Fight Aging!

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.

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

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

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.

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

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/

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.

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/

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

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."

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

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

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.

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.

Link: http://dx.doi.org/10.1016/j.annepidem.2015.01.017

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.

Link: http://sage.buckinstitute.org/who-funds-basic-research-in-aging-in-the-us/

Google is pouring a large amount of money into aging research via the Calico Labs initiative. Their declared aim is to produce treatments that impact the whole of age-related degeneration, and their open support of that goal is certainly going to make it easier for other initiatives to raise funding in the future - it adds that much more legitimacy to the space in the eyes of investors and philanthropists who have so far stayed away. That is the good part. However it has become increasingly clear that the Calico Labs approach, telegraphed pretty early on, is to broadly fund the central mainstream of research and development relating to aging, which at this time is the standard process of drug discovery and investigations of the genetics of longevity. In this they might be considered a second iteration of the Ellison Medical Foundation, a funding addendum to the present efforts of the NIA and pharmaceutical companies, but really introducing no fundamentally new and better strategy. So expect past performance to predict the next decade or so here.

The Ellison Medical Foundation achieved essentially nothing of great note over the course of its existence, a period when the same could be said of most NIA projects, because the mainstream approach to aging does not consist of strategies likely to produce any significant gains in healthy human life span. I've talked about why this is the case at length over the years, but in essence it boils down to the same reasons as to why I support the SENS programs for rejuvenation biotechnology development. The preponderance of evidence strongly suggests that aging is caused by an accumulation of damage to cells and tissues. The best approach, which is the SENS approach, is to repair that damage periodically but otherwise not tinker with the operation of our metabolism: it is complicated and we understand very little of it in comparison to our understanding of the damage that is linked to aging. This is not the mainstream approach, however. In the mainstream of aging research, where researchers are interested in treating aging at all that is, the focus is on finding ways to alter the operation of our metabolism so as to slow down damage accumulation.

It doesn't require a vast and detailed understanding of biology to grasp that slowing damage is a worse strategy than repairing damage in any system, complex or not. It cannot restore youthful function and is of limited utility to old people. Further, safely altering metabolism to achieve specific goals is much harder than repairing known and clearly demarcated forms of cellular damage. This is illustrated by the fact that a clear set of plans for damage repair exist with many different options for implementation, but at this time - and after decades of work and billions of dollars invested - researchers still don't have a clear understanding of how calorie restriction works or can be reproduced, and that is the simplest and most reliable altered state of metabolism known to extend life and improve health. Even if the calorie restriction response could be recreated with a drug, the outcome would be far less health and life gained than for even a partial implementation of repair treatments.

Here are some recent news reports on the Calico initiative that reinforce the point on the broad fundamental research strategy they are choosing to take, acting in essence as a supplemental fund for existing programs and approaches to drug development, with a heavy emphasis on genetics:

Broad Institute and Calico announce an extensive collaboration focused on the biology of aging and therapeutic approaches to diseases of aging

The Broad Institute of MIT and Harvard has entered into a partnership with Calico around the biology and genetics of aging and early-stage drug discovery. The partnership will support several efforts at the Broad to advance the understanding of age-related diseases and to propel the translation of these findings into new therapeutics. "This alliance is a key part of Calico's strategy to bring the best cutting-edge science to bear on problems of aging. The Broad Institute is one of the nation's preeminent research organizations whose outstanding research has repeatedly revealed fundamental mechanisms of the biology and genetics of disease," said Art Levinson, Chief Executive Officer of Calico.

Calico, QB3 Launch Longevity R&D Partnership

Google-back Calico said Tuesday it will partner with the University of California institute QB3 to study longevity and age-related diseases, as well as create and foster an interdisciplinary community of scientists in those fields. The four-year partnership is designed to generate discoveries that will translate into greater understanding of the biology of aging and potential therapies for age-related diseases. The partnership plans to identify, fund and support QB3 research projects focused on aging, using committed funding from Calico - which focuses on aging research and therapeutics. "We are all aging, and we will all benefit from the discoveries made in this program and the therapies that will result," QB3 director Regis Kelly said in a statement. "We are grateful to Calico for recognizing the deep expertise at the University of California that attracts so many scientists of exceptional ability."

For those of us who do support the SENS repair approach, the lesson to take home and remember is that we will see mainstream funding of SENS-related research and development when that work becomes mainstream. Not before. It is already the case for cancer and stem cell science, where there are strands of SENS-like work taking place in many laboratories, but for the other forms of tissue repair there must be demonstrations of effectiveness. We can learn from the growing interest in senescent cell clearance: that only emerged in earnest after the 2011 demonstration of improved health in accelerated aging mice. This year we are seeing the fruits of that interest in the form of new demonstrations of effectiveness in normal mice and the first company founded to commercialize an approach to clear senescent cells. More researchers, more results, more programs underway.

However frustrating it might be, funding follows success. This is why it is so important that we continue to raise funds for early stage SENS research in order to create the technology demonstrations that can pull in that attention and funding. We are, after all, winning at this game step by step. Five years ago senescent cell clearance was something that no research groups looked at in earnest, and now we have mice that are healthier as a result of treatments that remove senescent cells. Ten years from now there will be clinical trials underway in humans. Meanwhile there are four or five other important forms of damage repair that must make the same leap, and that is only going to happen with the support of you, I, and other philanthropists.

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.

Link: http://agingkills.org/

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."

Link: http://www.eurekalert.org/pub_releases/2015-03/mc-mcs032315.php

DNA methylation is an epigenetic alteration in which genes are decorated with methyl groups. It is one of a range of epigenetic processes that establish a feedback loop linking the pace at which specific proteins are built from genetic blueprints, the activities of those proteins once built, and environmental circumstances in tissues such as nutrient availability, temperature, damage, and disease. All of the switches and dials for molecular machinery inside cells are essentially built on top of the circulating levels of specific proteins, and these are altered via epigenetics: protein levels are in constant flux, as are countless epigenetic modifications to DNA.

In recent years researchers have demonstrated that specific patterns of DNA methylation within this broader tapestry correlate very well with age. Researchers can use these patterns in a tissue sample to identify an individual's age with an accuracy of five years or so. We all age due to the same underlying processes, some of us faster than others largely due to unfortunate lifestyle choices such as lack of exercise, excess weight, and smoking. Small differences in stochastic damage to cells and tissues snowball over the years into comparatively large differences in outcomes: the roots of variability in the mean time to failure in a very complex system. Given that the same forms of damage accumulate in all of us as a side effect of the same metabolic processes, it shouldn't be surprising to find that researchers can pull out patterns in the controlling mechanisms of metabolism - epigenetic alterations - that are tightly coupled to age. These are reactions to the environmental state of being damaged.

Studies that investigate DNA methylation from other perspectives should pick up the same signs of the same underlying processes, and same broad similarities between individuals. This is the case even when looking for signs of differences between old individuals, in search of a better explanation of the genetic contribution to extreme longevity in humans. So far genetic studies have turned up very few associations between genetic variants - meaning actual differences in the structure of specific genes - and longevity. Those that are found in one study rarely show up in others. This suggests that if variants are important in determining survival in extreme old age, then there must be a very large number of such variants with individually small effects, and the patterns of genetic differences must vary widely between regional populations. A very complex picture with little hope of complete understanding or any sort of resulting application in medicine in the near future, in other words. Is this in fact the case, however? These researchers suggest that epigenetic changes are instead where we should look, and that the picture isn't as complex as feared:

A Genome-Wide Scan Reveals Important Roles of DNA Methylation in Human Longevity by Regulating Age-Related Disease Genes

Human longevity is believed to be an integrating result of genetic and environmental factors. Although previous studies have shown that genetic variation may explain 20-30% contribution to human longevity, much remains to be known for its underlying genetic mechanism. In the past decade, a number of genes were discovered, in which some specifically genetic alterations may confer advantage in extending the organisms' lifespan, suggesting the existence of longevity genes. These findings however could not fully explain the significantly reduced incidence of age-related diseases in centenarians and their offspring, as it requires a broad effect of longevity genes, including conferring beneficial effects in extending life span as well as suppressing deleterious influence from the disease-associated genes. Alternatively, it is possible that the low prevalence of the age-related diseases in the long-lived people is attributed to a much lower frequency of risk alleles. Unfortunately, the latter notion fails to find support from a recent study in which the long-lived people were shown to carry similar frequencies of risk alleles as did in the young controls. This observation seems to echo with the suggestion that the longevity-related variants may compress the morbidity of long-lived people as these variants were significantly enriched in disease-related genes.

Hitherto, the obtained genetic evidence, based virtually on mutation screening, find no support for the hypothesis that lack of disease-related mutations contributes to healthy aging. However, taking into account the heterogeneity in longevity, in which multiple ways could be adopted to achieve longevity, and the crucial role of epigenetic modification in gene regulation, we hypothesize that suppressing the disease-related genes in the longevity individuals is likely achieved by epigenetic modification, e.g. DNA methylation. A reduction of genome-wide DNA methylation level and locus-specific hyper-methylation has been observed with aging, whereas changes in DNA methylation were reported to be associated with the occurrences of age-related diseases, such as cardiovascular disease, diabetes and cancer.

To test this hypothesis, we investigated the genome-wide methylation profile in 4 Chinese female centenarians and 4 middle-aged controls. 626 differentially methylated regions (DMRs) were observed between both groups. Interestingly, genes with these DMRs were enriched in age-related diseases, including type-2 diabetes, cardiovascular disease, stroke and Alzheimer's disease. This pattern remains rather stable after including methylomes of two white individuals. Further analyses suggest that the observed DMRs likely have functional roles in regulating disease-associated gene expressions. Therefore, our study suggests that suppressing the disease-related genes via epigenetic modification is an important contributor to human longevity.

I'd want to see a much larger study before taking this result at face value, but to find consistencies across populations in this sort of data shouldn't be too surprising given the points made above about the fact that we all age in the same way. Patterns of similarity should be there to be found in many different ways.

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.

Link: http://dx.doi.org/10.1021/nn505073u

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.

Link: http://dx.doi.org/10.3233/JAD-141884

It has been said that the only thing worse than using animals in medical research is to refrain from the use of animals in medical research. It is both terrible and necessary. Throughout the modern history of medical science animal studies have been needed in order to make progress, not just in human medicine, but also veterinary medicine. Many people are opposed to animal studies, and to the degree that this is motivated by compassion - and leads to sensible forms of advocacy - this is to their credit. Unfortunately all too few of these individuals follow the logic though to its end and thus devote near all of their efforts to oppose the animal farming, hunting, and fishing industries. These activities cause harms to animals that tower over those of research. All the animal studies carried out in a year are a rounding error against a few hours of the meat industry.

