$36,000
$24,120

The Tedium of Discussing Boredom in Connection With Enhanced Longevity

It seems I have become jaded - one might even say bored - by repeated discussion of the potential for longevity-induced boredom. My capacity to enjoy the novelty of each new appearance of this fairly simple exchange of views has been blunted. For now, at least - it'll take a couple of years for that to wear off. There really isn't much to it: one side says, without any real evidence to back it up, that longer lives will inevitably lead to the boredom of repetition, and a dulled, meaningless existence. Those of us with more sense and imagination pull out the numbers to show that this viewpoint is nonsense however you choose to look at it. There is more to be experienced than any person could undertake in a million years, even in this limited world of ours today.

And if you have the prospect of a million years on the table - or even a thousand, or even a few hundred - I'd suggest that you have ample time to figure out how to keep yourself entertained indefinitely. In my case, I'll just have to strike thinking about longevity and boredom from the list for a few years. I'm sure I won't miss it - there exist a countless multitude of other topics to think about, other debates to follow, other tasks to work on, none of which are in any way lacking in novelty.

Sadly, as for many of the debates over the development of engineered human longevity, those who argue for inevitable boredom aren't really debating from a position of rationality. Facts, figures, and logic don't do so well when emotion is driving. Atop that, advocacy of any sort is very much a business of holding the same debate over and over again with as many different people as possible. Even though there are novel things I would much rather be doing with my time, it is important to return time and again to the basics - for so long as there are a significant number of people out there who haven't yet heard them.

Given that, I'm always pleased to see other advocates taking up the slack for a while, even if they do so more even-handedly than the debate merits:

Technologies meant to help extend the human lifespan, such as cryonics, or the procedures investigated by gerontologist Aubrey de Grey under the name "Strategies for Engineered Negligible Senescence", are increasingly an object of discussion, including in the popular press. A recent example of this is John Walsh’s piece in The Independent earlier this month. He is one of several authors who find it worth telling us that they wouldn’t want to live forever, even if they could. At times his article appears to aim merely at being entertaining and polemical, yet his central idea has been put forward by respected philosophers such as Bernard Williams, in his famous essay The Markopulos case: reflections on the tedium of immortality. In short, the idea is that living forever would just be atrociously boring.

Should we draw normative conclusions from such pieces about the development and use of life extension technologies, regarding them as superfluous or even downright undesirable? I want to argue for a negative answer to that question.

Lessons From the Mouse

A reminder of the role of the laboratory mouse in aging research: "Aging, which affects all organ systems, is one of the most complex phenotypes. Recent discoveries in long-lived mutant mice have revealed molecular mechanisms of longevity in mammals which may contribute to our understanding of why humans age. These mutations include naturally-occurring spontaneous mutations, and those of mice genetically modified by modern genomic technologies. It is generally believed that the most fundamental mechanisms of aging are evolutionarily conserved across species. The following types of longevity mechanisms have been intensively studied: suppression of the somatotropic (growth hormone/insulin-like growth factor 1) axis, decreased metabolism and increased resistance of oxidative stress, reduced insulin secretion and increased insulin sensitivity, and delayed reproductive maturation and reduced fertility. In addition, many of the mutations have a sex-dependent effect on lifespan, and when present in different genetic backgrounds, the effects of the same gene mutation can vary considerably. ... We anticipate that these mouse studies will ultimately provide clues about how to delay the aging and prolong lifespan, and help to develop therapies for healthier human aging."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20667513

Aging of the Innate Immune System

The innate immune system declines with age, just like the adaptive immune system. The details are different: "The innate immune system is composed of a network of cells including neutrophils, NK and NKT cells, monocytes/macrophages, and dendritic cells that mediate the earliest interactions with pathogens. Age-associated defects are observed in the activation of all of these cell types, linked to compromised signal transduction pathways including the Toll-like Receptors. However, aging is also characterized by a constitutive pro-inflammatory environment (inflamm-aging) with persistent low-grade innate immune activation that may augment tissue damage caused by infections in elderly individuals. Thus, immunosenescence in the innate immune system appears to reflect dysregulation, rather than exclusively impaired function." Understanding the cause of the problem steers the search for solutions. Dysregulation means that the focus is on fixing errant signaling mechanisms, or on finding ways to directly instruct cells to act or not act. Cell transplants or repairs are not much use if the problem actually lies in the control systems.

Link: http://www.ncbi.nlm.nih.gov/pubmed/20667703

BRASTO Mice, an Example of Calorie Restriction Mimetic Research

A common path for metabolic - and now aging - research is as follows: firstly specific gene variants or changes in gene expression are identified in laboratory animals as the likely cause of a particular characteristic. Extended longevity, say, or enhanced regenerative ability. Some of these discoveries are fortunate accidents, and some are the result of deliberate test programs aimed at verifying a specific theory, but either way the next step is the production of genetically altered animals for further study. Genetic discoveries are rarely as clean-cut as researchers would like, in the initial stages at least. But gene engineering of laboratory animals - usually mice in the later stages of investigation - allows study of specific genes or metabolic processes under more controlled and useful circumstances that those of the original discovery. Pieces of the biochemical puzzle can be changed, moved around, or removed, and the resulting changes observed and incorporated into a growing understanding of the processes involved.

With genetically altered mice in hand - and at least a basic understanding as to why these genetic alterations produce observed changes in the mice - researchers can then proceed to design or screen for compounds that reproduce some of the effects of this specific gene engineering project. Recall that genes are blueprints for proteins, the cogs, switches, dials, and screws in the machinery of cells. The process by which proteins are produced from genes is complicated, full of feedback loops, and very open to manipulation in this age of biotechnology. Levels of a specific protein can be dialed up or down by the introduction of a suitable drug - though rarely without all sorts of other cascading side-effects. More precise are new tools that use RNA to very precisely target a single protein; there the side-effects stem from the fact that few proteins are involved in only one process in the body. Evolution loves reuse, and it is very challenging to turn just one dial at a time in our biochemistry.

In any case, from this point on in the path is the traditional one of drug development: discovery, testing, trials, high costs, and ridiculous regulatory barriers.

Here is an example of metabolic longevity research still in the gene engineered mouse stage, another spin-off from past years of investigation into sirtuins and the biochemistry of calorie restriction:

Aging and Longevity Tied to Specific Brain Region in Mice

At the start of the research project, the study's lead author Akiko Satoh, PhD, a postdoctoral research associate in developmental biology, saw that mice on low-calorie diets had increased amounts of SIRT1 in specific regions of the hypothalamus and that neurons in the same regions were activated.

So the research team developed mice that continually produced higher amounts of SIRT1 in their brains to see what the effect would be. That's when Satoh observed the mice's unusual level of activity under fasting conditions. "This is the first time that it has been demonstrated that SIRT1 is a central mediator for behavior adaptation to low-calorie conditions," Satoh says.

Interestingly, these mice, called BRASTO (brain-specific SIRT1-overexpressing) mice, also maintained higher body temperatures after a 48-hour fast than ordinary mice, which experience a drop in body temperature during fasting.

"The BRASTO mice have a better capability to come up with energy to achieve a higher body temperature and increased activity level when food is restricted," says Imai, associate professor of developmental biology and of medicine.

...

The scientists are continuing to study the BRASTO mice to see if they live longer than ordinary mice.

One of the things that this work underscores is that despite the vast sums of money devoted to understanding sirtuins over the past five years, there is still remains great deal yet to be accomplished. Further, consider that these are just a few out of thousands of potentially relevant proteins in the biochemistry of mammals, of interest to attempts to slow down aging. Manipulation of metabolism is the slow boat in this race: there are better strategies to extend the healthy human life span.

Harnessing Hormesis

Hormesis is here examined in the context of exploiting it to slow aging: "The process of aging is accompanied by a progressive reduction of biological dynamical sophistication, resulting in an increased probability of dysfunction, illness, and death. This loss of sophistication is inherent in all aging organisms. However, it may be possible to retard the rate of loss of biological complexity [by] exploiting the multiple effects of hormesis, through a wide range of challenges including physical, mental, and biological stress. Hormesis is widely encountered in biological systems, and its effects are also seen in humans. It is possible to use hormetic strategies [to] enhance the function of repair processes in aging humans and therefore prevent age-related chronic degenerative diseases and prolong healthy lifespan. Such techniques include dietary restriction and calorie restriction mimetics, intermittent fasting, environmental enrichment, cognitive and sense stimulation, sexuality-enhancing strategies, exposure to low or to high temperatures, and other physicochemical challenges. Current research supports the general principle that any type of a hormetic dose-response phenomenon has an effect that does not depend on the type of stressor and that it can affect any biological model. Therefore, novel types of innovative, mild, repeated stress or stimulation that challenge a biological system in a dose-response manner are likely to have an effect that, properly harnessed, can be used to delay, prevent, or reverse age-related changes in humans."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20662589

An Example of Early Life Damage Affecting Longevity

Per the reliability theory of aging, we should expect to see shorter life expectancies result from damage or stress in early life. Here, a historical analysis supports that line of thinking: "Nutritional conditions in utero and during infancy may causally affect health and mortality during childhood, adulthood, and at old ages. This paper investigates whether exposure to a nutritional shock in early life negatively affects survival at older ages, using individual data. Nutritional conditions are captured by exposure to the Potato famine in the Netherlands in 1846-1847, and by regional and temporal variation in market prices of potato and rye. The data cover the lifetimes of a random sample of Dutch individuals born between 1812 and 1902 and provide individual information on life events and demographic and socioeconomic characteristics. First we non-parametrically compare the total and residual lifetimes of individuals exposed and not exposed to the famine in utero and/or until age 1. Next, we estimate survival models in which we control for individual characteristics and additional (early life) determinants of mortality. We find strong evidence for long-run effects of exposure to the Potato famine. The results are stronger for boys than for girls. Boys and girls lose on average 4, respectively 2.5 years of life after age 50 after exposure at birth to the Potato famine. Lower social classes appear to be more affected by early life exposure to the Potato famine than higher social classes. These results confirm the mechanism linking early life (nutritional) conditions to old-age mortality."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20663577

Spurring Joint Regeneration

An alternative to stem cell transplants in regenerative medicine is the manipulation of existing cell populations in the body: using biochemical signals to direct these cells to rebuild damaged tissue. This has proven effective in the laboratory in recent years, spurring significant regeneration that would not normally have happened. Here is one example:

Researchers are reporting they have successfully persuaded damaged joints to regrow cartilage and bone, using a novel "cell homing" approach. The experiments, conducted in rabbits, are a proof of concept of a method that may one day replace artificial joint transplants in humans ... The method uses a carefully constructed "bioscaffold," impregnated with a growth factor that causes precursor cells to migrate to the site and become cartilage and bone cells

...

Animals treated with the method fully recovered weight-bearing and locomotion within a month, and the regenerated tissue was similar to naturally occurring cartilage and bone, the researchers said.

The research report is online at the Lancet. This general approach to regenerative medicine has both advantages and drawbacks: on the one hand using a patient's own cells removes the need to source cells for transplant, thus hopefully leading to a leaner and less costly technology platform. On the other hand, a person's stem cell populations decline in effectiveness with advancing age. It is still an open question as to whether the cause of this decline is that signalling mechanisms become age-damaged, that the population shrinks with age, or that the cells themselves become too damaged to function well. All three many be the case to some degree or another, or only important for some groups of stem cells in the body. A number of research groups are working hard on uncovering the truth of it, but the central problem remains: if you want to command the stem cells already present in a body to get to work, they have to be up to the job.

The most important potential applications of regenerative therapies apply to the old: restoring worn organs, and repairing the damage caused by aging. So broader development of these therapies will have to lead to some consideration of how to restore aged stem cell populations to youthful effectiveness along the way. I am optimistic that we will see progress on this front over the next decade, as the next wave of therapies are tested and evolved in the course of medical tourism, and their shortcomings for older people are better categorized and understood.

