, a type of white blood cell that is an essential part of the body's immune surveillance system for fighting infection. The findings pave the way for a new means of making purified T cells, which gets over one of many hurdles faced in the use of T cells in regenerative medicine and transplantations, and in addition will open up new avenues of research and applications in drug and toxicity testing in industry. ... It reveals for the first time how immature T cells can be grown without the need for supporting 'feeder' cells - these cannot be easily separated from T cell preparations, reducing their suitability for transplantation in the clinic. This may advance the field of regenerative medicine. ... This technology could enable the production of T cells for clinical applications such as their transplantation into immuno-compromised individuals."

Link: http://www.sciencedaily.com/releases/2010/01/100118092016.htm

Via ScienceDaily: researchers "have demonstrated that artificial muscles can restore the ability of patients with facial paralysis to blink ... the technique, which uses a combination of electrode leads and silicon polymers, could be used to develop synthetic muscles to control other parts of the body. ... electroactive polymer artificial muscle (EPAM) [is] an emerging technology that has the potential for use in rehabilitating facial movement in patients with paralysis. Electroactive polymers act like human muscles by expanding and contracting, based on variable voltage input levels. ... Facial muscles require relatively low forces, much less than required to move the fingers or flex an arm. ... The three-layered artificial muscle was developed by engineers [in] the 1990s. Inside is a piece of soft acrylic or silicon layered with carbon grease. When a current is applied, electrostatic attractions causes the outer layers to pull together and squash the soft center. This motion expands the artificial muscle. The muscle contracts when the charge is removed and flattens the shape of the sling, blinking the eye. ... researchers are now refining the technique on cadavers and animal models. They estimate the technology will be available for patients within the next five years."

Link: http://www.sciencedaily.com/releases/2010/01/100118091049.htm

Cure aging or die trying indeed - that is exactly the position in which we all find ourselves. The development of longevity science is a race, and not the good kind of race either; more the sort of race wherein a horror in the darkness is snorting behind you, and the consequences of failure are dire indeed. Worse, most of those running alongside you are oblivious to the beast that follows, and will not be woken from their daze. But this race we all win together, or we all lose, picked off one by one. There is no middle ground.

At the Sierra Sciences website you'll find an audio presentation from an anti-aging conference last year (I should note that I don't have a high opinion of such events, in which the frauds, potion-sellers, and scum far outnumber any serious presentations), and an update for 2010 on their work:

Sierra Sciences, LLC is a company devoted to finding ways to extend our healthspans and lifespans beyond the theoretical maximum of 125 years.

Scientific research has shown that this theoretical maximum is limited because of the length of our telomeres which shorten as we get older. Our reproductive cells don’t experience this shortening, and thus don’t age, because they contain an enzyme called telomerase that re-lengthens the telomeres as they shorten. Sierra Sciences is searching for pharmaceuticals that will induce the production of telomerase in all our cells.

On November 6th, 2007 Sierra Sciences found its first telomerase inducing chemical; called C0057684. This chemical is the first ever discovered that activates the telomerase gene without killing the cells. Efforts are presently underway to learn everything possible about C0057684. But, in addition, C0057684 has provided Sierra Sciences with the first positive control ever for detection of telomerase gene activity in normal human cells. This has served as a very powerful tool for the development of robust high throughput screening assays for finding additional telomerase inducing chemicals. As such, in the last year Sierra Sciences has discovered an additional 62 chemicals that activate the telomerase gene. This now enables the scientists at Sierra Sciences to design better chemicals with increased potency and specificity. Additional screening for even more chemicals is also underway.

...

We have screened 186,704 compounds. We have found 555 telomerase inducers. These represent 33 distinct drug families. Most potent compound = 6% of goal. We are screening 4,000 compounds per week.

I have written on Sierra Sciences in the past. You might stroll back into the archives to see what I had to say. In general I'm not sold on the theory that telomere length is in fact a limit upon life span, versus it being a secondary marker for the progression of numerous other processes that limit life span. Maybe it is a strongly contributing root cause of aging, maybe it isn't - but there are only two ways to find out for sure. Firstly, more research, and secondly try the telomere lengthening and see what happens. If the fastest path to a confident resolution for this uncertainty is accomplished by initiatives like Sierra Sciences, then more power to them.

The latest from the Immortality Institute, with updates on present projects after the introduction: "2010 has arrived and it is time to take stock of Imminst's position in the world of life extension. Thanks to generous member donations and an active website, Imminst grew its registration base and financial assets in 2009. This was accomplished during a poor economy and after spending large sums on two matching grants and student scholarships. We now have more funds and potentially more manpower to accomplish greater goals in 2010. The key to greater success will be transforming the activity of the forums into action in the real world. Contained within the daily discussions of life extension news and philosophy are a world of valuable ideas and actionable initiatives. I encourage everyone to formulate the many ideas into plans of action, post them in the Action Forum for evaluation, and then contribute some time to see the best ones through to success. A few minutes a week is all it takes to turn a good idea into a successful promotion, outreach effort, or fundraiser. Also, keep your eye out for more online charity contests in 2010. Facebook and other social networking platforms have proven to be great tools to promote charitable giving. Suddenly, just one click of the mouse can lead to serious grant money for Imminst and other like-minded organizations. Keep an eye out for periodic forum messages and emails containing information and instructions for competing in these contests. Let us make a bigger impact in 2010!"

Link: http://www.imminst.org/ImmInstNewsletter01_2010.html

An example of the sort of biochemical engineering research underway in this field: "the quest to create artificial blood is big business, with more than one billion pounds being spent over the last 20 years in an attempt to create a true alternative to blood. Among those around the globe seeking a viable blood alternative are scientists at the University of Essex who have just submitted a worldwide patent for their engineered hemoglobin. ... to date the world's scientists have failed to produce a safe alternative to blood. The reason for this failure, according to [the University of Essex researchers] lies in hemoglobin, the red molecule inside blood cells that carries oxygen around the body. Outside the protective environment of the red cell, hemoglobin can be toxic. Hemoglobin normally changes color from red to claret as it transfers oxygen around the body. However, when it is damaged the iron in hemoglobin is oxidized (like a car rusting) to produce dysfunctional brown and green products. ... Basically, hemoglobin produces free radicals that can damage the heart and kidneys. ... The trick with artificial blood is to modify the molecule to be less toxic, but still perform the vital role of carrying oxygen around the body."

Link: http://www.sciencedaily.com/releases/2010/01/100115204727.htm

Over at In Search of Enlightenment, you'll find some thoughts on what we can expect to see when the first longevity-enhancing drugs are introduced into the present (predatory, oppressive, and frankly insane) medical regulatory environment. These early longevity drugs will most likely be the results of work aimed at adjusting metabolism to slow down aging - calorie restriction mimetics of some sort, perhaps. They will probably have only a modest beneficial impact on human life span, something along the lines of that sought by the Longevity Dividend advocates.

The case is made that the early years of drugs to slow aging will look something like the progression of statins. Bear in mind while reading that that the FDA does not consider aging to be a disease, and will therefore not approve any treatment for aging. Thus any potential longevity therapy is sidelined into development for one specific age-related disease very early on in its life, trials would focus on that narrow use only, and the therapy would only be authorized for that narrow use at the outset:

Back in 2008 the results of the JUPITER trial [for a statin] were published, and they showed that statins could reduce the incidence of major cardiovascular events in people with normal cholesterol levels. The FDA is considering permitting as many as 6 million people whose cholesterol levels fall within a normal range to take statins.

...

I find the case of statins interesting to follow for I believe it foreshadows the challenges that await the first anti-aging drug that will come to market in the not-too-distant future ... Such a drug will first be prescribed only for patients suffering a particular disease, like diabetes. But if this drug not only has a therapeutic benefit, but also delays the other diseases of aging with little or no side effects, then the door would be open to prescribing everyone take it.

...

