There exists a fair-sized research community whose members think about extending healthy human life by manipulating the long term operation of metabolism. They are looking at small and incremental gains, however, and don't expect success in their work over the next ten to twenty years to go much beyond providing a few additional years of life and generally better health throughout life. This will be achieved through ways of mimicking calorie restriction or other life-extending genetic and epigenetic alterations discovered in mice. This is a far cry from the quality and quantity of life extension we'd expect to emerge from a mature SENS technology base, focused on repair of the low-level biological damage that causes aging, but it is the focus of the mainstream - much as we'd like that to be different.

In this world of incremental advances and manipulation of metabolism, researchers are becoming increasingly aware that they cannot ignore the vast population of symbiotic bacteria we carry with us throughout our lives. You can look back in the Fight Aging! archives to see that evidence has emerged in recent years to support the idea that changes in gut bacteria may be significant for long-term health:

• Intestinal Bacteria and Ageing
• Aging and the Role of Your Bacteria

The intestinal microbiota is important for maintenance of host health, providing energy, nutrients and protection against invading organisms. Although the colonic microbiota is relatively stable throughout adult life, age-related changes in the gastrointestinal (GI) tract, as well as changes in diet and host immune system reactivity, inevitably affect population composition. Recent studies indicate shifts in the composition of the intestinal microbiota, which may lead to detrimental effects for the elderly host.

Here is a more recent paper on the same topic, entitled "Gut microbiota as a candidate for lifespan extension", which looks toward turning understanding into action:

On the basis of recent knowledge in worms, flies, and humans, an important role of the gut microbiota in aging and longevity is emerging. The complex bacterial community that populates the gut and that represents an evolutionary adapted ecosystem correlated with nutrition appears to limit the accumulation of pathobionts and infections in all taxa, being able of affecting the efficiency of the host immune system and exerting systemic metabolic effects.

There is an urgent need to disentangle the underpinning molecular mechanisms, which could shed light on the basic mechanisms of aging in an ecological perspective. Thus, it appears possible to extend healthy aging and lifespan by targeting the host as a metaorganism by manipulating the complex symbiotic ecosystem of gut microbiota, as well as other possible ecosystems of the body.

I think we'll be seeing more of this line of thinking in the years ahead - it hasn't been greatly explored and there's an increasing level of interest in slowing aging through metabolic manipulation. This fits right in to that research community and its interests.

Another step forward for the field of regenerative medicine: researchers have "discovered a novel way to convert human skin cells into brain cells ... Rather than using models made in yeast, flies or mice for disease research, all cell-reprogramming technology allows human brain, heart and other cells to be created from the skin cells of patients with a specific disease. The new cells created from the skin cells contain a complete set of the genes that resulted in that disease - representing the potential of a far-superior human model for studying illnesses, drugs and other treatments. In the future, such reprogrammed skin cells could be used to test both drug safety and efficacy for an individual patient with, for example, Alzheimer's disease.
... This technology should allow us to very rapidly model neurodegenerative diseases in a dish by making nerve cells from individual patients in just a matter of days - rather than the months required previously. ... used two genes and a microRNA to convert a skin sample from a 55-year-old woman directly into brain cells. (MicroRNAs are tiny strands of genetic material that regulate almost every process in every cell of the body.) The cells created [exchanged] the electrical impulses necessary for brain cells to communicate ... Using microRNA to reprogram cells is a safer and more efficient way than using the more common gene-modification approach. In ensuing experiments, [the researchers hope] to rely only on microRNAs and pharmaceutical compounds to convert skin cells to brain cells, which should lead to more efficient generation of cells for testing and regenerative purposes."

