Fight Aging!

A couple of calorie restriction research papers caught my eye today, and I thought I'd share. First out of the gate is a study of one of a number of gene products associated with and necessary for the benefits of calorie restriction, but whose mechanisms are still poorly understood:

NQR1 controls lifespan by regulating the promotion of respiratory metabolism in yeast

The activity and expression of plasma membrane NADH coenzyme Q reductase is increased by calorie restriction (CR) in rodents. Although this effect is well established and is necessary for CR's ability to delay aging, the mechanism is unknown.

Here we show that the Saccharomyces cerevisiae homolog, NQR1, resides at the plasma membrane and when overexpressed extends both replicative and chronological lifespan. We show that NQR1 extends replicative lifespan in a SIR2-dependent manner by shifting cells towards respiratory metabolism. Chronological lifespan extension, in contrast, occurs via a SIR2-independent decrease in ethanol production. We conclude that NQR1 is a key mediator of lifespan extension by CR through its effects on yeast metabolism.

The function of SIR2 in yeast is basically the same as SIRT1 in mammals, so it's probably the case that we can learn about the function of plasma membrane NADH coenzyme Q reductase in mammals by looking at NQR1 in yeast. As things move forward in the investigation of metabolism and calorie restriction, I wouldn't be surprised to see many different (possibly interacting) mechanisms that lead to essentially the same result, where cells are pushed towards greater levels of efficiency and recycling of damage.

But onwards to look at another study that provides confirmation of benefits resulting from the practice of calorie restriction.

The molecular architecture of myelinated peripheral nerves is supported by calorie restriction with aging

Peripheral nerves from aged animals exhibit features of degeneration, including marked fiber loss, morphological irregularities in myelinated axons and notable reduction in the expression of myelin proteins.

...

While calorie restriction (CR) is known to slow the aging process in the central nervous system, its influence on peripheral nerves has not been investigated in detail. To determine if dietary restriction is beneficial for peripheral nerve health and glial function, we studied sciatic nerves from rats of four distinct ages (8-, 18-, 29- and 38-months) kept on an ad libitum (AL) or a 40% CR diet.

Age-associated reduction in the expression of the major myelin proteins and widening of the nodes of Ranvier are attenuated by the dietary intervention

...

The improvements in nerve architecture with diet restriction, in part, are underlined by sustained expression of protein chaperones and markers of the autophagy-lysosomal pathway. Together, the in vitro and in vivo results suggest that there might be an age-limit by which dietary intervention needs to be initiated to elicit a beneficial response on peripheral nerve health.

The part about chaperones and autophagy refers to increased signs of cleanup of damaged cellular components taking place - which is thought to be one important way in which calorie restriction extends life. If you have less damage hanging around, on average, that damage will cause fewer additional problems. In this case it means nerves work better for longer.

Here's a paper on the biochemistry of comparatively long-lived bats and their resistance to oxidative damage. "Altered structure, and hence function, of cellular macromolecules caused by oxidation can contribute to loss of physiological function with age. Here, we tested whether the lifespan of bats, which generally live far longer than predicted by their size, could be explained by reduced protein damage relative to short-lived mice. We show significantly lower protein oxidation [in] Mexican free-tailed bats [relative] to mice, and a trend for lower oxidation in samples from cave myotis bats ... Both species of bat show in vivo and in vitro resistance to protein oxidation under conditions of acute oxidative stress. These bat species also show low levels of protein ubiquitination in total protein lysates along with reduced proteasome activity, suggesting diminished protein damage and removal [of damaged proteins] in bats. ... Together, these data suggest that long lifespan in some bat species might be regulated by very efficient maintenance of protein homeostasis." This sounds similar to current thinking on the naked mole rat - lots of oxidative stress, but little resulting protein damage, perhaps due to a different, more resistant structure of cell membranes.

Link: http://www.ncbi.nlm.nih.gov/pubmed/19244163

Some small but important collections of cells in our body are as old as we are - they are never replaced. So for those cells, we should be interested in what happens to them as they grow old with us. Here, Ouroboros looks at a recently uncovered phenomenon: "How do cells get rid of their garbage? ... slowly dividing or postmitotic cells must activate degradative pathways [e.g. autophagy] in order to prevent accumulation of potentially toxic damaged macromolecules and dysfunctional organelles. ... As an example, let’s consider the nuclear pore complex (NPC): it's [huge, complex, and topologically challenging] (the pore crosses the nuclear envelope and creates a hole in the process). Many NPC components aren't in dynamic equilibrium with cytosolic pools, so if we want to turn over any of these proteins we would have to somehow take out the entire NPC, repair the ensuing damage to the membrane, and then either re-insert the NPC (which I don't believe actually happens) or synthesize a new NPC to restore the lost import/export capacity. Unfortunately, new nuclear pores are probably only created during [mitosis as a part of cell division] .... So how do postmitotic cells turn over and degrade NPCs? The answer [is] that they probably don't. Instead, NPCs get old, and accumulate damage, and eventually stop doing their job."

Link: http://ouroboros.wordpress.com/2009/02/27/cellular-incontinence-in-postmitotic-cells-nuclear-pores-become-leaky-with-age/

This press release shows the potential for stem cell transplants to spur regeneration of the kidney: "Cytori Therapeutics, Inc. finds adipose tissue-derived stem and regenerative cells (ADRCs) significantly reduce mortality and improve renal function in an acute kidney injury model ... Acute kidney injury is a tremendous medical and financial burden to the healthcare system due to high mortality rates and the lack of effective therapies beyond supportive treatments. ... acute kidney injury was induced in 29 preclinical research subjects by occluding blood flow into and out of both kidneys for 38 minutes. Twenty minutes after reperfusion of the kidneys, ADRCs or saline only were injected intra-arterially. All subjects were assessed daily for 7 days for markers of kidney function (serum creatinine and blood urea nitrogen) and survival. After seven days, 100% of ADRC-treated preclinical subjects survived compared to only 57% in the control group. The ADRC-treated subjects also showed statistically significant improvements in kidney function ... In addition, substantial improvement in the histologic structure within the kidney was observed ... This study suggests that ADRCs significantly accelerate renal repair and preserve renal function, offering a potential therapeutic approach in renal reparative medicine."

Link: http://www.businesswire.com/portal/site/google/?ndmViewId=news_view&newsId=20090225005505&newsLang=en

The latest h+ magazine is a flash / PDF offering that contains a couple of short pieces that might be of interest for pro-longevity readers. Take a look at "Is Anti-Aging Medicine Coming to the Mainstream" and "Nanorobots in the Bloodstream," for example. The rest is of more general futurist interest this time around. "A microscopic-sized vessel injected into the bloodstream to destroy a lung tumor? [Researchers] have created such a vessel using live, swimming bacteria coupled to polymer beads. [They] have successfully steered these nanobots through the carotid artery of a living pig at 10 centimeters per second using magnetic resonance imaging (MRI). Their latest research shows they can do this with human blood vessels as well. The bacteria bots contain magnetic particles and swim using tiny corkscrew-like tails, or flagella. ... [researchers are] confident that a stealth seak-and-destroy mission could be completed against a tumor before the body's immune system wipes out the bacteria."

Link: http://hplusmagazine.com/digitaledition/2009-spring/

Here's a Russian press interview with biomedical gerontologist and radical life extension advocate Aubrey de Grey - which you might want to read through the Bable Fish translator.

UPDATE 02/28/2009: The Google translation is much better, so read that one instead.

[Interviewer] But - but as it is possible to interfere without the [full] understanding [of processes of aging]?

[Aubrey de Grey] We indeed interfere, without having precise knowledge about why cancerous tumor arose. Medicine generally frequently accomplishes the effective actions, not based on the precise knowledge. To take, for example, atherosclerosis, this "killer number is one" in the developed countries. We approximately visualize, as it is developed also it leads to what. But to mechanically destroy the cloth of atherosclerotic platelet we quietly can also without the knowledge about how this platelet it grows.

...

[Interviewer] But there are hundreds of fundamental scientists, connected with the problem experimentally. For example, they study the so-called "genes of aging", but in this case they do not want to speak about the possibility to stop process itself. Why?

[Aubrey de Grey] The experiments of many scientists can prolong the life of cell, simplest organism, but I do not think that this will work at the level of man. However, the majority of researchers keep silent not therefore, but because they fear to lose financing. They depend on those average men themselves, who do not want to be charged by superfluous optimism, and therefore they are careful.

The quality isn't great (it can translate "nematode" just fine, but produces artifacts like "it is still more important, here to eat the biologists") but you'll get the gist. The points quoted above are two of the most important considerations for advocacy:

• Firstly, that we can make significant progress in developing solutions to a problem in advance of complete understanding. I see the present debate over the level of effort to devote to development based on today's knowledge to be the most important determinant of our future life spans. Will the research community get to work, or will it put off developing therapies for another few decades?
• Secondly that a strange self-perpetuating culture of conservatism and denigration about engineered longevity came into being in past decades, and must be shattered if we are to make progress.

An interesting opinion on the direction of aging research from a noted scientist in the field:

Virtually, all research on basic mechanisms of aging has used species that are short lived and thus demonstrably unsuccessful at combating basic aging processes. A novel comparative approach would use a diversity of populations and species, focusing on those with particularly long, healthy lives, seeking the causative mechanisms that distinguish them from shorter lived relatives.

Species of interest from this perspective include the naked mole rat, a mouse-size rodent that lives up to 30 years in the laboratory, and the little brown bat, which lives up to 34 years in the wild. Comparisons among dogs of different sizes, which differ by more than 50% in health span might also prove rewarding, as might novel species chosen because of their similarity to humans in certain key traits. Primates, because of their sophisticated cognitive ability, are a group of special value, and small, short-lived primates like the common marmoset might prove especially beneficial.

Cell repositories and tissue banks from key species, as well as genomic and analytic tools optimized for comparative studies, would make valuable contributions to a new comparative approach to basic aging research.

I see comparative studies - and the naked mole rat versus other rodents is a particularly good example - as a good way to reveal the relative importance of the various forms of cellular and molecular damage that cause aging. Is mitochondrial damage really so important in humans that it should be dealt with first of all, or are other types of damage just as limiting to life span, such that if mitochondria could be repaired, we wouldn't gain much overall benefit? We don't know for sure - though there's nothing to be lost by moving ahead at full speed on all fronts of longevity science outlined in the Strategies for Engineered Negligible Senescence at this stage.