Considering Cryonics and Neuronal Survival

From Depressed Metabolism: "The debilitating effects of a stroke are the result of the (delayed) neuronal death that follows an ischemic insult to the brain. In cryonics, biochemical or freezing damage to cells does not necessarily produce irreversible cell death because damaged cells are stabilized by cold temperatures. As such, morphological preservation of brain cells can co-exist with loss of viability. Therefore, securing viability of brain cells is a sufficient but not a necessary condition for resuscitation of cryonics patients. Future cell repair technologies are assumed to infer the original viable state of the cells from their morphological properties. This does not mean that conventional stroke research does not have any relevance for evaluating the technical feasibility of cryonics. Extensive delays between the pronouncement of legal death and the start of cryonics procedures could alter the structural properties of cells to such a degree that meaningful resuscitation is even problematic with advanced nanomedical cell repair technologies. This is one of the reasons why Alcor complements the cryopreservation process with stabilization procedures to secure viability of the brain after pronouncement of legal death."

Link: http://www.depressedmetabolism.com/2010/07/27/how-many-neurons-need-to-survive-for-cryonics-to-work/

Social Connectivity and Mortality Risk

This study crunches the numbers to show that being socially connected has an effect on life expectancy comparable to that of exercise. Why this correlation exists is still up for debate, but it is worth considering that skill at networking and possessing a large social network enable success in other aspects of life: "These findings indicate that the influence of social relationships on the risk of death are comparable with well-established risk factors for mortality such as smoking and alcohol consumption and exceed the influence of other risk factors such as physical inactivity and obesity. Furthermore, the overall effect of social relationships on mortality reported in this meta-analysis might be an underestimate, because many of the studies used simple single-item measures of social isolation rather than a complex measurement. Although further research is needed to determine exactly how social relationships can be used to reduce mortality risk, physicians, health professionals, educators, and the media should now acknowledge that social relationships influence the health outcomes of adults and should take social relationships as seriously as other risk factors that affect mortality, the researchers conclude."

Link: http://dx.doi.org/10.1371/journal.pmed.1?000316

The Rift in Longevity Science

From a recent article on the film To Age or Not to Age:

It's easier to change lifespan than previously thought, notes Dr. Austad. "We already know how to make animals live 25-40% longer." But no one really know what all this means for humans... yet.

Gerontology expert Aubrey de Grey, long dismissed as a fringe thinker in the field because he doesn't think we should have to age at all, believes it will be a short leap from a 150-year lifespan to 1000. He notes that, with the speed of the current research, "If you're only 50, ... there's a chance you could pull out of the dive." He is beginning to be considered more mainstream.

The current rift between de Grey's philosophy and the other scientists, records Pappas, is that de Grey wants to get rid of aging altogether, while they just want to extend a healthy lifespan.

I'm with de Grey on that point: if the opportunity is there to do the job properly, then do the job properly. No half measures in the face of the greatest destructive force suffered by humanity: more than a hundred thousand lives extinguished every day, and hundreds of millions of others suffering in their declining years.

By all reasonable arguments, it shouldn't actually be any harder or more costly to repair and reverse aging than to safely slow it down by a significant fraction. An additional and important point is that reversal of aging through damage repair will be beneficial to old people, unlike a slowing of aging, which only lowers the ongoing rate at which new damage occurs. The path ahead is quite clear from a technical perspective, but people who favor the repair of aging are still a minority in the scientific community. More is the pity - and this one of the many things that advocacy and education must change if we ourselves, rather than our descendants, are to live far longer healthy lives.

Exercise: Good at Any Age

Failing to exercise damages your prospects for healthy life in the future: "one in three men and one in two women over the age of 75 are not physically active at all. A recent study led by the National Institute on Aging (NIA) says this lack of exercise makes these seniors three times more likely to die sooner than their counterparts who do only light day-to-day activities. ... Any movement is better than no movement at all to lower your risk of death ... For every 287 calories per day a senior expended, there was a 32 percent reduction in death rate over the six-year period encompassed by the study. ... It is well-established that exercise leads to the reduction of heart disease, cancer and diabetes, and it can preserve mental sharpness. What is significant about the current findings is that the study is the first to provide credible evidence that everyday activity might be beneficial ... Researchers ask how much activity do we need, but the public approaches it by asking how little can I get away with ... experts caution against using the study as a basis to give up exercise, a conclusion not supported by the data." A little is better than none, but more is better than a little. Rejuvenation medicine is on the far horizon, and if you want the best chance of being alive and healthy to benefit from it, you'd better take care of the health basics here and now.

Link: http://senior-spectrum.com/news04_072710/

Lysosomal Dysfunction and Alzheimer's Disease

Your lysosomes are recycling units, but their function slowly fails with age - meaning your cells degrade as they fill with waste and junk. More rapid and selective lysosomal failure in brain cells is implicated in a variety of neurodegenerative conditions. Here, researchers dig more deeply: "Neurodegenerative disorders, like Alzheimer's disease, are a devastating group of conditions that exact a heavy toll on patients and their families. ... Research over the past two decades has strongly suggested that a fundamental problem in affected nerve cells relates to accumulation of cellular 'garbage,' or proteins and other material that is too old to function properly. Thus, understanding how the neuron handles these outdated molecules is of great significance. Here we find that upregulation of one such cellular degrading pathway, the lysosome, can have significant deleterious effects to the neuron. We specifically show that expanding the lysosomal compartment can markedly increase production of a very toxic form of tau, a protein strongly implicated in neuronal dysfunction and death in Alzheimer's disease and related disorders. Our findings have important implications for the development of neurodegenerative disease therapies that seek to manipulate the lysosome and the proteins within the lysosome." Therapies that can repair failing lysosomes may have general application to rejuvenation medicine - so the more groups working on that, the better.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904797/

On p53 and Aging

The cancer suppressor gene p53 has proven to be the center of a fruitful area of study in aging research: it is a master controller or important component in many critical biological processes - such as cell division, and even autophagy. While levels of p53 expression were thought to operate as a sliding scale between more cancer and slower aging at one end versus less cancer and faster aging at the other, researchers have in recent years demonstrated clever ways around this evolutionary trade-off. So gene-engineered mice have been created that suffer less cancer and still live longer:

A New Look At p53, Cancer and Aging

[Previous research] showed that a boost in p53 kept mice cancer free but also caused them to age more quickly. [But] in the new work, the normal regulatory mechanisms remain in place, so p53 is churned out only when needed. ... These mice produce more p53 protein when prompted to by cellular stress, such as DNA damage or lack of oxygen. As expected, mice with the extra copy of p53 had fewer tumours than regular mice, and their cells were less likely to turn cancerous when grown in a Petri dish. On average, the transgenic mice lived 16% longer than normal mice.

50% Maximum Life Extension in Mice Via p53 and Telomerase

Telomerase causes more cancer. So that there is a tumor, it must activate telomerase, and if a mouse has more telomerase than the normal thing, for example, making transgenic mice, we know that it will have more tumors. What we have done is to use [transgenic mice expressing more p53 than usual], because p53 protects against cancer and extends life of the mice 18%, and added the gene of immortality, telomerase, and we [found] that these multitransgenic mice live an average on a 50% more, without cancer.

I notice that the advance publication queue for the open access AGING Journal currently contains a couple of very readable editorials on the history and present state of p53 research:

p53: Pro-aging or pro-longevity?

p53 continues to surprise biologists. For nearly a decade, it was thought to be an oncogene, only to be subsequently declared a potent tumor suppressor. Initially characterized as a transcriptional activator, we now know p53 is also a transcriptional repressor. And just as it seemed p53 activities were confined to the nucleus, it became apparent that p53 also functioned in the cytoplasm to regulate mitochondrial responses. As a tumor suppressor and regulator of hundreds of genes, it was perhaps not surprising that p53 was shown to regulate numerous cellular processes related to cancer - cell cycle progression, apoptosis, cellular senescence and DNA repair, among others. It was another surprise, however, to learn that p53 might also regulate aging.

P53 and aging: A fresh look at an old paradigm

Multiple lines of evidence from animal models suggest that a functional p53 pathway favors prolonged survival. Aging mice show a decrease in p53 activity correlated with increased tumor incidence as well as an overall reduction in longevity. On the other hand, mice with an extra gene dosage of Arf and p53 show significant tumor protection, decreased oxidative damage and delayed aging.

...

As the ability of p53 to increase longevity becomes more evident, we should consider the role of its negative regulator, Mdm2 ... it is very tempting to imagine that just a slight inhibition of Mdm2 function in cells could both prolong full tumor surveillance mechanisms of p53, and in some circumstances increase longevity. Numerous molecular inhibitors of Mdm2 are in various stages of development with the goal of reactivating p53 activity in cancer. The idea that controlled pharmacological modulation of Mdm2 function might also have positive consequences in extension of human lifespan could be an unexpected benefit and an additional incentive for design of new compounds targeting Mdm2.

Like many other lines of life science research, genetic modification of longevity in mice leads fairly directly to the possibility of metabolic manipulation via drugs in humans. This is the dominant paradigm in those portions of the aging research community where people are thinking about engineered longevity: figure out a way to slow down aging through drugs that can mimic the biochemistry of longevity observed in other mammals.

Why Pay Attention to Accelerated Aging Studies?

In a nutshell, this is why research into so-called accelerated aging conditions may be relevant to longevity science: "One of the many debated topics in ageing research is whether progeroid syndromes are really accelerated forms of human ageing. The answer requires a better understanding of the normal ageing process and the molecular pathology underlying these rare diseases. Exciting recent findings regarding a severe human progeria, Hutchinson-Gilford progeria syndrome, have implicated molecular changes that are also linked to normal ageing, such as genome instability, telomere attrition, premature senescence and defective stem cell homeostasis in disease development. These observations, coupled with genetic studies of longevity, lead to a hypothesis whereby progeria syndromes accelerate a subset of the pathological changes that together drive the normal ageing process." This same viewpoint - that each of the accelerated aging conditions represents a different facet of normal aging run wild - holds up for well other conditions, such as Werner syndrome, given the evidence amassed to date.

Link: http://www.ncbi.nlm.nih.gov/pubmed/20651707

MDR Proteins and Cellular Longevity

An interesting study that provides another view of the relationship between accumulating damage, repair systems, and life span in cells: "Yeast cells, much like our own cells, have a finite ability to reproduce themselves. A 'mother' cell can only produce 20-30 'daughters' before it loses the ability to replicate and dies. ... Multidrug resistance (MDR) proteins are best known for helping cancer cells expel anticancer drugs - hence their name - but they also ferry compounds in and out of normal cells. [Researchers] found that yeast lacking certain MDR proteins have a shorter reproductive lifespan; they produce fewer daughter cells. Yeast engineered to contain more of these pumps, however, can produce more daughters. ... during division, the mother conserves damaged proteins and other cellular components that could prove harmful to the bud. ... Indeed, some research groups have posited that the mother's finite reproductive capability is the result of accumulating these damaged and toxic compounds. ... yeast division also results in an unequal distribution of MDR proteins. The mother cell retains the original MDR proteins while the bud gets young, newly formed MDR proteins. Because the mother's supply is never replenished, she has to rely on the pool of MDR proteins that she's born with. ... Over time these proteins decay. Some lose only part of their function; others may stop working altogether."

Link: http://www.nature.com/news/2010/100725/full/news.2010.373.html

A Near Future of Gymnomimetics

If, as seems to be the case, it is possible to design drugs to make a mammal's metabolism behave in a similarly beneficial way to the state induced by calorie restriction, then we should also believe that the same can be done for exercise. The results of exercise are, like the results of calorie restriction, nothing more than altered metabolic processes and the consequences thereof: better health and a modestly extended life span. However, as for all methods of slowing aging, this will be of little benefit to those of us already middle aged today. We will be old by the time therapies arrive, which means we need to see progress underway in ways to repair and reverse the damage of aging, not just slow it down.

Given that interest in slowing aging is dominant amongst gerontologists, I think it plausible that work on metabolic manipulation will continue to expand. If the controlling mechanisms of exercise-induced metabolic changes can be isolated and manipulated - and there is no reason to think that this is impossible, or that it will require more than a decade or two to accomplish - then the present excitement over calorie restriction mimetic drugs may soon grow to include potential exercise mimetics.

