One of the predictions of the reliability theory of aging and longevity is that we are all born damaged. Reliability theory evolved from the theories used to predict failure in mechanical systems; as such, it is a less an attempt to explain the roots of aging and more an attempt to frame an understanding of the way in which accumulating damage at the most fundamental levels of our biochemistry produces the observed patterns of aging.

The models of reliability theory only match up with reality if we assume that life starts with a certain level of preexisting biological damage, and that damage goes some way to determining later health and life expectancy. What happens in early life matters a great deal, it seems. This is why we are interested in such topics as the potential effects of solar radiation on the unborn, and the degree to which historical increases in longevity can be explained by a lower childhood burden of chronic disease.

I noticed another interesting data point today in an open access paper: a possible marker for the biological cost of being born to an older mother - something that we know bears an increased risk of health issues.

Parental ages and levels of DNA methylation in the newborn are correlated:

Changes in DNA methylation patterns with age frequently have been observed and implicated in the normal aging process and its associated increasing risk of disease, particularly cancer. Additionally, the offspring of older parents are at significantly increased risk of cancer, diabetes, and neurodevelopmental disorders. Only a proportion of these increased risks among the children of older parents can be attributed to nondisjunction and chromosomal rearrangements.

We found that methylation levels [associated with] 142 genes were significantly correlated with maternal age. A weaker correlation was observed with paternal age. ... Genes associated with [cancer] are significantly over-represented among the genes correlated with maternal age, and this suggests a link to known increased risks of cancer among the children of older parents. Similarly, gene functions related to neurodevelopment and neuroregulation are over-represented among the strongly correlated genes, and this may have relevance to the increasing risk of neurodevelopmental and psychiatric disorders in offspring as parental ages increase.

Biotechnology will be a great leveler of opportunity, a grand remover of adversity, offering the chance to repair deleterious consequences of ancestry, birth, and other biological circumstances beyond our control. Systematic altereration of DNA methylation will likely be a commonplace medical technology of the late 2020s, for example. This and many other potentially beneficial manipulations of DNA are almost within reach of the most advanced research groups today - and the biotechnologies of ten or fifteen years from today will far cheaper and more capable than the best machinery now available.

A look at current research on the definite health and potential longevity benefits of calorie restriction in humans: "Animals who consume fewer calories live longer and healthier lives. Now, a seminal study at the University of California, San Francisco (UCSF) is testing whether the same is true for extreme dieters. The calorie restriction study centers on two primary questions: What allows people to live in a manner many consider food deprived? And does it slow down aging? Called CRONA (Caloric Restriction with Optimal Nutrition and Aging Study), the investigation is probing the biological processes affected by extremely low caloric intake, including the impact on telomeres - tiny pieces of DNA that protect cell chromosomes. Short telomeres have been linked to a host of health problems including diabetes, heart disease and premature death. The UCSF study is the first to broadly examine the psychological profile of successful extreme dieters, gauging how their cognitive sharpness, impulse control, stress and personality differ from normal eaters and overeaters. ... Testing and data collection will continue through summer. The scientists are still recruiting control subjects who are either obese or 'free eaters' - not restricting food intake but not overweight. Interested parties can email cronastudy@gmail.com. ... We need information about what it takes to change your eating pattern for a long time. There are so many diets out there - people lose weight for six months, then regain it. We need to study what it is about the calorie restrictors that makes them able to do this for years and years." The new information on the biological response to calorie restriction is, I think, much more valuable than yet another study on willpower in humans.

Link: http://www.ucsf.edu/news/2011/04/9740/extreme-dieting-does-it-lead-longer-lives

Small scale efforts by a widespread people outside the academic and industry communities, and open and largely free access to plans and data are the future of biotechnology. It is a data-driven field, and will ultimately look just like the open source software community does today: "Following in the footsteps of revolutionaries like Steve Jobs and Steve Wozniak, who built the first Apple computer in Jobs's garage, and Sergey Brin and Larry Page, who invented Google in a friend's garage, biohackers are attempting bold feats of genetic engineering, drug development, and biotech research in makeshift home laboratories. ... For a few hundred dollars, anyone can send some spit to a sequencing company and receive a complete DNA scan, and then use free software to analyze the results. Custom-made DNA can be mail-ordered off websites, and affordable biotech gear is available on Craigslist and eBay. ... biohackers, like the open-source programmers and software hackers who came before, are united by a profound idealism. They believe in the power of individuals as opposed to corporate interests, in the wisdom of crowds as opposed to the single-mindedness of experts, and in the incentive to do good for the world as opposed to the need to turn a profit. Suspicious of scientific elitism and inspired by the success of open-source computing, the bio DIYers believe that individuals have a fundamental right to biological information, that spreading the tools of biotech to the masses will accelerate the pace of progress, and that the fruits of the biosciences should be delivered into the hands of the people who need them the most."

