Allow me to point you to the results of a long-running study on metabolic rate and mortality:

Higher metabolic rates increase free radical formation, which may accelerate aging and lead to early mortality. ... Our objective was to determine whether higher metabolic rates measured by two different methods predict early natural mortality in humans. ... Twenty-four-hour energy expenditure (24EE) was measured in 508 individuals, resting metabolic rate (RMR) was measured in 384 individuals.

The study ran with hundreds of participants over more than twenty years and concluded that there is a good correlation between these measures of metabolic rate and risk of death:

For each 100-kcal/24 h increase in EE, the risk of natural mortality increased by 1.29 in the 24EE group and by 1.25 in the RMR group, after adjustment for age, sex, and body weight in proportional hazard analyses.

The higher your resting metabolic rate, the greater your expected chance of death by aging or disease sometime soon - a cheerful prospect. My first thought was that these measurements should reflect levels of physical fitness achieved through exercise, which we know has a strong effect on mortality, but apparently not:

Studies published in 1992 and 1997 indicate that the level of aerobic fitness of an individual does not have any correlation with the level of resting metabolism. Both studies find that aerobic fitness levels do not improve the predictive power of fat free mass for resting metabolic rate.

There's a lesson there concerning the practice of quickly leaping to what might seem to be sensible conclusions. My slower second thought involved calorie intake: even mild levels of calorie restriction have measurable impacts on health in humans and on longevity in lower animals. Possibly also on longevity in humans, though that study will likely never be undertaken - if started tomorrow, by the time it was even half-way complete we'd be well into the era of rejuvenation biotechnology, making the whole exercise rather pointless.

In any case, the practice of calorie restriction does lower resting metabolic rate, and does so across a range of species: stick insects, rhesus monkeys, and humans, to pick a few. So it seems reasonable to theorize that differences in mortality seen in the study quoted above are reflections of the natural variance of calorie intake amongst the participants, and the biochemical - and existential - consequences of lower versus higher calorie diets.

The liver has the greatest capacity for regeneration amongst human organs - but there's always room for improvement. Here, cancer researchers incidentally uncover a potential mechanism to safely boost regenerative capacity: "During chronic liver damage repetitive waves of hepatocyte cell death and compensatory proliferation take place, eventually culminating in chronic liver failure and often in the development of hepatocellular carcinoma (HCC). A misregulated regenerative response to chronic liver injury may represent the base for development of HCC. Therefore, a more detailed understanding of signaling pathways involved in proliferation control of hepatocytes not only holds the great promise of informing new therapies to increase the hepatic regenerative potential but also to deduce new strategies for the treatment of HCC. We have established a unique system to perform in vivo RNAi screens to genetically dissect cellular signaling networks regulating hepatocyte proliferation during chronic liver damage. ... we identified shRNAs which showed strong enrichment during regeneration, therefore pinpointing new regulators of liver regeneration. Our top scoring candidate represents a kinase, which is accessible to pharmacological inhibition. Functional in vivo validation studies show that stable knockdown of the candidate gene by different shRNAs can significantly increase the repopulation efficiency of mouse hepatocytes and also increases the regenerative capacity of chronically damaged mouse livers. Despite the fact that some human HCCs show focal deletion of the candidate gene, a therapeutic window for regenerative therapy exists, as mice stably repopulated with shRNAs against the candidate did not develop liver tumors."

