Silencing FL2 Accelerates Wound Healing
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A reliable means to safely accelerate natural healing would be a generally useful technology for all stages of life, but it is the elderly who suffer the most due to slower and more dysfunctional healing of even minor injuries:

An experimental therapy cut in half the time it takes to heal wounds compared to no treatment at all. Researchers discovered that an enzyme called fidgetin-like 2 (FL2) puts the brakes on skin cells as they migrate towards wounds to heal them. They reasoned that the healing cells could reach their destination faster if their levels of FL2 could be reduced. So they developed a drug that inactivates the gene that makes FL2 and then put the drug in tiny gel capsules called nanoparticles and applied the nanoparticles to wounds on mice. The treated wounds healed much faster than untreated wounds. "We envision that our nanoparticle therapy could be used to speed the healing of all sorts of wounds, including everyday cuts and burns, surgical incisions, and chronic skin ulcers, which are a particular problem in the elderly and people with diabetes."

The wound-healing therapy uses molecules of silencing RNA (siRNAs) specific for FL2. The siRNAs act to silence genes. They do so by binding to a gene's messenger RNA (mRNA), preventing the mRNA from being translated into proteins (in this case, the enzyme FL2). However, siRNAs on their own won't be effectively taken up by cells, particularly inside a living organism. They will be quickly degraded unless they are put into some kind of delivery vehicle, and so the researchers collaborated with another group who had developed nanoparticles that protect molecules such as siRNA from being degraded as they ferry the molecules to their intended targets. The nanoparticles with their siRNA cargoes were then tested by topically applying them to mice with either skin excisions or burns. In both cases, the wounds closed more than twice as fast as in untreated controls. "Not only did the cells move into the wounds faster, but they knew what to do when they got there. We saw normal, well-orchestrated regeneration of tissue, including hair follicles and the skin's supportive collagen network."

Link: http://www.eurekalert.org/pub_releases/2015-03/aeco-nnt032615.php

Life Extension via Calorie Restriction Requires FOXO3
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The forkhead box (FOX) family of proteins includes members such as FOXO3 that seem to be important in longevity and regeneration in a variety of very different species. Here researchers show that FOXO3 is required for the additional longevity created by the practice of calorie restriction:

Forkhead box O (Foxo) transcription factors may be involved in the salutary effect of dietary restriction (DR). This study examined the role of Foxo3 in lifespan extension and cancer suppression in DR mice. Wild-type (WT) and Foxo3-knockout heterozygous (+/-) and homozygous (-/-) mice were subjected to a 30% DR regimen initiated at 12 weeks of age. Control mice were fed ad libitum (AL) throughout the study. The food intake by Foxo3+/- and Foxo3-/- mice was similar to those by WT mice under the AL condition, and thus, the daily allotments for each DR group were almost the same during the lifespan study. The average body weights of WT, Foxo3+/-, and Foxo3-/- mice were also similar under AL and DR conditions.

In contrast to WT mice, DR did not significantly extend the lifespan of Foxo3+/- or Foxo3-/- mice. However, DR reduced the prevalence of tumors at death in WT, Foxo3+/-, and Foxo3-/- mice. These results indicate the necessity of Foxo3 for lifespan extension but not cancer suppression by DR. The findings in Foxo3+/- mice contrast with those in Foxo1+/- mice reported previously by our laboratory and suggest differential regulation of cancer and lifespan by DR via Foxo1 and Foxo3.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12340/

Increased FGF21 May Spur Greater Liver Regeneration
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Fibroblast growth factor 21 (FGF21) has been the focus of some interest in the research community in recent years. Raised levels of FGF21 have been shown to notably increase mean life span in mice, most likely primarily by interfering in mechanisms related to growth hormone. After more than a decade of earnest research into the mechanisms of aging and longevity in mammals, the longest lived mice are still those in which growth hormone or its receptor are disrupted, a comparatively early discovery in the field. There are numerous ways to influence these biochemical pathways, and altering levels of FGF21 is one of them.

Some researchers classify manipulation of FGF21 as a calorie restriction mimetic treatment given that mice engineered to have more FGF21 show some of the same changes as produced by the practice of calorie restriction. In the other direction, calorie restriction increases circulating FGF21 levels. Restricting only dietary methionine intake also seems to increase FGF21 levels at the same time as it extends healthy life spans in mice. However, other studies have shown that FGF21 isn't required for the production of these benefits. It is probably best to think of any area of metabolism as a machine with many interconnected levers and dials. You can achieve similar results by changing different settings, but not all of the options or the machinery are required for any given outcome, and it is far from straightforward to determine what is actually happening under the hood.

Here researchers find another interesting role for FGF21, picking up on differences in the efficiency of liver regeneration when comparing mice and humans. The first results are a little indirect, but further research should confirm whether or not the observed outcome will hold up in a medically useful context.

FGF21 boosts regenerative ability in mice carrying human PPARα protein

Researchers have illuminated an important distinction between mice and humans: how human livers heal. The difference centers on a protein called PPARα, which activates liver regeneration. Normally, mouse PPARα is far more active and efficient than the human form, allowing mice to quickly regenerate damaged livers. However, the research shows that protein fibroblast growth factor 21 (FGF21) can boost the regenerative effects of human PPARα. The findings suggest that the molecule could offer significant therapeutic benefits for patients who have had a liver transplant or suffer from liver disease. "We found that FGF21 is a good rescuing molecule that facilitates liver regeneration and perhaps tissue repair. Our data suggests that FGF21 could help with liver regeneration, either after removal or after damage caused by alcohol or a virus."

