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.

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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.

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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.

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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.

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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.

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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.

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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.

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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."

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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

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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