If people are willing to tolerate a higher level of adverse side-effects from a drug that reduces cardiovascular risk than they are for cancer risk, I wonder what the attitude would be for a drug that reduced the risk of cancer, cardiovascular disease, AD, arthritis, disability and all the other afflictions of aging?

Hopefully development will proceed more rapidly in those parts of the world where it doesn't require a decade and countless millions of wasted dollars for the entrenched bureaucracy to unlock even the smallest of the shackles that bind research and commercial application of medical science.

Ultimately, however, I view the ongoing development of drugs to slow aging as a sideshow. Attempts to merely slow aging through manipulation of metabolism are inherently challenging by their very nature, even absent the oppressive regulatory environment. It is expensive to understand metabolism, and doubly expensive to alter it in any safe way. Even if real advances are made, drugs to slow aging will do little for people who are already old. If there is to be rapid progress towards enhanced longevity in our lifetimes, it must come from efforts like the Strategies for Engineered Negligible Senescence, where no attempt is made to alter metabolism, but researchers instead focus on the tools needed to reverse aging through the repair of biochemical and cellular damage. Ways to repair the damage and reverse the changes that occur in our cells with aging could bring great benefits to the aged, and once developed could be repeated over and again to keep damage at a minimal level across the years.

It is very clear to me that attempts to slow aging by altering human metabolism represent the wrong path for longevity science. These efforts will produce expensive, poor therapies that will do little for the old, and will take a long time to fully develop.

There are those who believe, completely and unquestioningly, that progress in medicine cannot occur without omnipresent regulation to suppress fraud. They point to the fraud that occurs anyway under heavily regulated development as the reason why. They believe that the vast overkill, perverse incentives, and needless hoop-jumping of FDA trials are needed to vet every last new therapy. But there will always be fraud, what works and what doesn't work will be established even without formal trials, and the most rapid progress in commercializing modern medicine, such as stem cell therapies, occurs in the least regulated of the wealthy regions of the world. This Economist article is an excellent example of the way in which people learn the wrong lesson from the state of the world, and accept without question what they are told by those politicians, bureaucrats, and businesspeople who have a vested short-term interest in the continuation of the US-styled system of medical regulation, no matter how harmful it is to progress.

Link: http://www.economist.com/sciencetechnology/displayStory.cfm?story_id=15268869

Here is a JAMA article on the epidemiological consequences of increased obesity, written from a conservative point of view - i.e. the author believes that advancing medical technology will not greatly increase life span in the foreseeable future. "In 1900, [infectious disease] was a major concern, and the most common causes of death in the United States and in many parts of the world at the time were pneumonia and tuberculosis. Today, most individuals die of cardiovascular disease or cancer. This dramatic shift in the illnesses that cause the majority of death and disability has been divided into 4 stages known as the epidemiologic transition. In the last 2 decades, however, a fifth stage, marked by an alarming increase in overweight and obesity and continued decreases in physical activity, has emerged. ... By the mid 1960s, the United States had entered the fourth stage of delayed degenerative diseases. Cardiovascular disease mortality declined, related to preventive strategies such as smoking cessation programs and effective blood pressure control, acute coronary care units, and technological advances that included coronary artery bypass surgery. Despite the many advances in preventive medicine and treatment that reduced cardiovascular disease, the new stage of the epidemiologic transition, the age of obesity and inactivity, emerged to threaten the progress made in postponing illness and death to later in adult life spans. The steady gains made in both quality of life and longevity by addressing risk factors such as smoking, hypertension, and dyslipidemia are threatened by the obesity epidemic."

Link: http://jama.ama-assn.org/cgi/content/full/2009.2025

The health and vigor of an advocacy community might be measured by the number of different initiatives presently underway. This is a marker for the number of people who feel strongly enough and sure enough about the envisaged end goals to get out there and spend their own money and time to make a difference. More of these people will bring a greater diversity of ideas to the community, and enable a more rapid exploration of what works and what doesn't work. Many hands make light work, and this is as true in advocacy as anywhere else.

So that said, allow me to point you towards the most recent addition to the stable of grassroots longevity science advocacy groups, the Campaign Against Aging. Insofar as science goes, the founders support the Strategies for Engineered Negligible Senescence viewpoint: don't try to slow aging, but rather identify the biochemical damage that causes age-related degeneration and work to repair it, thereby reversing aging. From a recent thread in their forum:

We will be starting a major awareness raising campaign in February, lasting through February and perhaps March. This campaign will use "feet on the ground" methods such as posting flyers, distributing business cards, speaking to groups of people, and so on. I'll provide more details as the plans solidify. The tentative goal is to reach about 5,000 to 20,000 people by these methods.

This is a good start. I don't recall this methodology being tried at this scale in recent years by the longevity science community. The more usual focus tends to be on online advocacy, networking in the fundraising and scientific communities, and conferences. Having the bandwidth and enthusiasm to try new things - or old things that have worked for established organizations in other fields - is one of the benefits of organizational diversity.

I see that the Campaign has a Facebook page, and a list of suggested ways to help advance their efforts. There is also this:

Hopefully the Campaign Against Aging will prosper, establish a solid means of raising funds, and ultimately advance the state of SENS-like scientific research. Whether that is the case is as much up to you as it is up to the founders - so take a look at what they have to say at their website, and see if you want to help out.

Researchers have shown that exercise boosts telomerase and slows the erosion of telomeres with age. Here is another small study that shows the telomere length association: "Telomere length (TL), a measure of replicative senescence, decreases with aging, but the factors involved are incompletely understood. To determine if age-associated reductions in TL are related to habitual endurance exercise and maximal aerobic exercise capacity (maximal oxygen consumption, VO(2)max), we studied groups of young (18 - 32 years) and older (55 - 72 years) sedentary and young and older endurance exercise-trained healthy adults. Leukocyte TL (LTL) was shorter in the older vs. young sedentary adults. LTL of the older endurance-trained adults was approximately [900 base pairs] greater than their sedentary peers and was not significantly different from young exercise-trained adults. LTL was positively related to VO(2)max due to a significant association in older adults. Stepwise multiple regression analysis revealed that VO(2)max independently explained approximately 60% of the variance in LTL. Our results indicate that LTL is preserved in healthy older adults who perform vigorous aerobic exercise and is positively related to maximal aerobic exercise capacity. This may represent a novel molecular mechanism underlying the 'anti-aging' effects of maintaining high aerobic fitness." Equally, it is still plausible that telomere length is only a marker for other processes. Either way, exercise is demonstrably good for your long term health - far better than any supplement or medical technology presently available.

Link: http://www.ncbi.nlm.nih.gov/pubmed/20064545

Via PhysOrg.com, a look at yet another of the many approaches to a targeted cancer therapy: "In their study, the investigators developed a system containing two different nanomaterials that can be injected into the bloodstream. One nanomaterial was designed to find and adhere to tumors in mice and then sensitize tumor cells for the second nanoparticle, which kills the tumors. These scientists and others had previously designed nanometer-sized devices to attach to diseased cells or deliver drugs specifically to the diseased cells while ignoring healthy cells, but the functions of those devices, the researchers discovered, often conflicted with one another. ... For example, a nanoparticle that is engineered to circulate through a cancer patient's body for a long period of time is more likely to encounter a tumor, However, that nanoparticle may not be able to stick to tumor cells once it finds them. Likewise, a particle that is engineered to adhere tightly to tumors may not be able to circulate in the body long enough to encounter one in the first place. ... the scientists demonstrated in their experiments that a tumor growing in a mouse can be arrested and then shrunk."

Link: http://www.physorg.com/news182629947.html

Telomeres are the protective caps of material at the ends of your chromosomes. As normal somatic cells divide, telomeres become shorter and shorter until the lack of telomere length halts the cell division process - in effect this limits normal cellular replication. But stem cells, the source of our tissues during growth and maintainers of adult tissue, use the enzyme telomerase to keep their telomeres long, enabling them to divide long past the point at which somatic cells would halt. In addition, cancers are spawned of mutant cells that hijack this telomerase mechanism in order to multiply rapidly and endlessly.