Even after having two-thirds of their livers removed, normal mice regained their original liver mass within seven to 10 days. By contrast, mice with human PPARα never fully regenerated, even after three months. However, by increasing FGF21, the team boosted human PPARα's ability to regenerate and heal mouse livers. While mouse PPARα has regenerative advantages over the human version, there is also a downside, as this ability can lead to cancer. Human PPARα does not cause cancer; however, as noted, it cannot match the mouse protein's regenerative capacity. This trade-off provides a number of advantages on the human side. For example, several popular drugs target PPARα to treat high cholesterol and triglycerides. Still, in the right context, a more active human PPARα could be a great boon for patients with liver conditions. Using FGF21 to boost this regenerative capacity is an important step in that direction.

Forced expression of fibroblast growth factor 21 reverses the sustained impairment of liver regeneration in hPPARαPAC mice due to dysregulated bile acid synthesis

The current study demonstrated that PPARα-humanized mice (hPPARαPAC) mice exhibit reduced hepatocyte proliferative capability during liver regeneration in comparison with WT mice. The presented data showed that human PPARα-mediated signaling that controls liver regeneration was less effective than that of mouse PPARα. Thus, in response to liver regeneration, hPPARα is not as effective as mouse PPARα in regulating lipid metabolism as well as hepatocyte proliferation. Metabolism, which is mainly controlled by the liver, is about 7 times faster in mice than humans. Liver regeneration, which can be completed within 7-10 days in mice, takes about 60-90 days to complete in humans. Thus, it seems that the metabolic rate and proliferative capability are correlated, and that the species difference of PPARα may account for such difference.

Because overexpression of FGF21 could restore the normal progression of liver regeneration in hPPARαPAC mice, FGF21 appears to not only repair injury, but also compensate for the reduced ability of human PPARα to hasten liver regeneration. These findings suggest that FGF21 infusion would be of therapeutic value to improve the outcome of liver transplantation and liver disease in humans.

More on Molecular Tweezers to Treat Amyloid Accumulation
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Amyloids are misfolded proteins that gather to form solid aggregates in tissues. Their presence grows with age and some types of amyloid are known to contribute to the pathology of specific age-related conditions: amyloid-β in Alzheimer's disease and misfolded transthyretin in senile systemic amyloidosis for example. Any potential rejuvenation toolkit must include a reliable technology platform for clearance of the various forms of amyloid. Of late researchers have been working on the use of what they call molecular tweezers for this purpose, and seem to be making meaningful progress:

An international team of more than 18 research groups has demonstrated that the compounds they developed can safely prevent harmful protein aggregation in preliminary tests using animals. The findings raise hope that a new class of drugs may be on the horizon for the more than 30 diseases and conditions that involve protein aggregation, including diabetes, cancer, spinal cord injury, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). Proteins are necessary for almost every cellular process. However, when cell machinery doesn't clear out old proteins, they can clump, or aggregate, into toxic plaques that lead to disease.

The researchers call the compounds that they developed molecular tweezers because of the way they wrap around the lysine amino acid chains that make up most proteins. The compounds are unique in their ability to attack only aggregated proteins, leaving healthy proteins alone. To develop a new drug, researchers typically screen large libraries of compounds to find ones that affect a protein involved in a disease. This team used a fundamentally different approach to develop the molecular tweezers. "We looked at the molecular and atomic interactions of proteins to understand what leads to their abnormal clumping. Then, we developed a tailored solution. So unlike many other drugs, we understand how and why our drug works."

The team is in the process of testing multiple versions of the tweezers, each with a slightly different molecular makeup. For CLR01, one of the most promising versions, the researchers have demonstrated therapeutic benefits in two rodent models of Alzheimer's disease, two fish and one mouse model of Parkinson's disease, a fish model of spinal cord injury and a mouse model of familial amyloidotic polyneuropathy, a rare disease in which protein aggregation affects the nervous system, heart and kidneys. "Our data suggest that CLR01, or a derivative thereof, may become a drug for a number of diseases that involve protein aggregation. We also found a high safety window for CLR01." In one of the safety tests, mice receiving a daily CLR01 dose 250 times higher than the therapeutic dose for one month showed no behavioral or physiological signs of distress or damage. In fact, blood cholesterol in the mice dropped by 40 percent, a possible positive side effect of CLR01.

Link: http://www.newswise.com/articles/new-compounds-could-offer-therapy-for-multitude-of-diseases

Investigating Hibernation and Longevity in Lemurs
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There has been some interest in deeper investigations of metabolism and aging in mammals via the study of hibernating species. For any stable altered state of metabolism, such as the calorie restriction response or hibernation, a greater understanding of the mechanisms involved may shed light on a range of issues. In the case of hibernation there is a long way to go yet, however. Research is still in the early stages, and comparatively few scientists study hibernation with this perspective:

The conventional wisdom in longevity research is that smaller species live shorter lives than larger ones. For example, humans and whales can live to be over 100; yet the average lab mouse doesn't live beyond its third birthday. The researchers found an exception to this pattern in a group of hamster-sized lemurs with a physiological quirk - they are able to put their bodies in standby mode.

Researchers combed through more than 50 years of medical records on hundreds of dwarf lemurs and three other lemur species for clues to their exceptional longevity. How long the animals live and how fast they age correlates with the amount of time they spend in a state of suspended animation known as torpor, the data show. Hibernating lemurs live up to ten years longer than their non-hibernating cousins. Dwarf lemurs were the most extreme examples in their study, spending up to half the year in deep hibernation in the wild. Dwarf lemurs go into a semi-hibernation state for three months or less in captivity, but even that seems to confer added longevity.