Link: http://www.technologyreview.com/biomedicine/37444/

It is unfortunate and noteworthy that the loudest institutional voices in Western culture seem to have an aversion to human enhancement. It is the ideal of equality run rampant, heading for its inevitable Harrison Bergeron endpoint - equality by leveling down to the lowest and preventing new heights from being achieved. Destruction is the only thing that politicians are really good at, sad to say, and egalitarianism, much like communism, is pretty in its abstract ideals but horrific when put into practice:

• The Terrible Urge to Tear Down the Successful
• Shunning Advances Through the Instinct to Equality

This rejection of human enhancement is in essence a rejection of the urge to improvement - and is thus one of a number of important hurdles standing in the way of widespread support for the development of rejuvenation biotechnology. Living longer than your parents did? That's an enhancement, and a great many talking heads would like to see laws written to prevent such technologies from ever seeing the light of day.

Yet the urge to improvement is everywhere else in evidence in our societies, as noted in this subtle injection of transhumanist ideals into the Discover Magazine website:

Just because I'm not ill [and] not injured, doesn't mean that I am, by default, as healthy as I could be. For some bizarre reason, we don't think about our bodies that way when it comes to health care and self improvement. We don't pursue excellent health the way we strive to be better in our hobbies and work. So, where did we get the idea that mediocre health is good enough?

...

But here's the interesting thing: neither the US nor the UK have regulations in place for prescription pharmaceuticals that are not therapeutic. Drugs that don't cure an illness but still have a beneficial effect have one of two paths: either find an illness they do cure or invent an illness that the drug seems to cure. An example of the latter is Viagra. I don't care what the DSM says, erectile dysfunction is not real illness. But Viagra works. It doesn't "cure" anything, but it sure makes a lot of people's lives better, which is [a] great thing. But it's a massive problem that there is no way for drugs that make our health better to find their way onto the market. And there in lies the problem. Save vaccines, modern medicine just doesn't know what to do with medicine that prevents disease or improves a person's life.

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Prevent and improve. Those are the two words I'd argue are most underused in every other aspect of human health care. Why does self-improvement not include pharmaceuticals that make us smarter or stronger or happier? Because we've been convinced and told and reminded and scolded that taking a pill means something is wrong with you.

And so to aging and longevity. The bureaucrats of the FDA do not recognize aging as a disease, and so will not approve treatments for it. In a culture that is hostile to human enhancement, winning support for the reversal of aging will be that much harder. This is one of many ways in which freedom matters greatly in medical research. Under the systems of regulation in place in the largest markets of the world, researchers and commercial developers are far from free to turn proven science into commercial products, and far from free to convince their fellow countrymen to try something new.

We humans are the species that improves ourselves and creates value from our surroundings. That is our defining characteristic - and yet, paradoxically, so much time and effort in this day and age is devoted to sabotaging the engines of progress.

Stem cell function, necessary to maintain tissue, declines with age. This most likely a part of the evolved balancing act between suppression of cancer and the need to keep tissues repaired and working - as you grow older, forms of molecular damage accumulate, increasing the risk of cancer resulting from the normal operations of cellular proliferation. That balance can already be shifted in mice in very beneficial ways, giving both less cancer and longer lives. While these are the early days yet, in our future lies a fusion of the fields of cancer research and stem cell science that will do the same for humans: "Adult stem cells exist in most mammalian organs and tissues and are indispensable for normal tissue homeostasis and repair. In most tissues, there is an age-related decline in stem cell functionality but not a depletion of stem cells. Such functional changes reflect deleterious effects of age on the genome, epigenome, and proteome, some of which arise cell autonomously and others of which are imposed by an age-related change in the local milieu or systemic environment. Notably, some of the changes, particularly epigenomic and proteomic, are potentially reversible, and both environmental and genetic interventions can result in the rejuvenation of aged stem cells. Such findings have profound implications for the stem cell-based therapy of age-related diseases."