That aside, animal studies will one day soon be a thing of the past. Some will be replaced by the use of engineered tissue sections, but eventually all will give way to experiments that run on simulation platforms, coupled with a much more modest use of engineered tissues to validate those simulations. Even the early steps on this road will be more effective and far cheaper than maintaining animal colonies and lineages for use in research. The only reason that this transition hasn't yet occurred is that only now has tissue engineering arrived at the point of mass production of functional tissue sections that mimic the real thing closely enough to be useful. I would hope that the farming of animals one day goes the same way, and that we as a species continue on a somewhat upward slope of culture and enlightenment that leaves this and other presently acceptable forms of institutional violence behind us. That is no doubt a much longer and harder road than merely transforming life science research.

Primate studies are already in decline. They are far more expensive than studies in shorter-lived species and far more difficult to arrange in the present climate. Any new study similar to the decades-long calorie restriction studies in rhesus macaques now coming to their final years is unlikely to take place given today's culture and pace of technological progress. Thus I think that these researchers are arguing for the last days of a paradigm that is firmly in its sunset period:

Lessons from the analysis of nonhuman primates for understanding human aging and neurodegenerative diseases

Why do we need animal models? The simplest answer to this question is to increase our general knowledge, to experimentally test theories. Animal model usefulness is manifold, from the study of physiological processes to the identification of disease-causing mechanisms. They are necessary tools for solving the most serious challenges facing medical research. In aging and neurodegenerative disease studies, rodents occupy a place of choice. However, the most challenging questions about longevity, the complexity and functioning of brain networks or social intelligence can almost only be investigated in nonhuman primates (NHPs). Beside the fact that their brain structure is much closer to that of humans, they develop highly complex cognitive strategies and they are visually-oriented like humans. For these reasons, they deserve consideration, although their management and care are more complicated and the related costs much higher.

NHPs have significantly contributed to understanding of aging and neurodegenerative diseases. Aging NHPs show striking similarities with elderly humans. Most of our understanding on the biological changes observed during aging comes from studies in rodents because they present clear advantages (short life span, fully characterized genetic aspects, easy genetic manipulation...). However, rodents and humans diverged much earlier than humans and NHPs, and this is likely to have led to fundamental differences in their aging processes. In one pioneering work, for example, researchers compared the transcriptome of the cerebral cortex in aging mice, rhesus macaques and humans, providing a broad view of the evolution of aging mammalian brain. They found that only a small subset of age-related gene expression changes are conserved from mouse to human brain, whereas such changes are highly conserved in rhesus macaques and humans.

Due to their genetic proximity to humans and their highly developed social skills, NHPs are extremely valuable as experimental animal models. However, as the number of available animals is restricted for ethical reasons and also because of the high cost and large space required for breeding colonies, NHPs should only be used when no other suitable method is available to fill the gap of our knowledge. In any case, rodent (or other small animal models) and primate experimental models need to be used in parallel in order to obtain robust and complementary information. Alongside other models, nonhuman primates should have a unique place in the overall aging and neurodegenerative research strategy.

There is relatively little study of sirtuin 7 (SIRT7) in comparison to the better known and greatly overhyped sirtuin 1 (SIRT1). All members of the sirtuin family have broad influence over a range of fundamental cellular processes, and thus cataloging their roles in metabolism is an enormous undertaking, still in the early stages despite the mountains of data and years of work to date. Still, inroads are being made, but it remains to be seen whether they are any more likely to result in practical applications than the past decade of work on SIRT1.

Mitochondria host a multitude of proteins that need to be folded properly to function correctly. When the folding goes awry, the mitochondrial unfolded-protein response, or UPRmt, kicks in to boost the production of specific proteins to fix or remove the misfolded protein. Researchers stumbled upon the importance of UPRmt in blood stem cell aging while studying a class of proteins known as sirtuins, which are increasingly recognized as stress-resistance regulators. The researchers noticed that levels of one particular sirtuin, SIRT7, increase as a way to help cells cope with stress from misfolded proteins in the mitochondria. Notably, SIRT7 levels decline with age. There has been little research on the UPRmt pathway, but studies in roundworms suggest that its activity increases when there is a burst of mitochondrial growth.

Adult stem cells are normally in a quiescent, standby mode with little mitochondrial activity. They are activated only when needed to replenish tissue, at which time mitochondrial activity increases and stem cells proliferate and differentiate. When protein-folding problems occur, however, this fast growth could lead to more harm. "We isolated blood stem cells from aged mice and found that when we increased the levels of SIRT7, we were able to reduce mitochondrial protein-folding stress. We then transplanted the blood stem cells back into mice, and SIRT7 improved the blood stem cells' regenerative capacity."

The new study found that blood stem cells deficient in SIRT7 proliferate more. This faster growth is due to increased protein production and increased activity of the mitochondria, and slowing things down appears to be a critical step in giving cells time to recover from stress, the researchers found. "When there's a mitochondrial protein-folding problem, there is a traffic jam in the mitochondria. If you prevent more proteins from being created and added to the mitochondria, you are helping to reduce the jam." Until this study, it was unclear which stress signals regulate the transition of stem cells to and from the quiescent mode, and how that related to tissue regeneration during aging. "Identifying the role of this mitochondrial pathway in blood stem cells gives us a new target for controlling the aging process."

Link: https://newscenter.berkeley.edu/2015/03/19/aging-research-finds-taking-it-slow-helps-cope-with-stress/

A broad range of methods are under development to engineer T cells that can selectively attack cancer cells. If aggressive enough and selective enough, the immune system should in theory be able to tame and destroy most cancers, but the devil is in the details as is always the case in these matters. The use of chimeric antigen receptors in altered T cells is one noteworthy approach, and here researchers report on their efforts to mine the biochemistry of another species for similarly useful additions to human T cells:

T cells are the linchpin in the attack of the immune system. On their surface they have anchor molecules (receptors) with which they recognize foreign structures, the antigens of bacteria or viruses, and thus can target and destroy invaders. Cancer researchers and immunologists are attempting to mobilize this property of the T cells in the fight against cancer. The objective is to develop T cells that specifically recognize and attack only cancer cells but spare other body cells.

Researchers have now developed human T cell receptors (TCRs) that have no tolerance toward human cancer antigens and specifically recognize the antigen MAGE-A1, which is present on various human tumor cells. First, the researchers transferred the genetic information for human TCRs into mice, thus creating an entire arsenal of human TCRs. When the humanized mouse T cells come into contact with human cancer cells, they perceive the tumor antigens as foreign - like viral or bacterial antigens. Thus, the T cells can specifically target, attack and destroy the tumor cells. The researchers subsequently isolated the human T-cell receptors of these mice, which are specifically targeted toward the tumor antigen MAGE-A1. Then they transferred the T-cell receptors into human T cells, thereby training them to recognize the cancer cells as foreign.

Some people possess T cells which naturally recognize MAGE-A1 on tumor cells, but only in the Petri dish. In studies using an animal model, only the human TCRs derived from mice were shown to be effective against the tumor. The TCRs from human T cells ignored the tumor completely. "The fact that our TCRs from the mouse are better is a strong indication that the T cells of a human are tolerant toward MAGE-A1." Using the T-cell receptors they developed, the researchers are planning an initial clinical trial with patients with MAGE-A1 positive multiple myeloma, a malignant disease of the bone marrow.

Link: https://mdc-berlin.de/44321220/en/news/2015/20150319-mdc_and_charit__researchers_tweak_the_immu

The first practical outcome of tissue engineering research is not therapies, but rather improved tools for further scientific work in this and other fields. At present the structured tissue sections created in the laboratory are largely too small or too dissimilar from natural organs for use in treatments, but these engineered tissues can nonetheless be very useful in drug testing, investigation of disease mechanisms, and many other aspects of medical research. Real tissue is a vast improvement over cells in a dish and animal models, and real tissue grown from patient cells is a tremendous step forward for work on genetic disorders. In the economic development of the field, the ability for companies to form and make money by providing these tools is a vital stepping stone on the way to improving the underlying technologies. That will lead in time to building whole organs to order, one step at a time.

Scientists grow 'mini-lungs' to aid the study of cystic fibrosis

Scientists have successfully created 'mini-lungs' using stem cells derived from skin cells of patients with cystic fibrosis, and have shown that these can be used to test potential new drugs for this debilitating lung disease. The research is one of a number of studies that have used stem cells - the body's master cells - to grow 'organoids', 3D clusters of cells that mimic the behaviour and function of specific organs within the body. Researchers used skin cells from patients with the most common form of cystic fibrosis caused by a mutation in the CFTR gene referred to as the delta-F508 mutation. Approximately three in four cystic fibrosis patients in the UK have this particular mutation. They then reprogrammed the skin cells to an induced pluripotent state, the state at which the cells can develop into any type of cell within the body.

Using these induced pluripotent stem cells, or iPS cells, the researchers were able to recreate embryonic lung development in the lab by activating a process known as gastrulation, in which the cells form distinct layers including the endoderm and then the foregut, from which the lung 'grows', and then pushed these cells further to develop into distal airway tissue. The distal airway is the part of the lung responsible for gas exchange and is often implicated in disease, such as cystic fibrosis, some forms of lung cancer and emphysema. "In a sense, what we've created are 'mini-lungs'. While they only represent the distal part of lung tissue, they are grown from human cells and so can be more reliable than using traditional animal models, such as mice. We can use them to learn more about key aspects of serious diseases - in our case, cystic fibrosis. We're confident this process could be scaled up to enable us to screen tens of thousands of compounds and develop mini-lungs with other diseases such as lung cancer and idiopathic pulmonary fibrosis. This is far more practical, should provide more reliable data and is also more ethical than using large numbers of mice for such research."

Researchers seek to make mini-guts that mimic life

"We are already making human mini-guts in the laboratory. We make them, we can freeze them." However, they are not a perfect model, and she hopes this project will result in better ones. Not only will they have the stretch and pull of living guts, but will also include the immune cells found underneath the epithelium of the gut and the mesenchymal and nerve cells that enhance the environment and function of the gut.

There are two major projects. Project one uses human intestinal enteroids (cells taken from the gastrointestinal tract) to analyze how those cell react to human rotavirus and vaccine replication as well as enteroaggreative E. coli, defining how the epithelial cell responses lead to pathology or disease. Project two will combine tissue engineering, biomaterial design and mechanobiology to develop specially tailored platforms for the human intestinal enteroids that can be stimulated mechanically, promoting cell and tissue polarity and differentiation of intestinal tissue to facilitate infection with the rotaviruses and E. coli. "Infectious disease labs that study enteric disease need better models that faithfully simulate the physiology of the intestine. This organ contains multiple types of cells that are arranged in complex patterns, and these tissues are constantly on the move. They contract and expand all the time."