Link: http://www1.easl.eu/easl2011/program/Orals/261.htm

Type 2 diabetes is a lifestyle disease, avoidable for vast majority of people. If you overeat, become fat, and live a sedentary life then the odds are good you'll develop the condition, or at least its precursor, metabolic syndrome. The cost of this neglect of health basics is measurable: "Middle-aged adults with diabetes are much more likely to develop age-related conditions than their counterparts who don't have diabetes, according to a new study ... Adults between 51 and 70 with diabetes developed age-related ailments like cognitive impairment, incontinence, falls, dizziness, vision impairment and pain at a faster rate than those without diabetes, the study found. ... Our findings suggest that middle age adults with diabetes start to accumulate these age-related problems. Because diabetes affects multiple organ systems, it has the potential to contribute significantly to the development of a number of issues that we associate with aging ... For adults aged 51-60 with diabetes, the odds of developing new geriatric conditions were nearly double those of their counterparts who didn't have diabetes, the researchers found. By the time people with and without diabetes reach 80, the overall effects of aging and impact of other diseases start to reduce the disparities between the two groups. ... The findings suggest that adults with diabetes should be monitored for the development of these conditions beginning at a younger age than we previously thought." Though of course your odds of making it to 80 to be compared to your healthier cohorts are not as good if you're diabetic. So don't get fat, don't stay fat, and exercise sounds like good advice.

Link: http://www.eurekalert.org/pub_releases/2011-03/uomh-acd033111.php

If you can have a range of single nucleotide polymorphisms and other quirks of your DNA analyzed by mail and presented via an online service, then why not the same for the length of your telomeres?

Telomeres - the terminal caps of chromosomes - become shorter as individuals age, and there is much interest in determining what causes telomere attrition since this process may play a role in biological aging. The leading hypothesis is that telomere attrition is due to inflammation, exposure to infectious agents, and other types of oxidative stress, which damage telomeres and impair their repair mechanisms. Several lines of evidence support this hypothesis, including observational findings that people exposed to infectious diseases have shorter telomeres.

At least two nascent companies presently aim to commercialize telomere measurement technologies: Telomere Health and Life Length were recently featured in Scientific American:

"Knowing whether our telomeres are a normal length or not for a given chronological age will give us an indication of our health status and of our physiological 'age' even before diseases appear," says Maria A. Blasco, who heads the Telomeres and Telomerase Group at the Spanish National Cancer Research Center and who co-founded the company Life Length in September. Telomere research pioneer Calvin B. Harley, who co-founded Telome Health last spring with Nobel laureate Elizabeth H. Blackburn, considers telomere length "probably the best single measure of our integrated genetics, previous lifestyle and environmental exposures." Beginning as early as this spring, the companies will offer telomere-measurement tests to research centers and companies studying the role of telomeres in aging and disease; the general public may have access by the fall through doctors and laboratories, perhaps even directly.

I think that these initiatives are not so interesting in and of themselves, but should be considered as part of a powerful trend now underway. The marketplace for personal biochemical information supplied on demand, via mail and internet, will only grow as the underlying technologies become cheaper, more reliable, and possible to run at scale. One very desirable next stage in the evolution of this marketplace is to do away with the mail portion - the need to send samples in envelopes to a central processing location. The tools of analysis are becoming ever cheaper, and it won't be too many more years before it is cost-effective for most people in the developed world to produce raw data from their own biochemistries with desktop devices at home. The results will be sent over the network to be processed, analyzed, and matched against sophisticated databases owned by for-pay subscription services.

This vision will of course be fought against tooth and nail by the myriad entrenched interests in the command and control style medical systems of the Western nations - those who benefit from medical regulation at the expense of progress. These interests can't stop the internet, however, and nor can they regulate devices that connect to encrypted services outside the US. Distributed medicine, in which a great deal of the process of managing diagnosis and data collection rests with ordinary people, is the inevitable end result of falling costs in biotechnology and communication technologies. This is a good thing, and the sooner all opposed give up and go home, the better.

A recent review: "The function of adult tissue-specific stem cells declines with age, which may contribute to the physiological decline in tissue homeostasis and the increased risk of neoplasm during aging. Old stem cells can be 'rejuvenated' by environmental stimuli in some cases, raising the possibility that a subset of age-dependent stem cell changes is regulated by reversible mechanisms. Epigenetic regulators are good candidates for such mechanisms, as they provide a versatile checkpoint to mediate plastic changes in gene expression and have recently been found to control organismal longevity. Here, we review the importance of chromatin regulation in adult stem cell compartments. We particularly focus on the roles of chromatin-modifying complexes and transcription factors that directly impact chromatin in aging stem cells. Understanding the regulation of chromatin states in adult stem cells is likely to have important implications for identifying avenues to maintain the homeostatic balance between sustained function and neoplastic transformation of aging."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21441951

