No great surprise here, given that calorie restriction in mammals slows almost all measures of aging investigated to date: "Long-term caloric restriction (CR) has been reported to extend the life spans, delay the onset and decrease the incidence of a broad spectrum of age-associated diseases. However, its effect on rat explorative behaviour is still unclear. In the present study, a number of behavioural measures were continuously monitored in 3-, 12-, 24-25-, 28-29- and 35-44-month-old male Wistar rats that were fed either ad libitum or placed on a caloric restricted diet. A gradual decline in locomotor activity of the ad libitum fed rats has been determined during aging in the open field test. In the CR groups, 3-month-old rats exhibited lower levels of exploratory behavior, compared to rats on the control diet. 24-25-month-old CR rats exhibited higher levels of exploratory behaviour, compared to ad libitum fed animals of the same age. Chronic dietary restriction nullified the age-dependent decline in locomotor activity and explorative behaviour of rats."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22590739

It is taken as a tenet around here that involuntary death is a bad thing, and the process of getting to be dead despite your own wishes on the matter is arguably worse - it involves a great deal of ongoing suffering and pain as the body progressively fails. Greatly diminishing the incidence of death is one aim of the longevity science movement, achieved through the elimination of degenerative aging, the greatest cause of death. Can we say why being dead is bad, however? That is supposedly a harder job than declaring suffering to be bad and worthy of amelioration - though most philosophers fail to consider the economic costs of destruction, and in the end it should all come down to "I've decided I don't like it, and so I'll work towards doing something about it through progress in medical science." Reasons beyond personal choice are unnecessary, but here is a brief tour of some of the philosophy of death and nonexistence: "We all believe that death is bad. But why is death bad? In thinking about this question, I am simply going to assume that the death of my body is the end of my existence as a person. But if death is my end, how can it be bad for me to die? After all, once I'm dead, I don't exist. If I don't exist, how can being dead be bad for me? ... there's a puzzle raised by the Roman philosopher Lucretius, who thought it a mistake to find the prospect of my death upsetting. Yes, as the deprivation account points out, after death we can't enjoy life's pleasures. But wait a minute, says Lucretius. The time after I die isn't the only period during which I won't exist. What about the period before my birth? If nonexistence is so bad, shouldn't I be upset by the eternity of nonexistence before I was born? But that's silly, right? Nobody is upset about that. So, he concludes, it doesn't make any sense to be upset about the eternity of nonexistence after you die, either. It isn't clear how best to reply to Lucretius. One option, presumably, is to agree that we really do need to treat those two eternities of nonexistence on a par, but to insist that our prebirth nonexistence was worse than we thought. Alternatively, we might insist that there's an asymmetry that explains why we should care about the one period but not the other. But what is that difference? Perhaps this: When I die, I have lost my life. In contrast, during the eternity before my birth, although I'm not alive, I have not lost anything. You can't lose what you never had. So what's worse about death is the loss."

Link: http://chronicle.com/article/Is-Death-Bad-for-You-/131818/

Much of the mainstream aging research community has little interest in building therapies for aging, being focused on investigation only - though, fortunately, this situation is changing rapidly these days. The past stigma associated with public discussion of treating and ultimately preventing aging has largely evaporated within the scientific world.

Among those researchers who are interested in therapies for aging, most are focused on the slow boat of metabolic alteration: work that will have comparatively little pay-off even if successful, but which fits more readily into established research programs and the prejudices of research funding institutions.

The principal downside of metabolic alteration strategies, from my point of view, is that even if successful they cannot produce any significant longevity benefit in a person already old. All it can do is slow down aging by a modest amount - which isn't terribly useful those already aged and damaged. Even under the most optimistic estimates it will take another twenty years and many billions of dollars to see the evolution of a robust market in commercially available human metabolic enhancements to slow aging. It is a challenging field of research, and progress to date has been slow even in this era of rapid advances in biotechnology.