The most prevalent causes of blindness are degenerative and associated with aging, the result of loss of cells and structure in the retina. There are numerous other causes, including optic nerve damage that can result from trauma, but these are fortunately less common. At the high level there are two main approaches that will lead to reliable future restoration of vision. The first is some form of cell therapy, inducing regeneration that would not normally take place in order to repair the damage such that the functional components of sight are restored. The second is to bypass dysfunctional tissues and replace them with machinery. At present regenerative medicine is much further ahead, while state of the art retinal prostheses consist of electrode grids that provide only a poor substitute for vision, not the real thing. Both will improve considerably in the years ahead.

Losing eyesight is a common problem, be it due to the process of aging or the development of a specific condition. A range of conditions exists where those who develop them are faced with a gradual loss of vision until their impairment is so severe that they are effectively blind. Retinal degeneration disorders have no cure. These diseases break down the retina, the layer of tissue found at the back of the eye containing cells that detect light entering the organ.

Embryonic stem cells could be used to build new retinal pigmented epithelial cells - cells that nourish retinal visual cells and absorb light - that could be transplanted into a patient. Doing this could slow or prevent the loss of the visual cells, and while deriving new visual cells from embryonic stem cells could lead to even more pronounced results, researchers have found it more difficult to successfully derive these cells and transplant them into the retina. Mouse studies have previously shown that this technique can work and that transplanted cells can integrate fully with the retina, restoring vision to the animals. Researchers have managed to derive rod cells from embryonic stem cells and are currently working on deriving cone cells and transplanting them into animals. If these trials prove successful, the next step could be human trials.

"In patients who have already lost their sight, our therapeutic goal is to restore vision. This has been successfully accomplished via the Argus II retinal prosthesis in patients with advanced retinitis pigmentosa." The 15th man in the US to receive the life-changing device is now able to make out the outlines of objects and people thanks to his new retinal prosthesis. He is now able to navigate through crowded environments - such as shopping centers - without the use of a cane. A camera connected to a pair of glasses transmits visual information to a small chip attached to the back of the eye via a small computer worn in a belt pack. The chip can send light signals directly to the optic nerve, bypassing the damaged retina and providing the patient with visual information in the form of flashes of light. While this form of vision could be considered basic compared with what normal-sighted people are used to, it is a marked improvement for many without sight. As he used his retinal prosthesis for the first time, the patient described the artificial vision as "crude, but significant."

Link: http://www.medicalnewstoday.com/articles/291090.php

It is perfectly possible to build a tremendously successful business while failing to deliver on any of the initial motivating goals and ideals. The modern "anti-aging" industry is a perfect example of this point, written thousands of times over in the careers of salespeople and founders. It began in earnest in the 1970s, a point in time when advocates for longevity science were a lot more optimistic, radically overoptimistic in fact, about what could be achieved in the near future. They built a supply pipeline for what they believed would come, but in the end, when the real thing never turned up, filled that pipeline with whatever junk happened to be available and would sell. Most of the original founders strongly believed in the declared goals of providing services that would extend healthy human life spans. Then they sold out. This is what happens when you build the supply chain in advance of the product.

Some of these folk are still very much believers, such as the principals at the Life Extension Foundation, an organization emblematic of the US supplement industry for the past four decades. They have over the years turned a portion of their profits towards real, meaningful research in cryonics and biotechnology, including SENS rejuvenation projects, far more money than I can claim to have helped raise. Nonetheless, the overwhelming majority of their activities lie in selling pills that have no real meaningful effect while loudly proclaiming the merits of those supplements - and the LEF is, I think, the best of that industry when it comes to the balance of ideals, meaningful action, and garbage. To my eyes when it comes to advocacy and obtaining support for rejuvenation research even enlightened "anti-aging" industry organizations like the LEF are probably doing more harm than good.

Yet this pipeline exists, and shows no signs of slowing down. At some point real therapies that address scientifically supported causes of aging will show up in the medical tourism pipeline, or as reapplications of existing widely available drugs, or something else that can be put out there by the existing infrastructure. These first treatments will no doubt be marginal, not very good at all in the grand scheme of things, but they will actually treat aging, and actually do some good. Think of the recent publication showing that a combination of existing drugs clears some portion of senescent cells in mice, for example. An organization outside the US could be selling that treatment today, and it is in effect a really terrible first pass at a SENS-like therapy that trims back one contributing cause of degenerative aging. But a really terrible first pass at a SENS-like therapy is already a league ahead of marginal scientific projects such as testing metformin in clinical trials and a whole different world from overhyped junk like resveratrol. It is step one on a road that actually goes somewhere.

The model for the way this will all unfold has already happened, and very recently too. If you want insight into the next fifteen years of treating aging outside the formalized mainstream of clinical trials, then look at the past fifteen years of applied stem cell research. A big melange of opportunists, entrepreneurs, rapid scientific progress, legitimate clinics, crooks, and the "anti-aging" market, all rolled into one and smeared out across half the world outside the US. At some point in the indefinite future I'm sure I'll be one of those folk out there buying treatments ahead of their availability in the US, sometime after the point at which the science, cost, and expected results make some kind of sense when balanced against the known gains of exercise and calorie restriction. We're not there yet, not by a good decade or more - probably more, frankly. But there will be a time when the "anti-aging" market stops being a bad joke and finally delivers on its original goal, set forty years back, after the good and the real chases out the bad and the fake.

Everyone makes their own calculations on these matters, of course, though I believe most of them are somewhat too eager to jump into the water now rather than supporting work on a pool that actually meets the minimal standards of usefulness. Being more skeptical than you feel you should be and more of a late adopter than you would like to be has many benefits.

Tomorrow's Anti-Aging Therapy, Available Today

For people who have a few hundred thousand dollars to spend and are willing to take on the risks of an "early adopter" and travel to South America, options are now becoming available that were inconceivable just a few years ago. This is a new vision for combining research with treatment, for treating diseases that have no proven therapies, and for aging itself.

You only have to read Time Magazine to notice that this is the year anti-aging medicine is coming of age. Promising life extension technologies are being debuted, with potential for preventing many diseases at once, adding decades to the human life span, and restoring youthful function to an aging body. These include telomerase therapies, stem cell therapies, epigenetic reprogramming, removal of senescent cells, plasma transfer, and hormonal therapies inspired by gene expression changes between young and old.

Inevitably, this has brought a surge in the number of companies eager to jump the gun and offer treatments to consumers based on early lab research, before the technology has proved safe and effective in humans. In an age of wildcat capitalism, we are well-advised to approach all claims with a skeptical eye, and assume that hucksterism is rampant. Anyone who considers signing on with a new company that is offering a promising but unproven anti-aging technology had best start with a foundation of second opinions and broad considerations of risk and rewards.

But I stop short of saying, "stay away". The field is too important, with too much at stake for us individually and as a human community, to sit on the sidelines, to wait for the research to be sorted out. Political control of medical research has protected us imperfectly, and has held back life-saving treatments, sometimes for decades. The system serves pharmaceutical profits more effectively than the public of medical consumers. Too often, the treatments that are approved are not those that offer the best risk/reward ratio, but those that are patentable and owned by someone who can afford to invest hundreds of millions of dollars in scientific advocacy.

The standard path to regulatory approval respects individual human life, and is "conservative" in the Hippocratic sense of "first do no harm". But it is far from the most effective way to move science forward, and probably is not the most efficient way to save the most lives, even in the short run. Many libertarians, anti-aging enthusiasts and ordinary citizens who find themselves with a condition for which there is currently no effective medical treatment want the freedom to participate in experimental medicine, and experimental medicine certainly wants to try to help them and to learn from successes and failures.

For people who see their options for an active and creative life being closed by age-related disabilities, for people who are willing to take personal risks to help move the science forward, for people who are bold and adventure-seeking, the choice to try experimental anti-aging technologies can be a rational decision.

Researchers have discovered a novel approach to spur greater regeneration in heart tissue:

The heart tissue of mammals has limited capacity to regenerate after an injury such as a heart attack, in part due to the inability to reactivate a cardiac muscle cell and proliferation program. Recent studies have indicated a low level of cardiac muscle cell (cardiomyocyte) proliferation in adult mammals, but it is insufficient to repair damaged hearts. Researchers have now shown that a subset of RNA molecules, called microRNAs, is important for cardiomyocyte cell proliferation during development and is sufficient to induce proliferation in cardiomyocytes in the adult heart. MicroRNAs, which do not generate proteins, repress gene expression by binding messenger RNAs, which do generate proteins, and promote their degradation.

The loss of the microRNA cluster miR302-367 in mice led to decreased cardiomyocyte cell proliferation during development. In contrast, increased expression of the microRNA cluster in adult hearts led to a reactivation of proliferation in the normally non-reproducing adult cardiomyocytes. This reactivation occurred, in part, through repression of a pathway called Hippo that governs cell proliferation and organ size. "The Hippo pathway normally represses cell proliferation when it is turned on. The cluster miR302-367 targets three of the major kinase components in the Hippo pathway, reducing pathway activity, which allows cardiomyocytes to re-enter the cell cycle and begin to regrow heart muscle. This is a case of repressing a repressor."

In adult mice, re-expression of the microRNA cluster reactivated the cell cycle in cardiomyocytes, resulting in reduced scar formation after an experimental myocardial infarction injury was induced in the mice. There was also an increase in the number of heart muscle cells in these same mice. However, long-term expression of more than several months of the microRNA cluster caused heart muscle cells to de-differentiate and become less functional. The investigators surmised that cardiomyocytes likely need to de-differentiate to divide, but they may lose their ability to contract over time. "We overcame this limitation by injecting synthetic microRNAs with a short half-life called mimics into the mice." Mimic treatment for seven days after cardiac infarction led to the desired increase in cardiomyocyte proliferation and regrowth of new heart muscle, which resulted in decreased fibrosis and improved heart function after injury.

Link: http://www.uphs.upenn.edu/news/News_Releases/2015/03/morrisey/

There are a surprisingly large number of studies on personality traits and psychological states as they relate to health status in aging. I can't help but feel that all those funds should perhaps have gone towards generating more practical outcomes in the sciences, but it is what it is. The association that consistently emerges from these studies is that positive traits and emotional states correlate with greater survival, health, and longevity. Optimism, conscientiousness, satisfaction, and so forth, all show up more often in healthier old people. I'm sure you can all theorize as to exactly why this is the case: on the one hand people predisposed to these traits will probably take better care of themselves over the long term, but - far more importantly - dying of old age, being sick and frail and in pain, just isn't a good place to find yourself. The worse your health, the worse you feel.

People spend a lifetime striving to forget what lies ahead, thinking it inevitable. That was a good strategy when aging was in fact inevitable, but now, in an age in which we could be developing therapies to defeat degenerative aging, most of the public still keep their heads in the sand, unwilling to even think about the topic, let alone provide the support and funding needed for rapid progress in medicine. The habits of the past are sabotaging prospects for the future.