Link: http://jcb.rupress.org/content/193/2/257.long

A reminder: "Biological aging is the greatest health threat to humanity today. It causes more disease and suffering in the world than all infectious diseases (HIV, malaria, etc.) or any other cause (e.g. poverty, war, natural disaster, etc.). The inborn aging process causes cancer, heart disease, stroke, AD, joint pain, vision and hearing impairment, etc. The harms of senescence (even if we exercise and eat a healthy diet) are certain, severe and universal. The diseases of aging afflict both rich and poor, and developed and developing countries. And, unless the biological clocks we have inherited from our Darwinian past are modified, it is highly likely that all future generations of human beings that shall ever live on this planet will suffer one or more of the diseases of aging. In light of the unique health challenges facing the world's aging populations, the most important knowledge humans can acquire today is knowledge about the biology of aging: why do we, as a species, age at the rate we do? why does aging leave our bodies and minds susceptible to disease? And, most importantly, how can we retard or ameliorate the harmful effects of biological aging?"

Link: http://colinfarrelly.blogspot.com/2011/04/time-waits-for-no-one.html

For everyday, average, healthy people, leading a good lifestyle makes a sizable difference both to your life expectancy and your chances of suffering the common age-related diseases in years to come. Refrain from smoking, regular moderate exercise, and a diet low in calories that still provides optimal nutrition - thereby avoiding the build up of visceral fat that happens on the way towards obesity - and you will gain a greater benefit than any presently available medical technology can offer.

For example:

A study of more than 100,000 men and women over 14 years finds nonsmokers who followed recommendations for cancer prevention had a lower risk of death from cancer, cardiovascular disease, and all-causes.

...

The participants were scored on a range from 0 to 8 points to reflect adherence to the American Cancer Society (ACS) cancer prevention guidelines regarding body mass index, physical activity, diet, and alcohol consumption, with 8 points representing adherence to all of the recommendations simultaneously.

After 14 years, men and women with high compliance scores (7, 8) had a 42% lower risk of death compared to those with low scores (0-2). Risk of cardiovascular disease death were 48% lower among men and 58% lower among women, while the risk of cancer death was 30% lower in men and 24% lower in women.

The best we can presently do for our health and longevity in this grand age of biotechnology is still exactly the same as the best was for our grandparents, and that is disappointing. There is a gaping chasm between the exciting advances and technology demonstrations taking place in laboratories and what becomes available for commercialization - or rather what the regulators grudging permit to become available for commercialization. The future will include rejuvenation biotechnology that can repair the damage of aging. That technology is clearly envisaged and understood today, but progress towards its development and deployment remains frustratingly slow.

As always, the way to change this situation lies in money and action: help out, persuade people to help out, and give your time and resources to speed matters along.

A number of research groups are looking into ways to manipulate muscle regeneration and maintenance, and an advance here could be useful as a therapy to address age-related loss in muscle mass and strength: "Researchers have long questioned why patients with Duchenne muscular dystrophy (DMD) tend to manage well through childhood and adolescence, yet succumb to their disease in early adulthood, or why elderly people who lose muscle strength following bed rest find it difficult or impossible to regain. Now, researchers [are] beginning to find answers in a specialized population of cells called satellite cells. Their findings [suggest] a potential therapeutic target for conditions where muscle deterioration threatens life or quality of life. ... Suspecting a genetic switch that might turn off satellite cell proliferation in these circumstances, the scientists looked to a gene called Ezh2, known to keep the activity of other genes in check. When they genetically inactivated Ezh2 in satellite cells of laboratory mice, the mice failed to repair muscle damage caused by traumatic injury - satellite cells could not proliferate. Ezh2 expression is known to decline during aging, and the new research in mice suggests that therapies to activate Ezh2 and promote satellite cell proliferation might eventually play a role in treating degenerative muscle diseases. ... in the elderly, tweaking the gene in satellite cells would not increase their lifespan, but could increase their quality of life by helping to prevent falls and enabling them to move and walk better and go about their daily activities."