Hibernating dwarf lemurs can reduce their heart rate from 200 to eight beats per minute. Breathing slows, and the animals' internal thermostat shuts down. Instead of maintaining a steady body temperature, they warm up and cool down with the outside air. For most primates such vital statistics would be life-threatening, but for lemurs, they're a way to conserve energy during times of year when food and water are in short supply. Hibernating lemurs not only live longer, they also stay healthier. While non-hibernators are able to reproduce for roughly six years after they reach maturity, hibernators continue to have kids for up to 14 years after maturity, the researchers found. Although all species they examined suffered from cataracts and other age-related eye diseases as they got older, the hibernators managed to stave off symptoms until much later in life.

Link: http://today.duke.edu/2015/03/longevity

Living Longer and Aging More Slowly
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The old are not as physically aged as they used to be. Today's old people are in better shape than their predecessors, with access to better medicine and having been exposed to a lesser burden of infectious disease and other causes of cell and tissue damage over the course of a lifetime. Given the pace of progress in medical science these improvements can be seen even over the course of the past few decades. Many of today's researchers look at this and see compression of morbidity, a popular viewpoint in which it is believed that healthy life span can be extended considerably without extending overall life span. This doesn't make a great deal of sense from the viewpoint of aging as a consequence of accumulated biological damage, however. In the damage perspective the risk of death and level of dysfunction and frailty are determined by the present levels of various forms of damage. Reducing the pace at which the damage load increases extends both overall life span and time spent in decline; you can't have one without the other. Making an immediate reduction in damage, such as through some form of rejuvenation treatment, will extend healthy life span and postpone the future decline, but absent further treatments that decline would look exactly the same when it does arrive.

The only way in which you might see something that looks like compression of morbidity is if the pace of accumulation for most forms of damage are slowed, but not for one or more late-onset types of damage that produce reliably fatal consequences. This may or may not be what has happened over the past fifty years or so; there is a lot of room for argument given the present state of data. One intriguing line of thought relates to senile systemic amyloidosis, which seems to be the cause of death for most supercentenarians. It isn't much seen in less aged individuals, and there is comparatively little known of its progression in old age.

Still, the old are getting younger. Not fast enough yet, but step by step as a side-effect of improvements across the board in health, wealth, and medical science. The goal for the future is to step away from this incidental improvement in favor of strategies that deliberately target the causes of aging for treatment and repair. The coming age of medicine will prove to be far more effective in extending healthy life: there is a great deal of difference between trying and not trying to achieve a given goal.

Aging Today Better Than It's Ever Been, With Fewer Diseases And Stronger Treatment

Looking at two stages of the Berlin Aging Study, the first carried out between 1990 and 1993 and the second between 2013 and 2014, the team made some large-scale assessments of how old-age vitality has changed, along with some speculations as to why. Overall, despite growing obesity concerns and a stagnant international smoking rate, people seem to be aging more gracefully. Past the advances that have kept people in better physical shape, cognitive tests showed 75-year-olds today were an average of 19.6 years "younger" relative to 75-year-olds in the early 1990s. That is, people tested at 75 today performed as well as a 55-year-old would have two decades ago. "This is, by any means, a huge effect."

Old age is getting younger

On average, today's 75-year-olds are cognitively much fitter than the 75-year-olds of 20 years ago. At the same time, the current generation of 75-year-olds also reports higher levels of well-being and greater life satisfaction. "The gains in cognitive functioning and well-being that we have measured here in Berlin are considerable and of great significance for life quality in old age." The researchers relate the gains to sociocultural factors such as education. In their opinion, the increase in well-being is also due to better physical fitness and higher levels of independence in old age. "However, we expect that these positive historical trends are attenuated at the end of life." During the final stage of life, the increase in good years of life is likely to give way to a rapid and marked drop in both cognition and well-being.

Secular Changes in Late-life Cognition and Well-being: Towards a Long Bright Future with a Short Brisk Ending? (PDF)

We compared data obtained 20 years apart in the Berlin Aging Study (BASE, in 1990-93) and the Berlin Aging Study II (BASE-II, in 2013-14). Relative to the earlier-born BASE cohort, the later-born BASE-II cohort showed better cognitive performance and reported higher well-being, presumably due to culture-based advances in the course of the past century. Our results suggest that historical trends favoring later-born cohorts in cognitive performance carry into old age, constitute strong effects at age 75 years, and generalize to multiple key indicators of perceived quality of life. The cognitive performance of BASE-II participants was on average 19.61 years "younger" relative to the BASE cohort.
Fitness Versus Mortality after Cancer Diagnosis
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A greater level of fitness in mid-life is shown in many large studies to correlate with improved health and greater life expectancy. The data from this study shows that increased fitness correlates with lower mortality from cardiovascular disease and some cancers in those patients with a cancer diagnosis in their medical history:

Cardiorespiratory fitness (CRF) as assessed by formalized incremental exercise testing is an independent predictor of numerous chronic diseases, but its association with incident cancer or survival following a diagnosis of cancer has received little attention. The study included 13 949 community-dwelling men who had a baseline fitness examination. All men completed a comprehensive medical examination, a cardiovascular risk factor assessment, and incremental treadmill exercise test to evaluate CRF. We used age- and sex-specific distribution of treadmill duration from the overall Cooper Center Longitudinal Study population to define fitness groups as those with low (lowest 20%), moderate (middle 40%), and high (upper 40%) CRF groups. Cardiorespiratory fitness levels were assessed between 1971 and 2009, and incident lung, prostate, and colorectal cancer using Medicare claims data from 1999 to 2009; the analysis was conducted in 2014.