High morale is defined as future-oriented optimism. Previous research suggests that a high morale independently predicts increased survival among old people, though very old people have not been specifically studied. Here we investigate whether high morale is associated with increased survival among very old people.

The Umeå 85+/GErontological Regional DAtabase-study (GERDA) recruited participants aged 85 years and older in northern Sweden and western Finland during 2000-02 and 2005-07, of whom 646 were included in this study. Demographic, functional- and health-related data were collected in this population-based study through structured interviews and assessments carried out during home visits and from reviews of medical records. The 17-item Philadelphia Geriatric Center Morale Scale (PGCMS) was used to assess morale.

The 5-year survival rate was 31.9% for participants with low morale, 39.4% for moderate and 55.6% for those with high morale. The relative risk (RR) of mortality was higher among participants with low morale (RR = 1.86) and moderate morale (RR = 1.59) compared with participants with high morale. Similar results were found after adjustment for age and gender. In a model adjusted for several demographic, health- and function-related confounders, including age and gender, mortality was higher among participants with low morale (RR = 1.36) than those with high morale. There was a similar but non-significant pattern towards increased mortality in participants with moderate morale (RR = 1.21). We conclude that high morale is independently associated with increased survival among very old people.

Link: http://dx.doi.org/10.1093/ageing/afv021

Calorie restriction mimetic treatments are those that recreate at least some part of the calorie restriction response. Calorie restriction with optimal nutrition alters near every measure of metabolism and slows near every measure of degenerative aging, producing improved short term metrics of health and extending longevity in those species where that has been evaluated. Thus there is a wide range of possible targets for calorie restriction mimetics, but this comes hand in hand with the continued challenge of identifying primary versus secondary mechanisms, and important versus unimportant mechanisms. One area gaining more attention of late involves the varied roles of nitric oxide in metabolism; having more of it in circulation seems like a good thing:

Calorie restriction is known to extend lifespan among organisms by a debating mechanism underlying nitric oxide-driven mitochondrial biogenesis. We report here that nitric oxide generators including artemisinin, sodium nitroprusside, and L-arginine mimics calorie restriction and resembles hydrogen peroxide to initiate the nitric oxide signaling cascades and elicit the global antioxidative responses in mice. The large quantities of antioxidant enzymes are correlated with the low levels of reactive oxygen species, which allow the down-regulation of tumor suppressors and accessory DNA repair partners, eventually leading to the compromise of telomere shortening. Accompanying with the up-regulation of signal transducers and respiratory chain signatures, mitochondrial biogenesis occurs with the elevation of adenosine triphosphate levels upon exposure of mouse skeletal muscles to the mimetics of calorie restriction.

In conclusion, calorie restriction-triggered nitric oxide provides antioxidative protection and alleviates telomere attrition via mitochondrial biogenesis, thereby maintaining chromosomal stability and integrity, which are the hallmarks of longevity.

Link: http://dx.doi.org/10.7717/peerj.822

Research institutions are willing to pour comparatively large sums into the pursuit of existing already developed and approved drugs that might, possibly, have some marginal, tiny effect on the course of degenerative aging. This is one manifestation of a large and harmful issue that plagues medical research as a whole, which is that there is very little interest in pursuing radical new improvements to the state of therapies. Rather the larger investments nowadays often go towards mining the existing catalog of approved drugs in search of different uses and slight gains that might have been overlooked in the past. Other groups delve into supplements to evade the FDA, with the similar goal of slight gains and overlooked substances. These are no paths to rapid progress or a future of greatly improved medicine.

Why is this the present state of affairs? I blame regulation. It is so enormously costly to obtain approval for any new drug, let alone a new technology that doesn't quite fall into any of the existing categories that regulators understand, that developers and researchers are steered at every step of the way towards reuse of existing drugs and other technologies. This is what you get when government influence over a field of human endeavor has risen to the point at which all that is not explicitly permitted is forbidden. Progress is greatly slowed and stifled.

Of course everyone puts on the best face for this. Look at these new and bold things we are doing, they say. They are neither new nor bold, however. Nor are they the road to greatly extended healthy lives or the defeat of aging, and those claims should be laughed out of the room when made. No existing drug such as those mentioned below can do more than slightly slow the accumulation of damage that causes aging. They don't repair that damage, they thus won't add significant numbers of years to life, and they are unlikely to even do as much good as calorie restriction or regular moderate exercise. In the case of the various drug candidates noted in the articles linked below, the evidence isn't even all that robust when it comes to extending healthy life in animal studies. This is marginal activity that will most likely do very little for the bottom line of healthy years lived. It is the business as usual of the research establishment of the yesterday, and something that must be disrupted and driven out by new and better approaches to the treatment of aging.

This is all made doubly frustrating by the fact that now, as a result of more than a decade of hard work and advocacy for aging research, many more researchers are willing to speak openly about treating aging as a medical condition. Yet they focus on strategic options for research and development that haven't much of a hope of producing meaningful gains in healthy life span. We are in the midst of a revolution in the capabilities of medical biotechnology: this is not a time to cling to past incrementalism, but rather a time to embrace new approaches and new strategies that could achieve rejuvenation and radical life extension.

Scientists' New Goal: Growing Old Without Disease

Some of the top researchers on aging in the country are trying to get an unusual clinical trial up and running. They want to test a pill that could prevent or delay some of the most debilitating diseases of old age, including Alzheimer's and cardiovascular disease. The focus of the project isn't to prolong life, although that could occur, but to make the last years or decades of people's lives more fulfilling by postponing the onset of many chronic diseases until closer to death.

Researchers expect to enroll more than 1,000 elderly participants in the randomized, controlled clinical trial to be conducted at multiple research centers and take five to seven years. The trial aims to test the drug metformin, a common medication often used to treat Type 2 diabetes, and see if it can delay or prevent other chronic diseases. (The project is being called Targeting/Taming Aging With Metformin, or TAME.) Metformin isn't necessarily more promising than other drugs that have shown signs of extending life and reducing age-related chronic diseases. But metformin has been widely and safely used for more than 60 years, has very few side effects and is inexpensive.

The scientists say that if TAME is a well-designed, large-scale study, the Food and Drug Administration might be persuaded to consider aging as an indication, or preventable condition, a move that could spur drug makers to target factors that contribute to aging. Fighting each major disease of old age separately isn't winnable. "We lower the risk of heart disease, somebody lives long enough to get cancer. If we reduce the risk of cancer, somebody lives long enough to get Alzheimer's disease." "We are suggesting that the time has arrived to attack them all by going after the biological process of aging."

An FDA spokeswoman, said the agency's perspective has long been that "aging" isn't a disease. "We clearly have approved drugs that treat consequences of aging," she said. Although the FDA currently is inclined to treat diseases prevalent in older people as separate medical conditions, "if someone in the drug-development industry found something that treated all of these, we might revisit our thinking."

Beyond Resveratrol: The Anti-Aging NAD Fad

NAD is a linchpin of energy metabolism, among other roles, and its diminishing level with age has been implicated in mitochondrial deterioration. Supplements containing nicotinamide riboside, or NR, a precursor to NAD that's found in trace amounts in milk, might be able to boost NAD levels. In support of that idea, half a dozen Nobel laureates and other prominent scientists are working with two small companies offering NR supplements.

The NAD story took off toward the end of 2013 with a high-profile paper by Harvard's David Sinclair and colleagues. Sinclair, recall, achieved fame in the mid-2000s for research on yeast and mice that suggested the red wine ingredient resveratrol mimics anti-aging effects of calorie restriction. This time his lab made headlines by reporting that the mitochondria in muscles of elderly mice were restored to a youthful state after just a week of injections with NMN (nicotinamide mononucleotide), a molecule that naturally occurs in cells and, like NR, boosts levels of NAD.

NMN isn't available as a consumer product. But Sinclair's report sparked excitement about NR, which was already on the market as a supplement called Niagen. In early February, Elysium Health, a startup cofounded by Sinclair's former mentor, MIT biologist Lenny Guarente, jumped into the NAD game by unveiling another supplement with NR.

This intersection of the supplement marketplace and scientific research is a sideshow and has little to do with any serious efforts that might produce treatments for the causes of aging. It will no doubt be successful in parting fools and their money, however. This sort of thing usually is, even absent a bevy of scientists willing to put their reputations on the line. Remember than nothing of any practical use came of resveratrol and sirtuin research, though it certainly generated a lot of data and new understanding of that small slice of human metabolism. Similarly nothing of practical use will emerge here. Don't fall for the hype, and don't spend time and effort advocating for or supporting efforts that cannot possibly produce meaningful gains in human life span.

Mitochondria, the power plants of the cell, are important in aging. They are the descendants of symbiotic bacteria and contain their own DNA, separate from that in the cell nucleus. This mitochondrial DNA is just a remnant, however, as over the course of evolutionary time most of its genes have moved to the nucleus. A complex set of mechanisms exists to transport proteins produced in the nucleus back into mitochondria where they are needed, one part of which is the TIM/TOM complex. This paper focuses on one of the proteins involved, TOM40, or TOMM40, and in particular its relationship with mutations known to play a role in one or more neurodegenerative conditions:

Mitochondrial dysfunction is an important factor in the pathogenesis of age-related diseases, including neurodegenerative diseases like Alzheimer's and Parkinson's spectrum disorders. A polymorphism in Translocase of the Outer Mitochondrial Membrane - 40 kD (TOMM40) is associated with risk and age of onset of late-onset Alzheimer's, and is the only nuclear- encoded gene identified in genetic studies to date that presumably contributes to Alzheimer's-related mitochondria dysfunction.

In this review, we describe the TOM40-mediated mitochondrial protein import mechanism, and discuss the evidence linking TOM40 with Alzheimer's (AD) and Parkinson's (PD) diseases. All but 36 of the more than ~1,500 mitochondrial proteins are encoded by the nucleus and are synthesized on cytoplasmic ribosomes, and most of these are imported into mitochondria through the TOM complex, of which TOM40 is the central pore, mediating communication between the cytoplasm and the mitochondrial interior. Amyloid precursor protein enters and obstructs the TOM40 pore, inhibiting import of OXPHOS-related proteins and disrupting the mitochondrial redox balance. Other pathogenic proteins, such as amyloid-β and alpha-synuclein, readily pass through the pore and cause toxic effects by directly inhibiting mitochondrial enzymes. Healthy mitochondria normally import and degrade the PD-related protein Pink1, but Pink1 exits mitochondria if the membrane potential collapses and initiates Parkin-mediated mitophagy. Under normal circumstances, this process helps clear dysfunctional mitochondria and contributes to cellular health, but PINK1 mutations associated with PD exit mitochondria with intact membrane potentials, disrupting mitochondrial dynamics, leading to pathology.