If we are to engineer an end to aging, we must engineer an end to cancer along the way. I believe that robust cancer therapies based on targeting mechanisms presently under development in the laboratory will be sufficient to this end. Or at least sufficient for long enough to enable far more advanced technologies to be developed. But biomedical gerontologist Aubrey de Grey of the SENS Foundation proposes a more radical and compete solution to the problem of cancer as a part of his Strategies for Engineered Negligible Senescence: whole-body interdiction of lengthening of telomeres, or WILT. In essence, if you remove all possibility of a cell being able to lengthen its telomeres, cancer will never happen. I have posted on the topic of WILT in the past:

This is a very ambitious but potentially far more comprehensive and long-term approach to combating cancer than anything currently available or in development. It is based on the one inescapable vulnerability that all cancer cells share in common: their absolute need to renew their telomeres, the long stretches of gibberish DNA that cap their chromosomes.

One of the many challenges inherent in blocking telomere lengthening is that telomerase is not the only path. There is another method of generating longer telomeres that must also be removed or sabotaged; it is known as alternative lengthening of telomeres, or ALT. I noticed a paper recently that provides a good overview of what is presently known about ALT:

In most human somatic cells, telomerase activity is very low. This leads to gradual telomere shortening which, in turn, can trigger replicative senescence, a process where a cell with critically short telomeres permanently exits from the cycle of division. In contrast, the great majority of cancers are able to maintain their telomere lengths indefinitely. In most cases, this occurs because of an up-regulation of telomerase activity. However, some cancers maintain their telomere lengths through a telomerase-independent process termed alternative lengthening of telomeres (ALT). The telomeres in ALT cells are highly heterogeneous, often extremely long and appear to be maintained through homologous recombination.

Much of what is known about recombinational telomere elongation (RTE) comes from studies in yeast, particularly Saccharomyces cerevisiae and Kluyveromyces lactis. Yeast mutants lacking telomerase undergo growth senescence and most cells eventually die. The cells that survive senescence are found to have lengthened telomeres through a process dependent upon RAD52 and other genes involved in homologous recombination. Recombination in and near telomeres is greatly increased when the telomeres become short. Work in both K. lactis and S. cerevisiae has suggested that RTE lengthens telomeric repeat arrays (Type II RTE) through a "roll and spread" mechanism. According to this model, a small duplex DNA circle consisting of telomeric repeats (t-circle), formed by recombination in cells with critically short telomeres, is used as a template for extending at least one telomere, through a rolling circle copying event. Once one long telomere is formed, other telomeres become extended by copying its sequence.

Interesting, the things that take place in our cells.

Basenko, E., Cesare, A., Iyer, S., Griffith, J., & McEachern, M. (2009). Telomeric circles are abundant in the stn1-M1 mutant that maintains its telomeres through recombination Nucleic Acids Research, 38 (1), 182-189 DOI: 10.1093/nar/gkp814

Via In the Pipeline, I see that research groups are suggesting that some of the data for resveratrol (and other possible calorie restriction mimetics developed by Sirtris) is invalid, and previously reported beneficial effects on mice cannot be replicated: "Last fall, a group at Amgen published a study suggesting that some of the SIRT1/resveratrol connections might be due an an experimental artifact caused by a particular fluorescent peptide. Now a group at Pfizer has piled on in the Journal of Biological Chemistry. They're looking over resveratrol and a series of sirtuin activators described by the Sirtris group in Nature. And unfortunately, they also find trouble due to fluorogenic peptides. The TAMRA fluorophore on their peptide substrates seems to pervert the assay. While the Sirtris compounds looked like activators initially, switching to the native peptide substrates showed them to be worthless. Further study (calorimetry) showed that the activator compounds bind to a complex of SIRT1 and the fluorescent peptide substrate, but not to SIRT1 itself (or in the presence of native substrate without the fluorogenic group). That's not good." The researchers also failed to replicate beneficial health effects in their studies on mice. "Basically, these folks have thrown down the gauntlet: they claim that the reported Sirtris compounds do not do what they are claimed to do, neither in vitro nor in vivo, and are worthless as model compounds for anything in this area of study."

Link: http://pipeline.corante.com/archives/2010/01/12/the_sirtris_compounds_worthless_really.php

We should expect gene variants associated with human longevity to also be associated with lowered risk of age-related disease. Here is one example: "In a 2003 study, Dr. Lipton and his colleagues identified the cholesteryl ester transfer protein (CETP) gene variant as a 'longevity gene' in a population of Ashkenazi Jews. The favorable CETP gene variant increases blood levels of high-density lipoprotein (HDL) - the so-called good cholesterol - and also results in larger-than-average HDL and low-density lipoprotein (LDL) particles. The researchers of the current study hypothesized that the CETP longevity gene might also be associated with less cognitive decline as people grow older. To find out, they examined data from 523 participants from the Einstein Aging Study, an ongoing federally funded project that has followed a racially and ethnically diverse population of elderly Bronx residents for 25 years. At the beginning of the study, the 523 participants - all of them 70 or over - were cognitively healthy, and their blood samples were analyzed to determine which CETP gene variant they carried. They were then followed for an average of four years and tested annually to assess their rates of cognitive decline, the incidence of Alzheimer's disease and other changes. ... We found that people with two copies of the longevity variant of CETP had slower memory decline and [a] 70 percent reduction in their risk for developing Alzheimer's disease."

Link: http://www.eurekalert.org/pub_releases/2010-01/aeco-gh010710.php

Sooner or later, we'll all develop cancer. The only people who fail to develop cancer are those struck down by other causes; you should think of cancer as less a disease and more a natural consequence of mammalian biochemistry, a form of runaway failure of cellular processes that are normally vital to health and longevity. The biochemical damage that occurs with aging makes the failures that cause cancer ever more likely to occur, and also renders the immune system ever less able to destroy cancerous cells in their earliest stages. If you're a mature individual, the chances are that your immune system has destroyed a few very early stage cancers already, and you are none the wiser. But that defense system is slowly failing with age, just like the rest of your biology.

I should add that there are, as ever in biology, a few noteworthy exceptions to my sweeping statements above, such as the naked mole rat. But even there I'd wager these animals would develop cancer if they but lived long enough - they just have a better first line of defense than we do.

Given the apparent inevitability of cancer, why am I unconcerned? In short, I have perhaps two or three decades to go before I enter the high risk years for developing cancer. I am confident that by that time, very effective targeted cancer therapies with few side-effects will be widely available. Consider that:

• Cancer research is perhaps the most highly funded and widely supported of any modern distributed medical development program.
• Over the past five years, very impressive anti-cancer technology demonstrations have been made. These are a new breed of targeted therapy, built using the latest tools of modern biotechnology. Immune cells, viruses, or nanoparticles are engineered to home in on the distinctive surface chemistry of cancer cells - and then destroy them.
• With a sufficiently good targeted therapy, even aggressive metastasis of cancer becomes a minor inconvenience. Those spreading cancer cells will still be found and killed, no matter where they are in the body.
• The new breed of cancer therapies are as well placed as any new biotechnology could expect to be to make their way through the horrors of an FDA approval process. A decade and many fortunes will be lost to regulation, but commercial therapies will emerge - and if not in the US, elsewhere in the world. Medical tourism to destinations outside the US will itself be a huge and thriving economy a decade from now if the FDA continues its present path.