There is another disadvantage, which is illustrated by the different degrees to which life span is enhanced by similar strategies applied in mice versus humans. It is taken for granted in the literature, and thus probably not emphasized to the degree it should be, that an extension of life by 50% in mice based on some genetic or metabolic alteration - such as calorie restriction or growth hormone knockout - is probably not going to map to a similar extension of life in humans. If humans could achieve that sort of life extension through simply eating well and eating less or being growth hormone mutants, we'd have known about it by now. Consider Laron dwarfism, for example, or the generation after generation of practitioners of various degrees of calorie restriction that exist in many cultures.

With an eye to this second disadvantage, I'll point out an open access paper that considers the evolution of aging from the point of view of the maintenance gap. This is the gap between the cost of maintenance required to keep an organism from aging and the resources actually devoted to maintenance - both of which are subject to evolutionary selection pressures, which operate to maximize success in genetic propagation rather than the comfort or longevity of individual members of a species. The paper was published last year, but showed up in a recent issue of Biogerontology.

The maintenance gap: a new theoretical perspective on the evolution of aging

One of the prevailing theories of aging, the disposable soma theory, views aging as the result of the accumulation of damage through imperfect maintenance. Aging, then, is explained from an evolutionary perspective by asserting that this lack of maintenance exists because the required resources are better invested in reproduction. However, the amount of maintenance necessary to prevent aging, 'maintenance requirement' has so far been largely neglected and has certainly not been considered from an evolutionary perspective. To our knowledge we are the first to do so, and arrive at the conclusion that all maintenance requirement needs an evolutionary explanation.

Increases in maintenance requirement can only be selected for if these are linked with either higher fecundity or better capabilities to cope with environmental challenges to the integrity of the organism. Several observations are suggestive of the latter kind of trade-off, the existence of which leads to the inevitable conclusion that the level of maintenance requirement is in principle unbound. Even the allocation of all available resources to maintenance could be unable to stop aging in some organisms.

This has major implications for our understanding of the aging process on both the evolutionary and the mechanistic level. It means that the expected effect of measures to reallocate resources to maintenance from reproduction may be small in some species. We need to have an idea of how much maintenance is necessary in the first place. Our explorations of how natural selection is expected to act on the maintenance requirement provides the first step in understanding this.

The point to take away from this argument is that we should expect to find a broad variation between species in their response to similar forms of metabolic and genetic alteration aimed at extending life span. So far, that is what is seen, with we humans having the short end of the stick - though obviously there is an ocean of data yet to be obtained on this topic. On the whole, though, it seems like one more slowly building argument for the research community to focus on repair-based strategies for treating aging: build biotechnologies that are explicitly designed to repair forms of biological damage that existing repair systems either cannot handle or handle too slowly. SENS is the most obvious example, though I expect other, competing repair-focused visions to emerge in the years ahead as the SENS Foundation obtains further scientific support and promising research results.

Insulin-like growth factor 1 (IGF-1) is one of the more studied areas of known overlap between metabolism and longevity, but given the innate complexity of biology in mammals there is always some debate over the degree to which IGF-1-related mechanisms are actually determinants of life span, or even correlated with life span. Here is a study in sheep, not the usual species in investigations of the biochemistry of aging: "Longevity in livestock is a valuable trait. When productive animals live longer fewer replacement animals need to be raised. However, selection for longevity is not commonly the focus of breeding programs as direct selection for long-lived breeding stock is virtually impossible until late in the animal's reproductive life. Additionally the underlying genetic factors or genes associated with longevity are either not known, or not well understood. In humans, there is evidence that insulin-like growth factor 1 receptor (IGF1R) is involved in longevity. Polymorphism in the IGF1R gene (IGF1R) has been associated with longevity in a number of species. Recently, 3 alleles of ovine IGF1R were identified, but no analysis of the effect of IGF1R variation on sheep longevity has been reported. In this study, associations between ovine IGF1R variation, longevity and fertility were investigated [in] 1716 New Zealand sheep belonging to 6 breeds and 36 flocks. ... Ovine IGF1R C was associated with age when adjusting for flock [and] a weak negative [correlation] between fertility and longevity traits was observed."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22585783