For example:

Regular physical activity and especially aerobic exercise are associated with reduced risk of disease and enhanced longevity, but the molecular mechanisms of these health benefits remain obscure. A comprehensive metabolomic approach was used to characterize the changes in blood levels of [more than] 200 metabolites upon vigorous exercise and identified two dozen that changed substantially. One, niacinamide, is intimately related to the metabolism of nicotinamide adenine dinucleotide (NAD+) and its reduced form NADH, which is in turn linked with exercise capacity as well as health status.

Intensive investigation of metabolic changes with exercise could lead to pharmacological attempts to mimic the beneficial effects of exercise, an approach we term "gymnomimetics."

If you dig back into the way in which mitochondrial damage contributes to aging, you'll see that the cycle of NAD+ to NADH and back again plays an important role in spreading the consequences of damaged mitochondria beyond the cell that contains them. But NAD+ and NADH appear in many other processes of interest to those who study aging and metabolism. It is not surprising to see their levels change with environmental circumstances that impact health and longevity.

Methuselah Foundation Newsletter, July 2010

The latest Methuselah Foundation newsletter is out: "2010: Where We Are Now: Methuselah Foundation took on a big challenge: extending healthy human life. From SENS to My Bridge 4 Life, we've supported and incentivized major initiatives and research to fulfill our mission. In 2010 we are focusing our attention on tissue and whole organ engineering. Read this newsletter and follow the links to our site to learn more about what we are doing now so you live longer and healthier. ... This year we are focusing our efforts on tissue engineering and organ replacement. We are looking ahead 10 years and projecting that, with our help, everyone who needs an organ will get an organ. ... Prizes have proven to be the most powerful tool for inspiring radical scientific breakthroughs. That's why we offer prizes, including the recently announced NewOrgan Prize. The end result will allow many people to live longer and - if history is an indicator - the many innovations that come as a result of this work are unimaginable today. To build a replacement organ, from a patients own cells, and have it fully function, scientists must first develop and preserve all the tissues that build that organ - including muscle, nerves, arteries and veins. ... Leaders in the science of organ engineering have joined the NewOrgan Advisory Board. ... The members of our Scientific Advisory Board are frontrunners in the research and development of new organ technology. "

Link: http://www.mfoundation.org/files/newsletters/july2010/newsletter.html

More on the FDA and Aging as a Disease

From ShrinkWrapped: "If a physical change affects half of all people as they age, this would seem to suggest that it is a normal variant of human aging, which to the best of our knowledge is an accumulation of metabolic and genetic errors that accrue as we get older until some sub-unit(s) of the processes reach a threshold at which continued functioning of the body is impossible. Our current regulatory apparatus remains trapped in a 20th century mindset which fails to recognize how various diseases are nothing more than unfortunate variants of the aging process that all of us will one day fall prey to. For example, in Alzheimer's 'Disease' errors of metabolism (malformed proteins) in neurons in the brain lead to an accumulation of defective protein parts which eventually disrupt the functioning of the neuron, ultimately killing it. When this process has gone on long enough to have damaged and destroyed some as yet unknown fraction of the brain, the person becomes neurologically symptomatic. This 'Disease' is not communicable, nor is it caused by an exogenous agent. The damage to the brain occurs as the result of biological failure that all of us will have to face in one form or another. ... The FDA does not recognize aging as a treatable condition and only approves treatment for 'Disease.' ... Because the FDA only evaluates treatments for Diseases, and its definition of disease versus aging is completely arbitrary (why is Type II Diabetes a disease while Sarcopenia, the loss of muscle mass and function that accompanies aging, is not?) we are forced to develop treatments that primarily address symptoms rather than either repairing damage or rejuvenating systems."

Link: http://shrinkwrapped.blogs.com/blog/2010/07/when-is-a-disease-not-a-disease.html

Following Up On Cryonics in the Media

A recent New York Times article on cryonics generated a fair amount of discussion online. I thought that I would provide a few quotes and pointers for those who would like to browse, but you should read the Times article first.

Picking On Cryo-Nerds:

Tyler Thursday on cryonics: "My question is: why not save someone else’s life instead?" ... Tyler’s argument is hard to follow here. Is he merely saying the world is better if anyone acts more contrary to type, expresses less relative to instrumenting, or donates more to charity? If so, why pick on cryonics and tech nerds in particular, why not just rail in general against all expressing, typed-acts, and non-charity?

The Presumption of Death:

Peggy Jackson, Robin Hanson’s wife, wonders “what’s so good about me that I’m going to live forever?” This is a strange presumption to make about life and death. Our culture generally does not have this presumption about moral worth and non-existence. As a general rule, we do not feel that someone has to justify her reason to seek medical care and try to remain alive.

Cryonics as Charity:

while many dislike cryonics because they see it as especially selfish, in fact cryonics has such huge scale effects that buying cryonics seems to me a pretty good charity in its own right.

Space Ash vs Cryonics:

Compared to cryonics, the ashes-into-space industry has over half as many delivered customers, collected in a far shorter time and with far less free publicity. While cryonics is on average more expensive, the cheapest cryonics option, $28,000 via CI, is cheaper than the most expensive ash launch. While space-ash customers are even more male dominated, and probably just as tech nerdy, my intuition guesses they suffer far less "hostile-wife phenomena" than cryonics. (Will someone please check?) And I’d guess this reduced hostility has much less to do with costs than image – cryonics freaks folks out more. Why?

Cryonics and the Hanson Family

Still, I would have written the piece a little differently. To me, the primary questions are "What is the probability that cryonics works?," and "What counts as 'working'"? If cryonics genuinely had a 5% chance of giving Robin ten extra years of healthy life, then Robin's right, and Peggy's just plain wrong. If, in contrast, cryonics had a 5% chance of eventually creating a mere computer simulation of Robin, but only a one-in-a-million chance of reviving the flesh-and-blood man, cryonics does indeed seem like an undue financial and emotional burden on his family.

While there are more than the usual number of people talking about cryonics of late, we shouldn't forget that the staff and volunteers of cryonics organizations continue to do their work in the background, just as they did before this latest burst of publicity. See this recent Alcor posting, for example, which is illuminating as ever as to how a cryonics provider actually works in practice:

In what has become the busiest 12 months of any previous year in Alcor's history, we have cryopreserved three additional members during this past month of June.

A-2371, who maintained confidentiality with respect to his membership, resided in Cleveland, Ohio. Alcor initiated an eight-day standby when the member fell critically ill during the month of May. The standby ended when the member's condition improved and he was inevitably discharged from the hospital. Roughly a month later however, the individual returned to the hospital and was placed on life support. When all efforts to correct his medical issues had failed the family made the decision to discontinue all supportive measures. Anticipating that this action would result in clinical death, the family preferred to wait until the entire team and equipment were in place at the member's bedside.

Suspended Animation was requested to join Alcor's Aaron Drake, already on standby, for a full deployment. All team members, including a surgeon and perfusionist, were in place prior to discontinuing the life support. The member's health continued to decline for another 18 hours before he was pronounced by hospital staff. Immediate stabilization, cool down and a field washout were performed and the patient was shipped to Alcor by air ambulance. We achieved full perfusion of the brain and an estimated net perfusion of 95%, including the body. On June 11th, A-2371 becomes our 96th patient.

Doing beats talking about doing. In a better world, we would all tend to pay more attention to the people who are getting things done rather than filling out column inches.

On Preventing the Global Aging Crisis

KurzweilAI looks at the recent scientific publication promoted by the LifeStar Institute: "Unfortunately, most biogerontologists see aging-intervention strategies as a considerable deviance from mainstream thinking, which is based on the notion that aging is a certainty and that pursuit of any kind of 'fountain of youth' or life-extension therapies will only end in failure. But de Grey is not swayed by the skeptics. He says perspectives are changing ... Five of the other authors [of the paper] are among the absolute top tier of biogerontologists, whose views are universally respected in the field. Their voice here will make a huge impact on thinking about the issue, both within the field and beyond. The surprising conclusion from the past two decades of research on biological aging is that aging is plastic. Within a species, maximum life span is not fixed, but can be increased by dietary manipulation (particularly calorie restriction) or genetic manipulation. ... But a new world of indefinite lifespans has also raised questions about potential population impacts. ... 'Contrary to what is widely assumed, however, the net effect should be relatively minor,' the authors respond, reasoning that new human births have a greater effect on population than adding a fraction of life span to existing humans. ... A policy of aging as usual will lead to enormous humanitarian, social, and financial costs. Efforts to avert that scenario are unequivocally merited, even if those efforts are costly and their success and full consequences uncertain. To realize any chance of success, the drive to tackle biological aging head-on must begin now."

Link: http://www.kurzweilai.net/how-to-prevent-a-global-aging-crisis

Profiling the New Mprize Competitors

The Methuselah Foundation provides profiles of the most recent Mprize competitors: "Holly Brown Borg’s acquaintance with Ames dwarf mice led her to aging research. While she was in a postdoctoral position she began working with these small but long-lived mice to do studies on immunology. At that time she was working with Andrzej Bartke, he holds the Mprize for Longevity for a mouse that lived almost 5 years, double the normal lifespan. After heading to North Dakota, where she became an Assistant Professor in Pharmacology, Physiology and Therapeutics, Holly continued to follow the progress of the mice. Their long life intrigued her. What was it that caused them to live so much longer than other mice? The human nutrition center on campus suggested that Holly turn her attention to methionine metabolism. This essential amino acid is critical for protein synthesis and growth, and is also integral to metabolism. To go a bit deeper, glutathione, an important antioxidant, is generated by the methionine (MET) pathway. Glutathione is made up of three amino acids, the key one in these studies is cysteine. The essential amino acids, MET and cysteine, can be easily modified in the diet. The Ames mice have highly active methionine metabolism but when they are given growth hormone, this activity goes down. This was the proof Holly needed that methionine metabolism is regulated by growth hormone."

Link: http://blog.methuselahfoundation.org/2010/07/new_mprize_competitors_alan_cash_holly_brown_borg.html

An Interview With David Stipp

David Stipp is the author of a recently released book on longevity science. Much like the mainstream of the research community, he is of the view that slowing aging is the only practical way forward. Which is a pity - we definitely need more of the popular science authors to lean towards advocating repair strategies like SENS, but I don't see it happening before opinions change within the scientific community.

In any case, here is an interview that presents a more nuanced version of Stipp's viewpoint than has appeared in articles to date. Regardless of his opinions on the science, you'll find things to agree with:

Q: What's the brass ring in anti-aging research?
A: The near-term, totally feasible prospect scientists are working toward is the development of a safe drug that delays by seven or eight years the onset of diseases associated with aging. The goal is to slow the rate of aging and postpone all the bad stuff: Alzheimer's, cancer and heart disease are the three main killers, and then there are lesser diseases, from osteoporosis to cataracts. A true anti-aging drug would also extend maximum lifespan.

...

Q: Is that the only barrier to clinical trials in humans?
A: No. The main barrier, as with all anti-aging research, is that there's no funding. We've got ever more promising basic research and yet I don't know of anybody funding clinical work on agents that will possibly slow aging.

Q: Why aren't pharmaceutical companies all over this?
A: There's no economic incentive. A single drug in clinical development generally costs around a billion dollars, from the very beginning to the end. A pharmaceutical company can only afford to spend that kind of money on trials of something it knows it can sell as a prescription drug, with a pretty high profit. The issue here is that you can't sell something as a prescription drug unless the Federal Drug Administration recognizes that there's an indication for it. And the FDA does not consider aging a disease, so it wouldn't give regulatory approval to a prescription drug used to treat aging.

...

Q: Why haven't anti-aging researchers been more successful at marshalling resources?
A: In a nutshell, the world of medical science doesn't recognize what's happened in the research on gerontology. Partly it's because the anti-aging field has historically been an area rich with snake oil and con artists, and partly it's because aging is extraordinarily complicated - so much so that unlike diseases, many biologists felt that figuring out exactly what was driving it was a hopeless cause. To a large extent, that's how the FDA and many physicians still think about anti-aging research. People just don't know how far the science has come and how promising it is.