Link: http://www.sciencedaily.com/releases/2011/07/110728123107.htm

An interview with one of the Thiel Fellows: "The goal is to extend the healthy human lifespan. In the past couple of decades, we've learned a lot about the basic science of aging. Now it's time to start translating the basic science into marketable therapies. I want to find and fund the projects creating those therapies. ... When I was eight, my mom told me about death and I couldn't stop crying for days. What a tragedy! Life is incredible, but death is inevitable. I already knew biology was fantastic fun. But that moment, for me, made science more than fun. It made it into a power that could save lives. And I couldn't imagine doing something more fascinating or important. ... When I was twelve, I was lucky enough to meet Cynthia Kenyon (biogerontologist and molecular biologist), who is a pioneer in the field of anti-aging research. She is amazing. I ended up working in her lab, at the University of California San Francisco, for a few years. She had a way of describing scientists as detectives, trying to solve mysteries and catch genetic culprits. Growing up at UCSF, getting to tinker with tiny worms in a biology lab and sit in on classes about genetics and biochemistry ... that was an incredible experience. ... Anti-aging is such an important field, but it is underfunded. Building business around an anti-aging therapy is no mean feat, especially when the FDA does not recognize aging as a disease. The goal here is to create a profitable, self-sustaining structure that will fund a portfolio of anti-aging projects, and then commercialize the research. It will be important that scientists get a stable source of funding for long-term lifespan projects, and a cut of the revenue from the projects they create."

Link: http://www.dailybrink.com/?p=1990

A recent long Popular Science article looks at Sierra Sciences and its founder, a group that has been working on telomere biology and its role in aging for some years. Alongside a number of other research groups, the Sierra crowd believe that telomeres are a lynchpin portion of our biochemistry and manipulating them might significantly extend life.

Make poor lifestyle choices, and you're likely to die of heart disease or cancer or something well before your telomeres would otherwise become life-threateningly short. But for the aerobicized Andrews, for anyone who takes reasonable care of himself, a drug that activates telomerase might slow down the baseline rate at which the body falls apart. Andrews likens the underlying causes of aging, free radicals and the rest, to sticks of dynamite, with truncated telomeres being the stick with the shortest fuse. "I believe there's a really good chance that if we defuse that stick," he says, "and the person doesn't smoke and doesn't get obese, it wouldn't be surprising if they lived to be 150 years old. That means they're going to have 50 more years to be around when somebody solves the other aging problems."

Telomeres, you might recall, are the frayed ends of our chromosomes, there in order to prevent problems during cellular replication - though more correctly they might be thought of as one portion of a more complex and regulated system that touches upon many cellular processes. You can't consider telomeres in isolation from the behavior of the telomerase enzyme that acts to rebuild telomere length, for example. Telomeres appear to erode away over a lifetime in many tissues, and their length in immune cells correlates decently with general health and levels of stress, shortened telomeres go hand in hand with increased cancer risk, and there's some interesting interplay between telomere length and levels of mitochondrial damage - both implicated in aging, and we might suspect these two things to be aspects of the same underlying process, though that remains a theory that can be argued either way at this time.

It would be hard to argue that telomeres are anything other than connected to aging - but are they a lynchpin that can be manipulated alone, in absence of other therapies, to significantly extend life? I am a skeptic on that count in the sense that I don't think the evidence presently in hand wholly supports that view. If you look at the most beneficial example of telomere manipulation in mice, a 50% life extension was achieved by combining genetic manipulation of p53 and telomerase levels together - but telomerase has a range of other potential effects on metabolism beyond affecting telomere length. I am not aware at this time of a study that categorically shows benefits accruing because of telomere length versus because of any other effects of telomerase - such as, for example, acting to protect mitochondrial DNA from damage, which in turn protects telomeres from shortening.

The bottom line for me is that this is certainly a line of research worth chasing further - there are a range of experiments that show benefits from telomerase therapies, such as improved immune system function, for example. But is the telomeres, or is it something else that's the important underlying mechanism? Either way, Sierra Sciences ran out of money for research in the end and now seems to be removing itself from the game through a mechanism we've sadly seen before, which is to get into bed with the supplement industry. I cannot think of a small company that has done this and remained a serious contender in advancing the state of medical science - the end result more often looks like the protandim debacle, in which whatever interesting scientific work once existed is abandoned and its echoes used to promote herbal compounds sold with a garnishing of lies. From the Popular Science article:

The stock-market crash of 2008 nearly wiped out two investors who had until then been his primary funders. Without the money to continue refining the nearly 40 telomerase-activating chemicals he and his team had already discovered, Andrews made the decision last September to cut a deal with John W. Anderson, the founder of Isagenix, an Arizona-based "network marketing" supplement company. This month, Isagenix will launch an anti-aging product containing several natural compounds that Sierra Sciences has verified to have "telomere-supporting" properties.