Cancer is, by and large, not a rapid or unexpected killer. It is certainly not faster than the time taken to apply a targeted therapy of the sort presently under development in the laboratory. Think of a worst case scenario: a brain cancer discovered late and already well into the process of metastasis. You started to have headaches and blurred vision, saw a physician, and learned that, without treatment, you only have a few months left to live. If that were today, you would have to come to terms with your fate and your ill luck. But in 2030, your status would place you at the head of the line for a clinical appointment, and within a week you would undergo an infusion of biological killing machines - viruses, assembled nanoparticles, or some form of natural or artificial cell - configured to recognize and slay your cancer. A month later, there isn't a trace left of your advanced tumor and its offshoots.

This is why I am not worried about cancer. The plausible future is one in which we will all develop cancer, and very few of us will be any more than slightly inconvenienced by it.

Yet another study to show that exercise likely does more to slow age-related mental degeneration than any presently available medical technology: "Moderate physical activity performed in midlife or later appears to be associated with a reduced risk of mild cognitive impairment, whereas a six-month high-intensity aerobic exercise program may improve cognitive function in individuals who already have the condition ... A total of 29 participants completed the study. Overall, the patients in the high-intensity aerobic exercise group experienced improved cognitive function compared with those in the control group. These effects were more pronounced in women than in men, despite similar increases in fitness. The sex differences may be related to the metabolic effects of exercise, as changes to the body's use and production of insulin, glucose and the stress hormone cortisol differed in men and women. ... In another report [a] total of 198 participants (median or midpoint age, 83 years) were determined to have mild cognitive impairment and 1,126 (median age 80) had normal cognition. Those who reported performing moderate exercise - such as brisk walking, aerobics, yoga, strength training or swimming - during midlife or late life were less likely to have mild cognitive impairment. Midlife moderate exercise was associated with 39 percent reduction in the odds of developing the condition, and moderate exercise in late life was associated with a 32 percent reduction. The findings were consistent among men and women."

Link: http://www.eurekalert.org/pub_releases/2010-01/jaaj-eaw010710.php

Via EurekAlert!: researchers have "revealed a previously unknown mechanism that may drive the early brain function deterioration of Alzheimer's victims, thus opening a new exploratory path in the quest for an Alzheimer's cure. ... Researchers have known for years that a substance called amyloid-beta gums up brain cells when it becomes too concentrated, because it forms damaging deposits on the cells known as plaques. These prevent normal electrical signal generation in the cells, eventually killing them. That drives the memory loss and other problems that plague Alzheimer's sufferers. Most Alzheimer's studies have focused on brain cells already damaged by amyloid-beta or the effects of high concentration of amyloid-beta. [This study] instead explored impacts of very low amyloid-beta concentrations on healthy cells in an effort to mimic the earlier stages of Alzheimer's. ... though there are no outward signs of damage, exposure to moderate amyloid-beta concentrations somehow prevents electrical signals from traveling normally through the cells. Because the effect is seen in otherwise healthy cells, [researchers believe] the team may have uncovered a critical process in the progression of Alzheimer's that could occur before a person shows any known signs of brain impairment."

Link: http://www.eurekalert.org/pub_releases/2010-01/uocf-uad010710.php

As we inch our way into 2010, let me point out a worthwhile fundraising project that I think you should strongly consider help to achieve its goals. Last year a few earnest folk started and publicized a Facebook Cause, a group pledge that aims to gather 10,000 members in support of the longevity research carried out by the SENS Foundation. This research aims to reverse critical biochemical changes that cause age-related degeneration, frailty, and disease, and thereby eliminate suffering and restore the aged to health:

SENS Foundation would like to draw your attention to an exciting initiative organised by a group of our supporters. The 10,000 people, $1 million to defeat aging Cause on Facebook asks each member to pledge just $100, which becomes payable once a total of 10,000 individuals have made the same pledge.

Those 10,000 donations will provide SENS Foundation with $1 million of additional funding, which will support our critical research into defeating the diseases and disabilities of aging. Over the course of 2010 we intend to increase funding to our LysoSENS program and ramp up work on MitoSENS, as well as continuing to pursue our work on atherosclerosis, immunosenescence, and macular degeneration.

I am impressed to note that the Cause has assembled more than 1600 pledges to donate $100, which I think shows that the stated goal of 10,000 supporters is viable and plausible. Achieving this end is within the capabilities of our extended community - those who support more research into extending healthy life spans, support reversing the effects of aging, and who have proven adept at persuading others to this viewpoint. Further, I agree completely with the Cause founders' reasons for fundraising for the SENS Foundation:

Since we believe SENS to be the only feasible set of strategies that could defeat age related disease and disability within our lifetime, funding SENS research is the best possible use of the donations our cause page will raise.

When it comes down to it, there are two horses we could back in modern longevity science. There are researchers who seek to change the operation of metabolism in order to slow down aging by slowing the rate at which damage occurs, and there are researchers who seek to reverse aging by repairing that biochemical damage caused by metabolism. If you look back in the Fight Aging! archives, you'll find that I explain why this is a very significant difference, and why we should support attempts to reverse aging over attempts to merely slow aging. In essence:

[Changing human metabolism to slow aging] does next to nothing for people who are already age-damaged to the point of disease and frailty.

[In addition], it is likely to be easier and less costly to produce rejuvenation therapies [to reverse aging] than to produce a reliable and significant slowing of aging. A rejuvenation therapy doesn't require a whole new metabolism to be engineered, tested, and understood - it requires that we revert clearly identified changes to return to a metabolic model that we know works, as it's used by a few billion young people already.

Those rejuvenation therapies will be far more effective than slowing aging in terms of additional years gained, since you can keep coming back to use them again and again. They will also help the aged, who are not helped at all by a therapy that merely slows aging.

But for a variety of poor reasons, today we find that attempts to change human metabolism to merely slow aging are the dominant paradigm for large scale funding of longevity research. If we want to live to see greatly extended healthy lives, and the frailties of aging repaired, then this state of affairs must be changed. That change starts right here, by deciding to support the better approach to engineering human longevity: repairing the damage of aging, and thereby reversing aging.

So sign up for the Cause, and be one of the 10,000!

From Nanowerk: "Proteins are the most important molecules inside our body. There are thousands of [types of] proteins in a single cell alone and they control our physiological reactions, metabolism, cellular information flow, defense mechanisms - pretty much everything. No wonder then that most human diseases are related to the malfunctioning of particular proteins. In contrast to gene therapy - where a gene is placed inside a cell to either replace a defective gene or to increase the amount of a specific gene in order to produce a higher amount of a desired protein - protein therapy works by directly delivering well-defined and precisely structured proteins into the cell to replace the dysfunctional protein. This approach avoids the difficulties and potential problems of gene therapy and is generally considered the most direct and safe approach for treating disease. The problem with protein therapy, which limits its practical use in medicine, is the mode of delivery. Administration of proteins via oral, intravenous, intra-arterial, or intramuscular routes show low delivery efficiency and often the therapeutic protein is metabolized or cleared before it can enter the target tissue. A team of scientists at UCLA has now demonstrated a general, effective, low-toxicity intracellular protein delivery system based on single-protein nanocapsules. This work opens a new direction not only for protein therapy but also for cellular imaging, tumor tracking, cosmetics and many other applications."