It is good to see more people pointing out the lunatic roadblock to progress that is the FDA. We stand upon the verge of therapies to treat aging, and the unelected, unaccountable bureaucrats forbid outright all application of such technology - so the funds aren't there for research and development. It is nothing less than insanity.

Envisioning Regrowth of Organs

From CBC News: "Scientists in Toronto are trying to crack the secrets of regeneration to trigger the human body to grow tissues and organs damaged by disease. In his lab at Mount Sinai Hospital, Dr. Ian Rogers is working on a replacement pancreas that would be grown in a lab and then placed in those with Type 1 diabetes to restore their insulin production. ... At this stage, Rogers's team is building a pancreas out of a surgical sponge, a three-dimensional structure seeded with insulin-producing islet cells. The pancreas would be grown in the lab and then placed under the skin of those with Type 1 diabetes to restore their insulin production. But making a pancreas is complicated, Rogers said. The most advanced research at his lab is simpler: regenerating blood vessels so people with Type 2 - or adult onset - diabetes who have damaged fingers and toes can avoid amputation. In theory, any condition where cells are damaged - from insulin-producing cells in diabetes to brain cells in Alzheimer's and Parkinson's disease, to retina cells in blindness, to damaged areas in the heart - could one day be repaired. ... If we can find a way to replace these cells back in to where it's missing, we can envision a cure for these diseases which are currently devastating."

Link: http://www.cbc.ca/health/story/2010/07/20/regenerative-medicine-toronto.html

Contemplating the Olm

From LiveScience: "Blind salamanders once thought to be baby dragons can live at least as long as most people, scientists now find. Adults of this species live nearly 69 years on average, with a predicted maximum age of more than 100 years, three times longer than related species Surprisingly, the long-lived amphibian doesn't seem to have an especially low metabolism nor unusual levels of protective antioxidant molecules to explain why it lives so long. As such, this salamander could help uncover mechanisms that could help keep us young. The olm or proteus (Proteus anguinus) lives in the limestone caves of southern Europe. ... Zoologists have been intrigued by the olm for centuries because of its longevity, as it often lives more than 70 years in zoos. The salamander's longevity is especially unusual given its tiny size. ... So why might the olm have such an outstanding life span? It might live a long time by not living very much at all. ... Although the olm does not have a remarkably low metabolic rate, it is extremely inactive during its life." Examining animals that are long-lived in comparison to similar species may give more of an insight in the biology of aging. Studies of naked mole-rats are proving fruitful, for example.

Link: http://www.livescience.com/animals/methuselah-salamanders-human-longevity-100719.html

Reminder: Singularity Summit 2010 in August

To go along with the upcoming Immortality Institute International Conference and TransVision 2010 over in Europe later this year, I should also note that the Singularity Summit 2010 will be held next month in San Francisco:

The first Singularity Summit was held at Stanford in 2006 to further understanding and discussion about the Singularity concept and the future of human technological progress. It was founded as a venue for leading thinkers to explore the subject, whether scientist, enthusiast, or skeptic. ... We invite you to join our extraordinary group of visionaries in business, science, technology, design, and the arts, as our community explores this exciting topic. Your participation offers a world of powerful ideas, a unique networking opportunity, and access to an exclusive directory of your peers.

We hope you will join us August 14-15th.

The development of Strong artificial intelligence, the neuroscience that may contribute to that goal, and its ultimate consequences form the main focus of the presentations - topics of only indirect interest to engineered longevity, I feel. Faster and more capably machines and faster and more capable minds will make advances in technology arrive more rapidly, but they aren't direct contributions to progress in longevity science. However, you'll also find Gregory Stock, who has written on the topic of radical life extension, and Ellen Heber-Katz, who has produced very interesting work on enhanced regeneration in mammals, speaking at the event. So there's a little of something for everyone.

You'll find coverage and videos from the Singularity Summits of past years at the conference website, as well as in a few posts back in the Fight Aging! archives:

Calorie Restriction, Mitochondria, and Hormesis

A recent paper points to mitochondrially induced hormesis as a root cause of increased longevity with reduced calorie intake - which meshes well with the role of autophagy in this process. It confirms the importance of mitochondria in longevity, and once again shows that a little ongoing damage is actually a good thing: "Calorie restriction (CR) is the only proven regimen which confers lifespan extension benefits across the various phyla right from unicellular organisms like yeast to primates. In a bid to elucidate the mechanism of calorie-restriction-mediated life span extension, the role of mitochondria in the process was investigated. In this study, we found that the mitochondrial content in CR cells remains unaltered as compared to cells grown on nonrestricted media. However, mitochondria isolated from CR cells showed increased respiration and elevated reactive oxygen species levels without augmenting adenosine triphosphate (ATP) generation. The antioxidant defense system was amplified in CR mitochondria, and in CR cells a cross protection to hydrogen-peroxide-induced stress was also observed. Moreover, we also documented that a functional electron transport chain was vital for the life span extension benefits of calorie restriction. Altogether, our results indicate that calorie restriction elicits mitohormetic effect, which ultimately leads to longevity benefit."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20640543

Nanoparticles and Stem Cells Versus Atherosclerosis

Via PhysOrg.com: "A technique that combines nanotechnology with adult stem cells appears to destroy atherosclerotic plaque and rejuvenate the arteries ... nanoparticles (microscopic particles with at least one dimension less than 80 nm) were infused into the heart of pigs along with adult stem cells. After the nanoparticles were heated by laser light, they burned away arterial plaque. However, nanoparticles were less effective at eliminating plaque if not combined with adult stem cells. ... Unlike angioplasty, a common treatment for atherosclerosis, this new technique seems to actually demolish the plaque. ... The researchers found that plaque volume shrunk considerably in the nanoparticle groups immediately after the procedure (an average of 28.9 percent across the three groups) and six months later plaque volume had declined 56.8 percent on average. ... both groups that received stem cells showed signs of new blood vessel growth (neovascularization) and restoration of artery function."

Link: http://www.physorg.com/news198775684.html

TransVision 2010: October in Milan

It seems to be conference season again. Time flies. While we're noting European conferences of interest to supporters of engineered longevity, I should mention this year's TransVision event:

TransVision 2010 is a global transhumanist conference and community convention, organized by several transhumanist activists, groups and organizations, under the executive leadership of the Italian Transhumanist Association (AIT) and with the collaboration of an Advisory Board. The event will take place on October 22, 23 and 24, 2010 in Milan, Italy with many options for remote online access.

While TransVision 2010 is not organized by or connected with Humanity+ (formerly WTA), the organizer of most previous TransVision conferences, we wish to thank the Humanity+ Board for allowing the use of the name.

Transhumanism, as I may have remarked on previous occasions, is simply common sense applied to technology and life in an age of change. But there are enough fools in the world for common sense to need its advocates.

The conference has a good list of speakers set up already - the usual suspects, plus some of the Eurozone folk who don't often make it to the US conferences. If you're in the area this October, you should make an effort to attend. Some of the speakers, such as Max More or David Pearce, have been advocating radical life extension and the defeat of age-related suffering for considerably longer than I have, their efforts dating back to the early days of the modern transhumanist movement. It would be a shame to miss a chance to see them in action.

Longevity as Housekeeping and a Role for Bile Acids

Better maintenance means a longer life, as illustrated by the importance of autophagy in calorie restriction (CR). Researchers are now branching out beyond CR to find other ways of influencing metabolism to better maintain cells: "The conserved insulin-signaling pathway has drawn a significant amount of attention over the past few years as a major lifespan determining signaling network. In many systems, impairing this pathway impedes the ability of caloric restriction (CR) to enhance lifespan, suggesting that nutrient sensing is key to CR. ... the Titorenko laboratory [tested] the hypothesis that networks exist within cells that are not inducible, but act constitutively to extend the lifespan of cells regardless of nutrient availability ... [the study] presents an original screen designed to isolate molecules that further lengthen the life span of yeast under calorie restriction rather than imitating this effect. ... Among the chemical compounds identified, the authors focus on one group representing 6 bile acids compounds, the most efficient of them being lithocholic acid (LCA). Bile acids are mildly toxic oxidized derivatives of cholesterol that play important roles in lipid uptake by the intestine."

Link: http://www.impactaging.com/papers/v2/n7/full/100173.html

Cosmic Log on Engineered Longevity

A long post from MSNBC's Cosmic Log: "The quest for immortality goes back to Adam and Eve, but now some smart people are getting serious about actually bringing it within their grasp. And they're getting more attention as well. Let's take Aubrey de Grey, for example: The British gerontologist has been beating the drum for anti-aging therapies for years. He plays a prominent role in a recently published book on the immortality quest titled 'Long for this World,' a new documentary called 'To Age or Not to Age' and a just-published commentary on the science of aging. In this week's issue of Science Translational Medicine, de Grey and nine other co-authors urge the United States and other nations to set up a Project Apollo-scale initiative to avert the coming 'global aging crisis.' The experts' prescription includes a campaign to raise the general public's awareness about lifestyle changes that can lead to longer and healthier lives; a lab-based effort to develop anti-aging medicines; and a push for new techniques to repair, restore or replace the cellular and molecular damage done by age. ... There is this misunderstanding that aging is something that just happens to you, like the weather, and cannot be influenced. The big surprise of the last decades is that, in many different animals, we can increase healthy life span in various ways."

Link: http://cosmiclog.msnbc.msn.com/_news/2010/07/15/4685717-reaching-for-immortality

LifeStar Institute Launches New Website

The LifeStar Institute is the public face of the Millard Foundation, a family organization whose principals decided a few years ago to throw their weight behind making rejuvenation medicine a reality. The LifeStar folk move in the same circles as the SENS Foundation and Methuselah Foundation, and have in the past advocated for the Strategies for Engineered Negligible Senescence as the best technological path forward.

The Institute volunteers recently launched a new website to coincide with their call for global collaboration in longevity science, a message which can also be viewed as a video:

Leaders in the biology and polices of aging research at the first LifeStar Institute Global Aging Science Summit conclude the time has come to launch an ambitious global effort to keep aging generations youthful, productive, and engaged to unprecedented ages.

In laboratories all over the world, using genome sciences, diets including calorie restriction, and techniques of cell science and regenerative medicine, scientists are now keeping living organisms alive and healthy for increasing lengths of time never before thought possible. The obvious question: When will medical science do the same for us?

At this stage, the Institute is more concerned with the strategy of mobilizing resources than with the tactics of implementation:

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. ... The LifeStar Institute was established to accelerate the development of solutions to this mounting aging crisis through extraordinary leadership, collaboration and advocacy.

So a great deal of networking and persuasion is taking place behind the scenes, and has been for a few years now. The LifeStar Institute list of advisors is a who's who of big names in modern aging research, for example. Keep an eye on the activities of the Institute: these first years of the new decade are the foundational stage for the next phase in longevity science.

The Case for Late-Life Interventions in Aging

A position paper by Aubrey de Grey, a number of other important biogerontologists, and folk from the LifeStar Institute: "The social and medical costs of the biological aging process are high and will rise rapidly in coming decades, creating an enormous challenge to societies worldwide. In recent decades, researchers have expanded their understanding of the underlying deleterious structural and physiological changes (aging damage) that underlie the progressive functional impairments, declining health, and rising mortality of aging humans and other organisms and have been able to intervene in the process in model organisms, even late in life. To preempt a global aging crisis, we advocate an ambitious global initiative to translate these findings into interventions for aging humans, using three complementary approaches to retard, arrest, and even reverse aging damage, extending and even restoring the period of youthful health and functionality of older people." This more or less reflects the LifeStar Institute position, complementary with that of the SENS Foundation, but with more of an organizational focus.