Compared with men with low CRF, the adjusted hazard ratios (HRs) for incident lung, colorectal, and prostate cancers among men with high CRF were 0.45, 0.56, and 1.22, respectively. Among those diagnosed as having cancer at Medicare age, high CRF in midlife was associated with an adjusted 32% risk reduction in all cancer-related deaths and a 68% reduction in cardiovascular disease mortality following a cancer diagnosis compared with men with low CRF in midlife. There is an inverse association between midlife CRF and incident lung and colorectal cancer but not prostate cancer. High midlife CRF is associated with lower risk of cause-specific mortality in those diagnosed as having cancer at Medicare age.

Link: http://dx.doi.org/10.1001/jamaoncol.2015.0226

Considering Alzheimer's Disease as a Type 3 Diabetes
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A number of researchers have pointed out similarities between some of the risk factors and mechanisms of type 2 diabetes and Alzheimer's disease, a few even going so far as to suggest that Alzheimer's should be classified as type 3 diabetes:

Type 2 diabetes mellitus (T2DM) is currently extremely common due to the prevalence of obesity, as well as the aging of the population. Prevention and treatment strategies for the classical macrovascular and microvascular complications of diabetes mellitus have significantly improved. Therefore, people are living longer with diabetes mellitus, which might lead to the emergence of new complications. Dementia is one example of these emerging new complications. Compared with the general population, the increased risk of dementia is 50%-150% in people with T2DM.

Over the past three decades, numerous epidemiological studies have shown a clear association between T2DM and an increased risk of developing AD. In addition, T2DM-related conditions, including obesity, hyperinsulinemia, and metabolic syndrome, may also be risk factors for AD. The exact mechanisms with clinical relevance are unclear. Several mechanisms have been proposed, including insulin resistance and deficiency, impaired insulin receptor and impaired insulin growth factor (IGF) signaling, glucose toxicity, problems due to advanced glycation end products and their receptors, cerebrovascular injury, vascular inflammation, and others.

In this review, we discuss insulin resistance and deficiency. Studies have shown that insulin resistance and deficiency can interact with amyloid-β protein and tau protein phosphorylation, each leading to the onset and development of AD. Based on those epidemiological data and basic research, it was recently proposed that AD can be considered as "type 3 diabetes". Special attention has been paid to determining whether antidiabetic agents might be effective in treating AD. There has been much research both experimental and clinical on this topic. Although the results of these trials seem to be contradictory, this approach is also full of promise.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360697/

A Tour of Pharmaceuticals that Extend Life in Nematodes
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Most threads of aging research start in studies of very short-lived species, most commonly the nematode worm C. elegans. These animals are cheap to maintain over the course of a study, live for only a few weeks, and are probably better understood at the cellular and genetic level than any other species. A mature and continually improving infrastructure of automation and provision exists to serve scientists running nematode studies. Despite the vast gulf between humans and nematodes many of the fundamental cellular mechanisms of metabolism are similar. Both degenerative aging and the basic structure of animal cells arrived early on in the evolution of multicellular life. Thus most of the better known phenomena of aging, such as the slowing of aging induced by calorie restriction, are preserved across near all species, whether nematodes or mammals. Researchers have learned a great deal about the fundamentals of aging by studying nematodes, and it makes good sense to pursue uncertain ideas with an unknown likelihood of success in a low-cost environment before moving to much more expensive mammalian studies.

Over the past twenty years researchers have developed scores of ways to slow aging and extend life in nematodes, some of which have translated to some degree into mice. There are outright genetic alterations and drugs that tweak some of the same levers of metabolism: genes produce protein that serve as machinery and signals, and a drug can be tailored to produce a similar effect to that of a genetic alteration upon the circulating levels of a specific protein. In many cases the goal isn't to find ways to extend life but rather to gain insight into portions of metabolism that would otherwise remain opaque, and it happens that slowing aging can be very useful for that purpose. Nematodes may be perhaps the most cataloged and understood form of life on the planet, but it remains that case that the present model of the operation of metabolism is woefully incomplete. There is a long way to go yet towards the grail of a complete, enormously complicated catalog of every last detail of the metabolism of a complete individual and how it changes over the course of aging.

Fortunately we don't need that catalog in order to build effective means to treat degenerative aging. Researchers just need the list of fundamental differences, forms of damage, that distinguish old tissues from young tissues. That list is much less complicated and essentially complete today. All that needs to be done is build therapies that can repair the damage: still a huge project, but well within the budget of the medical research community, something that might be completed in a decade or two were researchers to start in earnest today. If we want to safely slow down aging by altering the operation of metabolism, however, then the research community really would need to establish much more of the vast and incomplete catalog of metabolic processes. No-one has the knowledge today to produce a good plan for recreating even calorie restriction, the most studied altered state of metabolic operation. No-one has the knowledge to even estimate how long it would take to produce such a plan, or what it would look like. Scientists are a long, long way away from being able to safely alter metabolism to slow aging in a deliberate and planned way.