Thus, TOM40 plays a central role in the mitochondrial dysfunction that underlies age-related neurodegenerative diseases. Mitochondria underlie many cellular processes and it is not surprising functional and structural mitochondrial defects contribute to the pathogenesis of age-related diseases, including neurodegenerative diseases.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346331/

The brain is impacted by the processes of degenerative aging for decades before the damage rises to noticeable levels. When the technologies exist to repair this damage, treatments should ideally begin in the middle of life, not wait until there are obvious signs of degeneration. Prevention beforehand is better than restoration after the fact, for all that most of us are, at best, going to forced along the restoration route given the prospective timelines for the development of repair therapies:

Typical cognitive aging may be defined as age-associated changes in cognitive performance in individuals free of dementia. To assess brain imaging findings associated with typical aging, the full adult age spectrum should be included. Researchers compared age, sex and APOE ɛ4 effects on memory, brain structure (as measured by adjusted hippocampal volume, HVa) and amyloid [brain plaques associated with Alzheimer disease] positron emission tomography (PET) in 1,246 cognitively normal individuals between the ages of 30 and 95.

Overall memory worsened from age 30 through the 90s. HVa worsened gradually from age 30 to the mid-60s and more steeply after that with advancing age. Median amyloid accumulation seen on PET scans was low until age 70 but increased after that. Memory was worse in men than women overall, especially after 40. The HVa was lower in men than women overall, especially after 60. For both males and females, memory performance and HVa were not different by APOE ɛ4 carrier status at any age. From age 70 onward, APOE ɛ4 carriers had greater median amyloid accumulation seen on PET scans than noncarriers.The ages at which 10 percent of the population was "amyloid PET positive" were 57 years for APOE ɛ4 carriers and 64 years for noncarriers. Amyloid PET positive indicates individuals are accumulating amyloid in their brain as seen on PET scans and, while they may be asymptomatic, they are at risk for Alzheimer disease.

"Our findings are consistent with a model of late-onset AD [Alzheimer disease] in which β-amyloidosis arises later in life on a background of preexisting structural and cognitive decline that is associated with aging and not with β-amyloid deposits."

Link: http://media.jamanetwork.com/news-item/study-examines-memory-and-effects-on-the-aging-brain/

Scientist and advocate Aubrey de Grey is the co-founder of the SENS Research Foundation, one of the most important organizations in aging research today, given its goal of turning the focus of the scientific community towards the implementation of rejuvenation biotechnology. Too much of the aging research establishment has either no interest in treating aging as a medical condition, or they are only interested in expensive and uncertain ways to slightly slow the progression of aging. If we want meaningful progress towards an end to aging in our lifetimes, with the option of continued health and vigor in our extra years of life, then this must change.

The SENS Research Foundation is supported entirely by philanthropic donations, such as those that you and I can provide. Its staff fund and coordinate research, conferences, and advocacy with the aim of pushing forward critical technologies needed to treat the causes of degenerative aging. In most cases work on repair of the cellular and molecular damage that leads to frailty and disease lags far behind other, far less effective approaches that cannot possibly product actual rejuvenation if implemented. This present state of affairs is exactly why we need both more organizations like the SENS Research Foundation and more funding for these and similar efforts to reshape the aging research community.

My attention was drawn today to a longer interview with de Grey recently published online by London Real. At almost ninety minutes long, it covers a lot of ground.

Video: Aubrey de Grey - How To Live Forever

Aubrey de Grey is a true frontiersman, daring to push out against what seems the most natural and unstoppable forces of nature - ageing. He's not just another voice though, he's a scientist and identifies ageing as a disease, one that can be cured with the right medicine. His work calls for serious scientific exploration of what causes tissue to age and to then find solutions to those components - what he calls the roadmap to defeat biological ageing. In fact, he believes that the first humans who will live to be 1,000 years old are already alive today!

Here is a quote to consider from the opening minutes: "We've got to get people more comfortable with undergoing medical treatments while they are still healthy." As rejuvenation therapies are deployed there will be a change in the provision of medicine from treatments to preventative medicine, and eventually near all medicine will be preventative in nature. I'm on the fence as to whether this will in fact be a hurdle for adoption. People are willing today to pay at least lip service to prevention in the form of supplements and exercise. Equally I'm receptive to the argument that clinics are broadly seen as the place you go when you're sick, not the place you go to ensure that you don't get sick. Yet won't longevity assurance treatments be as irregular in life as vaccinations, once every few decades, once a mature technology? People keep up with vaccinations for the most part.

Autophagy is one of the housekeeping processes responsible for recycling damaged mechanisms and structures in cells before they can cause further harm. A type of organelle called the lysosome performs the recycling, but lysosomal activity is impacted over the course of aging by an accumulation of metabolic byproducts that cannot be broken down, such as the constituents of lipofusin most notably found in retinal cells. As a consequence of being laden with this waste, lysosomes bloat and become dysfunctional, especially in long-lived cells.

The immune system also declines and changes with aging, becoming less effective in its primary tasks of defending the body and eliminating potentially harmful cells, while at the same time also generating ever higher levels of chronic inflammation. Some of this is due to various forms of cellular and molecular damage known to contribute to degenerative aging, while some of it is structural, inherent in having what is a more or less fixed-sized system that tries to devote resources to remembering every pathogen it encounters. It works well at the outset but eventually runs out of space.

These researchers are investigating links between immune system function and declining autophagy, adding another voice to those already suggesting that ways to enhance natural levels of autophagy would be of general benefit in the treatment of aging and age-related disease:

Macrophages provide a bridge linking innate and adaptive immunity. An increased frequency of macrophages and other myeloid cells paired with excessive cytokine production is commonly seen in the aging immune system, known as 'inflammaging'. It is presently unclear how healthy macrophages are maintained throughout life and what connects inflammation with myeloid dysfunction during aging.

Autophagy, an intracellular degradation mechanism, has known links with aging and lifespan extension. Here, we show for the first time that autophagy regulates the acquisition of major aging features in macrophages. In the absence of the essential autophagy gene Atg7, macrophage populations are increased and key functions such as phagocytosis and nitrite burst are reduced, while the inflammatory cytokine response is significantly increased - a phenotype also observed in aged macrophages. Furthermore, reduced autophagy decreases surface antigen expression and skews macrophage metabolism toward glycolysis.

We show that macrophages from aged mice exhibit significantly reduced autophagic flux compared to young mice. These data demonstrate that autophagy plays a critical role in the maintenance of macrophage homeostasis and function, regulating inflammation and metabolism and thereby preventing immunosenescence. Thus, autophagy modulation may prevent excess inflammation and preserve macrophage function during aging, improving immune responses and reducing the morbidity and mortality associated with inflamm-aging.

Link: http://dx.doi.org/10.1159/000370112

Investor and philanthropist Peter Thiel has given millions to support the rejuvenation biotechnology research programs funded by the SENS Research Foundation and Methuselah Foundation before it. He was one of the first wealthy individuals to step forward and do this publicly and vocally, well ahead of the coming crowd, and continues to support this work.

I point out this article largely as a reminder that the biotechnology revolution has only just started its acceleration, and Thiel's activities in this space are now illustrative of the approach taken by many other funding institutions. Biotechnology today is greatly improved in comparison to just ten years ago, the tools ten times better, the cost of DNA sequencing and many other fundamental techniques plummeting. But this is just the warm up to the main event, in which the next two decades of life science research and its application will look a lot like the enormous growth and transition of the software industry between 1980 to 2000: a shift to openness, the breaking down of barriers between professional and amateur development as cost of participation falls, and a vast increase in output and experimentation:

What's less well known about Thiel is his affinity for biotechnology. By now he has invested in more than 25 startups, one of which has already turned into a $1 billion success story. That puts Thiel, 47, at the vanguard of prominent tech investors putting their money into biology. Google drew attention when it started Calico, a life-extension company, in 2013, and this year the accelerator Y Combinator said 10 of the 116 startups it accepted were biotechnology companies. Thiel, like Google, is motivated partly by the hope of defeating aging, an area of medicine that he says is "structurally underexplored." "The way people deal with aging is a combination of acceptance and denial," he says. "They accept there is nothing they can do about it, and deny it's going to happen to them."

The wider change is that biology is getting cheaper and easier to do. That means biotech companies are acting more like software startups. These days, you can order DNA online, crowdfund a genetic engineering project, or outsource experiments. Austen Heinz, CEO of Cambrian Genomics, a company that sells built-to-order DNA strands, says you can imagine what will happen if biotech becomes as easy as software to try and to test. An "explosion of biotech companies is coming," he says.

In 2011, the Thiel Foundation created Breakout Labs, an internal organization that gives small companies, often of just two or three people, investments of $350,000 to "de-risk" scientific ideas and prepare them to raise more cash. Breakout has become the foundation's largest effort. It has so far put $7 million into roughly two dozen hard science companies, nearly all them biotechnology firms. Lindy Fishburne, Breakout's executive director, says Thiel's hope is to "jailbreak" good technologies trapped in universities or other institutions and get them into the economy.

Link: http://www.technologyreview.com/news/535771/a-contrarian-in-biotech/

Yesterday I pointed out a prospective treatment that briefly disrupts the blood-brain barrier and by doing so appears to provoke glia, the immune cells of the brain, into clearing up amyloid deposits. The visible outcome is an improved state of cognitive function in a mouse model of Alzheimer's disease wherein the mice are engineered to generate amyloid in large amounts and show accelerated cognitive decline. That is one interpretation of the results, in any case. It is interesting that the researchers produced measurable benefits by temporarily opening the blood-brain barrier, as, like all structures in the body, its function declines and falters with age, and this is thought to contribute to neurodegenerative conditions such as Alzheimer's disease.

What is the blood-brain barrier? It is a layer of cells that wraps capillary blood vessels in the brain, wherein neighboring cell membranes overlap in an arrangement known as a tight junction that forms a barrier to fluids. It isn't just a wall, however: it is also a collection of molecular mechanisms that very selectively transport various privileged molecules back and forth between the brain and the blood supply. Everything else is blocked. With advancing age this barrier begins to leak, but the causes and mechanisms involved are not entirely clear at the detailed level, and nor is it completely nailed down as to exactly what sort of further damage is caused as a consequence of this leakage.

This open access paper on the topic is presently only available as a PDF, but is a good illustration of the current state of knowledge regarding the blood-brain barrier in aging: the sorts of questions that remain open and the direction of present research. As is often the case in specific manifestations of age-related degeneration, rising levels of chronic inflammation appear to play an important role:

Blood-brain barrier dysfunction developed during normal aging is associated with inflammation and loss of tight junctions but not with leukocyte recruitment

An accumulating body of evidence suggests that disruption of blood-brain barrier (BBB) function followed by blood-to-brain extravasation of circulating neuroinflammatory molecules may increase risk for the onset and progress of cerebrovascular-based neurodegenerative disorders such as Alzheimer's disease (AD), vascular dementia (VaD) and multiple sclerosis. We recently reported in wild-type mice maintained on standard diets, progressive deterioration of capillary function with aging was concomitant with heightened neuroinflammation. However, the mice used in this study were relatively young (12 months of age) and potential mechanisms for loss of capillary integrity were not investigated per se. The current study therefore extended the previous finding to investigate the effect of aging on BBB integrity in aged mice at 24 months and its potential underlying molecular mechanisms.