So you're basically looking at the genesis of another set of worthless products and magical thinking that apes the scientific method while rejecting everything that makes it work - just like most of the rest of the "anti-aging" marketplace. And beside that, another set of names who might have gone on to do good work will instead never be taken seriously again. Which is sad, given that they had a better vision of the necessary strategy for longevity science than most of the scientific community.

Via EurekAlert!: "There is a reason exercise becomes more difficult with age. [Research] ties the weakness of aging to leaky calcium channels inside muscle cells. But there is some good news: the researchers say a drug already in Phase II clinical trials for the treatment of heart failure might plug those leaks. Earlier studies [showed] the same leaks underlie the weakness and fatigue that come with heart failure and Duchenne muscular dystrophy. ... It's interesting, normal people essentially acquire a form of muscular dystrophy with age. The basis for muscle weakness is the same. ... Extreme exercise like that done by marathon runners also springs the same sort of leaks, [but] in that case damaged muscles return to normal after a few days of rest. ... The leaks occur in a calcium release channel called ryanodine receptor 1 (RyR1) that is required for muscles to contract. Under conditions of stress, those channels are chemically modified and lose a stabilizing subunit known as calstabin1. ... Calcium inside of muscle cells is usually kept contained. When it is allowed to leak out into the cell that calcium itself is toxic, turning on an enzyme that chews up muscle cells. Once the leak starts, it's a vicious cycle. The calcium leak raises levels of damaging reactive oxygen species, which oxidize RyR1 and worsen the leak. The researchers made their discovery by studying the skeletal muscles of young and old mice. They also showed that 6-month-old mice carrying a mutation that made their RyR1 channels leaky showed the same muscular defects and weakness characteristic of older mice. When older mice were treated with a drug known as S107, the calcium leak in their muscles slowed and the animals voluntarily showed about a 50 percent increase in the amount of time spent wheel running. Now in clinical trials for patients with heart failure, the drug is known to work by restoring the connection between costabilin and RyR1."

Link: http://www.eurekalert.org/pub_releases/2011-08/cp-wia072911.php

Singularity Hub here looks at some of the research work that will lead to the ability to generate blood as needed: "Researchers [have] found a way to hunt down and isolate the stem cells from which your entire blood supply is derived. Until now, these hematopoietic stem cells (HSC) have been remarkably hard to track and isolate ... researchers were able to identify the CD49f protein as a key surface marker for hemotopoietic stem cells. Single CD49f HSCs were placed inside immunosupressed mice, and monitored to see how they developed. The entire spectrum of blood cells were produced, and just as important: they were self-renewing. The CD49f HSC wasn't just creating blood, it was creating an expanding and sustaining blood supply that should theoretically survive long term in the body." This will lead to a number of potential ways to generate sufficient quantities of blood to remove the need for blood donations, and ultimately will allow a patient's own cells to be used to generate blood on demand.

Link: http://singularityhub.com/2011/08/03/scientists-bag-and-tag-the-stem-cell-that-may-create-an-endless-supply-of-blood/

Many of the worlds longest-lived people became the world's longest-lived people despite a history of what are considered to be poor lifestyle choices from the perspective of long term health. Amongst their number are smokers, the overweight, and the sedentary - all items shown to cause great harm to health in the long term. Studies have shown that each of these considered in isolation can shave as much as a decade from your life expectancy, and that's quite aside from what they will do to your quality of life via an increased risk of suffering chronic and debilitating medical conditions.

So how is it that we see a fair proportion of extremely old people with such a poor track record for basic good health choices over the course of their lives? So far it looks like that can be attributed to fortunate genes:

People who live to 95 or older are no more virtuous than the rest of us in terms of their diet, exercise routine or smoking and drinking habits ... Overall, people with exceptional longevity did not have healthier habits than the comparison group in terms of BMI, smoking, physical activity, or diet. For example, 27 percent of the elderly women and an equal percentage of women in the general population attempted to eat a low-calorie diet. Among long-living men, 24 percent consumed alcohol daily, compared with 22 percent of the general population. And only 43 percent of male centenarians reported engaging in regular exercise of moderate intensity, compared with 57 percent of men in the comparison group.