Link: http://www.ncbi.nlm.nih.gov/pubmed/20630854

Brain Size Correlates With Species Longevity

Via ScienceDaily: "Mammals with larger brains in relation to body size tend to live longer. This is the conclusion reached by researchers [after] having analysed almost 500 mammal species and obtaining new data on the relation between brain size and lifespan. ... The brain size of some mammals is larger than expected for their body size. This is the case of large primates, such as chimpanzees and gorilla, and of whales, dolphins and elephants. Scientists have spent years investigating why sometimes nature favours the development of large brains given that they require much more time to reach functional maturity and use up so much energy. ... the size of the brain affects lifespan regardless of the size of the body. Hyenas, for example, have a larger brain than giraffes in proportion to body size and on average live longer, although they are smaller than these herbivores. ... it is possible that a longer life works in favour of a delay in reproductive cycles and this would in turn allow progenitors to invest more resources and time in caring for their offspring. This also leads to the formation of stable social groups whose members, according to the Social Intelligence Hypothesis (SIH), must deal with more cognitive demands than animals living alone, and this would be the reason for larger brains."

Link: http://www.sciencedaily.com/releases/2010/07/100715110001.htm

Mentioned at NPR (By a Deathist)

I see that one of the NPR bloggers posted on the topic of longevity science today and linked to the Longevity Meme. Unfortunately that was done in the process of dismissing the whole exercise of working to extend human life span:

I confess that I find the whole trajectory to vastly miss the point of being alive which, I would say, is not how long it’s going to last but what it’s like to have it. Returning to the framing concept at the start of this piece, I think of my finite life cycle as a gift, or at least a gift by comparison with the dreary notion of endless existence. Its finiteness allows me to do my thing, make my mistakes, achieve my successes, love and nurture my family and community, run my course like every other critter, and then move out of the way.

Because, evidently, death is life. How very Orwellian. I will make the observation that the only people who say this sort of thing are those who keenly feel the bite of future loss. It is a compensation statement, a shield, a wrapper to hold in seeping existential fear and bitterness. No-one should take it at face value. Those folk who are truly unconcerned about the future state of being dead have no need to protest so loudly - in fact you won't hear them say much at all on the topic.

Sadly, there stands, slouching, a legion of people much like the author of the post quoted above. They sneer at actual research into aging and longevity, do nothing to help, and pretend to believe that death is life - all the while fearing what lies ahead, and working to convince themselves and others that nothing can be done. They will no doubt be jostling for a spot in line when, despite their inaction, rejuvenation therapies are developed and commercialized.

It's all human nature, standard issue, ugly as sin and twice as petty. Nothing to see here, business as usual.

A Conservative View of Longevity Science

This opinion piece is an example of the sort of viewpoint held by those who believe that metabolic manipulation to modestly slow aging is the only viable way forward in longevity science: "When I tell people that anti-aging drugs are no longer a distant prospect, they often assume I'm talking about the quest for immortality. That's not surprising, given the buzz generated in recent years by visionaries who speculate about re-engineering the human body to last thousands of years. But actually I don't find that far-out prospect very interesting - it bears the same relationship to serious aging science that warp-drive spaceships do to aeronautical engineering. What really grabs me are experimental advances that may impinge on the lives of people I know, maybe even mine. ... the only practical, near-term way to substantially increase healthy life span today is to simultaneously lower the risk of all diseases of aging. The way we now mainly buy time - administering therapies for one progressive, old-age disease at a time when it's too late to do much good - can't do that. Anti-aging drugs could, and at the same time they would go a long way toward ending the ruinously costly game of diminishing returns we're playing in geriatric medicine, as we eke out incremental gains with ever pricier palliatives. In effect, they would be preventive medicines of unprecedented scope and efficacy, drastically lowering the risk of everything from Alzheimer's to osteoporosis to wrinkles in the way that hypertension drugs now cut heart-attack risk."

Link: http://www.huffingtonpost.com/david-stipp/why-anti-aging-science-re_b_644308.html

Urging a Global Collaboration Against Aging

From the LifeStar Institute: "Leaders in the biology and polices of aging research at the first LifeStar Institute Global Aging Science Summit conclude the time has come to launch an ambitious global effort to keep aging generations youthful, productive, and engaged to unprecedented ages. In laboratories all over the world, using genome sciences, diets including calorie restriction, and techniques of cell science and regenerative medicine, scientists are now keeping living organisms alive and healthy for increasing lengths of time never before thought possible. The obvious question: When will medical science do the same for us? ... The scientific panel proposes that the United States and nations across the world create a global collaboration and launch an Apollo-like Project with the following goal: translate laboratory knowledge about the degenerative changes of aging into new kinds of medicines for humans that can prevent and repair those changes. The panel urges governments and the biomedical industry to fund three key initiatives: (1) Use public health agencies to inform citizens on how they can improve their lifestyles. (2) Develop the first genuine anti-aging medicines that are able to boost the body's ability to maintain health (3) Develop and apply regenerative methods that can remove, replace, repair, and neutralize the cellular and molecular damage that accumulate in aging bodies and restore youthful structure and function."

Link: http://www.lifestarinstitute.org/index.php?pagename=aging_science_meeting_paper

Cancer Immunotherapy in Action

I noticed a good example of the state of the art in immunotherapy aimed at cancer today:

Researchers at UCLA's Jonsson Comprehensive Cancer Center created a large, well armed battalion of tumor-seeking immune system cells and watched, in real time using Positron Emission Tomography (PET), as the special forces traveled throughout the body to locate and attack dangerous melanomas.

...

"We're trying to genetically engineer the immune system to become a cancer killer and then image how the immune system operates at the same time," said Dr. Antoni Ribas, an associate professor of hematology/oncology, a researcher at UCLA’s Jonsson Comprehensive Cancer Center and the senior author of the study.

...

"The novelty of our work is that we were able to pack together the cancer specific T cell receptor and the PET reporter genes in a single vector and use it in mice with an intact immune system that closely resembles what we would see in real patients," said Dr. Richard Koya, an assistant professor of surgical oncology at UCLA's David Geffen School of Medicine and first author of the study. "We were also gladly surprised to see the targeted tumors literally melt away and disappear, underscoring the power of the combined approach of immune and gene therapy to control cancer."

Equally impressive work of this sort is presently taking place in laboratories around the world. Cancer cells exhibit characteristic biochemical differences that distinguish them from normal cells, and the immune system can be directed to attack and destroy targets in the body based on those differences. The quality of our immune systems is already very important to long term health, but the emergence of therapies that harness the destructive powers of immune cells will make it ever more important to also build treatments that can reverse the characteristic decline of the immune system with age. An immunotherapy is only as good as the immune system it is working with - and cancer is predominantly a disease of old age.

Using Stem Cells to Build Test Platforms

Here is an example of the other use for stem cells: to grow tissue that can be used to test and understand specific diseases. "Researchers are applying new stem cell technology to use skin samples to grow the brain cells thought to be responsible for the onset of Parkinson's disease ... [the] team will be gathering data from over 1,000 patients with early stage Parkinson's disease and taking small samples of skin tissue to grow special stem cells - induced pluripotent stem cells (iPS cells). iPS cells can be generated from accessible tissue such as the skin and then used to generate specific types of cell. The researchers will use the iPS cells to grow dopamine neurons - the brain cells responsible for the production of dopamine, as it is these cells which die in patients with Parkinson's, leading to the onset of the disease. ... iPS cells provide new and exciting opportunities to grow and study dopamine neurons from patients for the first time. This technology will prove to be extremely important in diseases which affect the brain because of its relative inaccessibility - it's far easier to get a skin sample than a brain biopsy. Once we have neurons from patients we can compare the functioning of cells taken from patients with the disease and those without to better understand why dopamine neurons die in patients with Parkinson's."

Link: http://www.eurekalert.org/pub_releases/2010-07/babs-scc_1071210.php

LEF Funds Granulocyte Cancer Therapy

A press release: "In a discovery that made headline news around the world, Dr. Zheng Cui, of the Wake Forest University School of Medicine, developed a colony of mice with super-charged granulocytes that successfully fight off many forms of virulent cancer. ... In a surprising turn of events Dr. Cui also found that a similar cancer-killing activity is present in the granulocytes of some healthy humans. ... When the Life Extension Foundation learned that this potential cancer cure was not being funded, it immediately made a $200,000 grant to fund the study at the South Florida Bone Marrow/Stem Cell Transplant Institute ... This new clinical trial will test this approach in humans with advanced cancer, including metastases, who have not been helped by conventional cancer therapies. The trial has received an IND (investigational new drug) status from the Food and Drug Administration (FDA) and Institutional Review Board approval. ... In January of this year, Dr. Maharaj notified the Life Extension Foundation that progress was being slowed because expected funding sources had dried up. Life Extension responded with another grant of $600,000 to further advance what could be a cure for cancer."

Link: http://www.prweb.com/releases/2010/07/prweb4239704.htm

Analysis of Gene Expression and Longevity is Forging Ahead

The process of gene expression, in which a gene is used as a blueprint to construct a protein, is anything but static. Levels of gene expression for individual genes rise and fall with environmental circumstances, health, injury, and over the course of aging. It's a tremendously complex system, with a lot of feedback loops and switches, but fortunately the cost of analyzing gene expression profiles over a whole genome is falling rapidly. It is now feasible to run hundreds of such profiles over the course of a study. At the same time the tools of analysis are starting to catch up with the amount of data being generated: researchers are able to more rapidly and effectively draw conclusions from the mountainous databases they construct.

So, for example, see this study on flies, which compares groups of flies selected for their longevity versus a control group of average length lives. It demonstrates that systematically sweeping the whole genome for changes in gene expression with age is a viable way to evaluate the importance of other lines of research and find new avenues for future study:

We evaluated the gene expression profile in young, middle-aged, and old male flies, finding that 530 genes were differentially expressed between selected and control flies when measured at the same chronological age. The longevity-selected flies consistently showed expression profiles more similar to control flies one age class younger than control flies of the same age. This finding is in accordance with a younger gene expression profile in longevity-selected lines.

Among the genes down-regulated in longevity-selected lines, we found a clear over-representation of genes involved in immune functions, supporting the hypothesis of a life-shortening effect of an overactive immune system, known as inflammaging.

We judged the physiological age as the level of cumulative mortality. Eighty-four genes were differentially expressed between the control and longevity-selected lines at the same physiological age, and the overlap between the same chronological and physiological age gene lists included 40 candidate genes for increased longevity. Among these candidates were genes with roles in starvation resistance, immune response regulation, and several that have not yet been linked to longevity. Investigating these genes would provide new knowledge of the pathways that affect life span in invertebrates and, potentially, mammals.

Many research groups around the world are capable of running this sort of study. As the work shows value, more groups will do just that. We are a few years away from an avalanche of knowledge on the fine details of aging and existing differences in longevity: how it all works right down to the lowest biochemical levels in the body.

ResearchBlogging.orgSarup P, Sørensen P, & Loeschcke V (2010). Flies selected for longevity retain a young gene expression profile. Age (Dordrecht, Netherlands) PMID: 20607427

The Genetics of Hormesis-Induced Longevity

Hormesis is the process whereby suffering a little biochemical damage switches metabolism into a high-repair, damage-resistant mode, thereby extending life. Here, researchers examine changes in gene expression associated with hormesis: "Ionizing radiation generates oxidative stress, which is thought to be a major cause of aging. Although living organisms are constantly exposed to low levels of radiation, most studies examining the effect of radiation have focused on accelerated aging and diminished life span that result from high-dose radiation. On the other hand, several studies have suggested that low-dose radiation enhances the longevity of Drosophila melanogaster. Therefore, investigation of the biological effects of low-dose radiation could contribute to a more comprehensive understanding of the aging process. In this study, microarray and quantitative real time-PCR were used to measure genome-wide changes in transcript levels in low-dose irradiated fruit flies that showed enhanced longevity. In response to radiation, approximately 13% of the genome exhibited changes in gene expression, and a number of aging-related genes were significantly regulated. These data were compared with quantitative trait loci affecting life-span to identify candidate genes involved in enhanced longevity induced by low-dose radiation. This genome-wide survey revealed novel information about changes in transcript levels in low-dose irradiated flies and identified 39 new candidate genes for molecular markers of extended longevity induced by ionizing radiation. In addition, this study also suggests a mechanism by which low-dose radiation extends longevity."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20617381

The Cost of Obesity

A good example of what obesity does to your long term health: "Men who enter adult life obese face a life-long doubling of the risk of dying prematurely, new research has found. In a study presented today (Tuesday) at the International Congress on Obesity in Stockholm, researchers tracked more than 5,000 military conscripts starting at the age of 20 until up to the age of 80. They found that at any given age, an obese man was twice as likely to die as a man who was not obese and that obesity at age 20 years had a constant effect on death up to 60 years later. They also found that the chance of dying early increased by 10% for each BMI point above the threshold for a healthy weight and that this persisted throughout life, with the obese dying about eight years earlier than the non-obese. ... Body mass index (BMI) was measured at the average ages of 20, 35 and 46 years, and the researchers investigated that in relation to death in the next follow-up period. A total of 1,191 men had died during the follow-up period of up to 60 years. The results were adjusted to eliminate any influence on the findings from year of birth, education and smoking. ... At age 70 years, 70% of the men in the comparison group and 50% of those in the obese group were still alive and we estimated that from middle age, the obese were likely to die eight years earlier than those in the comparison group."