A functional consequence of increased cerebral capillary permeability with aging is enhanced blood-to-brain delivery of circulating neuroinflammatory molecules. Disturbed BBB has been reported in mid-aged rodent models independent of co-morbidities or the provision of pro-inflammatory diets. The cerebrospinal fluid/serum ratio of albumin, a surrogate marker of increased capillary permeability, is significantly elevated with aging. In addition, recent studies suggest that increased BBB permeability in aged rodent brains is associated with reduced expression of BBB tight junction proteins.

Only a few studies have investigated potential mechanisms involved in BBB breakdown with normal aging and these suggest heightened inflammatory processes. In vitro and in vivo studies show that TNF-α potentiates the permeability of BBB by suppressing the expression of tight junction complexes, whilst inhibition of TNF-α results in restoration of the tight junction protein expression and normalized BBB integrity. Similarly, anti-TNF-α antibodies were shown to attenuate BBB permeability via restored expression of BBB tight junction proteins in rat model of acute liver failure. In this study, exaggerated endothelial TNF-α in aged mice was associated with reduced expression of the BBB tight junction proteins.

Collectively, the findings of this study suggest that the mechanisms of BBB dysfunction that occurs in normal aging may result from the loss of endothelial tight junctions, induced by pro-inflammatory TNF-α through heightened peripheral inflammation.

Some people spent a fair amount of time debating philosophical points on what it would be like to live for centuries or longer, a prospect that will become an actual possibility before the end of the century, enabled by the development of rejuvenation biotechnologies. There is nothing wrong with that as a hobby, but the most disconnected, ridiculous arguments against a long life span have a way of finding their way back into discussions over today's funding for aging research. Even the polemics in favor of radical life extension drift away into points that have little to do with day to day experiences of life, such as this one in which the author considers that aging into different opinions and ideals a century from now is actually undesirable and a viable argument in favor of dying instead.

Yet that prospect is hardly terrible; we are all living with it comfortably already, after all. No-one really expects to be exactly the same person twenty years from now, let alone hundreds were they available. Life is change and motion. The best argument for radical life extension via the medical control of degenerative aging is the simple one: that today we'd like to be alive and active tomorrow, and that was the state of things in all of our past days.

In the future it is likely that advances in medicine will grant us the opportunity to prevent the process of ageing. The question of whether eternal life would be a good thing will then be of the utmost practical importance to humanity. In this essay, I claim that it would be. We need to begin by working out our answer to Lucretius' view that death is not a bad thing. Put another way, we first need to find out what it is that makes us think life is valuable and worth living, and then we can see if the beliefs we end up committed to in light of our answer to this question also commit us to believing that eternal life would be desirable.

The Lucretian shifts the scope of the argument to consideration of whether death is a bad thing for the person who dies. However, this separation of the interests and happiness of persons who have close relationships is problematic. While others conclude Lucretius is wrong merely because there must be at least something valuable in life, I want to draw attention to a specific good that I believe is, and we generally agree to be, valuable, namely having positive personal relationships with others. In arguing that death is not a bad thing or not a bad thing for the person who dies, Lucretius is forgetting that death is what all too often robs us of the opportunity of creating, continuing, and/or developing further, positive relationships with others.

If my body lived for another 200 years, but my beliefs, aims, and way of living were utterly different from what they are now by the end, would it really be me that was still alive? It would be extremely difficult to maintain one's personal identity, understood this way, over a long time. Other authors doubt that such a psychologically disjointed life, with mere bodily and no personal continuity, is desirable. In response, I suggest applying the idea that relationships with others are central to the meaning of life to the problem of personal identity. Though the existence of these sources may be finite, their influence need not be. While it would be difficult to keep these influences in mind as time passed, an immortal person could take measures to actively remind themselves of them in writing, visually (with photos etc.) or memory if she showed sufficient discipline.

Another concern about the prospect of immortality is that it may become boring and therefore meaningless. What pursuits could be so interesting they would never get boring? I do not think the dismissal of intellectual contemplation as a candidate is convincing. Further, we should not ignore that as time passes, radically new pursuits (and relationships) will become available that, at that present time, we may have no way of conceptualizing (just as a caveman would scarcely have been able to conceptualize a video game). Further, some pleasures do not have diminishing marginal returns, such as the enjoyment of fine food. This point can, again, be made more convincing if we consider the element of social relationships. It is no coincidence that a recurrent and problematic question that people frequently raise during discussion of this topic is whether one's loved ones would be immortal too. Eating nice food might eventually get boring, but would spending time enjoying life with loved ones?

Link: http://blog.practicalethics.ox.ac.uk/2015/03/oxford-uehiro-prize-in-practical-ethics-in-light-of-the-value-of-personal-relationships-is-immortality-desirable-by-fionn-odonovan/

Many elastic tissues harden with age in part due to calcification, an increased deposition of calcium between cells. In the cardiovascular system this is eventually fatal, as elasticity in blood vessels and the heart are essential to proper function. The usual focus for discussion here is the stiffening of blood vessel walls through this and other mechanisms, causing hypertension and all its attendant consequences, but heart tissue also stiffens and calcifies:

Calcific aortic valve disease (CAVD) is the third leading cause of heart disease. In CAVD, which can develop with age, heart valves begin to produce calcium, causing them to harden like bone. Scientists have long known that blood flow in the heart plays a role in the calcification of valves and arteries, but they did not understand how. In a new study, investigators reveal the chain of events that cause healthy valves to become bone-like. The researchers had previously discovered that disruption of one of two copies of a master gene called NOTCH1 can cause valve birth defects and CAVD. In the current study, the researchers report that NOTCH1 acts like a sensor on the endothelial cell - the cells that line the valve and vessels - detecting blood flow outside of the cell and transmitting information to a network of genes inside the cell. Activation of NOTCH1 by blood flow causes a domino effect, triggering numerous other genes in the network to turn on or off, resulting in suppression of inflammation and calcification. However, if this process is disrupted by a decrease in NOTCH1, the cells become confused and start to act like bone cells, laying down calcium and leading to a deadly hardening of the valve.

The scientists used stem cell technology to make large amounts of endothelial cells from patients with CAVD, comparing them to healthy cells and mapping their genetic and epigenetic changes as they developed into valve cells. The researchers used the power of gene sequencing and clever computational methods to uncover the "source code" for human endothelial cells and learn how that code is disturbed in human disease. "By understanding the gene networks that get disrupted in CAVD, we can pinpoint what we need to fix and find new therapeutics to correct the disease process." Sifting through this mountain of data, the scientists found three key genes that were altered by the NOTCH1 mutation and also acted as master regulators, turning off the critical pathways that normally prevent inflammation and calcification. Remarkably, when the researchers manipulated the activity of these three genes, almost all of the other genes in the network were corrected, pointing to novel therapeutic targets for CAVD. The scientists are now screening for drugs that restore the gene network to its normal state.

Link: http://www.eurekalert.org/pub_releases/2015-03/gi-phc030915.php

There is a good deal of evidence to show that lifestyle choices such as lack of exercise and putting on excess weight accelerate the decline of the brain. Lack of exercise means a more rapid deterioration in blood vessel integrity, and that in turn causes a growing number of tiny lesions in the brain, damage that adds up year by year until the cognitive effects become noticeable. Excess visceral fat tissue does the same thing via other mechanisms, spurring chronic inflammation that corrodes blood vessel structure. It does a lot more besides - most age-related conditions are accelerated by greater levels of inflammation, and that is handily provided by a fat and sedentary life.

Better lifestyle choices can add years of health and life expectancy per the consensus epidemiological data. You can't exercise your way to reliably living to age 90 or 100, however, and you're still going to be severely impacted by degenerative aging when you get there. So why bother? Well, for one, because you'll likely undergo much less pain, suffering, and frailty along the way. Perhaps more importantly, however, this is an age of very rapid, accelerating progress in medical biotechnology. A few years counts when that is how long it takes to develop a prototype therapy, or for a well-supported set of clinical trials to run to completion, or for a medical business to start up and put its products into the global supply chain. A few years means the difference between today's technology and the next version. As we move into an era in which researchers are now trying to treat the causes of aging with increasing vigor, it becomes an ever better idea to improve your own personal odds of living to see the results.

Better midlife fitness may slow brain aging

People with poor physical fitness in their 40s may have lower brain volumes by the time they hit 60, an indicator of accelerated brain aging. "Many people don't start worrying about their brain health until later in life, but this study provides more evidence that certain behaviors and risk factors in midlife may have consequences for brain aging later on." A subset of 1,271 participants from the Framingham Offspring Study participated in exercise treadmill testing in the 1970s, when their average age was 41. Starting in 1999, when their average age was 60, they underwent magnetic resonance imaging (MRI) of their brains as well as cognitive tests. The participants did not have heart disease or cognitive problems at the beginning of the study, and none were taking medication that alters heart rate.

In individuals with low fitness levels, the blood pressure and heart rate responses to low levels of exercise are often much higher than in individuals with better fitness. The researchers found that people who had a lower fitness level or greater increase in diastolic blood pressure (bottom number) or heart rate a few minutes into the low-intensity treadmill test (2.5 miles an hour) had smaller brain tissue volume later in life. People who had a larger increase in diastolic blood pressure during low-intensity exercise also performed more poorly on a cognitive test for decision-making function later in life.

Poor heart function could be major risk for Alzheimer's disease

The study associates heart function with the development of dementia and Alzheimer's disease. Participants with decreased heart function, measured by cardiac index, were two to three times more likely to develop significant memory loss over the follow-up period. "Cardiac index is a measure of heart health. It reflects cardiac output or the amount of blood that leaves the heart and is pumped through the body taking into consideration a person's body size. A low cardiac index value means there is less blood leaving the heart."

"We thought heart disease might be driving the increased risk of dementia and Alzheimer's disease. When we excluded participants with heart disease and other heart conditions, we were surprised that the risk of dementia and Alzheimer's disease got even worse. The risk we found between lower cardiac index and the development of dementia may reflect a subtle but protracted process that occurs over decades - essentially a lifetime burden of subtle reductions in oxygen and nutrient delivery to the brain."