...

In previous studies of our centenarians, we've identified gene variants that exert particular physiology effects, such as causing significantly elevated levels of HDL or 'good' cholesterol. This study suggests that centenarians may possess additional longevity genes that help to buffer them against the harmful effects of an unhealthy lifestyle. ... Although this study demonstrates that centenarians can be obese, smoke and avoid exercise, those lifestyle habits are not good choices for most of us who do not have a family history of longevity. We should watch our weight, avoid smoking and be sure to exercise, since these activities have been shown to have great health benefits for the general population, including a longer lifespan.

Why rely on having a genetic buffer against subtle forms of self-harm when the odds are good that you have no such thing? The only reliable ways to ensure that you live for a long, long time in good health will come from progress in medical technology aimed at engineering greater human longevity: repair biotechnologies capable of reversing the known forms of cellular and molecular damage that cause aging. That progress in turn depends on the degree to which we choose to support and advocate rejuvenation research today.

Many of the worlds longest-lived people became the world's longest-lived people despite a history of what are considered to be poor lifestyle choices from the perspective of long term health. Amongst their number are smokers, the overweight, and the sedentary - all items shown to cause great harm to health in the long term. Studies have shown that each of these considered in isolation can shave as much as a decade from your life expectancy, and that's quite aside from what they will do to your quality of life via an increased risk of suffering chronic and debilitating medical conditions.

So how is it that we see a fair proportion of extremely old people with such a poor track record for basic good health choices over the course of their lives? So far it looks like that can be attributed to fortunate genes:

People who live to 95 or older are no more virtuous than the rest of us in terms of their diet, exercise routine or smoking and drinking habits ... Overall, people with exceptional longevity did not have healthier habits than the comparison group in terms of BMI, smoking, physical activity, or diet. For example, 27 percent of the elderly women and an equal percentage of women in the general population attempted to eat a low-calorie diet. Among long-living men, 24 percent consumed alcohol daily, compared with 22 percent of the general population. And only 43 percent of male centenarians reported engaging in regular exercise of moderate intensity, compared with 57 percent of men in the comparison group.

...

In previous studies of our centenarians, we've identified gene variants that exert particular physiology effects, such as causing significantly elevated levels of HDL or 'good' cholesterol. This study suggests that centenarians may possess additional longevity genes that help to buffer them against the harmful effects of an unhealthy lifestyle. ... Although this study demonstrates that centenarians can be obese, smoke and avoid exercise, those lifestyle habits are not good choices for most of us who do not have a family history of longevity. We should watch our weight, avoid smoking and be sure to exercise, since these activities have been shown to have great health benefits for the general population, including a longer lifespan.

Why rely on having a genetic buffer against subtle forms of self-harm when the odds are good that you have no such thing? The only reliable ways to ensure that you live for a long, long time in good health will come from progress in medical technology aimed at engineering greater human longevity: repair biotechnologies capable of reversing the known forms of cellular and molecular damage that cause aging. That progress in turn depends on the degree to which we choose to support and advocate rejuvenation research today.

Depressed Metabolism here notes the existence of a double standard when it comes to the science and practice of cryonics - actually one you'll find exists for all serious endeavors in life extension, such as SENS research: "One of the most predictable features of public debates about cryonics is that those arguing in favor of cryonics are held to more rigorous standards than those seeking conventional medical treatment. Advocates of cryonics do not just have to prove that cryonics will work, they are also supposed to solve problems like overpopulation and the presumed boredom arising from expended lifespans. To some, people who make cryonics arrangements have an inflated perception of their own importance and should just forgo such selfish attempts to extend their lives. The default position seems to be that people should not exist and that life needs justification. Could you imagine such antinatalist rhetoric being employed when a person seeks conventional medical treatment to extend their life? We can't, and such responses are quite indicative of the fact that people are not interested in serious evaluation of the cryonics argument."