Link: http://www.nanowerk.com/spotlight/spotid=14262.php

Here is an open access review of what is presently known of the ways in which cellular senescence contributes to aging: "Cellular senescence is a mechanism that induces an irreversible growth arrest in all somatic cells. Senescent cells are metabolically active but lack the capacity to replicate. ... While induction of senescence is considered a major natural barrier against the uncontrolled proliferation characteristic of cancer, accumulation of senescent cells contributes to the process of aging and might promote tumor development. Senescent cells that appear to be resistant to apoptosis might be involved in the general organ dysfunction associated to aging and eventually promote cancer. It is widely accepted that the decline of organs and tissue function observed to occur with aging is associated with the accumulation of senescent cells. ... increased genomic instability is associated to inefficiency in DNA double strand repair ability of presenescent and senescent cells accumulating with aging. In addition, senescent cells might favor a [pro-cancer] tissue environment by secreting growth factors, extracellular matrix components and inflammatory cytokines that disrupt tissue integrity. Therefore, it has been suggested that senescence contributes to the process of aging and protects cells from uncontrolled growth makes it a cellular process beneficial or detrimental depending on the age of the organism. This suggests that senescence is an antagonistically pleiotropic phenomenon. For this reason senescence has been ironically defined as the Dr Jekyll and Mr. Hyde of aging." Therefore we should use targeted cell killing therapies to remove senescent cells.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2802848/

The Science for Life Extension Foundation is the Russian group behind the Science Against Aging initiative. Vladimir Skulachev, whose work I occasionally discuss here is amongst their advisory board, as are researchers you might more readily recognize such as Aubrey de Grey and Leonid Gavrilov. You might think of the Science for Life Extension Foundation as a sort of Russian language version of the Methuselah Foundation and SENS Foundation: similarities include strong relationships with the biogerontology community, advocacy initiatives driven by strong personalities from the transhumanist community, and fundraising for the research required to extend healthy human lives. This sort of message, and the goal of radical life extension, is apparently more popular in Russian culture than in the English-language West. (Not that this is saying much - it's an uphill battle for advocates in any culture to raise significant funds for engineered longevity research).

In any case, allow me to direct your attention to a rather well done English langage video from Maria Konovalenko, one of the Program Coordinators at the Science for Life Extension Foundation.

I'd like to tell you about a major issue. Its your personal concern. It's the concern of your nearest and dearest, of all the people living on the planet. It's inevitable absolutely for everybody! But surprisingly little is known about it. Its not a common practice to talk about this problem and moreover to try to solve it. What do you think about 30 million lives? Just imagine that all the people in Denmark, Austria, Finland, Israel and New Zealand disappeared in one year. Would you consider it a problem? But no one pays attention.

Quite so.

UPDATE 05/31/2010: As noted in a more recent post, Konovalenko also writes a blog focused on advocacy for engineered longevity that you may find interesting.

Infrastructure matters - as the cost and difficulty of commonly used techniques fall, more progress is accomplished more rapidly. Here is a promising development in stem cell research infrastructure: "Biologists have developed an efficient way to genetically modify human embryonic stem cells. Their approach, which uses bacterial artificial chromosomes (BACs) to swap in defective copies of genes, will make possible the rapid development of stem cell lines that can both serve as models for human genetic diseases and as testbeds on which to screen potential treatments. ... This will help to open up the whole human embryonic stem cell field. Otherwise, there's really few efficient ways you can study genetics with them. ... BACs are synthesized circles of human DNA, which bacteria will replicate just like their own native chromosomes. Commercially available BACs can be modified within bacterial cells to insert altered copies of specific genes. Once the modified BACs are introduced into human cells, they will sometimes pair up with a matching segment of a human chromosome and swap segments of DNA, a process called homologous recombination. ... Using BACs, the team was able to substitute modified genes in 20 percent of treated cells. Standard methods of genetic modification typically achieve modification in fewer than one percent of cells."

Link: http://www.eurekalert.org/pub_releases/2010-01/uoc--bde123009.php

Here is more on the charity seeking to develop the granulocyte therapy pioneered by Zheng Cui: "While researching mouse sarcoma 180 (S180) cells in 1999, Zheng Cui, Mark Willingham, and colleagues at Wake Forest University happened upon something incredible - a mouse innately resistant to cancer. Several generations of offspring of this spontaneous regression/complete resistance (SR/CR) animal have also proven to be cancer-proof, therefore suggesting a genetic link. Further study indicated that immune cells, such as macrophages, could be derived from the resistant mice and then transferred into non-resistant animals to protect them from advanced cancers. Out of an interest in Cui's novel work came the Direct Oncology (DO) Foundation, a 501(c)(3) charity that is banking on the potential for human cancer treatments based on innate oncological immunity. The DO Foundation now seeks to raise $100,000 to fund the complete sequencing of 6-10 cancer-resistant mice genomes ... To reach this goal, the foundation has enlisted the help of Livly, a non-profit organization based in Mountain View, CA, whose mission is to advance the development of cures for major diseases. ... There are a small number of [human] families who appear to have a genetic resistance to cancer, in the same way that Cui's mice are resistant to cancer ... The identification of the single nucleotide polymorphisms (SNPs) responsible for the cancer immunity observed in Cui's mice is crucial in order to determine whether orthologous SNPs exist in humans."

Link: http://www.biotechniques.com/news/Charity-aims-to-raise-100K-to-sequence-cancer-resistant-mice/biotechniques-185862.html

The view that the processes of aging are programmed fits well with the school of gerontology that believes the only viable path forward to increased human longevity is to slow down aging through the manipulation of metabolism. Changing the program, in other words. Programmed aging is one set of theories that can be built atop the evolutionary consideration of aging; that life span in any given species is what it is because of selection pressure, and some combination of biological programs that produce that life span will be selected for. But whether and to what degree aging is programmed is a hotly debated topic, with reputable researchers arguing the points on both sides. There are a good many scientists from the "slow aging" camp who don't support programmed aging theories.

You might want to head back into the archives for the posts in which I've mentioned the programmed aging viewpoint in the past:

• Programmed Aging
• Why Programmed Aging is an Attractive Idea
• Bear Consumption and the Appearance of Programmed Aging

Over at PubMed Steven Austad provides a good argument for considering aging as unprogrammed decay rather than a programmed process in the body. This sort of high level thinking about processes and purpose - like the reliability theory of aging - is an important part of effectively directing the research community. "Aging, except in exceptional cases such as the rapid decay and death of Pacific salmon, is not design but decay. The decay of senescence is not due to natural selection's designing hand, but to its absence. The empirical difference between programed and nonprogramed senescence becomes evident when comparing the stereotypical steps leading to death in salmon contrasted with the lack of such stereotypy in most organisms such as humans and mice." ...

On the other side of this debate Valter Longo and Paola Fabrizio have authored a paper suggesting that aspects of aging in mammals may indeed be programmed. "Programmed human aging is just a possibility. We don't know whether it's true yet or not. But if aging is programmed in yeast, and the pathway is very similar, then isn't it possible that humans also die earlier than they have to?" This discussion is still at the level of educated hand-waving - much more work is needed to settle it one way or another. My suspicion is that the genetics and biochemistry will turn out to be more complex than a simple yes or no.

My attention was recently directed to a website devoted to the background science that supports programmed aging. I think it's worth taking a look:

There are two main aging concepts as applied to humans and most other mammals. The programmed aging theories, also known as adaptive or active aging theories, propose that mammals purposely deteriorate with age because a limited life span provides evolutionary benefits. Non-programmed theories, also known as passive or non-adaptive theories, contend that a limited life span is entirely adverse and that aging is not genetically programmed for the purpose of causing deterioration or death.

Programmed theories provide a better match to observations, but are based on newer concepts regarding evolution mechanisms. Non-programmed theories have difficulty explaining many observations but are compatible with older evolutionary mechanics concepts.

This issue is important because most people in developed countries now die of age-related diseases. Understanding, preventing, and treating these diseases requires that we understand the aging process.

I agree with the general sentiments on the importance of aging research. However, I don't see that the evidence for programmed aging theories is as good as the author believes it to be, nor that a full understanding of aging is required to prevent and treat age-related diseases. The debate over programmed aging is yet another example of the way in which Aubrey de Grey's SENS approach shines by cutting straight to the desired goal of extending life. The scholarly divisions over theories of aging will continue for the foreseeable future, as thousands of researchers add their individual contributions to our knowledge of aging human biochemistry. But if instead of working on full understanding, we rather aim to identify and reverse all the specific age-associated biochemical changes that are the root cause of degenerative aging, then for this purpose it doesn't matter whether aging is programmed or not.