Nourishing the Aging Brain

Despite a wealth of research into why caloric restriction extends life, we are still rather far from pinpointing the mechanism behind the longevity effect of this dietary intervention. Of significant interest is how diets may affect aging in the brain, which is particularly sensitive to alterations in energy availability. Caloric restriction attenuates the progression of Alzheimer's disease in mouse models, for example, while diet-induced obesity exacerbates symptoms. By studying the influence of diet on aging in the brain, researchers have discovered a number of bioenergetic molecules and druggable targets that may serve as candidates for interventions to delay the onset of neurodegenerative disorders.

Calorie-restricted animals are smaller than their well-fed counterparts, perhaps corresponding to decreased cell proliferation, a phenomenon that occurs in response to energy deficits in both normal and cancer cells. Decreased cell proliferation may be important, as it also leads to slower division of stem cells, allowing these progenitor cell populations to supply the various cell types of the body for longer periods of time. This sparing of stem-cell pools could explain why dietary restriction is particularly effective in maintaining tissue homeostasis in rapidly proliferating tissues such as skin, hair, and bone marrow. Neural tissues, such as the brain and spinal cord, have a limited capacity to rejuvenate themselves through stem-cell renewal, however, perhaps explaining why dietary restriction may not impact these areas of the body as much as others.

Regenerative medicine for the brain that enables periodic repair in situ is essential to the future of human longevity. This is the only tissue in the body that cannot be outright replaced as a last resort, as its structure defines the data of the mind. Scientists are making some progress towards this goal, applying the tools developed in stem cell research in an increasingly refined way:

Researchers have taken an important step in the area of cell therapy: repairing the cerebral cortex of the adult mouse using a graft of cortical neurons derived from embryonic stem cells. The cerebral cortex is one of the most complex structures in our brain. It is composed of about a hundred types of neurons organised into 6 layers and numerous distinct neuroanatomical and functional areas. Brain injuries, whether caused by trauma or neurodegeneration, lead to cell death accompanied by considerable functional impairment. In order to overcome the limited ability of the neurons of the adult nervous system to regenerate spontaneously, cell replacement strategies employing embryonic tissue transplantation show attractive potential.

A major challenge in repairing the brain is obtaining cortical neurons from the appropriate layer and area in order to restore the damaged cortical pathways in a specific manner. The results show, for the first time, using mice, that pluripotent stem cells differentiated into cortical neurons make it possible to reestablish damaged adult cortical circuits, both neuroanatomically and functionally. These results also suggest that damaged circuits can be restored only by using neurons of the same type as the damaged area. This study constitutes an important step in the development of cell therapy as applied to the cerebral cortex.

Much research will be needed before there is any clinical application in humans. Nonetheless, for the researchers, "The success of our cell engineering experiments, which make it possible to produce nerve cells in a controlled and unlimited manner, and to transplant them, is a world first. These studies open up new approaches for repairing the damaged brain, particularly following stroke or brain trauma."

Link: http://presse-inserm.fr/en/repairing-the-cerebral-cortex-it-can-be-done/18316/

Researchers are investigating the use of ultrasound to reduce levels of harmful amyloid in the brain. At this point it is showing benefits in mice, but there is a way to go yet before there can be any certainty that this strategy can also work in humans:

From imaging babies to blasting apart kidney stones, ultrasound has proved to be a versatile tool for physicians. Now, several research teams aim to unleash the technology on some of the most feared brain diseases. The blood-brain barrier, a tightly packed layer of cells that lines the brain's blood vessels, protects it from infections, toxins, and other threats but makes the organ frustratingly hard to treat. Safely and temporarily opening the blood-brain barrier is a long-sought goal in medicine. About a decade ago, researchers began exploring a strategy combining ultrasound and microbubbles. The premise is that ultrasound causes such bubbles to expand and contract, jostling the cells forming the blood-brain barrier and making it slightly leaky.

Researchers hypothesized that the brief leakage would rev up the brain's inflammatory response against β amyloid - the toxic protein that clumps outside neurons in Alzheimer's and may be responsible for killing them. Disposing of such debris is normally the role of the microglia, a type of brain cell. But previous studies have shown that when β amyloid forms clumps in the brain, it seems to overwhelm microglia. Exposing the cells to antibodies that leak in when the blood-brain barrier is breached could spur them to wake up and do their jobs. Some antibodies in blood may also bind directly to the β-amyloid protein and flag the clumps for destruction.

Researchers recently tested the ultrasound strategy in a mouse model of Alzheimer's. After injecting these animals with a solution of microscopic bubbles, they scanned an ultrasound beam in a zigzag pattern across each animal's entire skull, rather than focusing on discrete areas as others have done. After six to eight weekly treatments, the team tested the rodents on three different memory tasks. Alzheimer's mice in the control group, which received microbubble injections but no stimulation, showed no improvement. Mice whose blood-brain barriers had been made permeable, in contrast, saw full restoration of memory in all three tasks. The team also found a two- to fivefold reduction in different types of β-amyloid plaques in the brain tissue of the treated group. The attempt to stoke microglia's appetite appeared to work; researchers found much more β-amyloid protein within the trash-eating cells of treated animals.

Link: http://news.sciencemag.org/biology/2015/03/ultrasound-therapies-target-brain-cancers-and-alzheimer-s-disease

Risk of cancer is very important in aging; as we become older we accumulate mutations in nuclear DNA at an accelerating rate. Sooner or later the right combination occurs to create a cancerous cell, set to divide without limit, its safeguard mechanisms broken. If that cell is not caught and destroyed by the immune system then its progeny form a tumor and mutate further at an increased pace. The tumor eventually grows large enough to disrupt a nearby vital organ or spreads copies of itself to a place where that can happen, and that is the end of the story for you. Cancer can happen at any age, but it is predominantly an age-related disease because the odds are based on the level and pace of DNA damage.

Any future rejuvenation toolkit has to incorporate a robust cure for cancer. Some combination of mature next generation targeted therapies and advanced detection for early stage, more easily cured cancers should be good enough when we're talking about supporting the addition of a few decades of additional healthy life expectancy. Being able to control 95% of all cancers would probably buy that much runway for most people, provided all the other necessary components of rejuvenation were also present and available. Once we consider more time spent alive and accumulating DNA damage, something more effective will be needed. Perhaps this will prove to be along the lines of blocking all telomere lengthening mechanisms as needed, or perhaps the current genetic revolution will lead - a few decades from now - to nanomachinery or gene therapies capable of cell by cell reversion of genetic alterations to a known good base sequence.

If we believe that a robust cancer cure is good enough to cover a few decades of additional healthy life added to the present human life span, then we shouldn't be all that worried about the state of progress in cancer research. Or at least, there is little we can do as advocates for longevity science that isn't already being done a hundred times more loudly and effectively by the present cancer advocacy community. Cancer research is very well funded indeed, and largely moving in the right direction. A great deal of innovation is taking place in the laboratory, for all that the present state of regulation makes it very slow going indeed for any of that to arrive in the clinic. If, as is the case at the SENS Research Foundation, we think that more than merely robust cancer cures are needed, then there are other lines of work to support, based on the aforementioned blocking of telomere lengthening.

At the detail level, and in the mainstream of cancer research, success over the next decade or two is driven by the degree to which researchers can find and exploit commonalities in cancer. Producing a treatment that works for twenty types of cancer is much better than one that is restricted to a single type. There are so very many types of cancer that meaningful progress over the field as a whole will be overwhelmingly determined by success or failure to identify and exploit such commonalities. Not all that many people are willing to go the whole hog and work on turning off telomere lengthening, which is the one clear thing that all cancers require, but in recent years scientists have identified a number of different mechanisms that may work as therapeutic targets for fairly broad collections of cancers. It is still very early days when it comes to seeing what will work and what will not, however. The researcher quoted in the interview below is working on one such cancer commonality, but like most of the mainstream he is fairly pessimistic on whether or not these commonalities will be enough:

Will there be a cancer cure in our lifetimes?

In graduate school, Barrie Bode conducted research aimed at expanding knowledge of the biochemistry and metabolism of a normal human liver. He was particularly interested in how the liver regulated the transport and metabolism of an amino acid known as glutamine. A year after earning his Ph.D., he came across two lines of cells from a cancerous liver. On a whim, he measured the rate of glutamine import into those cancer cells - and was stunned to find it was about 10 times higher than normal. That observation changed the course of his life's work. It also led to the identification of two specific amino acid transporters that are elevated in a wide spectrum of primary human cancers and aid tumor growth. For the past two decades, Bode has been working to develop highly targeted therapies to slow the uptake of glutamine and other nutrients that feed cancer.

"I think my research group is working in one of the hot areas of cancer research - identifying unique metabolic changes in cancer and developing ways to slow, stop or exploit these changes. We're not alone in this pursuit. These are exciting times. The scientific knowledge emerging annually is staggering. And it's really revealing the complexity of these diseases that we collectively call cancer. We are light years ahead of where we were just 20 years ago and are learning new things about the biology of cancer literally each week. In fact, we're generating so much data now - including sequences of nucleic acids, sequences of expressed proteins within a tumor, the chemical signatures of metabolic systems - that there is a little bit of a bottleneck. It's not a dearth of data that's limiting medical researchers but the necessary analyses of the available and emerging data. Those analyses will ultimately reveal cancer's complex fabric and vulnerabilities.

"I do not think there will be a cure for cancer in our lifetimes. It's still going to be a long road, but there is good news for cancer patients. Cancer is just a catchall phrase for dozens of different diseases that have the same endpoint - uncontrolled growth of tissue driven by mutated cells. Each cancer is complex and different, and even within a tissue there are distinct forms or cancer - different kinds of colon, breast, liver and brain cancers, for example, all driven by unique mutations and behaviors. Some types of cancer might be cured - that's happened already. But new pharmaceutical cures are rare. Over the next century, I'd say the chance is very remote that we will find a single 'cure for cancer.' Instead, treatments will become more refined and targeted, informed by the science and technologies that are available so that cancer can be managed much like other diseases, such as heart disease and diabetes. The plasticity, or ability to change, of cancer cells will require that these treatments be modified over time.

"There is a lot of cancer research going on, but there could be much more. The National Cancer Institute receives about 11 percent of the National Institutes of Health budget. The NIH budget likewise is about 10 percent of the national defense budget. So by deduction, we're funding cancer research at a penny for every dollar of defense."

Proteostasis is the continued normal balance of protein levels and uses in cells. Aging and age-related disease by definition involve loss of proteostasis, such as through cellular damage and reactions to that damage. A wide array of mechanisms work to maintain proteostasis, and the list should probably include near all of those involved in protein production, folding, and recycling. There are far more researchers focused on this aspect of aging than on damage repair after the SENS model, in which it is argued that we should focus on fixing underlying damage, at which point proteostasis mechanisms should be free to restore the normal balance of cellular operations:

Protein turnover decreases with age, resulting in a progressive accumulation of damaged proteins and propagation of the aging phenotype. Maintaining protein homeostasis (i.e., proteostasis) through coordination of mRNA translation, protein synthesis, protein folding, and protein breakdown may be a key component of slowed, or healthy aging. Therefore, models of slowed aging may provide valuable insight into the role of proteostasis and how proteostatic mechanisms are regulated during slowed aging. We have proposed that simultaneously assessing both protein and DNA synthesis through deuterium oxide incorporation (D2O) can provide insight into what proportion of new proteins is made in new versus existing cells.