Researchers are digging deeper into the mechanisms that lead to gray hair: "Going gray is caused by a massive build up of hydrogen peroxide due to wear and tear of our hair follicles. The peroxide winds up blocking the normal synthesis of melanin, our hair's natural pigment. ... All of our hair cells make a tiny bit of hydrogen peroxide, but as we get older, this little bit becomes a lot. We bleach our hair pigment from within, and our hair turns gray and then white. ... the build up of hydrogen peroxide was caused by a reduction of an enzyme that breaks up hydrogen peroxide into water and oxygen (catalase). ... hair follicles could not repair the damage caused by the hydrogen peroxide because of low levels of enzymes that normally serve this function (MSR A and B). Further complicating matters, the high levels of hydrogen peroxide and low levels of MSR A and B, disrupt the formation of an enzyme (tyrosinase) that leads to the production of melanin in hair follicles. ... The researchers speculate that a similar breakdown in the skin could be the root cause of vitiligo."

Link: http://www.sciencedaily.com/releases/2009/02/090223131123.htm

From ScienceDaily: "researchers were able to generate functionally mature motor neurons from induced pluripotent stem (iPS) cells, which are engineered from adult somatic cells and can differentiate into most other cell types. A potential new source of motor neurons that does not require human eggs or embryos could be an enormous boon to research into conditions such as amyotrophic lateral sclerosis (ALS) and spinal cord injury and could open the door to eventual treatments. ... To our knowledge, our results present the first demonstration of the electrical activity of iPS-derived neurons and further suggest the feasibility of using these cells to explore how changes in motor neuron activity contributes to the degeneration of these cells underlying these disorders. ... [the team] used skin fibroblasts and reprogrammed them back into an embryonic state, with the ability to differentiate into any cell type in the human body. They then took those cells and differentiated them into motor neurons."

Link: http://www.sciencedaily.com/releases/2009/02/090224133154.htm

The more work being done to tinker with our mitochondria, the power plants of our cells, the better. A growing, well-funded research and development community focused on mitochondrial engineering is a necessary step on the road to robust repair technologies that can remove or work around the mitochondrial damage that contributes to aging.

My attention was drawn today to the latest example of mitochondrial engineering:

the protein, rhTFAM (an abbreviation for recombinant-human mitochondrial transcription factor A), succeeded in entering and energizing the DNA of the mice’s mitochondria, enabling them to run two times longer on their rotating rods than a control group cohort.

Because many neurodegenerative diseases cause mitochondria to malfunction, medical researchers have been focusing on developing methods for repairing and restoring them. The new UVA study represents an important step toward achieving that goal. It shows that a naturally occurring protein, TFAM, can be engineered to rapidly pass through cell membranes and target mitochondria. Study findings show that rhTFAM acts on cultured cells carrying a mitochondrial DNA disease as well as lab mice.

...

Mitochondria are the cellular engines that transform food into fuel in our bodies and perform their work in the energy-intensive tissue of our brains, retinas, hearts and skeletal muscles. When damaged, mitochondria slow down, stop generating energy effectively and begin to over-produce oxygen free radicals. If produced in excess, oxygen free radicals chemically attack all cell components, including proteins, DNA and lipids in cell membranes.

"In simple terms, an overabundance of these free radicals cause cells to start rusting," notes lead study author James P. Bennett, Jr., M.D., PhD, a professor of neurology and psychiatric research at the UVA School of Medicine and director of its Center for the Study of Neurodegenerative Diseases.

While the UVA findings are preliminary, Bennett considers them encouraging. "We've shown that the human mitochondrial genome can be manipulated from outside the cell to change expression and increase mitochondrial energy production," he notes. "This is arguably the most essential physiological role of the mitochondria."

This particular research likely has little impact on the issue of mitochondrial damage and aging, but it is encouraging to see a breadth of work taking place in areas that will provide support to developing methods of repair for our mitochondria.

Letting yourself become very overweight and staying that way - something that is definitely a choice for most of us - is not good for your health and longevity, not to mention your wallet once those medical expenses start to roll in: "We prospectively assessed the association between an increase in body mass index (BMI) category since age 20 years and risk of all-cause, cardiovascular disease (CVD) and cancer mortality. Self-reported information pertaining to BMI was collected from 38,080 Japanese men and women aged 40-79 years at study entry in 1994 ... We observed an increased risk of all-cause mortality both among participants who had been persistently obese since early adulthood and participants who showed an increase in BMI category from normal to obese ... In contrast, we did not observe an increased risk of all-cause mortality for normal weight at age 20 years and overweight at study entry, and stable overweight. For CVD and cancer mortality, these results were consistently observed."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19223845

From U.S. News: "Cancer is characterized by cells dividing wildly, with no brakes; if a cell can't divide, it can't become cancerous. One solution that evolved: a whole class of naturally occurring tumor suppressor molecules that can disable cells in danger of going haywire. They do it either by telling the cell to kill itself, through a process called apoptosis, or by simply turning off the potentially dangerous cell's ability to divide, a process called senescence. ... But there's a tradeoff. The problem is that those senescent cells, while they have lost their ability to divide out of control, may trigger inflammation in nearby cells and tissues, and inflammation is linked with a host of age-related disease, including late-life cancers. Experiments in mice show that goosing one important tumor suppressor gene, p53, so it's a little bit activated all the time, does certainly hold off cancer ... but the mice age prematurely. It has been possible to regulate the action of p53 in a kind of Goldilocks mode - not too much, not too little - and that produces mice that are both tumor-free and don't age prematurely ... that's easy to do in mice, but difficult to do in people ... Some other possible tactics include figuring out why the senescent cells are secreting molecules that promote the dangerous inflammation and whether suppressing that secretion would help. Or [maybe] there's a way to get rid of the senescent cells entirely."

Link: http://health.usnews.com/articles/health/cancer/2009/02/20/cancer-and-age-why-we-may-face-a-tradeoff-between-cancer-risk-and-aging.html

Biomedical gerontologist Aubrey de Grey of the Methuselah Foundation will be in Moscow in early March, speaking at the Moscow State University.

From Feb 28 - Mar 4 Aubrey de Grey will be visiting Moscow. His schedule is already fully booked and includes two public lectures:

- 28.02, 12:30, Dom Uchenih
- 02.02 18:00, Moscow State University (main building)

There is a very high chance that the Russian translation of Ending Aging will become available upon Aubrey's arrival to Moscow. Aubrey's visit to Russia was made possible by Michael Batin's "Science Against Aging" campaign.

Some of the "Science Against Aging" foundation documents - in English - are posted to a recent Immortality Institute thread. They are comprehensive and impressive, to say the least, put together by people who have taken a great deal of time to survey the scientific landscape. Take a look for yourself:

• SCIENCE_AGAINST_AGING_POSTER.pdf ( 133.57K )
• SCIENCE_AGAINST_AGING_RESEARCH_PLAN.pdf ( 748.92K )

Given the breadth of research being condensed down into the diagrams in the first PDF document, and the level of debate within the scientific community, I think that everyone will find something in there to disagree with. You might actually want to start with the second document above, which is somewhat more readable for the layperson. All in all I think you'll agree that this work represents a worthy initiative of the sort we'd like to see more of. From the research plan:

The value of a long and healthy life is obvious to every reasonable person. Therefore, aging is a serious and until now unsolved problem. Slowly but inexorably, aging decreases the quality of life, makes people weak and powerless, prevents the realization of people’s aspirations. Sooner or later, it leads to death.

Today, the growing desire for a long, high-quality and healthy life becomes increasingly obvious in developed countries. This is confirmed by the strong demand for fitness, anti-aging services, etc. The share of people who openly express this desire for life extension is growing. According to a public opinion poll conducted in Russia in 2008, 78% of Russians do not ever want to age.

...

Leading gerontologists from 10 countries declared in an open letter that aging can be slowed down and healthy life can be prolonged. We share the view that the problem of aging can be solved in the next few decades and that humankind already has everything necessary.

1. Our society has financial resources for solving this problem - a major project to defeat aging would cost only about 30 billion dollars.
2. A large body of knowledge about aging has been accumulated that is being used to create a unified system model of human aging.
3. Powerful new technologies in genomics, drug design, mathematical modeling and other fields make it increasingly possible to control and direct processes inside the human body.
4. Many promising ideas and aging hypothesis that can help solve the remaining problems have been developed.

Unfortunately, these opportunities are not being fully used, the efforts of researchers are largely uncoordinated, science and society do not have a clear overarching goal - to defeat aging.

...

The task of eliminating aging is extremely complex - both in terms of science, and in organization, planning and implementation. Separate projects in biophysics, biochemistry, pharmacology, genomics, cryobiology, immunology and other fields should be joined within an integrated scientific framework. Gerontology must set the strategy for development of life sciences. We must realize that life extension is the primary purpose of scientific research. Scientific collaboration will create synergy between different research projects and will allow us to defeat aging faster than with uncoordinated and uncontrolled research. The difference in time - possibly tens of years can - save millions of lives.

To join the efforts of individual scientists, research and health institutions, non-government and political organizations at international coordinating center of the program is needed. It’s primary tasks are:

1. attracting renowned experts in life sciences and research management to the project
2. creating a scientific and organizational program
3. developing a plan to implement this program
4. promoting this program in social, business, and political circles.

In October 2008 a working group was created to develop and promote a comprehensive program to defeat aging. It was set up in Russia by the "Science for Life Extension" foundation. The project is supported by many Russian and international researchers.

If you read through the literature for the Science Against Aging program, you'll see something very like the early iterations of Aubrey de Grey's Strategies for Engineered Negligible Senescence in intent and motivation, but with a somewhat different focus on the scientific side of things. I'm always pleased to see new advocates with strong connections to the scientific community step up and start working, and this Russian group has quite the few members judging by the credits section of the plan document. The more the merrier - dozens of such groups forming independently in the zeitgeist of the time were evident in past successes in patient advocacy.