As outlined at the SENS Foundation, we can be reasonably certain that all the biochemical causes of aging that are important across the present human life span have been identified for more than 20 years. No new root causes in our biochemistry have been discovered in that time, despite a blossoming of biotechnology. Further, researchers presently know enough to outline ways to reverse all of these changes, and the required research and development programs are in some cases already underway. Advances in our general knowledge of aging and metabolism should generally be helpful - there's no such thing as useless knowledge in the life sciences - but are not required for progress at this point. If a resolution on programmed versus non-programmed aging occurred tomorrow, it would make no difference to the SENS approach to reversing aging.

A high level look at the search for the roots of regeneration in lower animals: "Each year, thousands of Americans lose fingers, hands or entire limbs in terrible accidents. Prosthetics can help amputees regain some function, and successful hand transplants have recently been achieved. But wouldn't it be great if humans could simply regrow missing parts on their own? Within the space of a generation, this seemingly superhuman power might become a reality, scientists say, and people may have a lowly amphibian to thank for it. Among the world's varied creatures, a Mexican salamander called the axolotl appears best at regrowing whole limbs lost to injury. And researchers are hot on the trail of finding out what the axolotl has that humans don't. ... Other animals can regrow complex segments of themselves (many fish regrow lost fins, for example) and the common frog has potent regenerative powers as a tadpole but loses them mysteriously as it matures. ... work with both the axolotl and the frog have turned up interesting clues to regeneration. ... [researchers are] busy comparing regenerative processes in the axolotl to those found in the tadpole but not in the mature frog. ... That will give us a handle, we hope, on why the frog loses the power of regeneration." Which should lead to insight into why humans do not regenerate, and how to induce that regeneration artificially.

Link: http://www.businessweek.com/lifestyle/content/healthday/634371.html

From GOOD: "How long do you think you'll be around for? Ninety years? One hundred and twenty? Aubrey de Grey, a biogerontologist and Cambridge-trained Ph.D. who studies aging, thinks we could engineer techniques that reverse the wear on our bodies by replacing lost cells in our bones and hearts and even tweaking the cells themselves to prevent their degeneration. If de Grey is right, these therapies could help us live for hundreds - if not thousands - of years. ... In my view, we probably can't [slow down aging] much at all. All we can do is reverse it. Yes, I know it seems paradoxical that reversal would be easier than slowing, but if you think about it, that's what we do with simple manmade machines such as cars or airplanes: We do periodic repair and maintenance. That's how we'll delay the ill health that aging eventually causes. ... It's impossible to say for sure [as to what social changes will result from radical life extension], but I think the changes would actually be rather slight. We don't make career or life choices today in early adulthood on the basis of only having 50 more years to live."

Link: http://www.good.is/post/going-de-grey

As a general rule, human organizations and human initiatives are not very long-lived. Those that make it out of the nascent stage in which 90% fail or are abandoned don't tend to last much longer than five to ten years. They either calcify and are superseded by new, more relevant ventures, or change so radically as to be effectively a different organization. Those human organizations that have lasted for decades in a fairly consistent form - many of which are familiar to all of us, I'm sure - are outliers, and very unusual.

This line of thinking applies just as much to advocacy as any other form of endeavor. You should expect that the organizations you support today - and that did not exist five years ago - will not exist five years from now. They will use your donations to important accomplish goals, help move matters forward, and create a legacy - and will then be replaced by the next generation, who will pick up that legacy and continue to work on progress. So, I think, it behooves any organization that has made it to the five year or ten year mark to consider its legacy. Better to think that through and be working to a plan while yet strong and well supported.

Legacies in advocacy for medical research in general, and longevity science in particular, tend to be a matter of information and people. Research produces life science data that moves us closer to the goal of a cure for aging. Educational materials translate the raw science and explain it to laypeople. The act of advocacy grows the research community, persuades supporters, and cultures alumni, all of whom will long outlast the organization that first nurtured their views. These folk are the seeds and supporters of the next generation of advocacy groups.

I've been poking away at the metaphorical keyboard of longevity science advocacy for near a decade now. Where did the time go? I'm just about old enough to instinctively think of 2010 as the mysterious science-fiction future ... and yet here we are, time-travelers, the lot of us. I have no plans to stop what I'm doing here at any time in the foreseeable future, but as I point out above, there are many good reasons to sort out your legacy while you're ahead of the game.

What is the legacy of Fight Aging! and the Longevity Meme? That is a good question. We might think of the history of folk persuaded or inspired by what they read here, some of the most generous of whom will forever remain mysterious. But that is all happened and done; I need to do little but give credit where it is due, to the many people who chose to donate, volunteer, or start their own initiatives in support of longevity science. So let us turn to the other side of the coin, the data. One thing I'm still missing is a good distillation of the Fight Aging! message. Something along the lines of:

Here is all that researchers know about aging. See how it all fits together and makes sense? Now here is a practical scientific plan to stop aging in its tracks, and a few useful suggestions for long term health while we're at it. Here is how you can best help the plan to stop aging, which we could complete in our lifetimes if we all take this seriously. What are you waiting for? People are dying, more from this one cause than all others combined.

If you've been reading for a while, you'll know the score. But I think that this message needs to be better framed and centralized. That is a good legacy, because this message can never be said often enough, well enough, or in too many different ways.

Even in advance of the full blossoming of regenerative medicine as a field, early progress in the laboratory can still lead to viable, useful therapies. Take this, for example: "Not even the most advanced experimental techniques have been able to restore nerve function to sites far from an injury. Smith thought he might facilitate fast nerve regeneration by using lab-grown nerves as a kind of scaffold that doctors could place where a patient's nerve has died. Though the implanted nerve would not transmit signals itself, the presence of the living tissue could guide the body's regenerating nerve back to the injury site while keeping the detached nerve sheath intact. To get the engineered nerves to grow long enough to span the injured area by the time they were transplanted, he applied slight, gradually increasing physical tension; this process, he found, encouraged nerves to grow almost 100 times as fast as scientists had believed possible. Smith and his team introduced these engineered nerves into rats that had part of their leg nerves cut out. Within four months, as the natural nerves began to regenerate in the rats' bodies, the transplants had helped guide those nerves across the chasms, successfully restoring function to the rats' legs. ... so far, the longest nerve they have grown is approximately 10 centimeters. ... Smith hopes to start testing the human-derived implants in patients with nerve injuries in the next two years."

Link: http://www.technologyreview.com/printer_friendly_article.aspx?id=24105

From Singularity Hub: "Researchers [are] hoping to save limbs and lives with the creation of their new artificial artery. Unlike current artery replacements, this grafting substance was created using nanotechnology and can pulse with the natural movements of the body. That pulsing will allow the polymer tube to be used in very small grafts, giving hope that damaged arteries which would normally lead to amputations or heart attacks can now be treated. ... The new artificial artery material [is] a polymer which has been embedded with different types of special molecules. Some of these molecules aid circulation, others encourage stem cells to coat its walls. That coating is very important and may allow the artificial tissue to bond better with the body and promote long term health. Most importantly though, the design of the artificial vascular tissue is resistant to clotting and can pulse." As researchers become more proficient in engineering nanoscale-featured scaffold material to support tissue regrowth, we will see more varied applications of the technology, like this one.

Link: http://singularityhub.com/2010/01/05/nanotechnology-creates-artificial-artery-for-clinical-trials/

All Fight Aging! posts - and the archives - are now published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite Fight Aging! content in any way you see fit, the only requirements being that you (a) link to the original, (b) attribute the author, and (c) attribute Fight Aging!. Have at it.

Fight Aging! has in fact been Creative Commons licensed for a long time, but under a license that restricted commercial reuse and derivative works. That it was that way for a good few years is more a measure of inertia than representative of my views on the topic of licensing and ownership of data in this brave new age of copy, paste, edit, and republish. In essence, I think it's sensible not to write laws that can't be enforced, and - for many of the same underlying reasons - it is either charmingly old-fashioned or hopelessly out of touch to ask people to refrain from doing whatever they like with data published to the internet.