Another hit in the search for compounds that extend life in lower animals: "Basic Yellow 1, a dye used in neuroscience laboratories around the world to detect damaged protein in Alzheimer's disease - [also] known as Thioflavin T, (ThT) - extended lifespan in healthy nematode worms by more than 50 percent and slowed the disease process in worms bred to mimic aspects of Alzheimer's. The research, conducted at the Buck Institute for Research on Aging, could open new ways to intervene in aging and age-related disease. The study highlights a process called protein homeostasis - the ability of an organism to maintain the proper structure and balance of its proteins, which are the building blocks of life. Genetic studies have long indicated that protein homeostasis is a major contributor to longevity in complex animals. Many degenerative diseases have been linked to a breakdown in the process. ... this study points to the use of compounds to support protein homeostasis, something that ThT, did as the worms aged. ThT works as a marker of neurodegenerative diseases because it binds amyloid plaques - the toxic aggregated protein fragments associated with Alzheimer's. In the nematodes ThT's ability to not only bind, but also slow the clumping of toxic protein fragments, may be key to the compound's ability to extend lifespan ... We have been looking for compounds that slow aging for more than ten years and ThT is the best we have seen so far. But more exciting is the discovery that ThT so dramatically improves nematode models of disease-related pathology as well. ThT allows us to manipulate the aging process, it has the potential to be active in multiple disease states and it enhances the animal's innate ability to deal with changes in its proteins."

Link: http://www.eurekalert.org/pub_releases/2011-03/bifa-nss032411.php

The many types of advanced glycation endproducts, or AGEs, build up with age. These are forms of sugary gunk that glue together important components in your cellular machinery, and enough of that going on would ultimately become a fatal problem. AGE levels are probably (for most people) more of a contributory cause than principle cause of age-related degeneration, however. The other things kill you first - but it's all a matter of accumulation, and every form of unrepaired biological damage plays its part in hastening the end.

It is likely that the way in which AGEs cause issues has just as much to do with making cells act in counterproductive ways as it does with outright destruction of essential mechanisms. An important focus of research is RAGE, the cellular receptor for AGEs, which is involved in the inflammatory response. As I'm sure you know by now, chronic inflammation is very bad for you over the long term, and goes a long way towards degrading health and remaining longevity. If your body is flooded with AGEs, then one consequence is inflammation - and that in turn will cause harm over time in many different ways.

The picture of AGEs and aging is already complicated by diet - some AGE levels are very variable, and depend on what you happen to be eating - and metabolic conditions such as diabetes wherein the overall behavior of human metabolism is quite different from that of an aged but otherwise normal person. Much of the modern populace eats far too much, and far too much sugar as well, which leads to these sorts of conditions of overnutrition.

Today I noticed an open access paper that adds another layer of complexity to the picture of AGEs and aging. Bacteria produce AGEs, and RAGE and its connection to the inflammatory response may be a component part of the immune system - a mechanism that evolved long before we humans had ready access to the damaging levels and types of food we presently consume.

Advanced Glycated End Products (AGEs) are formed by non-enzymatic protein glycation and are implicated in several physiological aspects including cell aging and diseases. Recent data indicate that bacteria - although short lived - produce, metabolize and accumulate AGEs. Here we show that Escherichia coli cells secrete AGEs by the energy-dependent efflux pump systems. Moreover, we show that in the presence of these AGEs there is an upshift of pro-inflammatory cytokines by mammalian cells.

Thus, we propose that secretion of AGEs by bacteria is a novel avenue of bacterial-induced inflammation which is potentially important in the pathophysiology of bacterial infections. Moreover, the sensing of AGEs by the host cells may constitute a warning system for the presence of bacteria.

So in short, it would seem plausible that the reaction to accumulating AGEs is yet another way in which both modern overnutrition and the established course of aging act separately but combine to sabotage the evolved workings of the immune system. We already know that the immune system is formed to be very efficient in youth but structurally fails over time, so one more mechanism that follows this pattern shouldn't be too surprising.