MRL mice, as you might recall, are a laboratory breed that demonstrates extraordinary powers of regeneration for a mammal. Here, EurekAlert! notes large differences in their inflammatory response as well: " A strain of laboratory mice that has 'superhealing' powers has been found to resist inflammation after a knee injury, and also to avoid developing arthritis at the injury site in the long term ... Their findings illuminate the mechanisms of post-traumatic arthritis and could point to therapies for this condition ... The superhealer can almost regenerate tissue. We thought, 'if they can regenerate cartilage in the ear, what about cartilage in the knee?' This happened in our pilot study, and we now have taken these results further and learned what happens in terms of inflammation. If you can figure out why the animal is a superhealer and apply that to people, then you may help prevent the development of arthritis ... control mice showed a greater than 700-fold increase in the expression of one cytokine, [interleukin], in the first four hours after a fracture and 37-fold difference in that cytokine level at 7 days after the fracture. ... Interleukin generally promotes inflammation and an increase in temperature. The superhealer mice showed a similar trend, but in much lower amounts: a 70-fold peak in expression at day 0 down to a 3.5-fold increase by day 7."

Link: http://www.eurekalert.org/pub_releases/2009-02/dumc-nct021909.php

Here is the concept document for this year's meeting of the World Congress for Freedom of Scientific Research. As for the last meeting in 2006, I can't help but feel that they're missing the forest for the trees. The problem is simply and only government and regulation - the structure of "representative" democracry produces a accelerating creep of lost freedom over time. From the document: "Does a constitutional protection of freedom of scientific research exist in some, or all, liberal democracies? Does this protection - where it actually exists – find some implementation in juridical criteria which guarantee the objectivity of facts, faced to political and personal interests in manipulating the scientific truth? Does the chance to elaborate a quantitative pointer-indicator of freedom of scientific research in different countries exist, adding it to other pointers-indicators of political and economic freedom? In which way bioethics has contributed to the promotion of, or otherwise has contrasted the freedom of scientific research? How can the prohibitionist flow of many bioethical committees be faced? How can the political agenda manage the 'precautionary principle', which is often formulated as internally irrational, and applied in order to paralyze scientific research and technological innovation?"

Link: http://www.freedomofresearch.org/node/82

We humans are already unusually long-lived when compared to many other mammals of our size, though nowhere near as long-lived as some of us would like to be. It is something of an open question as to what has influenced evolution to produce a number of social species that live far beyond their reproductive years - see, for example, the grandmother hypothesis:

How is it, then, that a woman's lifespan can greatly exceed her childbearing and childrearing years? Is this phenomenon simply a byproduct of improved standards of living, or do older women - grandmothers in particular - play a measurable role in increasing their family members' biological success?

As it turns out the same questions can be asked of killer whales. They also live long in comparison to many other mammals, far past the age at which they can no longer reproduce. I noticed a very readable paper recently that looks at the question of this sort of evolved longevity:

Menopause is a seemingly maladaptive life-history trait that is found in many long-lived mammals. There are two competing evolutionary hypotheses for this phenomenon; in the adaptive view of menopause, the cessation of reproduction may increase the fitness of older females; in the non-adaptive view, menopause may be explained by physiological deterioration with age. The decline and eventual cessation of reproduction has been documented in a number of mammalian species, however the evolutionary cause of this trait is unknown.

...

By extending their lifespans after reproduction ceases, post-reproductive females who help daughters or other kin raise offspring increase their own [chances of evolutionary success]

...

Although existing data do not allow us to examine evolutionary tradeoffs between survival and reproduction for this species, we were able to examine the effect of maternal age on offspring survival. Our results are consistent with similar studies of other mammals - oldest mothers appear to be better mothers, producing calves with higher survival rates. Studies of juvenile survival in humans have reported positive benefits of grandmothers on newly weaned infants; our results indicate that 3-year old killer whales may experience a positive benefit from helpful grandmothers.

I would expect there to be some evolutionary balance struck between older parents being better parents and older parents being more damaged by aging, though it isn't clear just how much of a selection effect is applied when you're looking at older parents. Perhaps only the best survive to older ages to be those better parents.

This paper doesn't firmly answer any of the questions posed, but is is a good overview of current thinking on how we humans ended up aging the way we do. As the broad diversity of the animal kingdom shows, there are plenty of other options on the table for natural life span, all too few of them better in terms of years of health attained. While it is interesting to look at our origins, it is also important to remember that we already have the knowledge and capabilities to step beyond them. Aging to death will one day be a barbaric thing of the past, eradicated along with smallpox. Just how soon that comes about is entirely up to our collective efforts.

An interesting paper that opens: "Being male is now the single largest demographic risk factor for early mortality in developed countries ... What causes this disparity between the sexes in longevity and parasite susceptibility? Most research has focused on the proximate mechanisms, such as endocrine or immunological pathways, that are immediately responsible for any one cause. Here, I take a different approach. Sex differences in infection rates or mortality may come about for the same reasons as other differences between males and females, such as morphology: selection acts differently on the sexes because they maximize their fitness in different ways. ... I discuss an evolutionary approach to the question of why males so often die sooner and develop more diseases than females. Some researchers are hopeful that the gap between men's and women's lifespans will close as we develop better medical care and education about health risks, but I will argue instead that the disparity is not going away any time soon." Though it will become negligible as advanced longevity science is put into practice in the decades ahead.

Link: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2628977

The end stage of Alzheimer's disease is complex and many-faceted - which is all the more reason to focus on prevention and early repair of the root causes rather than the present strategy of patching the cracks in the dam late in the process: "A protein long suspected as the culprit behind the brain disorder might actually release not just one, but two components that can cause nerve cells to self-destruct. In theory, the breakdown of the protein, called APP for short, could unleash a double whammy of harmful effects on nerve cells. Much of the drug research in the field now focuses on the first component of APP discovered to have a strong link to Alzheimer's disease. That component, the amyloid beta peptide, collects in abnormal plaques in the brain that are a diagnostic sign of the ailment. But a second molecule split off from APP, the N fragment or N-APP, was found to trigger a chain of events that also destroys neurons. ... The question is, how much of the neurodegeneration is triggered by the amyloid beta peptide and how much by N-APP?"

Link: http://www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2009/02/19/MN3H15T7KD.DTL

This sounds like progress in understanding the roots of the longevity and health benefits of calorie restriction and other light stresses on the body:

Cells have evolved a particular response to stay alive in adverse conditions. When a cell starts getting too hot, too hungry or too oxygen-deprived, certain proteins migrate into the nucleus. There, they latch onto sections of DNA and cause heat-shock proteins to be produced. Heat-shock proteins - so named because they were first discovered in cells experiencing high temperatures - cruise around the cell, fixing damaged or improperly folded proteins.

...

Normally the repair process falls off quickly, because heat-shock proteins inhibit the proteins that grab onto the cell's DNA and summon them in the first place. But Morimoto and his colleagues found that jacking up levels of SIRT1 keeps the protein-repair process going for hours and hours.

So processes, such as calorie restriction, that increase sirtuin levels are improving the performance of repair mechanisms in your cells - assuming you are also undergoing cirumstances that will release heat shock proteins. Calorie restriction will do that nicely.

It occurs to me to wonder to what degree this particular method of improved repair is important in longevity versus others mechanisms, such as autophagy for example, also increased during the practice of calorie restriction.

A mainstream article on calorie restriction from the Houston Press: "More than 1,000 studies dating back 70 years have shown that eating less, a lot less, retards the aging process and boosts health in a wide variety of laboratory animals: fruit flies, spiders, nematodes, mice, rats, dogs and rhesus monkeys. Calorie-restricted monkeys, for instance, look less wrinkled as they age. They have less gray hair, and look and act younger than their regular-diet counterparts. Eating less seems to make the metabolic processes in the body work more efficiently ... The body enters an altered state that puts the brakes on aging. In mice, flies and monkeys, that is. ... Calorie restriction works in the lower organisms, we know. But with humans it's anybody's guess so far. ... The best guess in the scientific community is that starting a program of calorie restriction in your thirties might add two years ... If you start in your forties, it's six months. Start later than that, it's negligible. It could be a few extra weeks." Longevity benefits are currently thought to be minimal, but the health benefits in humans - in terms of resisting age-related disease, for example - are demonstrated to be large whenever you start.

Link: http://www.houstonpress.com/2009-02-19/news/calorie-restrictors-stay-hungry-in-hopes-of-living-longer/

In this Science Daily release, an unexpected result in worm life span studies is being spun as evidence for oxidative stress not to be important in aging. I believe this is overreaching - it looks much more like a case of one (unexpected) effect that increases life span outweighing the expected effect that decreases life span. These things are never straightforward, however: "For more than 40 years, the prevailing explanation of why we get old has been tied to what is called oxidative stress. This theory postulates that when molecules like free radicals, oxygen ions and peroxides build up in cells, they overwhelm the cells' ability to repair the damage they cause, and the cells age. ... Collectively, these molecules are known as reactive oxygen species, or ROS for short. ... They progressively disabled five genes responsible for producing a group of proteins called superoxide dismutases (SODs), which detoxify one of the main ROS. Earlier studies seemed to show that decreased SOD production shortened an organism's lifespan, but [researchers] did not observe this. In fact, they found quite the opposite. ... It seems that reducing mitochondrial activity by damaging it with ROS will actually make worms live longer."

Link: http://www.sciencedaily.com/releases/2009/02/090217173040.htm

Researchers are demonstrating potential uses for self-assembling nanofibers in guiding the regeneration of damaged tissues. Biomolecules are injected into tissues, and nanofibers form spontenously from these compounds and remain for a few weeks before degrading once more. While they exist intact, they can lead to healing that would otherwise not have happened.

According to Capito, the cylinder-shaped nanofibers work by binding to a specific group of amino acids, the tiny molecules that form proteins. Nanofibers carry the amino acids to the injured area. The amino acids then bind to receptors on the cell surface, promoting the growth of nerve cells and inhibiting the growth of scar tissue.

Northwestern scientists tried the technique on mice with severed spines and found that five weeks after the injury, mice injected with nanofibers regained significantly more motion in their hind legs than a control group injected with glucose sugar.

Capito said when they tested the nanofibers on mice with Parkinson's symptoms, 83 percent of the ones injected with them recovered.

It is interesting that regeneration of two very different types of tissue damage are improved by nanofibers. The researchers are also investigating how nanofibers could be used to form scaffolds to support and encourage stem cells used in regenerative therapies - a self-assembling scaffold would be a jump ahead in efficiency over those which have to be carefully manufactured.