What researchers do have is a panoply of drugs that happen to alter some of the same mechanisms involved in the calorie restriction response, or produce other related changes in the biochemistry of nematode worms. All have side-effects, and none are resulting in exactly the same changes as are produced actual calorie restriction. When you mine the natural world for compounds that happen to do more good than harm, you take what you get. Again, you should probably look upon all this work as an investigation of metabolism that helps to build the grand catalog, not efforts aimed at producing treatments to extend life. Life extension is not a primary goal for most researchers in the field.

Pharmacological classes that extend lifespan of Caenorhabditis elegans

As a consequence of the seminal discoveries demonstrating that lifespan can be modulated by genes, it became clear that lifespan might also be extended using chemicals. This concept has certainly been demonstrated, and today many compounds have been identified that extend lifespan in model organisms such as worms, flies and even mice. Among all of these model organisms, Caenorhabditis elegans stands out because of the large variety of compounds known to extend lifespan. It is now possible to group these compounds into pharmacological classes, and use these groupings as starting points to search for additional lifespan extending compounds. For many of these compounds, mammalian pharmacology is known, and for some the actual targets have been experimentally identified.

There are two fundamentally different approaches to identify compounds that have a desired biological effect. These two approaches are often referred to as forward and reverse pharmacology, analogous to forward and reverse genetics. Forward pharmacology approaches, also called phenotypic screens, screen for compounds that elicit a desired phenotype, like the extension of lifespan. While forward pharmacology is intuitively appealing, as it searches for the desired effect, it has a number of drawbacks. The first is that screens must generally be conducted in vivo. In vivo screens are more complex, generally longer, and have higher costs associated than in vitro screens. Even if these disadvantages are overcome, elucidating the mechanisms by which a hit-compound achieves the desired effect is difficult. Elucidating drug mechanisms generally requires the identification of the drug target, which even today represents a major challenge (i.e., the binding target of the compound).

Reverse pharmacology circumvents the problem of target identification by screening for compounds that bind to, or inhibit, the function of a specific protein target. Reverse pharmacology screens are largely done in vitro, and offer the ability to screen very large chemical libraries (+500,000). Targets are validated based on prior knowledge, such as genetic studies in model organisms or gene association studies in humans affected by the disease. However, target validation, or choosing the protein target against which to develop a drug, also poses considerable difficulties. As the process of aging is not easily replicated in vitro, most lifespan extending compounds have been identified by simply testing whether or not a given compound extends lifespan in a model organism (forward pharmacology). Thus far, most compounds that have been tested for their ability to extend lifespan had prior known pharmacology. Initially, these compounds were developed to inhibit a specific target, independent of their effect on aging. Only later were they tested for their ability to extend lifespan in C. elegans or other organisms. Thus, at its current state, the pharmacology of aging is a hybrid of forward and reverse pharmacology.

Antioxidants

Because of Harman's theory of oxidative stress, antioxidants were some of the first compounds to be tested for their ability to extend lifespan. Indeed, antioxidants that extend C. elegans lifespan have been identified. These findings initially lent support to the idea that oxidative stress causes aging. However, later experiments guided by the theory of hormesis have challenged this view of aging. While lifespan extending antioxidants were found based on candidate approaches, unbiased screens testing many pharmacological classes for their ability to extend C. elegans lifespan did not result in any lifespan extending antioxidants. This observation suggests that, as a pharmacological class, antioxidants may not be a particularly strong candidate for identification of lifespan extending compounds.

Metabolites

The first ever intervention found to verifiably extend lifespan was dietary restriction. Thus, dietary restriction immediately linked the process of aging to metabolism. In recent years, metabolites have received increased interest, due in part to technical advances in metabolomics and the identification of metabolic enzymes important in the determination of lifespan. Today, multiple metabolites are known that play a role in the determination of adult lifespan.

Kinase Inhibitors

The first cloned gene found to be important for lifespan determination was the class-I phosphatidylinositol 3-kinase age-1. In addition to age-1, numerous mutations in various kinases have been found to extend C. elegans lifespan, including the receptor tyrosine kinase daf-2, akt-1, TOR, and S6 kinase, to name a few. Mutations in kinases like age-1 and the insulin/IGF receptor daf-2 cause some of the most dramatic effects on lifespan. As mutations in kinases are also frequently found in cancers and other diseases many kinase inhibitors were found to extend C. elegans lifespan with the most promising being rapamycin. However, thus far none of the tested kinase inhibitors has been able to reproduce the spectacular longevity seen in age-1 or daf-2 mutants.

Nuclear Hormone Receptors

Nuclear hormone receptors are an important class of regulatory proteins that activate or repress gene expression patterns in response to cellular signals. The fact that these signals generally consist of small molecules, like steroid hormones, makes nuclear hormone receptors important drug targets. One problem with studying nuclear hormone receptors using C. elegans is its vastly expanded repertoire of 284 nuclear hormone receptors, compared to 49 in mammals making it difficult to translate C.elegans findings to mammals.

G Protein Coupled Receptor Ligands

Compounds affecting GPCR are among the most important pharmacological classes for drug discovery. In medium scale screens for compounds with known pharmacology that extend lifespan, 50% of all hit compounds targeted GPCRs. It appears that GPCRs exist that must be active during development in order to affect lifespan when blocked in adults, probably because their function is to modulate lifespan in response to environmental change.

Natural Compounds

What makes a natural compound approach attractive is that plant extracts are generally regarded as safe, and are often used as food supplements. However, natural compounds are hard to synthesize and modify, and thus target identification is particularly difficult for natural compounds. The ongoing dispute on the mechanism of action of resveratrol certainly gives testimony on such difficulties.