Researchers continue to investigate why the ApoE4 gene variant is associated with Alzheimer's disease: "A well-known genetic risk factor for Alzheimer's disease triggers a cascade of signaling that ultimately results in leaky blood vessels in the brain, allowing toxic substances to pour into brain tissue in large amounts, scientists report ... a gene called ApoE4 makes people more prone to developing Alzheimer's. People who carry two copies of the gene have roughly eight to 10 times the risk of getting Alzheimer's disease than people who do not. [Scientists] found that ApoE4 works through cyclophilin A, a well-known bad actor in the cardiovascular system, causing inflammation in atherosclerosis and other conditions. The team found that cyclophilin A opens the gates to the brain assault seen in Alzheimer's. ... In the presence of ApoE4, increased cyclophilin A causes a breakdown of the cells lining the blood vessels in Alzheimer's disease in the same way it does in cardiovascular disease or abdominal aneurysm ... In studies of mice, the team found that mice carrying the ApoE4 gene had five times as much cyclophilin A compared to other mice in cells known as pericytes, which are crucial to maintaining the integrity of the blood-brain barrier. Blood vessels died, blood did not flow as completely through the brain as it did in other mice, and harmful substances like thrombin, fibrin, and hemosiderin, entered the brain tissue. When the team blocked the action of cyclophilin A, either by knocking out its gene or by using the drug cyclosporine A to inhibit it, the damage in the mice was reversed. Blood flow resumed to normal, and unhealthy leakage of toxic substances from the blood vessels into the brain was slashed by 80 percent."

Link: http://www.urmc.rochester.edu/news/story/index.cfm?id=3512

Naked mole-rats are becoming very well studied. Researchers are attempting to find the root causes of cancer immunity and exceptional longevity in this species, with an eye to creating beneficial medical biotechnologies for humans. Fight Aging! has seen a couple of items on naked mole-rats already this month, which is illustrative of the present pace:

• More on NRG-1 in Naked Mole-Rats
• Enhanced Proteasome Activity in Naked Mole Rats

Present theories are varied, but on the longevity side of the house the consensus appears to lean towards an increased resistance to forms of cellular membrane damage - naked mole rat membranes are built of a more resilient mix of proteins than those of comparable species. This is known as the membrane pacemaker hypothesis of aging:

The membrane pacemaker hypothesis predicts that long-living species will have more peroxidation-resistant membrane lipids than shorter living species. ... Resistance to oxidative damage is of particular importance in mitochondria, cellular power plants that progressive damage themselves with the reactive oxygen species they produce as a byproduct of their operation - and that gives rise to a chain of further biochemical damage that spreads throughout the body, growing ever more harmful as you age. Less damage to the mitochondria should mean slower aging, and thus more resistant mitochondrial membranes should also mean slower aging.

Continuing the naked mole-rat theme for May, here is another just-published open access paper on the resilience of naked mole-rat biology (abstract, and full article):

Studies comparing similar-sized species with disparate longevity may elucidate novel mechanisms that abrogate aging and prolong good health. We focus on the longest living rodent, the naked mole-rat. This mouse-sized mammal lives ∼8 times longer than do mice and, despite high levels of oxidative damage evident at a young age, it is not only very resistant to [cancer] but also shows minimal decline in age-associated physiological traits.

...

Like other experimental animal models of lifespan extension, naked mole-rat fibroblasts are extremely tolerant of a broad spectrum of cytotoxins including heat, heavy metals, DNA-damaging agents and xenobiotics, showing [median lethal dose] values between 2- and 20-fold greater than those of fibroblasts of shorter-lived mice. Our new data reveal that naked mole-rat fibroblasts stop proliferating even at low doses of toxin whereas those mouse fibroblasts that survive treatment rapidly re-enter the cell cycle and may proliferate with DNA damage. Naked mole-rat fibroblasts also show significantly higher constitutive levels of both p53 and Nrf2 protein levels and activity, and this increases even further in response to toxins.