Losordo said he is collaborating with Capito's team to find ways nanofibers and stem cells can work together. For example, the low blood supply in the areas he wants to regenerate makes it hard for the stem cells to take effect. The job might be easier if nanofibers could shelter them.

"It’s a challenging environment for the cells to survive," Losordo said. "We thought, if we could provide the cells with some survival cues, or a matrix or a soil, if you will, that they’re happier in, maybe we’ll have better luck with retention, survival, proliferation, differentiation of those cells into the target organ."

The Daily Galaxy outlines Aubrey de Grey's vision for the defeat of aging and age-related disease: "Some people look forward to dying. But de Grey says that's only because we all believe getting old and frail is inevitable - something he refers to as the 'pro-aging trance' society is currently 'trapped' in. De Grey's version of the future is where everyone can stay perpetually healthy and young through a combination of innovative longevity sciences, and he believes it will be more affordable alternative to caring for elderly, frail bodies. He has nothing against old people, he just thinks people should have the option to avoid ageing and death if they want to. There could be other benefits, as well. He says people would welcome eternity if they understood the benefits. ... If we want to hit the high points, number one is, there will not be any frail elderly people. Which means we won't be spending all this unbelievable amount of money keeping all those frail elderly people alive for like one extra year the way we do at the moment. That money will be available to spend on important things like, well, obviously, providing the health care to keep us that way, but that won't be anything like so expensive."

Link: http://www.dailygalaxy.com/my_weblog/2009/02/aging-is-it-opt.html

An overview of what scientists see ahead for regenerative medicine: "Stem cell therapy based on the safe and unlimited self-renewal of human pluripotent stem cells is envisioned for future use in tissue or organ replacement after injury or disease. A gradual decline of regenerative capacity has been documented among the adult stem cell population in some body organs during the aging process. Recent progress in human somatic cell nuclear transfer and inducible pluripotent stem cell technologies has shown that patient-derived nuclei or somatic cells can be reprogrammed in vitro to become pluripotent stem cells, from which the three germ layer lineages can be generated, genetically identical to the recipient. Once differentiation protocols and culture conditions can be defined and optimized, patient-histocompatible pluripotent stem cells could be directed towards virtually every cell type in the human body. Harnessing this capability to enrich for given cells within a developmental lineage, would facilitate the transplantation of organ/tissue-specific adult stem cells or terminally differentiated somatic cells to improve the function of diseased organs or tissues in an individual."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19219637

There are plenty of apologists for aging out there, sad to say:

Weil calls anti-aging advocates "false prophets who are putting out a message that aging is reversible or that we can stop it." ... "I think those are very wrong ideas," he says during a recent interview at his Vail ranch, about 30 miles southeast of Tucson. "Aging is a universal natural process, and I think if you set yourself up in opposition to it, you're in a very wrong relationship with nature."

And so forth. I have long been greatly puzzled by medical professionals who devote themselves to preserving human health and life under all other circumstances but preach that we should not do anything about aging - the root cause of the greatest ongoing toll of suffering and loss of life. Nothing else even comes close, yet all too many people close their eyes to the possibilities offered by medical science when it comes to addressing the biochemical and cellular damage that is aging.

On this topic, I notice that one of the few vocal pro-longevity bioethicists is working his way through a discussion of attitudes to longevity science at the moment:

most rational people [think] we should strive to reduce the deaths caused by poverty, malaria, HIV, cancer, car accidents, smoking, war, etc ... how many people think it is desirable to try to prevent disease and death by retarding human aging? Well, that changes everything!! Now the apologists come out in full force. People who agreed with me so far will all of a sudden do an about face and raise objections to the goal of keeping people healthy and alive. "That is unnatural!" they might say. Or they worry "This will cause overpopulation!" or "There will be massive unemployment!" etc., etc ...

There is almost no end to the reasons people will give to justify why the current rate of aging, and its ever growing disease burden, is actually a good (rather than bad) thing!

...

Dawkins has a great line that we are all atheists about most of the gods humans have believed in (thor, zeus, etc.)... some of us just go one god further. Likewise, we are all "pro-longevity" for most things that kill humans (war, cancer, poverty), champions of aging research just go one step further by acknowledging that aging itself is a big problem we should strive to mitigate.

...

Having said that, I can also appreciate why it is hard for so many people to abandon their "pro-aging" or "pro-magic" belief system. Indeed, I myself used to hold those beliefs and it has been a long and sometimes difficult journey to go from the beliefs I once held as a young adult to those I have today. Giving up these beliefs requires a major re-orientation of one's perception of the world, something few people are keen to undertake. Indeed, I would describe my own transformation as one that involved a good deal of cognitive dissonance

As for everything else in our biochemistry, the shortening of telomeres with age is more complex than we'd like it to be: researchers "have shown that the shortening of telomeres, the protective structures at the end of chromosomes, as people age varies between individuals and depends on the telomeres' original length. Although prior population studies have indicated that telomeres might be used to predict lifespan, the new research shows that the process is in fact much more complicated than had previously been assumed. ... [researchers] investigated the shortening of telomeres in 959 individuals who had donated blood samples at 9- to 11-year intervals. ... while the shortening rate was strongly correlated with the initial length of the telomeres, it was not related to later tumour development. ... In roughly a third of the subjects, the telomeres actually lengthened over the study period. ... those with the longest telomeres at the first blood draw demonstrated the most pronounced telomere shortening over time, and vice versa. ... The results indicate that the telomere-maintenance machinery protects the shortest telomeres. However, other factors are likely to influence the rate of shortening as well. Telomere length at first blood draw could only explain 57% of the variation in the rate of shortening; 43% remains to be accounted for, and may well include lifestyle factors, oxidative stress or inflammation."

Link: http://cordis.europa.eu/fetch?CALLER=EN_NEWS&ACTION=D&RCN=30470

From Chemistry World, a look at naked mole rats, which "can live for up to 30 years, far longer than the 3 year average life span of a laboratory mouse. ... Traditionally, aging in mammals is attributed to oxidative damage of cells, caused by reaction with inhaled oxygen. ... levels of oxidative stress in young naked mole rats were actually higher than in mice - but that although naked mole rats have high levels of oxidative damage, these stay the same throughout their lifetime. ... In most animals you get an accumulation of oxidative damage with age, but with mole rats, young and old animals have the same protein profile. The mole rats have between two to ten times more oxidative damage in all tissues than mice, and yet they live another 26 years with this damage. ... The rats are able to maintain functionality because they effective mop up damaged proteins in cells. For example, Buffenstein found that, in mice, the liver enzyme GAPDH decreased in activity as the animals aged. However, in naked mole rats, the same enzyme maintained its activity over a 24 year life span. ... Oxidative damage is not the be all and end all of aging. It's rather tolerance to damage and finding ways to cope with those stresses without impacting on functionality that are more important."

Link: http://www.rsc.org/chemistryworld/News/2009/February/16020901.asp

Intermittent fasting and calorie restriction are two ways of reducing your calorie intake to obtain health benefits. Intermittant fasting might be accomplished by eating every other day, for example, while calorie restriction means eating every day, but eating less. In both cases, you have to make sure your intake of micronutrients is optimal, and your physician agrees, as for any sane dietary choice. On the scientific side:

• Both calorie restriction and intermittent fasting produce significant health and longevity benefits in shorter-lived mammals such as mice, and at least significant health benefits in primates, including humans.

• Far more research has been accomplished for calorie restriction, and uncertainty remains as to whether intermittent fasting is as good, definitely increases longevity, has a preferred method of practice, or whether it could even be harmful to long-term health if done incorrectly.

• It seems plausible that calorie restriction and intermittent fasting produce their benefits in similar but different ways, based on research in lower animals, but I know of no research confirming this in mammals.

From the point of view of actively practicing either intermittent fasting or calorie restriction, intermittent fasting is much easier for anyone whose eating habits interact with those of other people, or who is already fairly set in his ways with good dietary habits. You just don't eat some days - very simple, and few other changes to the routines of life are needed.

Starting to practice calorie restriction, on the other hand, requires greater effort and more thought in terms of changing your diet. It's not hard, especially given the good resources available to walk you through the obvious pitfalls, but it isn't as simple as just saying "I'm not eating right now."

So the traditional trade-off in labor and knowledge:

• Intermittent fasting is usually much easier to introduce into your life, but has far less scientific support or a body of research to indicate the optimum methodology.

• Calorie restriction requires more initiative to organize, but has a great weight of science backing it up, and a wide range of resources based on decades of practical experience.

Given what I know of human nature, I suspect that intermittent fasting will rapidly become more popular than calorie restriction as soon as it accumulates a little more research in mammals than presently exists.

Science News surveys the role of accumulating mitochondrial damage and dysfunction in aging and age-related disease: "Today, scientists suspect that millions of people may be suffering from mitochondria gone awry, in more subtle but nonetheless insidious forms. Evidence suggests that malfunctioning mitochondria could explain Alzheimer's disease, Parkinson's, diabetes, cardiovascular disease, obesity, cancer and other consequences of aging. Given the organelle's core function in the body, some think mitochondria might even be the biological epicenter of aging itself: If you live long enough, all your cells might experience a kind of energy crisis. ... I strongly believe that mitochondrial metabolism is the key to aging ... In Mattson's view, and that of other researchers who suspect that people are only as young as their mitochondria, mild amounts of stress force mitochondria to make better use of the glucose available - whether that stress is from calorie restriction or another source. Stress also causes cells to produce proteins that protect the mitochondria from free radical damage. And Mattson points out that other conditions that strain energy production - such as physical and mental activity - also appear to strengthen tissues at the same time."