Myostatin Insufficiency Produces 15% Life Extension in Mice
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Targeting myostatin and related biochemistry is well demonstrated to increase muscle mass and strength in mammals such as laboratory mice. There are even rare natural mutants, including a few cows and humans, who lack normal myostatin and are as a result exceptionally strong in comparison to their peers. Here researchers show that loss of myostatin mutations in mice produce extended life spans, but too much suppression of myostatin may remove that benefit due to the cardiac issues that can accompany an overly large heart:

The molecular mechanisms behind aging-related declines in muscle function are not well understood, but the growth factor myostatin (MSTN) appears to play an important role in this process. Additionally, epidemiological studies have identified a positive correlation between skeletal muscle mass and longevity. Given the role of myostatin in regulating muscle size, and the correlation between muscle mass and longevity, we tested the hypotheses that the deficiency of myostatin would protect oldest-old mice (28-30 months old) from an aging-related loss in muscle size and contractility, and would extend the maximum lifespan of mice. We found that MSTN+/− and MSTN−/− mice were protected from aging-related declines in muscle mass and contractility. While no differences were detected between MSTN+/+ and MSTN−/− mice, MSTN+/− mice had an approximately 15% increase in maximal lifespan. These results suggest that targeting myostatin may protect against aging-related changes in skeletal muscle and contribute to enhanced longevity.

The mechanism behind the increased longevity of MSTN+/− mice is not known, but inhibition of myostatin can reduce systemic inflammatory proteins and body fat. Given the increase in relative heart mass, the contribution of aging-associated cardiomegaly to mortality and that inhibition of myostatin can increase heart mass, it is possible that positive effects of increased skeletal muscle mass on the longevity of MSTN−/− mice was offset by cardiac pathologies. Most genetic models of enhanced longevity in mice have identified an inverse relationship between body mass and longevity, which has lead to the observation that 'big mice die young'. However, the results from the current study support the epidemiological observations in humans that when it comes to skeletal muscle mass and longevity, bigger may be better.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12339/

Leucine Supplementation as a Sarcopenia Treatment
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The systematic loss of muscle mass and strength with age is given the name sarcopenia. One of the potential contributing causes involves progressive dysfunction in processing of the amino acid leucine, and this might in theory be partially offset by leucine supplementation in the diet. This meta-analysis of past studies indicates that as a treatment it modestly improves muscle mass but not strength:

The primary objective of the present systematic review and meta-analysis was to synthesize the available literature relating to leucine supplementation in the elderly with respect to its effects on anthropometrical parameters and muscle strength. The secondary aim was to perform a selective subgroup analysis when possible differentiating between healthy and sarcopenic subjects.

A literature search was performed with restrictions to randomized controlled trials or studies. Parameters taken into account were body weight, body mass index, lean body mass, fat mass, percentage of body fat, hand grip strength, and knee extension strength. For each outcome measure of interest, a meta-analysis was performed in order to determine the pooled effect of the intervention in terms of weighted mean differences between the post-intervention (or differences in means) values of the leucine and the respective control groups.

A total of 16 studies enrolling 999 subjects met the inclusion criteria. Compared with control groups, leucine supplementation significantly increased gain in body weight [mean differences 1.02 kg], lean body mass [mean differences 0.99 kg], and body mass index [mean differences 0.33 kg/m2], when compared to the respective control groups. With respect to body weight and lean body mass, leucine supplementation turned out to be more effective in the subgroup of study participants with manifested sarcopenia. All other parameters under investigation were not affected by leucine supplementation in a fashion significantly different from controls.

It is concluded that leucine supplementation was found to exert beneficial effects on body weight, body mass index, and lean body mass in older persons in those subjects already prone to sarcopenia, but not muscle strength. However, due to the heterogeneity between the trials included in this systematic review, further studies adopting a homogenous design with respect to participant characteristics duration as well as the kind and amount of daily supplement in use are required.

Link: http://dx.doi.org/10.1007/s12603-014-0559-4

Genes Become Increasingly Important in Extreme Old Age
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The lesson to take away from the last fifteen years of study of the genetics of longevity is that genetic variation in humans is simply not all that important throughout most of life. Aging is caused by damage, and certainly during the period of life in which damage levels in cells and tissues are still comparatively low, all the way into early old age, the vast majority of genetic variants identified in our species have little to no effect on survival. Given that the best possible path forward to treat aging is to build treatments to periodically repair damage levels so as to keep them low, this tells me that the study of the genetics of longevity variance is not very important from a practical point of view, meaning from the standpoint of building new medical technologies to extend healthy life. It is the study of how extremely damaged biology works, and how normally unimportant genetic variants can suddenly become much more relevant to survival in frail individuals suffering advanced stages of the degeneration of aging. That is an interesting area of study, as is true of all biochemistry, but not a good focus if we want to see extended healthy life, more time spent alive with little accumulated damage.

When it comes to aging, damage, and repair, to a first approximation we are all the same. Treatments for repair of aging will be mass-manufactured once developed, exactly the same therapy for every individual: it will be the polar opposite of the often envisaged future of personalized medicine. The genetics of variations in the longevity of physically old people will become a historical curiosity, like the genetics of smallpox survival. Outside of narrow specialties in history and biochemistry we don't care as to how genetic variations influence smallpox survival, and rightly so. The research community found the means to eliminate the condition for everyone and the world moved on. This is an age in which genetics is the newest tool in the toolbox, the technologies suddenly cheap and capable, and it is being applied to everything. Hence the existence of ventures like Human Longevity, Inc. Genetic studies of aging won't provide a straightforward path to much greater healthy longevity, however, because - as noted - genetic variants are only important to the course of aging and disease in the old and the frail. Meaningful treatments for aging will be those that prevent people from ever being old and frail, or rescue them from that state, by repairing the damage that causes aging.