The only good news here is that safely getting rid of AGEs should be one of the least challenging aspects of aging for the present pharmaceutical research and development community to tackle over the next few decades - as and when they get around to deciding that they should be working on that. Producing drugs, bioremediation therapies, or immune therapies to break down specific forms of unwanted chemical will soon enough be the core competency of the pharmaceutical industry.

An introductory article at h+ Magazine looks at the role of telomeres and telomerase in aging: "Several thousand studies have been published on telomeres and telomerase, which are now known to maintain genomic stability, prevent the inappropriate activation of DNA damage pathways, partially determine disease susceptibility/resistance and regulate cellular and organism-wide viability and aging. Telomerase expression [in conjunction with other genetic alterations] also extends the lifespan and reverses senescence-associated pathologies in mice. ... In humans telomere length and integrity plays a role in some diseases, disease susceptibility, aging and even in mediating the deleterious effects of long-term psychological stress. Several human genetic diseases are caused by alterations in telomerase function. For example, individuals with dyskeratosis congenita (DC) ... Many aspects of DC resemble normal aging, although at an accelerated rate. Individuals with DC are born with unusually short telomeres and not surprisingly, the expression of unmutated telomerase in DC cells corrects many of their molecular defects and lengthens their telomeres. ... Normal cellular telomerase expression is insufficient to prevent telomere shortening with each cell division and hence, telomeres shorten with aging, eventually causing age-related changes. The process is complex, and different cell types and organs show different rates of telomere shortening, although overall telomere shorten most rapidly in growing cell populations. Interestingly, high telomere stability correlates with human longevity while caloric restriction (the only known intervention that increases the [maximum] mammalian lifespan), reduces the rate of telomere shortening, although it does not increase telomerase expression. Last, malignant tumors overexpress telomerase, allowing them to grow indefinitely. One reason why most normal cells of the human body do not express high levels of telomerase might be to prevent cancer."

Link: http://hplusmagazine.com/2011/03/28/telomeres-telomerase-and-aging/

One approach to developing targeted therapies is to co-opt existing biological structures, such as cells and bacteria: "Scientists have developed bacteria that serve as mobile pharmaceutical factories, both producing disease-fighting substances and delivering the potentially life-saving cargo to diseased areas of the body. ... [Researchers] chose the term 'bacterial dirigibles' because the modified bacteria actually have the fat-cigar look of blimps and zeppelins, those famous airships of yesteryear. ... We're building a platform that could allow bacterial dirigibles to be the next-generation disease fighters. ... traditional genetic engineering reprograms bacteria so that they produce antibiotics, insulin, and other medicines and materials. The bacteria grow in nutrient solutions in enormous stainless steel vats in factories. They release antibiotics or insulin into vats, and technicians harvest the medicine for processing and eventual use in people. The bacterial dirigible approach takes bioengineering a step further. Scientists genetically modify bacteria to produce a medicine or another disease-fighting substance. Then, however, they give the bacteria a biochemical delivery address, which is the locale of the disease. Swallowed or injected into the body, the bacteria travel to the diseased tissue and start producing substances to fight the disease. ... We have created a genetic circuit that endows E. coli with targeting, sensing and switching capabilities. ... The 'targeting' molecule is attached to the outer surface of the bacteria. It gives the bacteria an ability to 'hone in' on specific cells and attach to them - in this instance, the intestinal cells where other strains of E. coli cause food poisoning symptoms. Inside the bacteria is a gene segment that acts as 'nanofactory.' It uses the bacteria's natural cellular machinery to make drugs, such as those that can fight bacterial infections, viruses, and cancer. The nanofactory also could produce signaling molecules that enable the dirigible to communicate with natural bacteria at the site of an infection. Some bacteria engage in a biochemical chit-chat, termed 'quorum sensing,' in which they coordinate the activities needed to establish an infection. Bacteria dirigibles could produce their own signaling molecules that disrupt quorum sensing."

Link: http://www.sciencedaily.com/releases/2011/03/110329134120.htm