Link: http://www.sciencenews.org/view/feature/id/40762/title/Mitochondria_Gone_Bad

You might recall the research by Cuervo's group demonstrating a restoration of youthful levels of autophagy in mouse livers. We know that autophagy is important to longevity: it clears out biochemical junk and damaged cellular components, of which the most important are probably damaged mitochondria. Furthermore, autophagy is enhanced by calorie restriction, and appears necessary for the longevity benefits of calorie restriction to take place. The most interesting tidbit from this ABC News article is that it looks like Cuervo's method of restoring autophagy levels does in fact increase life span (as measured by survival rates at various ages) in mice: "In experiments, livers in genetically modified mice 22 to 26 months old, the equivalent of octogenarians in human years, cleaned blood as efficiently as those in animals a quarter their age. By contrast, the livers of normal mice in a control group began to fail. ... While her paper does not show increased survival rates among the mice, le Couteur, who has advised her recently on the research, says Cuervo does have data on improved survival rates which she intends to publish. He also says she is now working with pharmaceutical companies to identify drugs that will turn the receptors on, or make them more active. Cuervo believes maintaining efficient protein clearance may improve longevity and function in all the body's tissues."

Link: http://www.abc.net.au/science/articles/2008/08/11/2331197.htm

Another proof of principle in the bag for induced pluripotent stem (iPS) cells: "A little more than a year after [scientists] showed they could turn skin cells back into stem cells, they have pulsating proof that these 'induced' stem cells can indeed form the specialized cells that make up heart muscle. ... [the] research team showed that they were able to grow working heart-muscle cells (cardiomyocytes) from induced pluripotent stem cells, known as iPS cells. The heart cells were originally reprogrammed from human skin cells ... It's an encouraging result because it shows that those cells will be useful for research and may someday be useful in therapy. If you have a heart failure patient who is in dire straits - and there are never enough donor hearts for transplantation - we may be able to make heart cells from the patient's skin cells, and use them to repair heart muscle. That's pretty exciting ... It's also a few more discoveries away. The researchers used a virus to insert four transcription factors into the genes of the skin cell, reprogramming it back to an embryo-like state. Because the virus is taken up by the new cell, there is a possibility it eventually could cause cancer, so therapies from reprogrammed skin cells will likely have to wait until new methods are perfected. Still, the iPS cardiomyocytes should prove immediately useful for research."

Link: http://www.eurekalert.org/pub_releases/2009-02/uow-hdy021009.php

Interesting research: the cutting edge is becoming quite sophisticated. "Current treatments for diseases like cancer typically destroy nasty malignant cells, while also hammering the healthy ones. Using new advances in synthetic biology, researchers are designing molecules intelligent enough to recognize diseased cells, leaving the healthy cells alone. ... We basically design molecules that actually go into the cell and do an analysis of the cellular state before delivering the therapeutic punch ... When you look at a diseased cell (e.g. a cancer cell) and compare it to a normal cell, you can identify biomarkers - changes in the abundance of proteins or other biomolecule levels - in the diseased cell ... [the] research team has designed molecules that trigger cell death only in the presence of such markers. ... A lot of the trick with developing effective therapeutics is the ability to target and localize the therapeutic effect, while minimizing nonspecific side effects."

Link: http://www.eurekalert.org/pub_releases/2009-02/su-eci021309.php

I noticed an open access paper today that describes an unexpected effect on life span of genetic manipulation in the nematode worm species Caenorhabditis elegans. It's a good illustration that metabolism is complicated - much more so than we'd like.

In this paper, we examine the oxidative stress theory of aging using C. elegans as a model system. This theory proposes that aging results from the accumulation of molecular damage caused by reactive oxygen species (ROS). To test this theory, we examined the effect of deleting each of the five individual superoxide dismutase (SOD) genes on lifespan and sensitivity to oxidative stress. Since SOD acts to detoxify ROS, the oxidative stress theory predicts that deletion of sod genes should increase oxidative stress and decrease lifespan.

However, in contrast to yeast, flies, and mice, where loss of either cytoplasmic or mitochondrial SOD results in decreased lifespan, we find that none of the sod deletion mutants in C. elegans exhibits a shortened lifespan despite increased sensitivity to oxidative stress. Surprisingly, we find that sod-2 mutant worms have extended lifespan and even worms with the primary cytoplasmic, mitochondrial, and extracellular sod genes deleted can live longer than wild-type worms. By examining genetic interactions with other genes known to extend lifespan and by comparing the phenotype of worms lacking sod-2 to that of known long-lived mitochondrial mutants such as clk-1 or isp-1, we provide evidence that the loss of sod-2 extends lifespan through alteration of mitochondrial function.

It looks like a case of the unexpected effect - the slowed mitochondrial function, and thus less generation of mitochondrial ROS, a noted cause of aging - far outweighing the deliberate effect, the engineered lack of the antioxidant SOD. This doesn't happen in higher animals: we can learn a lot from worms, flies, and the like, but there are always lurking differences. If we're lucky, as here, those differences will illustrate or support other important points about the way in which aging occurs.

When looking at a goal of research and development programs that could stretch across two decades or longer, such as those proposed to repair aging in the Strategies for Engineered Negligible Senescence (SENS) outline, you have to settle in for the long haul. Fundraising and advocacy is important in the here and now - if you don't get started, you don't get started - but you have to think for the long haul.

In the broader research community, thinking for the long haul means setting out to build a community of interested, networked researchers. It also means culturing the students who will be researchers of note five or ten years from now. This is one of the goals of the Methuselah Foundation's Undergraduate Research Initiative: it's not just that talented students can help accomplish early SENS research, but it's also a means of teaching the researchers of tomorrow to look at aging as an engineering problem. Some of those students will be a part of the research community working to repair aging in 2015 or 2020. Some will start biotech companies in the years ahead, or contribute their own novel research to the fundamental challenges of reversing the biochemical changes of aging.

On the topic of building a community of existing researchers interested in reversing aging, the next SENS conference to be held later this year is presently open for registration. The SENS conference series of past years have gone a long way to demonstrating the scientific legitimacy of work to repair and reverse the effects of aging. Take a look at the videos of SENS3 presentations, for example, as an exhibit of just how plausible a project this all is.

The real challenge is people, not technology: it's the long bootstrapping process of any new paradigm. You must convince the public and funding sources to support this work, at the same time as providing a continuing stream of supporting research achievements, and growing the research community. If enough people become interested, then the work will be done - and it is just a matter of getting the work done. The science is about as clear as these things can ever be: we know more than enough to get started on work to repair aging.

Thanks to bureaucrats who don't think people should be allowed to make their own decisions, a great deal of risk attends the organization of cryopreservation. Take this case for example: "Alcor member A-1407 suffered cardiac arrest while snorkeling in Barbados and was subsequently pronounced legally dead. He was traveling with a companion who knew to contact Alcor immediately. Because of the circumstances and the local legal requirements, an autopsy was unavoidable. After some negotiation, the coroner limited the investigation to the minimum necessary to determine the cause of death (heart attack), and he did not touch the brain. Alcor received good cooperation from a funeral director, who had once attended a seminar on cryonics. ... The paperwork required to transport the patient was extensive, and necessitated the police conclude their investigation. Alcor involved the local US embassy to expedite the process, and the Deputy Consul in particular was quite helpful." Cryonics has a lot in common with the right to choose the time and method of one's own death - a right denied to most people in the western world. In a truly free country, a person would be free to arrange their own cryopreservation at any time they chose, and so maximize the chances of success. Unfortunately, that is not the case in the US.

Link: http://www.alcornews.org/weblog/2009/02/case_summary_a1407.html

Depressed Metabolism would like to see some distance put between transhumanism and cryonics, which seems to be a common variation on making a field more approachable by jettisoning the visionaries who created it in the first place: "The association of cryonics with 'transhumanism' seems inevitable but is problematic. It seems inevitable because cryonics should be most attractive to people with a very positive perspective on the future capabilities of technology. Barring rapid advances in mitigating aging, cryonics offers the only credible option for transhumanists to become a part of that future. It is unfortunate because it can have adverse effects on the objective of making cryonics a part of conventional medicine, and further alienates people who are open to the idea of human cryopreservation but fear the future." I can't say I agree with this overall strategy. You don't grow by competing for existing, blinkered viewpoints; rather, you grow by creating new viewpoints. Expanding the bounds of the debate and creating acceptance for new possibilities are the best ways forward. Work to push the boundaries out as far as possible, or else you'll settle into the rut of little progress and general mediocrity.

Link: http://www.depressedmetabolism.com/2009/02/11/cryonics-and-transhumanism/

I noticed a paper today whose abstract provides a good cross-section of the never-to-be-settled debate over what exactly constitutes a disease of aging, versus the other descriptive categories for the things that go wrong with the human body over time:

In a recent book, Dr. Peter Whitehouse describes Alzheimer's disease as a myth that cannot be separated from aging and, as such, the "disease" is simply an accelerated brain aging. While it is factually true that the aging brain and Alzheimer's disease are on a pathological continuum, this is true only in the most general sense - that is, the quantities of plaques and tangles in the brain.

It is well known that standard pathological criteria do not address such factors as the nature and onset of clinical signs, kinetics of disease progression, and presence or absence of age-related co-morbidities such as hypertensive cerebrovascular disease and diabetes mellitus. Clearly, a 68 year old patient who dies of pneumonia while in a vegetative state after a four year history of progressive dementia, and who is found later to have met Alzheimer's disease criteria at autopsy, has a "disease." Further, it would be an offense to the patient's family and to the condition itself to suggest that this mind-destroying process, occurring at an age where many individuals of the same age are vacationing and/or working New York Times crossword puzzles, is simply a manifestation of advanced age.

Moving Alzheimer's disease to an aging disorder may take some of the stigma and fear from the disease, and for this, Dr. Whitehouse is commended; however, such well intentioned motives should not lead us down the path of minimizing Alzheimer's disease and "lumping" a condition into a category before that condition is adequately understood. It might also be noted that the term "Alzheimer's disease," suggested first by Emil Kraepelin, was justified because of early age at onset, and clinical signs that differed from "dementia senilis." So perhaps Dr. Whitehouse is confusing Alzheimer's disease as it was originally intended, with senile dementia in the very old - a term and an age group that is more in line with the idea that "Alzheimer's disease" is a manifestation purely of advanced age.

If we lived in a world in which the market for research and development of medicine was completely free and unregulated, this sort of debate over nomenclature would be an amusing side-show to the process of developing methods of prevention and cure. Unfortunately, all medical research in the US operates in the shadow of the FDA, and treatments for aspects of aging that are not clearly defined and recognized by the slowly-turning wheels of bureaucracy will not be approved for use. Those potential treatments therefore won't be funded for development, and basic research in that area will be lacking - few people are willing to embark upon work that will not attain recognition or profit, and fewer fund it. In this way the FDA and similar regulatory bodies suppress innovation before it has even started.

