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.


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.


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."


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.


Education Correlates With Longevity
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It is known that greater educational achievement is associated with greater longevity, and this is one facet of a web of related correlations between various measures of intelligence, wealth, and health. To my eyes this probably all boils down to influences on the degree to which people look after the health basics over a lifetime: exercise, weight, and smoking are the most important factors under individual control. Maintaining a good, healthy lifestyle in this sense certainly doesn't require wealth, but it happens that wealthy communities and networks do better than their less wealthy counterparts. People tend to adopt the culture that surrounds them.

Educational attainment may be an important determinant of life expectancy. However, few studies have prospectively evaluated the relationship between educational attainment and life expectancy using adjustments for other social, behavioral, and biological factors. The data for this study comes from the Reasons for Geographic and Racial Differences in Stroke study that enrolled 30,239 black and white adults (≥45 years) between 2003 and 2007. Demographic and cardiovascular risk information was collected and participants were followed for health outcomes. Educational attainment was categorized as less than high school education, high school graduate, some college, or college graduate. Proportional hazards analysis was used to characterize survival by level of education.

Educational attainment and follow-up data were available on 29,657 (98%) of the participants. Over 6.3 years of follow-up, 3673 participants died. There was a monotonically increasing risk of death with lower levels of educational attainment. The same monotonic relationship held with adjustments for age, race, sex, cardiovascular risk factors, and health behaviors. The unadjusted hazard ratio for those without a high school education in comparison with college graduates was 2.89. Although adjustment for income, health behaviors, and cardiovascular risk factors attenuated the relationship, the same consistent pattern was observed after adjustment. The relationship between educational attainment and longevity was similar for black and white participants. The monotonic relationship between educational attainment and longevity was observed for all age groups, except for those aged 85 years or more.

Thus educational attainment is a significant predictor of longevity. Other factors including age, race, income, health behaviors, and cardiovascular risk factors only partially explain the relationship.


Who Funds Basic Aging Research in the US?
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Here is an interesting post from the Buck Institute on sources of funding for fundamental research into aging, with tables listing the various contributing organizations. While looking through the list, it is worth bearing in mind that for really early stage, high risk, novel research the largest sources are unavailable. NIA grants, for example, only become a possibility once you've actually made the initial breakthrough and have early proof that you have achieved something new. This is a systematic issue in medical research, and it is why philanthropic donations are essential for progress. Few really important novel attempts to advance the state of the art are directly funded at the outset by large institutional sources like the NIA or large pharmaceutical companies, though there is certainly a lot of creative bookkeeping that takes place in larger laboratories in order to split off the necessary funds for early stage, prospective work. Without that very early stage work there would be no progress, but most funding sources - public and private - act as though the prototypes they are willing to fund come into existence from nothing, as if by magic.

Where does the money to fund basic aging research come from? After all, scientists need to be paid, purchase supplies for their research, and somehow find the money to attend conferences to talk about their results. In the US at least (the funding situation is different in the UK), money comes primarily in the form of grants from the federal government, which both pay the salaries of researchers and provide them with money for their experiments.

The National Institute of Health (NIH, a federal agency) is huge and awesome. The main mechanism by which money it distributes money is through "R" grants. These are large (~$1 million), multi-year grants awarded to principal investigators (usually professors) at research institutions who go through a competitive process to apply for them. About 90% of non-profit aging research project funding comes from the NIH, and most of that is in the form of "R" grants. NIH funding has shrunk in real terms by 11% since 2003. Thankfully the NIA, the wing of the NIH, is one of the few institutes who have seen extra budgetary support in recent years.

Apart from the NIH, there are several private foundations that support aging research and specific diseases of aging. Budgets are from the latest available information, and frankly I was surprised by how small this chunk is. Don't get me wrong, each of these foundations are great and their funds support promising scientific projects and programs. But all together, they're less than 10% of the annual R-grant budget (note that a different situation exists in the UK, where the giant Wellcome Trust funds about $600 million in biomedical research). A lot of private giving to aging research is not structured as annual grant programs, though. For example, at the Buck we receive generous one-time donations from local businesses, individuals, and some of the aging foundations listed below to support our facilities.

There are also a bunch of institutes and research departments dedicated to basic aging research. A lot of universities and medical schools have some department with "aging" or "gerontology" or "geriatrics" in their name. Each of these typically distributes intramural funds. Want their money? Get a job there.

But if we move outside academic research to money spent on commercialized research applications by private companies, the pie changes quite a bit. In aggregate, drug companies outspend the NIH on R&D every year by over $20 billion. The precise portion of this going towards "aging research" is hard to measure. While most aging research at drug companies is not focused on aging itself, diseases of aging such as diabetes, heart disease, and cancer are intense areas of study. Recent years have seen the founding of private companies dedicated specifically to aging research. It is hard to guess at annual budgets for these new players, but they're pretty huge. Calico's $500 million in committed funds, for example, is over half the amount the NIA spends on R grants in a year.