...

Enhanced cell signaling via p53 and Nrf2 protects cells against proliferating with damage, augments clearance of damaged proteins and organelles and facilitates the maintenance of both genomic and protein integrity. These pathways collectively regulate a myriad of mechanisms which may contribute to the attenuated aging profile and sustained healthspan of the naked mole-rat. Understanding how these are regulated may be also integral to sustaining positive human healthspan well into old age and may elucidate novel therapeutics for delaying the onset and progression of physiological declines that characterize the aging process.

You might also look back a few years at other research into the role of Nrf2 in determining species longevity. The details can be a little overwhelming, but the big picture remains one of damage at the level of cells and protein machinery: less damage and more resilience to damage means a longer life span.

Researchers here analyze the proteome of the hypothalamus and argue for an important role in coordinating bodily responses to ongoing changes caused by aging: "The aging process affects every tissue in the body and represents one of the most complicated and highly integrated inevitable physiological entities. The maintenance of good health during the aging process likely relies upon the coherent regulation of hormonal and neuronal communication between the central nervous system and the periphery. Evidence has demonstrated that the optimal regulation of energy usage in both these systems facilitates healthy aging. However, the proteomic effects of aging in regions of the brain vital for integrating energy balance and neuronal activity are not well understood. The hypothalamus is one of the main structures in the body responsible for sustaining an efficient interaction between energy balance and neurological activity. Therefore, a greater understanding of the effects of aging in the hypothalamus may reveal important aspects of overall organismal aging and may potentially reveal the most crucial protein factors supporting this vital signaling integration. In this study, we examined alterations in protein expression in the hypothalami of young, middle-aged, and old rats. ... Based upon our rigorous analyses, we show that endogenous physiological responses to aging may be strongly orchestrated by the expression level of the GIT2 protein. The relevance of the hypothalamic expression level of this protein to the aging process in both neuronal and energy-controlling tissues reinforces the importance of this organ in the potential future development of targeted pharmacotherapeutics designed to interdict a multitude of age-related disorders."

Link: http://dx.doi.org/10.1371/journal.pone.0036975

A possible method of boosting muscle repair, and thus treating muscle wasting conditions - such as the sarcopenia that attends aging: "a lipid signaling molecule called sphingosine-1-phosphate or 'S1P' can trigger an inflammatory response that stimulates the muscle stem cells to proliferate and assist in muscle repair. ... mdx mice, which have a disease similar to Duchenne Muscular Dystrophy, exhibit a deficiency of S1P, [and] boosting their S1P levels improves muscle regeneration ... The ability of muscles to regenerate themselves is attributed to the presence of a form of adult stem cells called 'satellite cells' that are essential for muscle repair. Normally, satellite cells lie quietly at the periphery of the muscle fiber and do not grow, move or become activated. However, after muscle injury, these stem cells 'wake up' through unclear mechanisms and fuse with the injured muscle, stimulating a complicated process that results in the rebuilding of a healthy muscle fiber. S1P is a lipid signaling molecule that controls the movement and proliferation of many human cell types. ... S1P is able to 'wake up' the stem cells at the time of injury. It involves the ability of S1P to activate S1P receptor 2, one of its five cell surface receptors, leading to downstream activation of an inflammatory pathway controlled by a transcription factor called STAT3. [This results] in changes in gene expression that cause the satellite cell to leave its 'sleeping' state and start to proliferate and assist in muscle repair. ... If these findings are also found to be true in humans with Duchenne Muscular Dystrophy, it may be possible to use similar approaches to boost S1P levels in order to improve satellite cell function and muscle regeneration in patients with the disease. Drugs that block S1P metabolism and boost S1P levels are now being tested for the treatment of other human diseases including rheumatoid arthritis. If these studies prove to be relevant in Duchenne patients, it may be possible to use the same drugs to improve muscle regeneration in these patients. Alternatively, new agents that can specifically activate S1P receptor 2 could also be beneficial in recruiting satellite cells and improving muscle regeneration in muscular dystrophy and potentially other diseases of muscle."