That is the context for the quote above: defining a condition away from being a "disease" is an attack on funding legitimacy for many, given the way in which the FDA's pronouncements determine directions in research. It's a pretty sad situation all round.

Metabolic syndrome and then type 2 diabetes appear to be the most avoidable of age-related conditions: don't get fat and exercise regularly. It's not rocket science. Here's another good reason to keep up with good health practices: "cognitive functioning abilities drop as average blood sugar levels rise in people with type 2 diabetes. ... The tests used in the study measured several aspects of memory function. For example, we tested one's ability to switch back and forth between memory tasks or to 'multitask,' an important skill for people needing to manage their diabetes. ... The results showed that a 1 percent increase in [average blood glucose levels] corresponded to slightly lower scores on tests of psychomotor speed, global cognitive function, memory and multiple task management. ... One of the little known complications of type 2 diabetes is memory decline leading to dementia, particularly Alzheimer's dementia. This study adds to the growing evidence that poorer blood glucose control is strongly associated with poorer memory function and that these associations can be detected well before a person develops severe memory loss."

Link: http://www.eurekalert.org/pub_releases/2009-02/wfub-hbs021109.php

Via EurekAlert! which also provides a link to the open access PDF of the paper: "mice lacking the protein AT1A live substantially longer than normal mice. As drugs that antagonize AT1A are currently used to treat high blood pressure and heart failure, the authors suggest that future studies should investigate whether such drugs prolong life in humans. Further analysis revealed that the increased lifespan in mice lacking AT1A was likely a result of decreased oxidative damage to cells, a key factor in ageing, and increased levels of genes involved in cell survival (such as Sirt3). ... At 29 months, when all wild-type animals died, 17 AT1A-deficient mice (85%) were still alive. These remaining mice lived for an additional 7 months. ... The life span of the AT1A-deficient mice was approximately 26% longer than controls." It's nice to see that the researchers carefully controlled for calorie intake - this isn't an accidental form of calorie restriction.

Link: http://www.eurekalert.org/pub_releases/2009-02/joci-ala020409.php

Freedom and other necessities for prosperity (such as the rule of law, absence of taxation, and so forth) have been in decline in the US over the past decade. The specific proximate causes for the legislation and social changes that brought this decline don't really matter all that much - there is always some sequence of events that politicians and populace can use as justification and cover to further destroy all the qualities that once made their society great.

Interestingly, the field of medicine has escaped lightly in this time of rapidly declining freedoms. Perhaps this was in part because medical research and development is already hopelessly shackled and wedded to the control of central bureaucrats - innovation is already crushed to a fraction of what it might otherwise be.

Just because something is bad doesn't mean it can't become worse, of course. The present scaremongering over the economy is a grand opportunity for political opportunists to manipulate the system in ways far beyond the pale. Great leaps and bounds are taken down the slope of knives to the natural end of any government. It's only a matter of time before medicine and scientific research is further harmed. Take this for example, in reference to the "stimulus" bill presently being enacted:

Tragically, no one from either party is objecting to the health provisions slipped in without discussion. These provisions reflect the handiwork of Tom Daschle, until recently the nominee to head the Health and Human Services Department.

...

The goal, Daschle’s book explained, is to slow the development and use of new medications and technologies because they are driving up costs. He praises Europeans for being more willing to accept "hopeless diagnoses" and "forgo experimental treatments," and he chastises Americans for expecting too much from the health-care system.

...

Daschle says health-care reform "will not be pain free." Seniors should be more accepting of the conditions that come with age instead of treating them. That means the elderly will bear the brunt.

I don't think I need to comment on the intent, beyond noting that it is unusually honest. This approach has been underway in Europe for some time now: see for example, the "fair innings" philosophy.

The fair innings argument (FIA) is frequently put forward as a justification for denying elderly patients treatment when they are in competition with younger patients and resources are scarce.

...

The whole debate has to be put in context, however. This is related to the operation of the universal health care system in the UK, a system that has long been in the doleful steady state of all such socialist, centralized systems: waste, terrible services, and - most importantly - rationing. Every taxpayer involuntarily funding this behemoth feels that they own a piece of it, and everyone has that tug on their human nature urging them to make sure that no-one gets more than they do. It's ugly, and it's why socialism fails. Along the way to failure, however, it produces dangerous ideas, such as "human beings have a fixed length of life, after which they should be cut off and left to die."

All rapid legislation turns into a wish-list for those closest to power: the faster it is enacted, the greater the scale of corruption, and the more you can be sure that your interests are being directly harmed. The legislation discussed above is a good example of the way in which the politics of central control turn what would be a golden opportunity for a free market in healthcare into the modern equivalent of putting the old people out into the snow.

Don’t be afraid of [healthcare]; it’s actually the leading industry. The demands of healthcare are going to pull all other industries forward. Of course they require new technologies in steel and heavy industry and as well as delivery systems. I think they should be looked at positively. Again I say if this were a privatized system, we would all say "gee it’s wonderful. All these people want more health care, this industry is thriving". Let me put one other analogy. Suppose we made cars a government entitlement. Instead of cheering when auto production went up, we’d say, "Oh my God, we can’t afford this!". How you finance it may greatly affect the psychology and actually the freedom of the economy to take advantage of these new opportunities.

At the end of the road ahead there will be ruins. We can hope that the decline of the US and failure of its current political system is peaceful and rapid, such that growth and honest toil to create prosperity can begin again as soon as possible. It's an unpleasant thing to say for one who came to America with high hopes, but history ever repeats itself, and the downward slope has taken a steeper turn.

Economic ignorance is the death of cultures; it is presently eating away at the US, and is sadly most advanced in medicine and medical research. People who favor equality and envy over wealth and progress are, unfortunately, usually comparatively wealthy themselves and thus largely insulated from the short-term consequences of their ignorance. These dangerous philistines will have to decide in the years ahead whether their dearly-held positions are worth losing their lives to, not to mention the lives of everyone they manage to kill - at the rate of 100,000 with each and every day of delay on the way to working anti-aging technologies.

The 4th Strategies for Engineered Negligible Senescence (SENS) conference is open for registration and abstract submission. SENS4 is "to be held at Queens' College, Cambridge, England on September 3rd-7th 2009. The early registration and abstract submission deadlines are both June 15th. All details, including forms for abstract submission and online registration, are at the conference website ... The preliminary program already has 35 confirmed speakers, all of them world leaders in their field. As for previous SENS conferences, the emphasis of this meeting is on "applied gerontology" - the design and implementation of biomedical interventions that may, jointly, constitute a comprehensive panel of rejuvenation therapies, sufficient to restore middle-aged or older laboratory animals (and, in due course, humans) to a youthful degree of physiological robustness. ... In addition, there will be at least a dozen short talks selected from submitted abstracts, as well as poster sessions each evening. Authors of short talks and posters will, like the invited speakers, be invited to submit a paper summarising their presentation for the proceedings volume, which will be published in the high-impact journal Rejuvenation Research early in 2010."

Link: http://blog.methuselahfoundation.org/2009/02/registration_and_abstract_subm_2.html

Alagebrium is an AGE-breaker, a compound that dissolves some forms of advanced glycation end-products (AGEs), compounds implicated in the damage of aging. Unfortunately, the specific types of AGEs affected by alagebrium, also known as ALT-711, are more important in rats than humans. The promising results in animals were never replicated in human studies. It now seems that the company running human trials to find some beneficial use for alagebrium is giving up the ghost: "Synvista Therapeutics, Inc. today announced that, following a review of its clinical development portfolio and its current financial status, the Board of Directors and management have determined that it is in the best interest of the Company to focus its resources on maximizing the value of its diagnostic assets and to terminate all ongoing clinical trials of its product candidates alagebrium ... In light of the Company's cash position and current negative economic and capital markets conditions, if the Company is unable to enter into such transactions in a timely manner, the Company's ability to continue operations beyond the second quarter of 2009 is in doubt."

Link: http://phx.corporate-ir.net/phoenix.zhtml?c=100218&p=irol-newsArticle&ID=1249435

Intermittent fasting (IF) as an alterative approach to obtaining the health benefits of calorie restriction (CR) seems to be attracting more research interest these days, though given the comparatively sparse studies and variation in results, I think it's early to be guessing whether IF is better or worse than straight calorie restriction as a practice in humans. The most interesting result to date is that CR and IF work in quite different ways, in worms at least - not what I would have expected. From Ouroboros: researchers "established a fasting diet regimen in C. elegans to study molecular pathways involved in fasting induced longevity. They found that alternate day fasting (ADF) had a 40.4% increase in lifespan, and intermittent fasting (IF: every two days) had a 56.6% increase in lifespan over ad libitum fed worms. In contrast, chronic CR only increased lifespan by an average of 13.2%. CR and IF may have similar effects on lifespan, but results reported in this paper indicate that signals in each of these processes are distinct. skn-1 and pha-4 have been shown to be essential genes in the CR longevity phenotype, but are dispensable in IF longevity."

Link: http://ouroboros.wordpress.com/2009/02/09/an-intermittent-fasting-pathway-to-longevity/

The February 2009 issue of the Global Spiral is a collective reply by transhumanist writers to earlier disparagement from conservative religious thinkers. A piece by biomedical gerontologist Aubrey de Grey is amongst the articles: "What is realistic is to work toward anti-aging medicine as an engineer would take on an engineering problem: repairing and reversing aging and making the damage already caused by metabolism harmless. ... Two thirds of all deaths worldwide, and about 90% of all deaths in the developed world, are from causes that only rarely kill young adults. These causes include Alzheimer's, cardiovascular disease, type 2 diabetes and most cancers. They are age-related because they are expressions of the later stages of aging, occurring when the molecular and cellular damage that has accumulated in the body throughout life exceeds the level that metabolism can tolerate. Moreover, before it kills them, aging imposes on most elderly people a long period of debilitation and disease. For these reasons, aging is inarguably the most prevalent medically-relevant phenomenon in the modern world and the primary ultimate target of biomedical research. ... Unfortunately, the regenerative medicine approach to combating aging is not yet being adequately pursued by major funding bodies: only a small number of laboratories worldwide are funded (either publicly or privately) to develop therapies that could rejuvenate aged but otherwise undamaged tissues."