I do think that the whole notion of intellectual property as an edifice of government is a great malignancy forced upon human creativity. It isn't required for common politeness on the matter of respecting an author's work, nor for businesses to be built upon that work. But it does serve to stifle vital competition, hold back progress, and breed a legion of rent seekers, ranging from the high-tech patent troll to Walt Disney's legacy and beyond. Unfortunately a great deal of medical science is also well infected by intellectual property, and the damage to progress is done there as well.

So one should act as one talks. The Attribution license is a good compromise between the natural state of do as you will with the data and the impulse to offer a modicum of respect for the original author. It's a request to be a good citizen and generally decent human being if you find value in anything published here, and want to build upon it.

Exercise is undeniably good for long term health, far better than any medical technology presently available - but why? Here is an overview of some of what is now known: "Physical activity has long been known to bestow such benefits as helping to maintain a healthy weight and reduce stress, not to mention tightening those abs. Now, a growing body of research is showing that regular exercise - as simple as a brisk 30- to 45-minute walk five times a week - can boost the body's immune system, increasing the circulation of natural killer cells that fight off viruses and bacteria. ... No pill or nutritional supplement has the power of near-daily moderate activity in lowering the number of sick days people take ... Regular exercise has been shown to combat the ongoing damage done to cells, tissues and organs that underlies many chronic conditions. Indeed, studies have found exercise can lower blood pressure, reduce bad cholesterol, and cut the incidence of Type 2 diabetes. ... exercise-induced changes in the body's immune system may protect against some forms of cancer. ... Researchers are also investigating whether exercise can influence aging in the body. In particular, they are looking at whether exercise lengthens telomeres, the strands of DNA at the tips of chromosomes."

Link: http://online.wsj.com/article/SB20001424052748704350304574638331243027174.html

From the Wall Street Journal: "Scientists looking for ways to repair damaged cartilage - a leading cause of osteoarthritis - are employing horses to test a new method of tissue regeneration that uses concentrated stem cells. ... but there isn't any good way of detecting cartilage breakdown until the cartilage is broken or lost or osteoarthritis develops. And though cartilage-repair surgery has improved over the years, the repaired scar tissue isn't as strong as real cartilage and isn't able to bear the same weight. ... For about two decades, [researchers] have been trying to improve treatment by regenerating cartilage tissue. While many scientists have been successful at creating new tissue in the lab, they haven't been able to grow cartilage in humans. The main challenge is that the structure of cartilage, which is critical to its supporting weight, is hard to mimic ... It's easy to generate a piece of tissue, but it's not so easy to generate a tissue that works ... [researchers] hypothesize that the more stem cells that are used to repair cartilage at the site of the damage, the better the regeneration of the tissue should be. They first create a dime-sized cartilage injury in the horse's stifle joints, which resemble the human knee, and then test two different ways of concentrating the stem cells after taking them from the horse's own bone marrow."

Link: http://online.wsj.com/article/SB10001424052748704350304574638132988984884.html

Diet is the key to a great many evolution-driven adaptations in the machinery of our bodies; changes in dietary intake cause the controlling mechanisms of metabolism to sit up and take notice. In particular, lowering the intake of calories by 30-40% or so, and while maintaining an optimal level of micronutrients, causes metabolic processes to operate in a mode that extends life and provides numerous other health benefits. Practiced as a lifestyle, this is known as a calorie restriction diet, and the laboratory version for animals is often called dietary restriction. Calorie (or dietary) restriction provides similar health and longevity benefits in almost every species tested to date.

Diet, of course, is more than a simple count of calories. Composition of food varies enormously, here thinking in terms of the proportions of different proteins, carbohydrates, fats, and so forth. This matters. Take methionine for example: this is one of the essential amino acids that we humans, and other mammals, cannot create and so must obtain through our diet. Through experimentation, researchers are starting to see that restricting the content of methionine in the diet of mammals - while leaving the calorie count unchanged - has many of the same results as restricting overall calories. Is the biological switch for the better state of human metabolism, that brought on by calorie restriction, essentially no more than a methionine sensor?

This is an interesting question, and one still up for debate. The experimentation in rats continues, as illustrated by recently published research. Here the focus is largely on mitochondrial function and damage. To see why this is important you might want to head back into the archives to read about the link between mitochondria, the free radicals they produce, and aging. But on with the paper:

Eighty percent dietary methionine restriction (MetR) in rodents (without calorie restriction), like dietary restriction (DR), increases maximum longevity and strongly decreases mitochondrial reactive oxygen species (ROS) production and oxidative stress. Eighty percent MetR also lowers the degree of membrane fatty acid unsaturation in rat liver.

Mitochondrial ROS generation and the degree of fatty acid unsaturation are the only two known factors linking oxidative stress with longevity in vertebrates. However, it is unknown whether 40% MetR, the relevant methionine restriction degree to clarify the mechanisms of action of standard (40%) DR, can reproduce these effects in mitochondria from vital tissues of strong relevance for aging. Here we study the effect of 40% MetR on ROS production and oxidative stress in rat brain and kidney mitochondria.

Male Wistar rats were fed during 7 weeks semipurified diets differing only in their methionine content: control or 40% MetR diets. It was found that 40% MetR decreases mitochondrial ROS production [and] lowers oxidative damage to kidney mitochondrial DNA

...

Forty percent MetR, differing from 80% MetR, did not inhibit the increase in rat body weight. These changes are very similar to the ones previously found during dietary and protein restriction in rats. We conclude that methionine is the only dietary factor responsible for the decrease in mitochondrial ROS production and oxidative stress, and likely for part of the longevity extension effect, occurring in DR.

So there is one research group who think that the important parts of calorie restriction are based upon a methionine sensing mechanism. Given the research to date, I'll wager that there is a great deal of money to be made in establishing a competitively priced and reasonable range of very low methionine foods for humans - if humans can tolerate methionine levels low enough to inhibit weight gain in addition to other benefits, and if very low methionine in humans works as we would expect given all the data on human calorie restriction.

If I had to take an educated guess at what is going on under the hood, I'd say that reduction in visceral fat is at the root of some of the benefits of calorie restriction - though perhaps not to the same degree as mitochondrial changes and enhanced autophagy. Removing visceral fat via surgery in mice has been shown to extend life, for example, and we know that excess fat causes harm in the long term through chronic inflammation. We shall see how it all pans out, as the researchers continue their work. But there's more than enough evidence to date for you and I to give serious thought to practicing calorie restriction as a lifestyle.

Caro P, Gomez J, Sanchez I, Naudi A, Ayala V, López-Torres M, Pamplona R, & Barja G (2009). Forty percent methionine restriction decreases mitochondrial oxygen radical production and leak at complex I during forward electron flow and lowers oxidative damage to proteins and mitochondrial DNA in rat kidney and brain mitochondria. Rejuvenation research, 12 (6), 421-34 PMID: 20041736

The Immortality Institute volunteers have put together an interesting article: "Current government projections may significantly underestimate the future life expectancy of Americans, according to new research from the MacArthur Research Network on an Aging Society published in The Milbank Quarterly. The research finds that by 2050 Americans may live 3.1 to 7.9 years longer than official government projections, resulting in sharply higher costs for government programs that serve older citizens. The findings are based on the premise that the risk of death in the coming decades will be reduced by accelerated advances in biomedical technology that delay the onset and progression of major fatal diseases or that slow the aging process." There is great uncertainty in actuarial projections in recent years, which reflects great uncertainty over the course of future biotechnology. It is clearly the case that vast improvements in life span are possible in a few decades with the right levels of funding and support - the big question is whether that funding and support materializes in time. That is the challenge facing advocates for engineered longevity.