Link: http://www.nih.gov/news/health/apr2011/niams-15.htm

A Science 2.0 article looks at the work of researcher Michael Rose over past decades: "Over the years, Rose and his lab have bred fruit flies to live four times the life span of an average fruit fly. Reasoning from those studies, Rose has proposed that, because the life spans of fruit flies have the genetic capability to be extensively prolonged, human life can be manipulated in the same way. ... Wattiaux was a French scientist working at the University of Leuven in Belgium. His study used the same fruit flies that Rose had been working with ... Wattiaux found that when he made each new generation of fruit flies that were the offspring of old parents exclusively, the flies showed an increased life span after each generation. But Wattiaux didn't know why his fruit flies lived longer. He felt that longevity increased because of a nongenetic effect, but he didn't have any direct evidence. Rose did. Wattiaux's results, he saw, showed the importance of the force of natural selection. He believed that, because natural selection stops working at a late age and fails to eliminate genes with detrimental effects, these bad genes would not be removed by natural selection. Instead, they would accumulate. In populations that reproduce early, natural selection declines early. Alternatively, populations that are old when they reproduce will continue to be subject to powerful selection until they begin to reproduce. Thus, by allowing older flies to reproduce over generations, natural selection would continue to choose the flies that are able to breed at a later age - the fittest flies."

Link: http://www.science20.com/forever_fly/forever_fly_forever_diet-78126

Yes, we're back to clams again: four hundred year old clams in this case. The ocean quahog, Arctica islandica, is a very long-lived bivalve that, like other unusually long-lived species, is attracting the attention of researchers. How is it that these animals manage to live so much longer than their near relatives? You'll find some background reading in the archives:

• Ageless Animals, Clam Edition
• Digging Into Clam Biochemistry
• Ageless Animals, the Pearl Mussel Edition

Researchers to date have focused on resistance to oxidative damage in quahogs, but the more research is done, the more ambiguous that picture becomes. It doesn't seem to be the case that we can simply point to very high levels of antioxidants or an aggressive antioxidant response that preserves cells from the accumulating damage caused by oxidative byproducts of metabolism. In many ways this parallels research into the biochemistry of the naked mole-rat: the initial focus on examining natural antioxidants gave way to the present view that their comparatively long life span depends on differences in the construction of their vulnerable cell membranes. They are better built in the places where it matters - their cells are buzzing with reactive oxidant compounds, but their resistant cell membranes shrug it off.

That may be the case for the quahog as well, but researchers aren't there yet. This recent paper manages to continue the present trend of muddying the waters:

We assess whether reactive oxygen species production and resistance to oxidative stress might be causally involved in the exceptional longevity exhibited by the ocean quahog Arctica islandica. We tested this hypothesis by comparing reactive oxygen species production, resistance to oxidative stress, antioxidant defenses, and protein damage elimination processes in long-lived A islandica with the shorter-lived hard clam, Mercenaria mercenaria. We compared baseline biochemical profiles, age-related changes, and responses to exposure to the oxidative stressor tert-butyl hydroperoxide (TBHP).

Our data support the premise that extreme longevity in A islandica is associated with an attenuated cellular reactive oxygen species production. The observation of reduced protein carbonyl concentration in A islandica gill tissue compared with M mercenaria suggests that reduced reactive oxygen species production in long-living bivalves is associated with lower levels of accumulated macromolecular damage, suggesting cellular redox homeostasis may determine life span. Resistance to aging at the organismal level is often reflected in resistance to oxidative stressors at the cellular level.

Following TBHP exposure, we observed not only an association between longevity and resistance to oxidative stress-induced mortality but also marked resistance to oxidative stress-induced cell death in the longer-living bivalves. Contrary to some expectations from the oxidative stress hypothesis, we observed that A islandica exhibited neither greater antioxidant capacities nor specific activities than in M mercenaria nor a more pronounced homeostatic antioxidant response following TBHP exposure. The study also failed to provide support for the exceptional longevity of A islandica being associated with enhanced protein recycling.

Which is really saying little that is new and definitive - just better ruling out some of the options. The quahog could be producing fewer oxidants, or it could be efficiently mopping up oxidants at their source in the mitochondria due to a natural source of localized antioxidant compounds. In either case, that says nothing about how it or its cells might react to an externally provided and artificial source of oxidative stress like TBHP. Given the present pace of work, however, I'd expect that researchers will have developed a well-supported consensus explanation for the extreme longevity of this species and the naked-mole rat by the time 2020 rolls around.