Link: http://www.metanexus.net/magazine/tabid/68/id/10688/Default.aspx

Reverse engineering the brain is just a matter of time. If we get our collective act together with respect to supporting and developing longevity science then many of us will see the age of artificial brains.

Cognitive Computing Project Aims to Reverse-Engineer the Mind:

"The plan is to engineer the mind by reverse-engineering the brain," says Dharmendra Modha, manager of the cognitive computing project at IBM Almaden Research Center.

In what could be one of the most ambitious computing projects ever, neuroscientists, computer engineers and psychologists are coming together in a bid to create an entirely new computing architecture that can simulate the brain's abilities for perception, interaction and cognition. All that, while being small enough to fit into a lunch box and consuming extremely small amounts of power.

A Preliminary Roadmap to Whole Brain Emulation

As this review shows, [whole brain emulation] on the neuronal/synaptic level requires relatively modest increases in microscopy resolution, a less trivial development of automation for scanning and image processing, a research push at the problem of inferring functional properties of neurons and synapses, and relatively business‐as‐usual development of computational neuroscience models and computer hardware.

Functional artificial brains will bring the potential for a great many changes, such as a phase change in the nature of humanity itself, but the most interesting potential for those of us chasing personal longevity is the replacement of neurons with more reliable machinery:

Neurons made from exotic nanomaterials could one day enable humans to survive even the most horrendous accident, and as a bonus, provide amazing new capabilities.

...

Burch describes how we would switch to the new brain. A daily pill would supply nanomaterials and instructions for nanobots to format new neurons and position them next to existing biological brain cells to be replaced. These changes would be unnoticeable to us, but within six months, we would be enjoying our new brain.

...

Should a person with the new damage-resistant brain die in an accident, their body could be a total loss, but the brain would survive. Biological brains die within minutes after the heart stops; our new brain will simply turn itself off and wait for a new power supply.

As I examined in a post back in the achives, the major stumbling block to extreme longevity - after the necessary medical technology has been developed - is that the standard issue human brain and body are fragile. Accidents happen, and we're not well equipped to survive them. The technologies that will be developed in the decades following the culmination of the biotechnology revolution will help overcome that limitation.

It's a tough road between here and there of course: we're still struggling with the first step in the process, sufficiently good repair of aging to live into the next age of technological development. First things first, but it can't hurt to occasionally look ahead to see the golden future that awaits should we succeed in repairing the cellular and molecular damage that causes aging.

An interesting paper from the owner of senescence.info and collegues: "Numerous microarray studies of aging have been conducted, yet given the noisy nature of gene expression changes with age, elucidating the transcriptional features of aging and how these relate to physiological, biochemical, and pathological changes remains a critical problem. ... We performed a meta-analysis of age-related gene expression profiles using 27 datasets from mice, rats, and humans. Our results reveal several common signatures of aging, including 56 genes consistently overexpressed with age, the most significant of which was APOD, and 17 genes underexpressed with age. We characterized the biological processes associated with these signatures and found that age-related gene expression changes most notably involve an overexpression of inflammation and immune response genes and of genes associated with the lysosome. An underexpression of collagen genes and of genes associated with energy metabolism, particularly mitochondrial genes, as well as alterations in the expression of genes related to apoptosis, cell cycle, and cellular senescence biomarkers, were also observed. ... We suggest these molecular signatures reflect a combination of degenerative processes but also transcriptional responses to the process of aging." Supplementary data is available over at senescence.info.

Link: http://www.ncbi.nlm.nih.gov/pubmed/19189975

Aging is exactly an accumulation of biochemical damage and the resulting disarray caused by that damage. We all know that smoking is bad for you, but it seems that smoking causes some of the same effects as one of the genetic conditions that causes accelerated aging: "Smoking can accelerate the aging process and shorten the lifespan by an average of more than 10 years. We focused on what happens within the lungs because of the similar aging effects, including atherosclerotic diseases and cancer, seen in people with Werner's syndrome and people who smoke ... Werner's syndrome involves a genetic mutation that causes a deficiency in what's known as Werner's syndrome protein. The protein normally helps repair DNA damage. Smoking does not appear to cause the same mutation, but our study showed that it does decrease Werner's syndrome protein ... The team also applied cigarette smoke extract to cultured lung fibroblasts taken from nonsmokers. They saw that Werner's syndrome protein expression was decreased, and the cells had lost their ability to repair wounds. In contrast, when the team caused the lung fibroblasts in petri dishes to overexpress Werner's syndrome protein, it had a protective effect and helped resist the damaging effects of cigarette smoke."

Link: http://www.scienceblog.com/cms/effects-smoking-linked-accelerated-aging-protein-18505.html

Wherever you see the heavy hand of government, you can be sure there is a great deal of waste: activities taking place that provide no great benefit. They are there to pad a budget, or as the result of political favor, and certainly wouldn't be undertaken in a more competitive environment. People take up occupations they probably shouldn't be in, and people who could be doing more productive work elsewhere sideline themselves.

Given that something like a third of all medical research in the US is funded by the US government, one would expect to see a great deal of useless research - programs and studies that have no real end beyond consuming dollars and provide second-class information that doesn't advance the boundaries of the possible. Which is exactly the case.

Take this for example:

Thomas B. Shea, PhD, of the Center for Cellular Neurobiology; Neurodegeneration Research University of Massachusetts, Lowell and his research team have carried out a number of laboratory studies demonstrating that drinking apple juice helped mice perform better than normal in maze trials, and prevented the decline in performance that was otherwise observed as these mice aged.

In the most recent study Shea and his team demonstrated that mice receiving the human equivalent of 2 glasses of apple juice per day for 1 month produced less of a small protein fragment, called "beta-amyloid" that is responsible for forming the "senile plaques" that are commonly found in brains of individuals suffering from Alzheimer's disease.

We live in an age of stem cells, cell cultures, rapidly pulling apart biochemistry to establish mechanisms, and designer drugs. Is it not plausible that this sort of work linked above should be beneath someone who is looking to make an actual difference to the future of medicine? Would any self-respecting biotech startup start there? If you're into pulling down government grant funds (or selling food products), then it might be your thing: you could keep on running mouse studies on random dietary alteration after random dietary alteration from here until doomsday. All a complete waste of time in comparison to more modern methods and lines of research.

This sort of work is why I'm always dubious of any government funding budget for science. There's no incentive for it to go towards research that will actually make a difference, and every incentive for it to be wasted on people who could be accomplishing better work elsewhere, or on tasks that only exist in order to fill out a budget.

You'll recall I mentioned the LifeStar Project initiative of the Millard Foundation recently:

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

From the LifeStar website, a look at what they're presently up to:

What is needed - and does not yet exist - is a concerted, focused, competent, and fully-funded effort to finish the development of the complete set of therapies and protocols that will prevent the occurrence of the diseases of aging.

...

Our focus right now is developing the basic "Foundation Document" - which will set forth the mission clearly; of course, the formal project plan and proposal will be thousands of pages and will take most of a year - and funding - to prepare. In the meantime, we are working to set forth the mission and the basic plan in a book to be published later this year, which we hope will elicit the necessary support for humanity to embark on this exciting and historic endeavor.

I'm sure we'll be hearing more about this book in due course. I can't say as I agree with their apparent focus on inducing government funding and participation as the best path forward, however. I'm in the philanthropic funding camp: culture the visionaries who will pay for research and development most likely to succeed, bootstrap the proof of principle onto the table, and the rest will follow as people see what can be achieved. Involving politicians in anything, let alone something of vital importance, does not have a good track record.

For a long development process - such as the tissue engineering of replacement organs - to run to completion, there must be profitable uses for early, intermediate progress. Profit makes the world go round, after all. This EurekAlert! release looks at what can be done with slight advances in building complex tissue from scratch: "biomedical engineers can now grow and assemble living microtissues into complex three-dimensional structures in a way that will advance the field of tissue engineering and may eventually reduce the need for certain kinds of animal research. ... There is a need [for] tissue models that more closely mimic natural tissue already inside the body in terms of function and architecture ... We think this is one step toward using building blocks to build complex-shaped tissues that might one day be transplanted." Research using cultured tissue will in due course be far cheaper than animal studies, which means that it will be widely adopted. This in turn will help to fuel advances towards the ultimate goal of building new tissue to repair age-damaged human organs.

Link: http://www.sciencedaily.com/releases/2009/02/090202175327.htm

This path to creating pluripotent stem cells is becoming simpler: "the introduction of four ingredients could transform differentiated cells taken from adult mice into 'induced pluripotent stem cells' (iPS) with the physical, growth, and genetic characteristics typical of embryonic stem cells ... Subsequent studies found that the four-ingredient recipe could in some cases be pared down to just two or three essential ingredients, [and] Now we've come down to just one that is sufficient. In terms of the biology, it's really quite amazing. ... adult cells could be reprogrammed by adding four factors – specifically Oct4, Sox2, Klf4, and c-Myc. Recently, [researchers] demonstrated that Oct4 and Klf4 are sufficient to induce pluripotency in neural stem cells. By omitting Klf4 in the new study, they have now established that Oct4 is the 'driving force' behind the conversion of the neural stem cells into iPS cells. The lone transcription factor is not only essential, but it is also sufficient to make neural stem cells pluripotent." Simpler means cheaper, and cheaper means a broader range of applications in further development.

Link: http://www.eurekalert.org/pub_releases/2009-02/cp-sfc020209.php

In a free world you'll find high-profile freeloaders, gleefully exploiting the human tendency towards magical thinking by adopting, misusing, and ultimately corrupting the best-known terms made popular by progress in medical science. This is particularly widespread and pernicious in the "anti-aging" marketplace, or indeed anything to do with cosmetics products.

The scientific method is the cure for problems caused by magical thinking, such as a lack of progress towards better lives, and all the limitations - dramatic or trivial - that stem from an incorrect understanding of the way in which the world works. To make progress happen, you must tackle complex systems in a methodical way: propose, explore, test, verify, record, repeat. But that requires more work than merely guessing, and so there will always be some market for those willing to take the "shortcut" to the wrong answer. When the wrong answer doesn't have clear, obvious and rapid bad consequences attatched to it, magical thinking will prosper. Such is the downside of human enonomic preferences - there is always a market for "incorrect" when "incorrect" is sold more cheaply than "correct."