Link: http://www.eurekalert.org/pub_releases/2010-07/iaft-sfl071210.php

Immortality Institute International Conference: October 2010 in Brussels

If you'll allow me to direct your attention: registration is now open for the Immortality Institute International Conference, which will be held on the weekend of October 9th in Brussels, Belgium. It's a great chance for Eurozone folk to gather and meet like-minded supporters of longevity science: there are far too few such gatherings held on that side of the pond, so make the most of this one.

Many of the usual suspects from the longevity science community will be speaking or presenting, as well as a fair few faces you might not be so familiar with. Not too many of the European advocates for extended healthy life spans make it out to the US-based conferences on a regular basis, so it should be a different crowd from the circuit of the past few years.

Dr. Aubrey de Grey: Chief Science Officer of the SENS Foundation; he works on the development of what he calls "Strategies for Engineered Negligible Senescence" (SENS), a tissue-repair strategy intended to rejuvenate the human body and allow an indefinite lifespan. To this end, he has identified seven types of molecular and cellular damage caused by essential metabolic processes. SENS is a proposed panel of therapies designed to repair this damage.

Prof. Dr. Bart Braeckman: Internationally known for his research on aging in C. elegans. His team was the first to succeed in increasing the lifespan of C. elegans by sixfold. He has studied everything from calorie restriction to the free radical theory and the metabolic rate theory in C. elegans.

Dr. Chitty Chen: Discovered that the ratio of sugars in the glycan structures on immunoglobulins are an indication of biological age. In other words, she probably discovered the very first age biomarker. This investigation was done in mice and the biomarker seemed to measure the slowing of aging in CR and ames dwarf mice very well. She's now busy in setting up a human study to investigate this biomarker further. If succesfull then this biomarker can one day be used to establish the anti-aging effects of an intervention in humans (such as supplements, drugs, calorie restriction, etc) in a few years instead of decades.

Mr. Danila Medvedev: Chairman of KrioRus, Chief Planning Officer and a Vice-President of the Science for Life Extension Foundation. Also a politician and a member of coordination council of the Russian Transhumanist Movement.

The program is still being updated, but there are already a range of other interesting folk signed up to attend, such as researchers Leonid Gavrilov, Michael Rose, and Stephen Coles of the Supercentenarian Research Foundation.

On Calorie Restriction

Christopher Westphal of Sirtris is writing a series of guest columns in the Boston Globe: "Last week, I wrote that the best way to live healthier longer was to eat less and exercise more. Meticulous readers asked which of these two approaches, precisely, had more scientific support. Such questions may reflect wishful thinking: Those who exercise a lot might wonder if they can eat the equivalent of steak and fries every night. And for those who don't want too much exercise, might they focus instead on eating less? Unfortunately for those who, like me, have modest will power at the table, the data are clear. The most robust way to increase healthy lifespan in a broad variety of organisms is in fact calorie restriction. In other words, it behooves us to cut our calorie intake markedly, while still maintaining a balanced diet that includes essential vitamins and minerals. Whether we can bring ourselves to do so is another question entirely. ... Who among us, you might ask, would have the fortitude to emulate the calorie restriction studies conducted on animals? It turns out that there are at least hundreds of Americans, and many more individuals worldwide, who are severely restricting their calorie intake in the hopes of extending their healthy lifespans. Studies have indeed found that key cardiovascular measurements, such as blood pressure and heart rate, are much improved in individuals who significantly restrict their calorie intake."

Link: http://www.boston.com/bostonglobe/editorial_opinion/oped/articles/2010/07/12/eat_a_lot_less_live_a_lot_longer/

PTEN and Nerve Regeneration

Via EurekAlert!: "Scientists have discovered a way to enhance nerve regeneration in the peripheral nervous system. This important discovery could lead to new treatments for nerve damage caused by diabetes or traumatic injuries. Peripheral nerves connect the brain and spinal cord to the body, and without them, there is no movement or sensation. Peripheral nerve damage is common and often irreversible. ... [Researchers] used a rat model to examine a pathway that helps nerves to grow and survive. Within this pathway is a molecular brake, called PTEN, that helps to prevent excessive cell growth under normal conditions. In addition to discovering for the first time that PTEN is found in the peripheral nervous system, [the team] demonstrated that following nerve injury, PTEN prevents peripheral nerves from regenerating. The team was able to block PTEN, an approach that dramatically increased nerve outgrowth. ... We were amazed to see such a dramatic effect over such a short time period. No one knew that nerves in the peripheral system could regenerate in this way, nerves that can be damaged if someone has diabetes for example. This finding could eventually help people who have lost feeling or motor skills recover and live with less pain."

Link: http://www.eurekalert.org/pub_releases/2010-07/uoc-ndi070910.php

A Strange But True Cultural Obstacle to Cryonics

In cryonics circles, it is not unusual to hear tales of a spouse - usually a wife, as most people presently signed up for cryopreservation at clinical death are male - who is adamantly opposed to cryonics, even to the point of requiring the potential cryonics patient make a choice between cryonics or the partner. This has always struck me as odd, but it is clearly more than just an urban myth or a few anecdotal couples; there is some core incentive or common aspect of human psychology at work here that generates these conflicts often enough to make the situation well known. (Well known to cryonics supporters, at least).

Via Robin Hanson of Overcoming Bias, I see that his own tale of conflicting spousal views on cryonics has made it into the New York Times as an example of the type:

Robin, a deep thinker most at home in thought experiments, says he believes that there is some small chance his brain will be resurrected, that its time in cryopreservation will be merely a brief pause in the course of his life. Peggy finds the quest an act of cosmic selfishness. And within a particular American subculture, the pair are practically a cliche.

Among cryonicists, Peggy's reaction might be referred to as an instance of the "hostile-wife phenomenon," as discussed in a 2008 paper by Aschwin de Wolf, Chana de Wolf and Mike Federowicz. "From its inception in 1964," they write, "cryonics has been known to frequently produce intense hostility from spouses who are not cryonicists." The opposition of romantic partners, Aschwin told me last year, is something that "everyone" involved in cryonics knows about but that he and Chana, his wife, find difficult to understand. To someone who believes that low-temperature preservation offers a legitimate chance at extending life, obstructionism can seem as willfully cruel as withholding medical treatment. Even if you don’t want to join your husband in storage, ask believers, what is to be lost by respecting a man’s wishes with regard to the treatment of his own remains? Would-be cryonicists forced to give it all up, the de Wolfs and Federowicz write, "face certain death."

The article goes on to speculate as to just what may be the roots of this spousal opposition, and you'll find even more suggestions in the comments at Overcoming Bias.

For my part, I'd say it seems unreasonable (to say the least) to expect your partner to commit suicide to make you feel better - and abstaining from cryopreservation on death is exactly a form of suicide. The practice of suttee, in which widows were compelled to die upon their late husband's funeral pyre, is now generally acknowledged as barbaric and murderous. But at the high level it is little different from brow-beating a partner into abandoning cryonics, or worse, actively working to ensure that a partner's cryonics arrangements go awry. Still, a great many people for a long period of years accepted suttee as good and proper - just as a great many people today accept all sorts of correctable malignancies in cultures and the human condition.

What is accepted is no guide to what is right.

Alcor Executive Director's Report, June

The Alcor executive director's reports provide a good window into the day to day operations of a cryonics provider - which is as much a community as it is a business. For example: "In mid-May, we cryopreserved 92-year-old Paul Garfield, a neuropreservation patient. Paul was a dedicated member of Alcor for 20 years and a long-time volunteer at the organization. Even in his 90's Paul maintained an active lifestyle, often going dancing and visiting Alcor weekly. After being hospitalized in early 2009, he moved out of state to live with relatives. Alcor developed a cordial relationship with his son, who expressed a desire to honor his father's wish for cryopreservation, despite personal reservations. The son informed Alcor in March that Paul had suffered a stroke and was undergoing physical therapy. On May 11, Paul was admitted to hospice care after his condition deteriorated, possibly due to another stroke. Alcor immediately deployed Aaron Drake and Suspended Animation to perform a standby that ultimately lasted about a day. Several Alcor Texas team members also offered assistance gathering supplies, providing transportation, and participating in the standby. Following pronouncement, Suspended Animation immediately began stabilization procedures and performed a successful field washout. He arrived in Alcor's operating room approximately 20 hours post-pronouncement, and we achieved terminal perfusion. Paul became Alcor's 95th patient."

Link: http://www.alcornews.org/weblog/2010/06/executive_directors_report_jun.html

Spurring Neural Growth Improves Memory

Via EurekAlert: "Scientists have discovered a compound that restores the capacity to form new memories in aging rats, likely by improving the survival of newborn neurons in the brain's memory hub. ... This neuroprotective compound, called P7C3, holds special promise because of its medication-friendly properties. It can be taken orally, crosses the blood-brain barrier with long-lasting effects, and is safely tolerated by mice during many stages of development. ... Physical activity, social, or other enriching experiences promote neurogenesis – the birth and maturation of new neurons. This growth takes place in the dentate gyrus, a key area of the brain's memory hub, the hippocampus. But even in the normal adult brain, most of these newborn neurons die during the month it takes to develop and get wired into brain circuitry. To survive, the cells must run a gauntlet of challenges. Newborn hippocampus neurons fare much worse in aging-related disorders like Alzheimer's, marked by runaway cell death. In hopes of finding compounds that might protect such vulnerable neurons during this process, [researchers] tested more than 1000 small molecules in living mice. ... To find out if P7C3 could similarly stem aging-associated neuronal death and cognitive decline, the researchers gave the compound to aged rats. Rodents treated with P7C3 for two months significantly outperformed their placebo-treated peers on a water maze task, a standard assay of hippocampus-dependent learning. This was traced to a threefold higher-than-normal level of newborn neurons in the dentate gyrus of the treated animals."

Link: http://www.eurekalert.org/pub_releases/2010-07/niom-mdt070110.php

Immunosenescence and What Can Be Done About It

Immunosenescence is the steady degeneration of the immune system that occurs with age. For the adaptive immune system at least, researchers have a good picture as to why and how this happens - which means that they also have starting points to develop ways to reverse immunosenescence.

Here is an open access review paper on the topic:

The elderly frequently suffer from severe infections. Vaccination could protect them against several infectious diseases, but it can be effective only if cells that are capable of responding are still present in the repertoire. Recent vaccination strategies in the elderly might achieve low effectiveness due to age-related immune impairment.

...

Ageing dampens the ability of B cells to produce antibodies against novel antigens. Exhausted memory B lymphocyte subsets replace naive cells. Decline of cell-mediated immunity is the consequence of multiple changes, including thymic atrophy, reduced output of new T lymphocytes, accumulation of anergic memory cells, and deficiencies in cytokines production. Persistent viral and parasitic infections contribute to the loss of immunosurveillance and premature exhaustion of T cells.