Link: http://www.imminst.org/archive/articles/aging-america

The Detroit News looks at the Cryonics Institute: "Robert Ettinger, a former Wayne State University professor and Clinton Township resident, founded the institute more than 30 years ago. Unable to persuade scientists to preserve bodies at low temperatures after death in hopes of rejuvenation by yet-invented technology, Ettinger did it himself. The Cryonics Institute opened in Detroit in 1976 before moving in 1993 to Clinton Township.
For years, membership was in the single digits, but it has exploded 500 percent since 2000 to 830 worldwide folks who want to preserve themselves, DNA or pets. The facility has preserved 64 animals, mostly dogs and cats, but a few birds and a hamster.
Some credit the Internet for the growth. Others chalk it up to contemporary advances in science, including research into aging and disease, resuscitation after deep cooling and regenerative medicine. Joseph Kowalsky likens cryonics to 'an ambulance to the future' and thinks of it this way: Most people would have considered someone dead in the 1800s if they had dropped to the ground of a heart attack. But defibrillators and other technologies have evolved to normalize the heart and allowed many people to live. ... The whole question of cryonics is, when does somebody die? If you can hold someone in stasis, stop decomposition so that we can find out later with medical technology if the person is really dead. It may be that person needed some form of medication, gene therapy, things we may not have even heard of yet."

Link: http://www.detnews.com/article/20100104/LIFESTYLE03/1040344/Cryonics-believers-aim-to-return-from-dead

An interesting paper: "Many laboratory models used in aging research are inappropriate for understanding senescence in mammals, including humans, because of fundamental differences in life history, maintenance in artificial environments, and selection for early aging and high reproductive rate. Comparative studies of senescence in birds and mammals reveal a broad range in rates of aging among a variety of taxa with similar physiology and patterns of development. ... Individuals of potentially long-lived species, particularly birds, appear to maintain high condition to near the end of life. Because most individuals in natural populations of such species die of aging-related causes, these populations likely harbor little genetic variation for mechanisms that could extend life further, or these mechanisms are very costly. This, and the apparent evolutionary conservatism in the rate of increase in mortality with age, suggests that variation in the rate of senescence reflects fundamental changes in organism structure, likely associated with the rate of development, rather than physiological or biochemical processes influenced by a few genes. Understanding these evolved differences between long-lived and short-lived organisms would seem to be an essential foundation for designing therapeutic interventions with respect to human aging and longevity." You might compare this with the strong correlations in life span and mitochondrial structure between mammals, and other thoughts on birds, metabolic rate, and aging.

Link: http://www.ncbi.nlm.nih.gov/pubmed/20041859

A good survey of the next generation of cancer therapies can be found at Emergent Fool. I do not expect cancer to be a major threat to health in 2030 thanks to the development of robust cures for even late stage metastasis. "Biris and Zharov are making some exciting progress in using nanotubes to tag and then track cancer cells inside the body as they move around. They propose to kill the cancer cells by heating up the nanotubes using lasers ... The immune system is really good at identifying and killing cells behaving badly (although the majority of the time the immune system's targets are foreign invaders like viruses). But what if we could boost the immune system so that it was better able to deal with cancer cells? Essentially create a vaccine for cancer. ... Modifying genes, either by enhancing tumor suppressors or reducing tumor promotors, has been a popular appoach in recent years. Often the approach has been to focus on individually important genes or to try to find exhaustive sets of genes which, when modified appropriatly, stop cancer progression. ... De Grey proposes [that] the only real approach is [to] take specific steps to intervene on a regular basis so that somatic evolution stays in check and we don’t get the unregulated proliferation and invasiveness that is cancer. His WILT approach argues we achieve this by regulating the length of telomeres which are critical to the proliferation process. Carlo Maley says that the WILT approach should work, but the technology is a far way off and it's hard work to go this route. Maley believes that we may be closer on the prophylactic front with by boosting cancer-suppression genes, as in the super p53 approach."

Link: http://emergentfool.com/2009/12/28/approaching-a-cure-for-cancer/

Bioremediation is the process of using plants and microorganisms (or aspects of their biochemistry) to restore a damaged or polluted environment. Medical bioremediation applies this same philosophy to the aging body - many aspects of aging can be thought of as having roots in damage and pollution at the level of our cells and cellular machinery. For example, as we grow older, the garbage removal and recycling functions in our cells are increasingly hampered by a buildup of metabolic byproducts and other materials that cannot be broken down and removed by human biochemistry. As this state of affairs becomes progressively worse with time, other forms of biochemical damage - normally kept in check by recycling of damaged cellular components - start to spiral out of control. Developing bioremediation techniques to remove this unwanted chemical gunk is one of the lines of research funded by the SENS Foundation:

The most promising approach is to enable cells to break the junk down so that they don't fill up after all. This can be accomplished by equipping the lysosome with new enzymes that can degrade the relevant material. The natural place to seek such enzymes is in soil bacteria and fungi, as these aggregates, despite not being degraded in mammals, do not accumulate in soil in which animal carcasses are decaying, nor in graveyards where humans are decaying. This suggests that the micro-organisms present in soil have enzymes capable of breaking these aggregates down, and work now being carried on at Arizona State University, has already confirmed this analysis.

Removing this gunk should restore cellular garbage collection and recycling to youthful levels, which in turn will address a number of secondary causes of age-related degeneration. Such a result would in effect be a reversal of one contributing factor to aging, a therapy beneficial to everyone who is old and suffering - just the sort of thing we want to see more of. With that in mind, I note that the December 2009 issue of Rejuvenation Research is available online, and contains an update on the SENS Foundation bioremediation research under the title "Medical Bioremediation: A Concept Moving Toward Reality":

A major driver of aging is catabolic insufficiency, the inability of our bodies to break down certain substances that accumulate slowly throughout the life span. Even though substance buildup is harmless while we are young, by old age the accumulations can reach a toxic threshold and cause disease. This includes some of the most prevalent diseases in old age - atherosclerosis and macular degeneration. Atherosclerosis is associated with the buildup of cholesterol and its oxidized derivatives (particularly 7-ketocholesterol) in the artery wall. Age-related macular degeneration is associated with carotenoid lipofuscin, primarily the pyridinium bisretinoid A2E.

...

We report on an enzyme discovery project to survey the availability of microorganisms and enzymes with these abilities. We found that such microorganisms and enzymes exist. We identified numerous bacteria having the ability to transform cholesterol and 7-ketocholesterol. Most of these species initiate the breakdown by same reaction mechanism as cholesterol oxidase, and we have used this enzyme directly to reduce the toxicity of 7-ketocholesterol, the major toxic oxysterol, to cultured human cells. We also discovered that soil fungi, plants, and some bacteria possess peroxidase and carotenoid cleavage oxygenase enzymes that effectively destroy with varied degrees of efficiency and selectivity the carotenoid lipofuscin found in macular degeneration.

Look closely enough and all life science work starts to resemble the production process in a chemical factory. The next steps in this development cycle will involve establishing methods to introduce new enzymes into the body and determine which of those discovered are safe for use - which of course will require more fundraising. Because we humans can tolerate several decades of buildup in unwanted biochemicals like 7-ketocholesterol and A2E without undue harm, it seems plausible that a treatment similar to a course of drugs or chemotherapy will result at the end of the day. It will be a procedure that a person undergoes once every 20 years or so, in which the body is temporarily suffused with enzymes that clear out unwanted chemical gunk, thereby restoring the cellular recycling machinery of the lysosomes to pristine condition.

Schloendorn, J., Webb, T., Kemmish, K., Hamalainen, M., Jackemeyer, D., Jiang, L., Mathieu, J., Rebo, J., Sankman, J., Sherman, L., Tontson, L., Qureshi, A., Alvarez, P., & Rittmann, B. (2009). Medical Bioremediation: A Concept Moving Toward Reality Rejuvenation Research, 12 (6), 411-419 DOI: 10.1089/rej.2009.0917