The "Aging Kills" Initiative
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A number of the efforts undertaken by the ever industrious Alex Zhavoronkov of InSilico Medicine involve reaching out into new communities to educate and raise awareness on the need for longevity science and the prospects for developing the means to treat aging. He was presenting at a computing hardware conference recently, for example, talking about the path to greater healthy life spans to people who have probably never given the subject much thought. In advocacy experimentation is always necessary: success is obvious in hindsight, but you never really know where you are going to find significant new support for the cause. This, for example, is presently an effort to make inroads into the electronic music and information technology communities:

Aging is humanity's greatest challenge killing more people every year than any war in human history. It is the central cause of many diseases like cancer, cardiovascular diseases, Alzheimer's, Parkinsons, and many others. And since we could not do anything about aging for millions of years, we take it as given and accept our fate. With the advances in biomedical sciences and information technology this no longer needs to be the case. We understand aging better than ever before and many promising interventions are being discovered in labs around the world every year. We already demonstrated that stopping aging will lead to unprecedented economic growth and prosperity and will not cause overpopulation and if we don't cure aging soon, we will find ourselves in a state of economic decline and possibly even collapse of the modern civilization as we know it.

Trillions of dollars are being wasted every year on patching the breaches in our economic systems and on marginally extending patients' lives on the deathbed instead of looking for interventions that will prevent diseases and return our bodies to healthy state. What is more appalling is that most people don't want to cure aging. They got comfortable with the concept and don't want to give themselves hope and set the bar too high. This is wrong and we need to change this! We need to tell the world that it is sick and help people realize that aging is a disease.

Many people in information technology and other fields can make a major impact in aging. Nowadays most of biology is data, which needs to be analyzed, structured, interpreted and used to develop working interventions to slow down pathologic changes. We need to motivate thousands or even millions of programmers, hackers, rebels to get into aging research and start a massive campaign to defeat death. This is a worthy cause to unite the world against the common problem.


Another Study to Argue that Tau is Primary and Amyloid Secondary in Alzheimer's Disease
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The struggle to show meaningful progress in treatment of Alzheimer's disease via clearance of amyloid has fueled significant investment into alternative hypotheses regarding the disease process. The biochemistry of Alzheimer's - and the brain in general - is so very complex that at this point it is a challenge to say whether the issue is that it is intrinsically hard to produce a useful clearance therapy via the present approaches, or whether amyloid is the wrong target for best effect. A leading alternative candidate is a different form of metabolic waste, neurofibrillary tangles made of an altered form of the tau protein. Here is one of a number of studies that point the finger at tau rather than amyloid accumulation as the primary source of pathology:

By examining more than 3,600 postmortem brains, researchers have found that the progression of dysfunctional tau protein drives the cognitive decline and memory loss seen in Alzheimer's disease. Amyloid, the other toxic protein that characterizes Alzheimer's, builds up as dementia progresses, but is not the primary culprit, they say. The findings suggest that halting toxic tau should be a new focus for Alzheimer's treatment. "The majority of the Alzheimer's research field has really focused on amyloid over the last 25 years. Initially, patients who were discovered to have mutations or changes in the amyloid gene were found to have severe Alzheimer's pathology - particularly in increased levels of amyloid. Brain scans performed over the last decade revealed that amyloid accumulated as people progressed, so most Alzheimer's models were based on amyloid toxicity. In this way, the Alzheimer's field became myopic."

Researchers were able to simultaneously look at the evolution of amyloid and tau using neuropathologic measures. "Studying brains at different stages of Alzheimer's gives us a perspective of the cognitive impact of a wide range of both amyloid and tau severity, and we were very fortunate to have the resource of the Mayo brain bank, in which thousands of people donated their postmortem brains, that have allowed us to understand the changes in tau and amyloid that occur over time.

"Tau can be compared to railroad ties that stabilize a train track that brain cells use to transport food, messages and other vital cargo throughout neurons. In Alzheimer's, changes in the tau protein cause the tracks to become unstable in neurons of the hippocampus, the center of memory. The abnormal tau builds up in neurons, which eventually leads to the death of these neurons. Evidence suggests that abnormal tau then spreads from cell to cell, disseminating pathological tau in the brain's cortex. The cortex is the outer part of the brain that is involved in higher levels of thinking, planning, behavior and attention - mirroring later behavioral changes in Alzheimer's patients."

"Amyloid, on the other hand, starts accumulating in the outer parts of the cortex and then spreads down to the hippocampus and eventually to other areas. Our study shows that the accumulation of amyloid has a strong relationship with a decline in cognition. When you account for the severity of tau pathology, however, the relationship between amyloid and cognition disappears - which indicates tau is the driver of Alzheimer's. Our findings highlight the need to focus on tau for therapeutics, but it also still indicates that the current method of amyloid brain scanning offers valid insights into tracking Alzheimer's. Although tau wins the 'bad guy' award from our study's findings, it is also true that amyloid brain scanning can be used to ensure patients enrolling for clinical trials meet an amyloid threshold consistent with Alzheimer's - in lieu of a marker for tau."