There is no perfect solution to the issue of short-sighted fools who've found a way to make money through flaws in human nature and the poor choices of others, and along the way make life difficult for people who are aiming at real progress. You can - and should - shame them for their idiocy, and you can - and should - do your own due diligence for any product you buy, but any sort of law or proscription will always wind up causing more harm than good. The FDA is the end result of just such an impetus to regulate and prohibit, and it's probably causing more harm to scientific progress in medicine than any other single source in the world.

I noticed a particularly outrageous example of Star-Trek-like bio-babble associated with an "anti-aging" cosmetics product today:

The list of ingredients is certainly staggering - but for no other reason than that their very names sound as if they were dreamed up by a group of stoned science students, each trying to outdo the last with a more ridiculous suggestion: Phyto-CelTec Malus Domestica, Anti-Cyto Stressor, Happybelle, Nano-Claire GY.

Seriously? I feel like saying: 'Pull the other one, it's got Happybelles on it.' And that's before I read the bit that tells me this is: 'The first cosmetic product that contains stem cells from the rare Uttwiller Spatlauber Swiss apple, so rare that only three trees remain in existence!'

Apparently 'stem cells' from this tree - yes, apple trees do have stem cells too, but only a few years ago, I bet they'd just have called it 'an extract'.

Sadly, there's a market for these sorts of near-outright falsehood, and there will continue to be a market for this sort of thing until the buyers stop buying. All these folk should be free to continue in their foolishness for so long as they care to, but feel free to let them know what you think of their actions.

From Ouroboros: "Aging is what geneticists like to call a 'complex trait' - simply put, a trait that is controlled by a large number of genes and the interactions between them. Complex traits differ from simple traits in the following way: When one is studying a simple trait, one simply identifies a mutant in the relevant trait and, after an ingenious combination of clever crosses and muscular cloning steps, finds the defective gene - thus gaining a great deal of explanatory power about the trait in question. When one is studying a complex trait, however, approaches like a mutant screen fall short. They don't fall totally flat - one of the great innovations of the last decade or so is the realization that we can learn quite a bit by studying aging at the single-gene level - but they can't get us all the way home. Suppose you do a screen and find fifty mutants that all lengthen lifespan by forty percent (not far from the situation in worms) - or, speaking more generally about complex traits, you find fifty loci in the human genome that are associated with a higher risk of schizophrenia. What then? What have you really learned about how the system works?" This complexity is why slowing aging by metabolic manipulation is a much harder path forward than aiming to preserve the metabolism we have by repairing the known damage of aging.

Link: http://ouroboros.wordpress.com/2009/02/04/systems-biology-of-aging-understanding-yeast-cr-by-network-inference/

From Ouroboros: "The eighth installation of Hourglass, a monthly blog carnival devoted to the biology of aging, will appear at SharpBrains on Tuesday, February 10th. Alvaro is particularly interested in entries having to do with brain aging or other neuroscience topics, but will of course accept any post in the general area of aging and biogerontology ... Topics of posts should have something to do with the biology of aging, broadly speaking - including fundamental research in biogerontology, age-related disease, ideas about life extension technologies, your personal experience with calorie restriction, maybe even something about the sociological implications of increased longevity. Opinions expressed are not necessarily those of the management, so feel free to subvert the dominant paradigm. If in doubt, submit anyway. Submissions should be emailed to [hourglass.host][at][gmail][dot][com]. In the meantime, feel free to check out previous editions of the carnival."

Link: http://ouroboros.wordpress.com/2009/02/03/hourglass-viii-call-for-submissions/

Two posts on a recent presentation by philosophers Julian Savulescu and Nick Bostrom, and biomedical gerontologist Aubrey de Grey:

Savulescu, Bostrom and de Grey: Why we need a war on aging

There is no normal human life span, or if there is, it was very short. Life-expectancy for the ancient Romans was about 23 years; today the average life-expectancy in the world is close to 64 years. For the past 150 years, best-performance life-expectancy has increased at a very steady rate of 3 months per year.

Why We Need a War on Aging

Many people fear that a longer life would result in boredom and a gradual loss of meaning. This would be more likely if one was a solitary Methuselah. But in a world where many of those close to us also lived longer, the greatest source of human well-being - deep human relations - would remain intact and arguably grow richer as that network expanded across generations.

...

And surely it is up to individuals to decide whether their lives come to lack meaning. For our part, we would take the longer life.

Our goal should be more, much more, longer and better life. We need a war on aging.

Billions of dollars have been spent preparing for a flu epidemic. The Spanish flu killed 20 million people. Aging kills 30 million every year. It is the most under-researched cause of death and suffering relative to its significance. Whatever breakthroughs occur in medicine or health care generally, at the moment we face the inevitability of ageing. That might not be necessary.

As I remarked a few days ago, the argument for longevity science to avert mass suffering and death gets less traction than it should. People care in the abstract, but unquestioningly accept what they have always known to be the case, no matter how horrible - so the deaths of tens of millions each year receives far less attention than less usual and much smaller disasters.

The FOXO3A gene is linked to the web of biochemical research surrounding calorie restriction, sirtuins and calorie restriction mimetics, and the rest of the major efforts in understanding how metabolism determines longevity. It is the human version of a gene already demonstrated to influence longevity in lesser animals: "A variation in the gene FOXO3A has a positive effect on the life expectancy of humans, and is found much more often in people living to 100 and beyond - moreover, this appears to be true worldwide. A research group [has] now confirmed this assumption by comparing DNA samples taken from 388 German centenarians with those from 731 younger people. ... We have now eliminated that uncertainty about the connection between FOXO3A and longevity, both by our results from the German sample study and by the support from our French partners in Paris, whose research on French centenarians showed the same trend. ... We can now conclude that this gene is probably important as a factor in longevity throughout the world."

Link: http://www.uni-kiel.de/aktuell/pm/2009/2009-012-langlebigkeit-e.shtml

The view of Alzheimer's disease as a form of diabetes - and thus largely as avoidable as diabetes - continues to gather strength: "The relationship between insulin and brain disease has been under scrutiny since doctors found evidence that the hormone was active there. The latest [study] looked at the effects of insulin on proteins called ADDLs, which build up in the brains of Alzheimer's patients and cause damage. ... Sensitivity to insulin can decline with aging, which presents a novel risk factor for Alzheimer's disease - our results demonstrate that bolstering insulin signalling can protect neurons from harm. Recognising that Alzheimer's disease is a type of brain diabetes points the way to novel discoveries that may finally result in disease-modifying treatments for this devastating disease. ... People with diabetes are at higher risk of developing Alzheimer's. It is well known that insulin affects how the brain works, and this research adds more evidence to the possibility that Alzheimer's could be a type of brain diabetes."

Link: http://news.bbc.co.uk/2/hi/health/7866022.stm

Have I really been writing an engineered longevity advocacy blog for five years? It seems so. The raison d'etre remains the same as outlined in past years:

This is a game in which all who choose to win will win big, should enough of us choose to win - but otherwise we all lose, suffer and die far sooner than we might. Significant progress in healthy life extension science requires the widespread support and understanding necessary for large-scale funding, just as it requires the early advances in science and advocacy that encourage that support.

...

Life is good, and the future is golden - you stand a good chance of living to see far more of it if you step up to the plate and help support the scientists who will make it happen.

Present miseries and woes, economic or otherwise, are always transient. The overall trajectory of human endeavor is an accelerating upward slope, and this despite the procession of momentary pitfalls. We are all extremely fortunate to live in an era of technological progress that can provide many of us a chance at living far longer healthy lives - if we band together, seize the day, and make it happen.

The worst of all possible futures, to my eyes at least, is the one in which we let slip away the chance to develop the technologies capable of repairing aging. A golden future it would still be, but one we would not live to enjoy, and whose inhabitants would build the biomedical wonders we could have achieved had we but set our minds to it.

Our knowledge of what causes aging is far and away definitive enough for development to be moving far more rapidly than it presently is. This state of affairs is a grand shame in the making, that we could be working more aggressively towards alleviating the greatest cause of suffering and death in the world - but are not.

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

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

Another example of what will be in the clinics a decade from now via EurekAlert! - and would be in the clinics now if the FDA didn't exist: "Hollow gold nanospheres equipped with a targeting peptide find melanoma cells, penetrate them deeply, and then cook the tumor when bathed with near-infrared light ... Active targeting of nanoparticles to tumors is the holy grail of therapeutic nanotechnology for cancer. We're getting closer to that goal ... When heated with lasers, the actively targeted hollow gold nanospheres did eight times more damage to melanoma tumors in mice than did the same nanospheres that gathered less directly in the tumors. ... The researchers packaged hollow, spherical gold nanospheres with a peptide - a small compound composed of amino acids - that binds to the melanocortin type 1 receptor, which is overly abundant in melanoma cells. They first treated melanoma cells in culture and later injected both targeted and untargeted nanospheres into mice with melanoma, then applied near-infrared light. ... The targeted nanospheres were actively drawn into the cells through the cell membrane. When the researchers beamed near-infrared light onto treated cultures, most cells with targeted nanospheres died, and almost all of those left were irreparably damaged."

Link: http://www.eurekalert.org/pub_releases/2009-02/uotm-tnf013009.php

The Los Angeles Times looks at the science of intermittent fasting, one approach to calorie restriction: "In normal health subjects, moderate fasting - maybe one day a week or cutting back on calories a couple of days a week - will have health benefits for most anybody ... We're not good at responding to too many calories, but we're very good at responding to fasting. Fasting, in itself, is not an unhealthy process ... During fasting, almost every system in the body is 'turned down,' ... The body changes how it uses fuel. Certain hormone levels fall. Growth stops. Reproduction becomes impossible. ... By the end of three weeks of fasting you are a completely different metabolic creature. It affects many, many processes - but in a somewhat predictable way that takes you toward disease prevention. ... intermittent fasting appears to offer the same advantages as long-term calorie restriction - defined as eating at regular times but consuming 25% to 30% fewer calories than what is recommended for that person based on age, size and gender."

Link: http://www.latimes.com/features/printedition/health/la-he-fasting2-2009feb02,0,7813891,full.story