None of this is preventing considerable growth in the study of the genetics of longevity and aging in humans, of course. It is very much a part of the research mainstream. As more data accumulates, the present picture of genes and aging is refined to show that the increase in the relevance of genetic variants to survival in a damaged state just keeps on growing the further into extreme old age you go. The more damaged you are, the more your particular genetic quirks matter.

BU/BMC study finds the role of genes is greater with living to older ages

Genes appear to play a stronger role in longevity in people living to extreme older ages. The study found that for people who live to 90 years old, the chance of their siblings also reaching age 90 is relatively small - about 1.7 times greater than for the average person born around the same time. But for people who survive to age 95, the chance of a sibling living to the same age is 3.5 times greater - and for those who live to 100, the chance of a sibling reaching the same age grows to about nine times greater. At 105 years old, the chance that a sibling will attain the same age is 35 times greater than for people born around the same time - although the authors note that such extreme longevity among siblings is very rare. "These much higher relative chances of survival likely reflect different and more potent genetic contributions to the rarity of survival being studied, and strongly suggest that survival to age 90 and survival to age 105 are dramatically different phenotypes or conditions, with very different underlying genetic influences."

The study analyzed survival data of the families of 1,500 participants in the New England Centenarian Study, the largest study of centenarians and their family members in the world. Among those families, the research team looked at more than 1,900 sibling relationships that contained at least one person reaching the age of 90. The findings advance the idea that genes play "a stronger and stronger role in living to these more and more extreme ages," and that the combinations of longevity-enabling genes that help people survive to 95 years are likely different from those that help people reach the age of 105, who are about 1,000 times rarer in the population. For a long time, based upon twins' studies in the 1980s and early '90s, scholars have maintained that 20 to 30 percent of longevity or even life span is due to differences in genes, and that the remainder is due to differences in environment, health-related behaviors or chance events. But the oldest twins in those studies only got to their mid- to late-80's. Findings from this and other studies of much older (and rarer) individuals show that genetic makeup explains an increasingly greater portion of the variation in how old people live to be, especially for ages rarer than 100 years."

A New Era of Aging Research
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Using the recent development of killifish as a model organism as a starting point, this popular science article looks at some of the more recent high profile developments in the study of aging. It largely takes the longevity dividend party line of talking about extending healthy life span without extending overall life span, however. This is probably an impossible goal, and not even a desirable goal in comparison to extending both measures, but one that is politically easier to sell for various reasons. So there is no discussion of approaches leading to rejuvenation and the prospects for radical life extension here. This gap in the conversation is a persistent remnant of the recent past in which researchers were very reluctant to talk about or attempt to work on any form of intervention in aging:

Aging is inherently interesting, because we're all doing it. Like it or not, our bodies are slowly winding down as time passes. But what actually happens in our tissues and cells? It's clear that we are subject to a plethora of depressing outcomes, including sagging tissues (hello, wrinkles), reduced cognitive capacity (where did I put my car keys?) and a slowing metabolism that (tragically) favors belly padding over muscle building. Inside our cells, the situation looks even more dire. DNA mutations begin to accumulate, our cells' energy factories begin to wind down, and proteins policing gene expression appear to "forget" how to place the chemical tags on DNA that serve as runway lights for the appropriate production of proteins. The protein production, transportation and degradation network that cells depend on to deliver these molecular workhorses to all parts of the cell at exactly the right times also falls into disarray. Proteins are degraded too soon, or begin to clump together in awkward bundles that interfere with cellular processes. These events have obvious, previously inescapable, outcomes.

"As we age, time becomes compressed and we tend to develop many chronic diseases or health problems simultaneously. Many elderly people are dealing with a constellation of health conditions. We'd like to imagine ways to stretch out the healthy period of our lives, so it comprises more of the totality. This is something we call 'health span,' and it would be tremendously advantageous to stretch out that portion of our lives."

Nationwide, both public and private efforts have been launched to better understand and prolong our golden years. Associated with the growth in funding is an expansion in laboratory research that suggests the possibility of intervening in the aging process and extending the human health span. "It may one day be possible to avoid chronic diseases, living into old age free from dementia, diabetes and heart disease. Our tissues will still age, but we may be able to delay or prevent the onset of the decline in function that comes with passing years. We have high hopes that our research strategy will help move collaborative efforts to the next level. What has come out of our work is a keen understanding that the factors driving aging are highly intertwined and that in order to extend health span we need an integrated approach to health and disease with the understanding that biological systems change with age."

Link: http://stanmed.stanford.edu/2015spring/the-time-of-your-life.html

Further Investigations of Neuropeptide Y and the Hypothalamus in Calorie Restriction
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A number of lines of research suggest that the benefits of calorie restriction for health and longevity largely derive from increased cellular housekeeping processes such as autophagy. For example, the calorie restriction response requires neuropeptide Y (NPY), and here researchers explore the linkage of NPY with autophagy. They suggest that the role of autophagy in calorie restriction is indirect, and that it is a lynchpin part of the process only because a portion of the brain involved in the global control of metabolism responds to the level of autophagic activity:

One thing that has been clear for a while now is that autophagy is at the center of the aging process. Low levels of autophagy (cells with impaired "housekeeping") are linked to aging and age-related neurodegenerative disorders. This is easily explained as autophagy clears the cells "debris" keeping them in good working order. That the process is so important in the brain is no surprise either, because neurons are less able to replenish themselves after cell damage or death. But about a year ago a remarkable new discovery was made: the hypothalamus, which is a brain area that regulates energy and metabolism, was identified as a control center for whole-body aging.