In essence, the immune system fails because the thymus, source of immune cells, ceases production and withers away. At the same time, the population of immune cells becomes ever more biased towards memory cells and away from cells capable of fighting new infections - and this is largely due to persistent viruses like cytomegalovirus. Eventually the immune system becomes so focused on the viruses it cannot clear from the body that it has no resources left to perform its other functions.

These problems suggest their own solutions: replace or rejuvenate the thymus, for example, or apply new targeted cell-killing methods developed for cancer therapies to destroy unwanted memory cells. On that note it's worth recalling that thymus transplants have been shown to extend life in mice, but there is plenty of other evidence to support these and similar attempts to restore the aging immune system to youthful levels of activity.

ResearchBlogging.orgOngrádi, J., & Kövesdi, V. (2010). Factors that may impact on immunosenescence: an appraisal Immunity & Ageing, 7 (1) DOI: 10.1186/1742-4933-7-7

Shorter Telomeres, Greater Cancer Risk

News of a study linking telomere length and cancer risk, but it's still the case that the relationship could be indirect, such as both sides of the correlation being based on levels of biochemical damage. For example, it might reflect the state of mitochondrial biochemistry in a person: "A new study suggests that shorter length of leukocyte telomeres - chromosome markers of biological aging - are associated with an increased risk of cancer and death from cancer. ... Telomeres are a structure at the end of a chromosome involved in the replication and stability of the chromosome. Genetic factors and environmental stressors can shorten the length of the telomere, and telomere length has been considered to be an emerging marker of biological age. Some research has suggested that short telomeres and chromosomal instability contribute to malignant cell transformation. ... [Researchers] conducted a study to assess the association between leukocyte telomere length and risk of both new-onset cancer and cancer death. Leukocyte telomere length was [measured] in 787 participants, free of cancer in 1995 ... Analysis indicated that short telomere length at the beginning of the study was associated with new cancer independently of standard cancer risk factors. Compared with participants in the longest telomere length group, participants in the middle length group had about twice the risk of cancer, and those in the shortest length group had approximately three times the risk. Cancer incidence rates were inversely related to telomere length, with participants in the group with the shortest telomere length having the highest rate of cancer."

Link: http://www.eurekalert.org/pub_releases/2010-07/jaaj-lob063010.php

General Improvement in Cancer Mortality Rates

Much like the slow and steady lengthening of life expectancy, there is a general improvement in cancer treatment outcomes thanks to progress across the board in modern medicine: "The continued drop in overall cancer mortality rates over the last 20 years has averted more than three-quarters of a million (767,000) cancer deaths according to a new report from the American Cancer Society. The American Cancer Society's annual Cancer Statistics article reports that the overall death rate from cancer in the United States in 2007 was 178.4 per 100,000, a relative decrease of 1.3 percent from 2006, when the rate was 180.7 per 100,000, continuing a trend that began in 1991 for men and 1992 for women. In that time, mortality rates have decreased by 21 percent among men and by 12 percent among women, due primarily to declines in smoking, better treatments, and earlier detection of cancer. ... Cancer incidence rates decreased in men 1.3 percent per year from 2000 to 2006 and in women 0.5 percent per year from 1998 to 2006. Death rates for all cancer sites combined decreased 2 percent per year from 2001 to 2006 in males and 1.5 percent per year from 2002 to 2006 in females."

Link: http://www.eurekalert.org/pub_releases/2010-07/acs-cdc070710.php

A Reminder that Science is Hard and Studies are Often Flawed

Scientific work is very challenging, and most projects have a significant chance of failure - meaning they generate no good data, or worse, bad data that looks good enough to use. That's not an issue in the long term, however. The scientific method is a process by which a good rate of progress and reliable data can be produced from many diverse efforts that individually have poor odds of success.

This means that you shouldn't read too much into the results of any one study. The odds of it being flawed in some way are fairly good, especially if it's recent. The scientific consensus on any given topic only comes about after a great many researchers have examined and published, and fought long and hard over discrepancies and points of confusion - and in enormously complex and rapidly changing fields like biology and medicine, consensus is often hard to find.

As a case in point, and a good insight into what actually goes into making the scientific sausage, here is an update on a recent study of longevity genes:

Remember that Science study from last week linking a whole bunch of genes - including unexpectedly powerful ones - to extreme old age in centenarians? Newsweek reported that a number of outside experts thought it sounded too good to be true, perhaps because of an error in the way the genes were identified that could cause false-positive results. Since last Thursday, they’ve been trying to figure out what might be lurking in the data, and now there’s a suspect: a DNA chip called the 610-Quad, which is used to identify and sequence the chemical letters of DNA, and which has an apparent tendency to get some small but critical details wrong. The flaw with the chip and the way it was used could cast serious doubt on the study’s strongest results, suggesting that they stem from a lab mishap rather than a real link to long life.

The great thing about this modern age of low-cost communication is that flawed papers can be pulled apart fairly rapidly when there is interest in the community. All bugs are shallow given enough eyes, and science can work exactly like the open source software development community in this respect. The publication model of the future is far more dynamic than the present model of journals: publish early, publish often, publish as a part of engaging a community in conversations on the research. The more collaboration that occurs along the way from ideation to completed research the better.

On Mitohormesis

A little stress improves our biochemistry: "Recent evidence suggests that calorie restriction and specifically reduced glucose metabolism induces mitochondrial metabolism to extend life span in various model organisms, including Saccharomyces cerevisiae, Drosophila melanogaster, Caenorhabditis elegans and possibly mice. In conflict with Harman's free radical theory of aging (FRTA), these effects may be due to increased formation of reactive oxygen species (ROS) within the mitochondria causing an adaptive response that culminates in subsequently increased stress resistance assumed to ultimately cause a long-term reduction of oxidative stress. This type of retrograde response has been named mitochondrial hormesis or mitohormesis, and may in addition be applicable to the health-promoting effects of physical exercise in humans and, hypothetically, impaired insulin/IGF-1-signaling in model organisms. Consistently, abrogation of this mitochondrial ROS signal by antioxidants impairs the lifespan-extending and health-promoting capabilities of glucose restriction and physical exercise, respectively. In summary, the findings discussed in this review indicate that ROS are essential signaling molecules which are required to promote health and longevity. Hence, the concept of mitohormesis provides a common mechanistic denominator for the physiological effects of physical exercise, reduced calorie uptake, glucose restriction, and possibly beyond."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20350594

KrioRus in the Press

Russian cryonics provider KrioRus is starting to receive the sort of mixed press attention that Alcor did five years ago or so: "'I don't ever want to die... It wouldn't suit me,' said Innokenty Osadchy. Fortunately, the 35-year-old investment banker is certain he has found a loophole out of death. Osadchy is ready to pay a small fortune to freeze his brain until future technology allows him to continue his life - after being transplanted into a new body and resuscitated. 'Why do I have to die in a couple decades? I don't see any logic in this. It won't be another life, it'll be the continuation of my life. I don't ever want to die ever. Not in a year, not in a million years.' Osadchy and other clients of Russian cryonics company KrioRus believe the brain operates like a computer hard-drive and its contents can be frozen and stored for the future. 'We know that the personality is stored in the brain. So when a person's body is old, there's no reason to keep it,' said Danila Medvedev, who runs KrioRus, the first cryonics outfit outside the United States. ... Since its 2005 launch, KrioRus has been building new vats, in anticipation of the 30 clients, like Osadchy, with whom it already has contracts."

Link: http://www.google.com/hostednews/afp/article/ALeqM5hcee6gk4tTAqxAfRk1MhcG5dMELw

SENS Foundation Los Angeles Chapter Meeting, July 9th

Via Accelerating Future, I see that the SENS Foundation is hosting an initial informal meeting this coming Friday with the aim of establishing a Los Angeles chapter of supporters:

On behalf of SENS Foundation I am writing to you to invite you to join Dr Aubrey de Grey for our first SENSF L.A. Chapter meeting to be held on Friday, July 9th, 2010, at the Westwood Brewing Company (1097 Glendon Avenue, Los Angeles, CA 90024-2907) from 5pm until Aubrey has had enough beer :-)

This will be an informal gathering to create a local initiative to promote the Foundation’s interests and mission.

The idea of forming a SENSF L.A. Chapter, which is planned to have monthly meetings, is to create a network of enthusiasts, field professionals, potential donors, sponsors, collaborators, students, etc. Also to promote educational efforts in the area, and to reach out to the Hollywood community and gain their support.

Please RSVP.
We hope you will come and join us!

Cheers!
Maria Entraigues
SENSF Volunteer Coordinator
maria.entraigues@sens.org

If you're in that neck of the woods and interested in advancing the cause of engineered longevity, then you should send Maria Entraigues an email and plan to drop by.

On Mitochondria, Genetic Variation, and Longevity

This paper suggests that the relationship between mitochondrial DNA variants and longevity is complex: "There is substantial evidence that mitochondria are involved in the aging process. Mitochondrial function requires the coordinated expression of hundreds of nuclear genes and a few dozen mitochondrial genes, many of which have been associated with either extended or shortened life span. Impaired mitochondrial function resulting from mtDNA and nuclear DNA variation is likely to contribute to an imbalance in cellular energy homeostasis, increased vulnerability to oxidative stress, and an increased rate of cellular senescence and aging. The complex genetic architecture of mitochondria suggests that there may be an equally complex set of gene interactions (epistases) involving genetic variation in the nuclear and mitochondrial genomes. Results from Drosophila suggest that the effects of mtDNA haplotypes on longevity vary among different nuclear allelic backgrounds, which could account for the inconsistent associations that have been observed between mitochondrial DNA (mtDNA) haplogroups and survival in humans. ... We hypothesize that aging and longevity, as complex traits having a significant genetic component, are likely to be controlled by nuclear gene variants interacting with both inherited and somatic mtDNA variability."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20601194

Provision of Cryonics Scales Up Well

This post at Less Wrong makes the case for cryonics as a business that would work well at large scale: "Cryonics scales very well. People who argue from the perspective that cryonics is costly are probably not aware of this fact. Even assuming you needed to come up with the lump sum all at once rather than steadily pay into life insurance, the fact is that most people would be able to afford it if most people wanted it. There are some basic physical reasons why this is the case. ... Surface area is where heat gains entry. Thus if you have a huge container holding cryogenic goods (humans in this case) it costs less per unit volume (human) than is the case with a smaller container that is equally well insulated. ... liquid nitrogen, the super-cheap coolant used by cryonics facilities around the world, is vastly cheaper (more than a factor of 10) when purchased in huge quantities of several tons. The scaling factors for storage tanks and high-capacity tanker trucks are a big part of the reason for this. ... The conclusion I get from this is that there is a very strong self-interested case (as well as the altruistic case) to be made for the promotion of megascale cryonics towards the mainstream, as opposed to small independently run units for a few of us die-hard futurists."

Link: http://lesswrong.com/lw/2f5/cryonics_wants_to_be_big/

On the View of Death as Oblivion

Here are two quotes from writers of antiquity, letters in a bottle to demonstrate that for all the great differences in time and place, the core of human nature in complex civilizations remains much the same. So far, at least:

Death: There's nothing bad about it at all except the thing that comes before it - the fear of it.
   - Seneca

I think the slain care little if they sleep or rise again.
   - Aeschylus

Insofar as death is oblivion, the destruction of the self, it is rational to be unconcerned about being dead. You won't exist to have feelings on the matter - which is exactly the same situation as for all time prior to the point in your development at which you like to think that you became yourself.

Equally, it is rational to be very concerned about being dead at some point in the future. Humans are creatures of action. We like to achieve, observe, and experience. We place value upon these things, and death will stop us from gathering that value.

So the world of people might be divided at any point in time into (a) the group that is horrified by the prospect of oblivion, and (b) the group that is unbothered by personal extinction. It's a very sharp dividing line, not often explored in casual conversation, for all that one person's views might cross back and forth between camps over the years. Try a poll of the folk you know at some point in time: I think you'll find the results interesting.