Link: http://www.sciencedaily.com/releases/2012/05/120515070307.htm

You might recall that late last year I pointed out a large Japanese longitudinal study on incidental moderate exercise and lifetime medical costs:

The authors followed up 27,738 participants aged 40-79 years and prospectively collected data on their medical expenditure and survival covering a 13-year-period. ... The present results indicate that the multiadjusted lifetime medical expenditure from the age of 40 years for those who walked ≥1 h per day was significantly lower by 7.6% in men and non-significantly lower by 2.7% in women than for those who walked <1 h per day. This decrease in lifetime medical expenditure was observed in spite of a longer life expectancy (1.38 years for men and 1.16 years for women) among those who walked ≥1 h per day.

In another, more open access recent paper, the same authors have crunched the numbers for variations in weight among study participants. The story is much the same, as one would expect:

Although four previous studies have examined the association between obesity and lifetime medical expenditure, the results were inconsistent. ... We therefore conducted a 13-year prospective observation of 41,965 Japanese adults aged 40-79 years living in the community, which accrued 392,860 person-years. We examined the association between BMI and lifetime medical expenditure, based on individual medical expenditure and life table analysis. We collected data for survival and all medical care utilisation and costs, excluding home care services provided home health aides, nursing home care and preventive health services in participants of this cohort study.

...

In spite of their short life expectancy, obese men and women had approximately 14.7% and 21.6% higher lifetime medical expenditure in comparison with normal weight participants, respectively.

Don't get fat, don't stay fat, and don't be a couch potato. Thus speaks the weight of evidence - but then we all knew that, right? Being unhealthy has definitive material costs in the long term: years of life shaved off, the rot of your body and mind, and the monetary cost of medical services you would otherwise not have needed. There are plenty of people in this world, far too many, who don't presently have the luxury of choice when it comes to being healthy: the genetically impaired, the immune-damaged, the infected, the wounded. Why fritter away your choice for the sake of eating and laziness? It is almost a gesture of contempt.

The media and public at large have been trained to think of medicine, and especially longevity-related medicine, in terms of pills - things you can consume, colorful drug capsules produced in the old-style fashion by Big Pharma. This is somewhat ridiculous, and leads to a focus on the entirely the wrong branches of research, those unlikely to deliver meaningful healthy life extension. The future of rejuvenation biotechnology involves gene therapies, infusions of bacterial enzymes, and so forth; for the foreseeable future little of that will be stuff that you stick into your mouth. Calling these medicines drugs rather than procedures cheapens the complexity of what is being designed and developed. Nonetheless, the oral fixation in regard to public perceptions of medicine continues, fed by the lazy press and the self-interested supplement industry. Here is an example of that sort of headlining: "But imagine if there were a drug that would slow down the aging process itself, a drug that didn't just treat a single disease but instead targeted multiple diseases of old age at once? It may sound far-fetched, but that's precisely what longevity scientists are working hard to produce. ... It's not just that we're trying to make people live longer; we're trying to make people live healthier. This is an exciting time for research. ... Indeed, top-notch research labs are rolling out studies at a rapid rate, and a growing chorus of experts believe the advances being made will ultimately lead to a crop of drugs capable of extending healthy lifespans. Signs of progress are abundant in medical journals. ... [researchers] published results showing they could markedly delay the onset of age-related diseases in mice by killing off the rodents' senescent cells. Senescent cells have stopped dividing and accumulate as organisms age. Though seemingly dormant, they're not: Just as old cars in junkyards can leak oil for years, they emit harmful substances that appear to fuel many of the diseases that strike older people. ... And it's not just senescence research that is stoking excitement. Another team of scientists [has] managed to control the aging process by targeting specialized structures at the tips of chromosomes called telomeres. ... Other scientists have found that feeding aging mice rapamycin - an immunosuppressant that's used to prevent organ rejection after transplants - can extend the lifespan of mice significantly."