Calorie restriction increased autophagy in the hypothalamus but also boosted levels of the molecule NPY, and mice without NPY do not respond to calorie restriction. Furthermore NPY, like autophagy, diminishes with age. All this, together with the new identified role of the hypothalamus suggested that this brain area and NPY were the key to the rejuvenating effects of calorie restriction. The researchers started by taking neurons from the hypothalamus of mice and put them growing in a medium that mimicked a low caloric diet, to then measure their autophagy. Like expected, their autophagy levels in this calorie restriction-like medium were much higher than normal. But if NPY was blocked, the medium had no consequences on the neurons. So calorie restriction's effect on hypothalamic autophagy appeared to depend on NPY.

To test this, next the researchers tested mice genetically modified to produce higher than normal quantities of NYP in their hypothalamus, and found higher levels of autophagy supporting their theory that autophagy was controlled by NPY. In conclusion, calorie restriction seems to work by increasing the levels of NPY in the hypothalamus, which in turn trigger an increase in autophagy in these neurons, "rejuvenating" them and delaying aging signs by restoring their ability to control whole-body aging.

Link: http://www.science20.com/catarina_amorim/mechanism_to_delay_aging_identified-154209

Excess Fat is Bad, Intentional Loss of that Fat is Good
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One of the things that turns up in large sets of data on weight and mortality - by which I really mean amount of fat tissue and mortality - is that both maintaining excess fat tissue and later the loss of that fat tissue are associated with increased mortality. This is because visceral fat tissue causes chronic inflammation and other forms of metabolic dysregulation. The more of it you have, the worse off you are over the long term: it is actively causing harm that accumulates to significantly raise the risk of all of the common age-related disease. Later in life, the progression and treatment of many of these age-related conditions, such as cancer, are accompanied by involuntary weight loss. There are many reasons for this ranging from simple loss of appetite to disease mechanisms that impact the normal operation of metabolism in pathological ways. If you pick out a group of people who are sharply losing weight, especially older people, the mortality rate for that group will tend to be higher than for those who maintain their weight. This is because the losing group contains a larger number of individuals who are suffering the later stages of age-related disease.

This does not mean, as some have said in the past, that it is good to be overweight. You can't lump this data together and make that claim. Involuntary weight loss is so very joined at the hip to high mortality risk that it distorts the picture, and most of the good data sources for large numbers of people make no distinction as to how or why weight changes occur. Any number of people in the world want to be told that is is fine to be overweight and nothing bad is going to happen as a result: there is always a market for comforting lies. Even a moderate level of excess fat tissue has a significant impact on the future risk of incurring all of the common age-related diseases, however. If you want the best odds of living a healthy life for as long as possible, then don't allow yourself to become fat. It is a choice, and one that you can avoid or reverse with sufficient exercise of willpower.

Unlike involuntary weight loss, deliberately setting out to lose your excess fat tissue is a good thing and produces benefits. You are cutting out a source of damage to your health, and that makes a difference over the long-term to your mortality risk. That shows up in epidemiological data, as demonstrated here.

Intentional Weight Loss and All-Cause Mortality: A Meta-Analysis of Randomized Clinical Trials

Advanced age and obesity are risk factors for disability, morbidity, and mortality. Weight loss interventions in overweight and obese older adults positively affect several strong risk factors for mortality. Yet, many observational studies in middle-aged and older adults report an association between weight loss and increased mortality. Difficulty reconciling these contradictory findings (the so-called "obesity paradox"), coupled with the strong negative prognostic implication of rapid involuntary weight loss with advanced age, has led to a reluctance to recommend weight loss in older adults. Attempts to refine observational analyses to avoid confounding (i.e. distinguishing between intentional and unintentional weight loss, and restricting populations to those without co-morbid conditions or non-smokers) typically reveal no increase, and perhaps some decrease, in mortality risk with intentional weight loss.

Although results from a randomized controlled trial (RCT) of weight loss would theoretically resolve these issues, such a trial would require a large sample size over a long duration to detect clinically meaningful differences in mortality. In light of the high prevalence of obesity, its negative impact on health and quality of life, and the discrepancy between the proven risk factor improvements of short-term intentional weight loss and the inverse association of weight loss with increased all-cause mortality frequently seen in observational studies, we conducted a meta-analysis to estimate the effect of interventions which included intentional weight loss on all-cause mortality in overweight and obese adults. We hypothesized that intentional weight loss would be associated with reduced all-cause mortality. Further, as weight loss in older persons is a cause of clinical concern that may lead health care providers to recommend against weight loss for obese, older adults, we sought to examine the effects in a subset of trials with a mean baseline age of at least 55 years.

Trials enrolled 17,186 participants (53% female, mean age at randomization = 52 years). Mean body mass indices ranged from 30-46 kg/m2, follow-up times ranged from 18 months to 12.6 years (mean: 27 months), and average weight loss in reported trials was 5.5±4.0 kg. A total of 264 deaths were reported in weight loss groups and 310 in non-weight loss groups. The weight loss groups experienced a 15% lower all-cause mortality risk. There was no evidence for heterogeneity of effect.