Whatever your opinions on oblivion, however, it seems near universally agreed that the process of becoming dead is something to be feared - so much so that we work to hide the ugly reality from daily life:

Are you afraid of getting older? You should be. Degenerative aging isn't pretty. That said, we live in an era characterized by a fascination with youth; aging and the old are put to one side, and the ugly details of the way in which the body and mind break down are glossed over or shoved under the carpet. Move on a step from that and you'll see the bevy of folk trying to sell you the message that aging into frailty and death before you're ready is just fine - that you shouldn't worry about it, that you should just relax into your life being taken from you, one piece at a time. But those talking heads are spouting nonsense. You should absolutely be afraid of aging.

Terrible pain, injury, and degeneration are not on anyone's wish list. But we'll all be receiving these dubious gifts anyway - unless something is done about it. The difference between our age and the age of the Greek stoics is that we have the chance to do something about it: defeat aging by repairing its damage, improve our biochemistry, and ultimately replace our bodies with superior technology that is immune to all that plagues us now.

There is a school of thought that suggests selling the concepts of radical life extension as indefinite postponement of death is inefficient. In this view, half the people the world don't really care about the future state of being dead; what they care about is the prospect of pain, injury, and degeneration. Therefore the better pitch for engineered longevity focuses on elimination of the pain and degeneration of aging, and the continuation of youthful health for as long as a person desires.

The Simple Answer That No-One Wants to Hear

There's nothing you can do right now that will have a greater immediate effect on your life expectancy than exercise and calorie restriction. The best thing you can do for future improvement is to help researchers raise funds to develop repair technologies for human aging. But no-one wants to hear that. Everyone wants a silver bullet now, and it doesn't exist: "Friends occasionally ask me how they might best live healthy, longer. They inquire because I went to medical school, work in biotech, and focus professionally on developing drugs to treat diseases of aging by targeting aging genes. My response seems to surprise them, because it does not center on pharmaceutical products. The current answer on how to increase healthy human lifespan is simple: 'Eat less, and exercise more.' ... Modern medicine has discovered an impressive number of lifesaving new drugs for devastating diseases such as cancer, diabetes, heart disease, and infectious diseases. Nevertheless, for most of us, active lifestyles and less food will have a more profound effect than taking more medicines. Hard as it is, we should walk, run, and bike more, and reduce our food intake. The best way we can increase our chances to live healthy, longer is simple: eat less and exercise more."

Link: http://www.boston.com/bostonglobe/editorial_opinion/oped/articles/2010/07/05/a_simple_hard_answer_to_long_life/

A Religious Viewpoint

A response to recent discussion of the Catholic hierarchy's views on engineered longevity: "Michael Anissimov and Aubrey de Grey call our attention to Pope Benedict's Holy Saturday address from 3 April of this year. In the address, the Pope presents perspective on immortalism, suggesting that radical extension of life as we currently know it is not a cure for death, but rather a cure for death must 'transform our lives from within' and 'create a new life within us, truly fit for eternity'. The Pope's message contains some ideas with which I disagree. For example, he questions the value of extending life hundreds of years and suggests it would be condemnation; does he consider us already condemned as a consequence of extending life well beyond the few decades that were available to our ancestors? Perhaps he does, as do many Catholics, embracing a doctrine of original sin and assuming life as we now know it to have no possibility of naturally improving beyond the consequences of that original sin. He reasons that immortalism would leave no room for youth, yet youth is precisely the goal of immortalism - not merely a perpetuation of geriatric hacks. He also reasons that immortalism would kill capacity for innovation, yet capacity for innovation has only improved as we've extended our lifespans. Finally, he implies that death itself is where we should look to find the beginning of the fullness of life. While I don't consider death the absolute end of identity, I consider it to be among the worst of hollow and meaningless contradictions to equate death with life."

Link: http://lincoln.metacannon.net/2010/06/pope-benedict-and-immortalists.html

Afraid of the Future, or Working Towards It

For every human who thrives on novelty, there are a hundred who quite deliberately engineer lives of stasis and routine, or at least as much stasis as can be achieved in this age of rapid technological progress. Despite being the species that builds wonders and improves our overall situation at a breakneck pace, we are also the species that loathes any and all change. It is the human condition to be unhappy at the prospect of vastly beneficial progress - because it will upset the mundane routines of our lives.

Over at Depressed Metabolism, you'll find some thoughts along these lines applied to cryonics. Why has cryonic preservation of the fine structure of the brain remained an unpopular option over the decades since its invention? Everyone and their dog has an opinion on that topic, but this one focuses on fear of the future - a form of distaste for change.

Cryonics and fear of the future:

One reason why advocates of cryonics are not successful in identifying the cause of its limited popularity may be that they are inclined to exempt cryonics as such from its explanations. The assumption is that cryonics as such is a good idea but technical or practical problems prevent its widespread acceptance. But there is a major problem at the heart of cryonics itself. Many people have little difficulty recognizing that cryonics requires a person to choose to be resuscitated in a far and unknown future. In a sense, this property of cryonics is more about being "reborn" than about "extending life": Humans have evolved to want to survive but this instinct does not appear to assert itself when faced with the choice to go into biostatis in anticipation of resuscitation in a far and unknown future.

Little change is more radical than that which will be experienced by a revived cryonics patient: possibly a century removed in time, with a newly manufactured body, new society, new life. Starting over with next to nothing after a journey to an unfamiliar land, in other words. We've all done this at least once, but that doesn't mean it's an appetizing prospect in the later years of life - no matter how well understood and accepted intellectually, the grumbling ape that lives within us all is not going to like it.

In this sense, signing up for cryonics and following through with cryopreservation is yet another in the long list of battles we have to fight with our base nature. Day in and day out we wrestle with the ape within so as to be somewhat better than our instincts alone would make us. It is a noble war, for all that it generally goes poorly from moment to moment in vast majority of folk.

Induced Pluripotent Stem Cells From Blood

From Wired: "Blood drawn with a simple needle stick can be coaxed into producing stem cells that may have the ability to form any type of tissue in the body, three independent papers report... The new technique will allow scientists to tap a large, readily available source of personalized stem cells. ... Because taking blood is safe, fast and efficient compared to current stem cell harvesting methods, some of which include biopsies and pretreatments with drugs, researchers hope that blood-derived stem cells could one day be used to study and treat diseases. ... Three research groups used similar methods to prod certain immune cells in human blood to become induced pluripotent stem cells. Because they are reprogrammed adult cells, these stem cells share many of the same regenerative abilities as true embryonic stem cells but may not have as much versatility. ... Scientists' manipulations turned the stem cells in the new studies into several types of mature blood cells, including infection-fighting T cells. What's more, all the groups showed that a batch of the stem cells implanted into mice developed into the three main types of progenitor cells found in human embryos."

Link: http://www.wired.com/wiredscience/2010/07/stem-cells-from-human-blood-can-be-reprogrammed/

Improved Association of Longevity Genes With Longevity

Via ScienceNews: "In the new study, researchers looked at genetic markers called single nucleotide polymorphisms, or SNPs, in 1,055 centenarians and 1,267 younger people, all of European descent. The scientists found 150 genetic SNP variants linked to extreme longevity. Initially, the team identified only 33 SNPs found more often in people aged 90 to 114 years but not in a control group made up of people who will presumably live an average lifespan. ... biostatistician Paola Sebastiani [devised] a different statistical method to identify additional SNPs that would improve the team's ability to predict longevity. The team tested their predictions on a separate group of centenarians and controls. With the 150 SNPs, the researchers could correctly predict who was a centenarian 77 percent of the time. ... Now on one side, 77 percent is a very high accuracy for a genetic model, which means that the traits that we are looking at have a very strong genetic base ... On the other hand, the 150 SNPs can't explain why the remaining 23 percent of centenarians in the study have reached such ripe old ages. It could mean that those people have other, rare genetic variants or lifestyles responsible for their longevity or some combination of the two."

Link: http://www.sciencenews.org/view/generic/id/60772/title/For_most_centenarians,_longevity_is_written_in_the_DNA

Aubrey de Grey in the Media

Longevity advocate and biomedical gerontologist Aubrey de Grey presented at the technology gathering Activate 2010 in London today, and here's a short interview:

I plan to focus [my presentation] on the acceleration of progress in technology (with an emphasis on biomedical technology, naturally) that arises from the internet's facilitation of communication between scientists, technologists and the general public. Public enthusiasm for new advances is a key ingredient in influencing policy-makers to stimulate follow-up work with suitable funding, and it can be achieved far faster now that interested non-specialists can explore new research autonomously and can also be appealed to directly by scientists. I will illustrate this with a few examples from my foundation's work.

One of the Guardian bloggers gives a little space to de Grey's presentation in his live coverage of the event.

10.18am: Emily Bell now orchestrating a Q&A. Aubrey de Grey went down a storm with the audience. A plethora of contenders for Quote of the Day.

Question to de Grey: What about overpopulation?

de Grey: Those of us who want to be our own next generation have the right to be. How do we know that we're going to have any problem in this way. Birth rate going down, average age of women having first child is going up, which is very important. Unless you think it's okay to condemn people to death just because they were born a long time ago...[audience laughter stops him short of finishing].

Continuing the theme, I see that the BBC World Service has published a recent audio interview with de Grey at their website:

"Who wants to live forever?" sang Freddy Mercury. Fair question, though from the discussions on our Facebook site, few people actually do. Forever seems like, well, such a long time. One Planet's considering the question thanks to a conference taking place in Barcelona entitled the "Congress on controversies in longevity, health and aging". In short, scientists will debate age prevention.

In this week's show we catch up with Dr Aubrey de Grey, one of the world's leading thinkers in the field of gerontology (the study of aging). Before heading off to that conference, Dr Aubrey debates with Mike the ethics and practicalities of age prevention.

If you like what you hear, consider donating to the SENS Foundation to help advance the science of human rejuvenation: finding ways to repair the known biochemical damage of aging.

Organs Made to Order

As the Smithsonian notes, "It won't be long before surgeons routinely install replacement body parts created in the laboratory. ... Anthony Atala works in the body shop of the future. ... he and his colleagues use human cells to grow muscles, blood vessels, skin and even a complete urinary bladder. Much of the work is experimental and hasn't yet been tested in human patients, but Atala has implanted laboratory-grown bladders into more than two dozen children and young adults born with defective bladders that don't empty properly, a condition that can cause kidney damage. The bladders were the first lab-generated human organs implanted in people. If they continue to perform well in clinical tests, the treatment may become standard not only for birth defects of the bladder but also for bladder cancer and other conditions. ... Regenerative medicine's once-wild ideas are fast becoming reality. Late last year, Organovo, a biotech company in San Diego, began distributing the first commercially available body-part printer. Yes, you read correctly: a printer for body parts. Using the same idea as an ink-jet printer, it jets laser-guided droplets of cells and scaffold material onto a movable platform. With each pass of the printer head, the platform sinks, and the deposited material gradually builds up a 3-D piece of tissue. Regenerative medicine laboratories around the world have relied on the printer to generate pieces of skin, muscle and blood vessels. Atala's lab has used the technology to construct a two-chambered mouse-size heart in about 40 minutes."

Link: http://www.smithsonianmag.com/specialsections/40th-anniversary/97123514.html

Some People Have Better Mitochondrial DNA, Part II

Some people have demonstrably better mitochondrial DNA, others worse. Here, a study shows correlations between some variants and old-age frailty: "Mitochondria contribute to the dynamics of cellular metabolism, the production of reactive oxygen species, and apoptotic pathways. Consequently, mitochondrial function has been hypothesized to influence functional decline and vulnerability to disease in later life. ... mitochondrial DNA (mtDNA) variation was compared in frail and non-frail older adults. Associations of selected SNPs with a muscle strength phenotype were also explored. Participants were selected from the Cardiovascular Health Study (CHS), a population-based observational study ... Three mtDNA SNPs were statistically significantly associated with frailty across all pilot participants or in sex-stratified comparisons." Given the degree to which mitochondrial composition correlates with species life span differences, we should not be surprised to find some variations significant in human life span.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2883558/