Link: http://health.usnews.com/health-news/articles/2012/05/14/the-hunt-for-an-anti-aging-pill-is-on

Calorie restriction extends healthy life span, and that seems to largely work through the level of methionine in the diet, though minimizing visceral fat tissue looks to be an important effect as well: "It is known that a global decrease in food ingestion (dietary restriction, DR) lowers mitochondrial ROS generation (mitROS) and oxidative stress in young immature rats. This seems to be caused by the decreased methionine ingestion of DR animals. This is interesting since isocaloric methionine restriction in the diet (MetR) also increases, like DR, rodent maximum longevity. However, it is not known if old rats maintain the capacity to lower mitROS generation and oxidative stress in response to MetR similarly to young immature animals, and whether MetR implemented at old age can reverse aging-related variations in oxidative stress. In this investigation the effects of aging and 7 weeks of MetR were investigated in liver mitochondria of Wistar rats. MetR implemented at old age decreased mitROS generation, percent free radical leak at the respiratory chain and mtDNA oxidative damage without changing oxygen consumption. Protein oxidation, lipoxidation and glycoxidation increased with age, and MetR in old rats partially or totally reversed these age-related increases. ... In conclusion, treating old rats with isocaloric short-term MetR lowers mitROS production and free radical leak and oxidative damage to mtDNA, and reverses aging-related increases in protein modification. Aged rats maintain the capacity to lower mitochondrial ROS generation and oxidative stress in response to a short-term exposure to restriction of a single dietary substance: methionine."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22580750

A few years ago, a Spanish research team created transgenic mice that lived significantly longer than normal by combining increased p53 with increased telomerase. p53 is a cancer suppressor that under usual circumstances reduces the ability of stem cells to replace worn cells in aging tissue - less cell proliferation means a lower chance of cancer over time, but also faster aging as the tissues of the body wear and fail more readily. More telomerase, on the other hand, achieves the opposite end: dynamic, longer lasting cells that also produce way more cancers in the course of their more energetic operations. This, in any case, is the consensus view of how these elements work in the biochemistry of mammals:

The standard reading is that the "Super p53" mice are getting less cancer, but are having their [life spans] restrained by lack of tissue replenishment due to stem cell loss, while the telomerase transgenics are on the opposite horn of the same dilemma. It seems at least possible that if one overlaid the strong cancer resistance conferred by the former, with the increase in stem cell mobilization and proliferative capacity of the latter, you'd wind up with a long-lived, slow-aging mouse.

I should note in passing that it is possible through clever techniques to have enhanced p53 provide both a cancer and longevity benefit in and of itself. But in the case of the Spanish research team, their work is more simply a case of balancing one mixed benefit with the opposite mixed benefit - and coming out ahead of the game. The researchers recently published results for the next stage of their research program: taking the modifications that had been transgenic to date and instead applying them as gene therapies to adult mice. This is a step on the road to building some form of beneficial medical technology for humans:

CNIO scientists successfully test the first gene therapy against aging-associated decline:

Mice treated at the age of one lived longer by 24% on average, and those treated at the age of two, by 13%. The therapy, furthermore, produced an appreciable improvement in the animals' health, delaying the onset of age-related diseases - like osteoporosis and insulin resistance - and achieving improved readings on ageing indicators like neuromuscular coordination.

The gene therapy utilised consisted of treating the animals with a DNA-modified virus, the viral genes having been replaced by those of the telomerase enzyme, with a key role in ageing. Telomerase repairs the extremes of chromosomes, known as telomeres, and in doing so slows the cell's and therefore the body's biological clock. When the animal is infected, the virus acts as a vehicle depositing the telomerase gene in the cells.