Ceria Nanoparticles Enhance Autophagy
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Autophagy is one of the cellular housekeeping processes responsible for promptly clearing out damaged proteins and cell components before they cause more harm. Autophagic activity declines with age, in part due to a build up of resilient metabolic waste in lysosomes, the organelles responsible for breaking down materials and structures for recycling. The SENS strategy for this contribution to degenerative aging is to aim to remove that waste in order to restore function. Globally increased autophagy is also a factor in many genetic and other alterations shown to slow aging and increase healthy life span in laboratory animals. Thus some researchers are investigating ways to boost this form of cellular housekeeping, and there have been some interesting demonstrations over the years, such as restoration of youthful liver function in old mice. Here one research group finds that nanoparticles can spur greater autophagy:

Cerium oxide nanoparticles (nanoceria) are widely used in a variety of industrial applications including UV filters and catalysts. The expanding commercial scale production and use of ceria nanoparticles have inevitably increased the risk of release of nanoceria into the environment as well as the risk of human exposure. The use of nanoceria in biomedical applications is also being currently investigated because of its recently characterized antioxidative properties. In this study, we investigated the impact of ceria nanoparticles on the lysosome-autophagy system, the main catabolic pathway that is activated in mammalian cells upon internalization of exogenous material.

We tested a battery of ceria nanoparticles functionalized with different types of biocompatible coatings expected to have minimal effect on lysosomal integrity and function. We found that ceria nanoparticles promote activation of the transcription factor EB, a master regulator of lysosomal function and autophagy, and induce upregulation of genes of the lysosome-autophagy system. We further show that the array of differently functionalized ceria nanoparticles tested in this study enhance autophagic clearance of proteolipid aggregates that accumulate as a result of inefficient function of the lysosome-autophagy system.

This study provides a mechanistic understanding of the interaction of ceria nanoparticles with the lysosome-autophagy system and demonstrates that ceria nanoparticles are activators of autophagy and promote clearance of autophagic cargo. These results provide insights for the use of nanoceria in biomedical applications, including drug delivery. These findings will also inform the design of engineered nanoparticles with safe and precisely controlled impact on the environment and the design of nanotherapeutics for the treatment of diseases with defective autophagic function and accumulation of lysosomal storage material.


Theorizing that the Brain is Destroyed by the Pulse
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It is uncontroversial that the age-related deterioration of the vascular system leads to damage to the brain, causing cognitive decline and then dementia. Progressive stiffening due to cross-links and calcification and inflammation-driven remodeling of blood vessel walls reduces structural integrity at the same time as it causes hypertension, raised blood pressure that puts more stress on those same blood vessel walls. This paper presents a novel way of looking at this contribution to the aging process:

The brain and its blood vessels are very different tissues. The nerve and glial cells of the brain (its processing machinery) develop from the ectoderm of the embryo; the brain's blood vessels (its system of oxygen supply and metabolite removal) develop from mesoderm, growing from the heart to surround and then penetrate the developing brain. By birth, vessels have branched through every millimeter of brain tissue, and they become involved in most, if not all, diseases or injuries of the brain.

Age-related dementia has seemed, to Alois Alzheimer and to most observers since, to be a degeneration of the brain, of its nerve cells. This review brings together two bodies of evidence, from which we propose that the dementia is primarily vascular, caused by the destructive effective of the pulse on cerebral blood vessels, with the loss of neurons occurring secondarily to vascular breakdown. We argue, further, that dementia is age-related because the pulse becomes more intense and more destructive with age.

The idea is uncongenial and counterintuitive. It is uncongenial because it does not appear to offer a simple path to therapy, counter-intuitive because we are used to thinking of the brain as a dependent ward of the heart, not as a victim of its beat. The idea may be correct, however counter-intuitive, for its explanatory power is considerable. It links the puse to hemorrhage, and to the neuropathology and arteriosclerosis that Alzheimer described; it explains the link from age to dementia, in the stiffening of the walls of the great arteries, and the effect of that stiffening on blood pressure. Here we review the evidence that pulse-induced destruction of the brain, and of another highly vascular organ, the kidney, are becoming the default forms of death, the way we die if we survive the infections, cardiovascular disease, and malignancies, which still, for a decreasing minority, inflict the tragedy of early death.

There are, in fact, comparatively straightforward paths to therapies that can mitigate this contribution to the aging process, though at present their development is given far too little attention and support by the research community. Firstly prevent and reverse loss of elasticity in blood vessels, such as by breaking down persistent cross-links, and secondly target the mechanisms of atherosclerosis responsible for remodeling blood vessel walls to suppress inflammation and clear plaques. Target the root causes and natural repair mechanisms should do much to clean up the rest of the issue.