Link: http://www.depressedmetabolism.com/2011/07/29/the-double-standard-about-cryonics/

Changes in stem cell biology and capabilities are considered important in age-related degeneration. For example: "A decline in cellular homeostasis in older individuals underlies age-related pathologies like osteoporosis and osteoarthritis. [Researchers] report key differences in the patterns of expressed mRNAs in bone-marrow mesenchymal stem cells (bmMSCs) of young donors compared with old human donors. The distinct subsets of expressed genes associated with glycobiology are consistent with the underlying age-related decline in bone marrow function. ... It is now well established that in older individuals stem cells can become 'aged' and thus incapable of renewing surrounding tissues and organs as efficiently as young individuals. Experimental and clinical evidence has revealed the importance of stem cell aging in bone marrow transplants, as recipients of bone marrow from older donors do not fare as well as recipients of bone marrow from younger donors. However, the molecular mechanisms governing stem cell aging are not well understood. An important first step towards this goal is to delineate the gene expression differences between stem cells from young and old individuals. Bone marrow stem cells are particularly well suited for such studies, as they are relatively easy to purify to homogeneity. ... bmMSCs showed age-increases in the expression of genes associated with the degradation of N-glycans and glycosaminoglycans and with the biosynthesis of glycosphingolipids. These results reveal major differences in the glycobiology and glycan compostion of young and old bmMSCs, associated with age-related changes in the cellular responses to autocrine and paracrine signals. The difference in glycan pathways may not be limited to bmMSCs or even to stem cells, but could be more widely prevalent among other cell types."

Link: http://impactaging.com/papers/v3/n7/full/100356.html

Up until comparatively recently the scientific consensus was that neurogenesis, the process by which new neurons are created and assimilated into the workings of the brain, simply didn't happen in adults to any significant degree. Fortunately we are supplied with a modest flow of new brain cells as life goes on, and this post is a reminder that, amongst all the other benefits caused by calorie restriction, it also increases neurogenesis. Eat fewer calories whilst still obtaining an optimal amount of nutrients and you gain more functional brain cells as a result:

Adult neural stem cells in the dentate gyrus of the hippocampus are negatively and positively regulated by a broad range of environmental stimuli that include aging, stress, social interaction, physical activity, and dietary modulation. Interestingly, dietary regulation has a distinct outcome, such that reduced dietary intake enhances neurogenesis, whereas excess calorie intake by a high-fat diet has a negative effect.

This has actually been known for at least a decade, as you'll see if you look back into the scientific archives. For example, this from 2000:

We found that maintenance of adult rats on a DR regimen results in a significant increase in the numbers of newly produced neural cells in the dentate gyrus of the hippocampus ... The increase in neurogenesis in rats maintained on DR appears to result from decreased death of newly produced cells, rather than from increased cell proliferation. We further show that the expression of brain-derived neurotrophic factor, a trophic factor recently associated with neurogenesis, is increased in hippocampal cells of rats maintained on DR. Our data are the first evidence that diet can affect the process of neurogenesis, as well as the first evidence that diet can affect neurotrophic factor production. These findings provide insight into the mechanisms whereby diet impacts on brain plasticity, aging and neurodegenerative disorders.

Or this from 2002:

We now report that neurotrophin expression and neurogenesis can be modified by a change in diet. When adult mice are maintained on a dietary restriction (DR) feeding regimen, numbers of newly generated cells in the dentate gyrus of the hippocampus are increased, apparently as the result of increased cell survival. The new cells exhibit phenotypes of neurons and astrocytes.

So what exactly does a modest increase in the creation of new functional brain cells mean for humans? That remains to be determined in detail, and seems to boil down to quantifying the effects of increased plasticity in the brain. There is the expectation in the scientific community that increased plasticity will be shown to be beneficial in a range of ways, but to date few lines of research have managed to definitively link changes in plasticity with cognitive ability, resistance to age-related neurodegenerative diseases, and so forth. That would seem to be just a matter of time, however.

Meanwhile, the benefits of calorie restriction are so broad and large - on a par with exercise in humans, and thus still better for healthy people than any presently available medical technology - that it would seem foolish not to give serious thought to trying it.