...

In 2007, Blasco's group proved that it was feasible to prolong the lives of transgenic mice, whose genome had been permanently altered at the embryonic stage, by causing their cells to express telomerase and, also, extra copies of cancer-resistant genes. These animals live 40% longer than is normal and do not develop cancer. The mice subjected to the gene therapy now under test are likewise free of cancer. Researchers believe this is because the therapy begins when the animals are adult so do not have time to accumulate sufficient number of aberrant divisions for tumours to appear.

...

As Blasco says, "ageing is not currently regarded as a disease, but researchers tend increasingly to view it as the common origin of conditions like insulin resistance or cardiovascular disease, whose incidence rises with age. In treating cell ageing, we could prevent these diseases".

You'll have to wait for the paper to show up at the EMBO Molecular Medicine website to get more details on the lifespan data, degree to which cancer is removed from the picture, and what type of mouse is being used here - e.g. are they using the transgenic enhanced p53 mouse as a baseline? That shouldn't take too long, and it is an open access publication so we'll all have a chance to read the details.

As an aside, aging defined as a disease is a topic that crops up frequently - but only because of the structure of medical regulation. Regulators in the US, for example, will only approve medical technologies for named, defined diseases. Aging is not on their list, but the problem is not that fact, but rather that a list of what is permitted and an organization to enforce it even exists in the first place.

The employees and appointees of the US Food and Drug Administration have caused an incredible destruction of value and progress over the time that the agency has existed. Their regulatory policies become ever more onerous with each passing year, as unaccountable bureaucrats follow their incentives: nothing good can happen to their careers as a result of approving new technologies, and nothing bad tends to happen to their careers as a result of making it really, really hard to bring new medicine to the clinic. So of course you wind up with an organization whose members collectively pay nothing more than lip service to their declared mission, while working to make sure that medicine stays moribund in a slow-motion stasis.

Bone morphogenetic protein 2 (BMP-2) has been used to spur healing in regenerative medicine research in past years. Here researchers are investigating its use in bone regrowth: scientists are "concentrating on the creation of new bone tissue with the aid of a biomolecule called BMP-2, which is a protein that makes bones grow. The problem with BMP-2 is that it breaks down in the body in just a few minutes. ... What's new, and what I show in my dissertation, is that by having a gel-like substance carry the protein, a so-called hydrogel, you can control both how and where the new bone is to grow ... This hydrogel can be injected and is moreover made from a type of sugar (hyaluronic acid). It occurs naturally in the body in humans and animals and is otherwise used in cosmetic products for treating wrinkles. This offers major advantages. ... On the one hand, you avoid open surgery and the risk of complications and infections that entails, and, on the other hand, there is no risk that the body will reject it. ... Applications in healthcare include both healing complicated bone fractures and growing bone tissue where there is too little or none at all. This involves defects following bone fractures and cancer or when the jawbone is too weak to support a tooth implant. Clinical testing is already underway. ... The tests show that it's working well, but the problem we need to solve is how to determine the optimal dosage of the protein. Otherwise inflammations can occur in surrounding tissue."

Link: http://medicalxpress.com/news/2012-05-smart-material-bone.html

Researches make an incremental step forward in understanding the root causes of rheumatoid arthritis: "Untangling the root cause of rheumatoid arthritis has been a difficult task for immunologists, as decades of research has pointed to multiple culprits in our immune system, with contradictory lines of evidence. Now, [researchers] announce that it takes a diverse array of regulatory T cells (a specialized subset of white blood cells) to prevent the immune system from generating the tissue-specific inflammation that is a hallmark of the disease. Regulatory T cell diversity, the researchers say, provides a cumulative protective effect against rheumatoid arthritis. ... regulatory T cells (or Tregs) are a necessary component to either restrain (or encourage) the immune system's inflammatory response. Tregs are activated as molecules on their surface membranes called T cell receptors interact with 'friendly' or 'self' molecules - a way for the immune system to recognize friend from foe. Mismanagement of these Tregs, which normally serve to restrain the immune system from over-reacting to healthy tissue, could then lead to runaway inflammation. In this study, the researchers sought to examine how T cell receptors affect the ability of Tregs to suppress arthritis in a mouse that had been bred to express a 'self' molecule that drives arthritis. They showed that an array of Tregs given to the mice effectively stops arthritis. Unexpectedly, however, Tregs that are specific for the surrogate 'self' molecule do not prevent arthritis. ... We find that [a] diverse repertoire of Tregs are very effective. All of these Tregs, together, influence other components of the immune system which serves to slow down the inflammatory process that causes RA."

Link: http://www.sciencedaily.com/releases/2012/05/120508142626.htm

Metformin is a drug that shows up in discussion here every so often. It is thought to be a calorie restriction mimetic, recapitulating some of the metabolic changes caused by the practice of calorie restriction. Its effects on life span in laboratory animals are up for debate and further accumulation of evidence - the results are on balance more promising than the generally dismal situation for resveratrol, but far less evidently beneficial than rapamycin. Like rapamycin, metformin isn't something you'd want to take as though it were candy, even if the regulators stood back to make that possible, as the side effects are not pleasant and potentially serious.

I should note as an aside that while ongoing research into the effects of old-school drugs of this nature is certainly interesting, it doesn't really present a path to significantly enhanced health and longevity. It is a pity that such research continues to receive the lion's share of funding, given that the best case outcome is an increase in our knowledge of human metabolism, not meaningful longevity therapies. Even if the completely beneficial mechanism of action is split out from the drug's actions - as seems to be underway for rapamycin - the end results will still only be a very modest slowing of aging. You could do better by exercising, or practicing calorie restriction.

For the billions in funding poured into these drug investigation programs, there should be a better grail at the end of the road - such as that offered by the SENS vision of rejuvenation biotechnology. Targeted repair of the biological damage of aging is a far, far better strategy than gently slowing the pace of damage accumulation through old-style drug discovery programs. This is a biotechnology revolution: time to start acting like it.

Anyway, aside done, let me point you to a recent open access review on metformin: the interesting work that won't really be in any way relevant to the future of your longevity, but which I'll wager has raised more funding as an object of study than the entire present extant SENS program and directly related scientific studies:

Metformin, an oral anti-diabetic drug, is being considered increasingly for treatment and prevention of cancer, obesity as well as for the extension of healthy lifespan. Gradually accumulating discrepancies about its effect on cancer and obesity can be explained by the shortage of randomized clinical trials, differences between control groups (reference points), gender- and age-associated effects and pharmacogenetic factors. Studies of the potential antiaging effects of antidiabetic biguanides, such as metformin, are still experimental for obvious reasons and their results are currently ambiguous.

...

The wave of interest, with periodical decays and increasing surges, was associated with the attempts to use antidiabetic biguanides [such as metformin] to control body weight and tumor growth. Another facet of the situation is that almost 45 years ago these drugs were suggested to promote longevity. Over the last years, the expanding bodies of relevant evidence, which mainly related to metformin, started to merge and occupy increasing place in current literature. The objective of the present essay is to attract more attention to accumulating inconsistencies. The first two sections of the essay, which are related to obesity and cancer, are based mostly on clinical data. The third section, which is related to aging or, rather, antiaging, is based predominately on experimental evidence obtained in rodents. Clearly, obesity and cancer have numerous interrelationships with aging, [however], we will separate these aspects for the sake of clarity in discussing the relevant effects of metformin.

See what you think; it makes for an interesting read - and includes a table of results from a number of life span studies that are, indeed, all over the map. It somewhat reinforces the point that unambiguous success in extending healthy life is not going to arrive from this quarter. Think SENS, not drug discovery - what will come from the drug discovery clade is a slow, grinding, and expensive cataloging of the fine details of genetics, metabolism, and aging in mammals.