Here, we present a tissue- and sex-specific assessment of proteostasis using DNA and protein synthesis in long-lived Snell dwarf mice. We demonstrate that proteostatic mechanisms, as assessed by the new protein to new DNA synthesis ratio, were increased by threefold in skeletal muscle and heart of Snell compared to normal controls. Mean lifespan in female Snell is increased by approximately 50% compared to normal controls, while male Snell dwarfs have an approximate 29% increase in mean lifespan compared to their respective sex-specific controls. With the exception of protein synthesis in skeletal muscle, there were no sex differences in protein or DNA synthesis. Although differences in proteostatic mechanisms do not explain subtle sex differences in lifespan extension, it is important to note that both sexes have increased proteostatic mechanisms as well as significant lifespan extension. Collectively, our data further suggest proteostasis is a shared characteristic of slowed aging.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12329/

There are very many speculative theories on mechanisms of aging that await studies to prove or disprove their effects, as well as to demonstrate whether or not those effects are significant over a human life span. Here is one of them:

We propose to focus on cells that either do not replicate in adults or accomplish very few divisions during the lifespan of an organism - that is, far less than set by the Hayflick limit. For the purpose of this review, we will term these cells below Hayflick limit (BHL) cells. Below Hayflick limit cells include postmitotic cells such as terminally differentiated neurons and muscle cells, and female ova, which are formed during embryonic development and remain in a nonproliferating state for decades. Below Hayflick limit cells are interesting for the following reason: On the one hand, they are far from entering the replicative senescence state; on the other hand, due to the constant molecular turnover and active metabolism in these cells (even in the absence of replication), the lifespan of an adult organism should lead to accumulation of irreversible changes, which could contribute to organismal aging.

One principal carrier of epigenetic information is chromatin - a hierarchically organized complex of DNA, histones, and nonhistone proteins. Not surprisingly, the recent interest in 'all things epigenetic' begat new ideas on the role of chromatin in aging. It has been known since the 60s that DNA methylation is progressively lost with aging. Could epigenetic changes also irreversibly accumulate with time in BHL cells thus contributing to organismal, but not replicative, senescence?

We discuss the possibility that in nonreplicating cells, epigenetic modifications, and more specifically very particular changes in chromatin structure - the gradual replacement of canonical histones H3.1/H3.2 with variant histone H3.3 - could contribute to organismal aging by inducing aberrations in gene regulation and other functions in BHL cells. Although this hypothesis has not been directly supported by a plethora of experimental data as yet, the aggregation of existing claims and accumulating evidence leads almost inevitably to paradoxical conclusions about the role of H3.3 in BHL cells with tempting implications with regard to the aging process. The 'H3.3 dilemma', as we term this situation in the field, is both sufficiently intriguing and convincing to be worth-raising, in the hope that it will trigger new directions and efforts for research.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12332/

Adding decades or adding centuries of health and vigor to human life spans are in fact much the same thing: success in adding decades in an environment of rapid progress in biotechnology means that all those people have time to wait for new technologies that add yet further decades. As soon as future rejuvenation treatments reach that point of initial effectiveness, at which years are added more rapidly than the passing of time erodes them, then most recipients are on a trajectory towards indefinite healthy life. This is shocking for many people when they first think it through, but it is a very straightforward, logical outcome of progress in medicine. Aging is just a medical condition; it is not set in stone, nor is it so mysterious that researchers cannot today be working on ways to remove its causes. In fact there are groups now, such as the SENS Research Foundation and Methuselah Foundation, that have been advocating and funding scientific work in this area for more than a decade.

It always takes far too long to sell the mainstream of any field on a new idea, even when that idea is obviously excellent and obviously an improvement on present affairs. So it is with the goal of repairing the causes of aging, and even the very concept of treating aging as a medical condition. Interest in treating aging in the medical research community has lagged very far behind the bounds of the possible these past two decades, and it has required a great deal of advocacy to get to where we are today. Ten years ago talking about rejuvenation via an implementation of SENS biotechnologies that repair various forms of cellular and molecular damage thought by the consensus to be involved in aging was called fringe, laughed at, or rejected out of hand. Today we see the start of mainstream researchers working on exactly the projectsproposed by SENS and companies founded to build commercial treatments. It is good to be right, but much better when everyone else starts to agree with you and, more importantly, work what has to be done.

Further, now we're in a time where large organizations like Google Ventures are openly putting a lot of money towards the goal of radical life extension. As of the moment they are not actually funding any work that has a hope of achieving that goal, rather mainstream efforts likely only to produce therapies capable of marginally slowing aging, but it is an important step in the growing support and legitimacy granted to longevity research. It is hard for talking heads to laugh at this work now, and from here on out that means increased funding, while the lines of research with a good chance of success will slowly overtake the current mainstream by demonstrating their better prospects at each stage of development. As that happens organizations like Google Ventures will begin to pour funding into that work. The first steps in this process are happening right now for senescent cell clearance, and will happen for other repair based technologies from the SENS portfolio as they bootstrap their way to success - something that depends very much on people like you and I helping philanthropists to deliver the needed funding, by the way.

Google Ventures and the Search for Immortality

Bill Maris has $425 million to invest this year, and the freedom to invest it however he wants. He's looking for companies that will slow aging, reverse disease, and extend life. "If you ask me today, is it possible to live to be 500? The answer is yes," Bill Maris says one January afternoon in Mountain View, California. The president and managing partner of Google Ventures just turned 40, but he looks more like a 19-year-old college kid at midterm. He's wearing sneakers and a gray denim shirt over a T-shirt; it looks like he hasn't shaved in a few days. "We actually have the tools in the life sciences to achieve anything that you have the audacity to envision," he says. "I just hope to live long enough not to die."

Google puts huge resources into looking for what's coming next. In 2014, it started Google Capital to invest in later-stage technology companies. Maris's views on the intersection of technology and medicine fit in well here: Google has spent hundreds of millions of dollars backing a research center, called Calico, to study how to reverse aging, and Google X is working on a pill that would insert nanoparticles into our bloodstream to detect disease and cancer mutations. "There are plenty of people, including us, that want to invest in consumer Internet, but we can do more than that," he says. He now has 36 percent of the fund's assets invested in life sciences, up from 6 percent in 2013. "There are a lot of billionaires in Silicon Valley, but in the end, we are all heading to the same place," Maris says. "If given the choice between making a lot of money or finding a way to make people live longer, what do you choose?"

I also recently noticed the online post for an NPR interview from late last year. You might have missed the first time around, so here it is again:

Achieving Immortality: How Science Seeks to End Aging

The dream to live forever has captivated mankind since the beginning. We see this in religion, literature, art, and present day pop-culture in a myriad of ways. But all along, the possibility that we'd actually achieve such a thing never quite seemed real. Now science, through a variety of medical and technological advances the likes of which seem as far fetched as immortality itself, is close to turning that dream into a reality. This hour, we talk with experts who are on the cutting edge of this research about the science and implications of ending aging:

Wendell Wallach - consultant, ethicist, and scholar at Yale's Center for Bioethics where he chairs the working research group on Technology and Ethics. His upcoming book, "A Dangerous Master: How To Keep Technology From Slipping Beyond Our Control," will be out May 12th of 2015.

Aubrey de Grey - leading expert on anti-aging medicine and technology as well as the Chief Science Officer of the SENS Research Foundation. He's the co-author of "Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime"

Stephen Cave - Fellow of the Royal Society of Arts. He holds a PhD in Metaphysics from Cambridge, and has worked as a diplomat for The Queen of England. He's the author of "Immortality: The Quest to Live Forever and How It Drives Civilization"

The present consensus on Alzheimer's disease focuses on the accumulation of misfolded proteins into amyloid plaques as the crucial mechanism, and thus clearing amyloid is a major research focus. Turning this focus into working therapies is taking far longer than expected, however, with numerous disappointing outcomes along the way so far. This state of affairs leads to a research environment in which other theories and approaches are multiplying, in search of better results. The example noted below is one of a great many initiatives that incorporate a quite different way of looking at the mechanisms of Alzheimer's disease:

The lipid Ceramide is pervasive throughout the human body as well as other animal and plant species. Researchers have identified elevated ceramide levels as a risk factor for Alzheimer's and have shown that amyloid triggers excess production of the lipid, although precisely how and why remain a mystery. That synergy had the scientists expecting that generating antibodies against ceramide would hamper plaque formation. Instead they found that the excessive ceramide had already worked its way into the bloodstream, generating antibodies that supported disease progression, particularly in female mice. This appears to support the theory that Alzheimer's is an autoimmune disease, which tends to be more common in women and is characterized by the immune system producing antibodies against a patient's tissue.

It also has researchers thinking that measuring blood levels of the lipid or some of its byproducts could be an early test for Alzheimer's since ceramide levels were elevated well before mice showed signs of substantial plaque formation. "It's a chicken-egg situation. We don't know if the anti-ceramide antibodies that may develop naturally during disease might be a result or a cause of the disease." The researchers are now circling back to a previous approach of directly blocking ceramide, this time, using a genetically engineered mouse that from birth lacks an enzyme needed to make ceramide, then crossbreeding it with an Alzheimer's mouse model. They expect that the mice genetically programmed to get Alzheimer's will produce less ceramide and less amyloid.

Link: http://www.eurekalert.org/pub_releases/2015-03/mcog-sfp030915.php

Here is a brief look at one small slice of research efforts focused on aging as it pertains to the extracellular matrix, the intricate structure of proteins that surrounds and supports cells. The arrangement of extracellular matrix proteins determines the mechanical properties of a given tissue, such as elasticity or ability to bear load:

The Blackwell lab focuses on research in healthy aging and lifespan by studying the model organism C. elegans, which is a type of worm. The lab specifically focuses on understanding oxidative stress responses and collagen development profiles in relation to lifespan. A simplified way of thinking about how collagen and extracellular matrix relate to lifespan is that as one grows older, the collagen and extracellular matrix slowly breakdown and are not as quickly repaired when injured. This is seen most prominently in cartilage-based injuries. Cartilage is made of collagen and extracellular matrix. A knee injury affecting the cartilage will heal much faster in young individuals than older individuals.

In C. elegans the SKN-1 gene plays a key role in promoting longevity through various pathway regulation including proteasome maintenance, stress resistance, immunity and lipid metabolism. One of the more surprising findings from these studies was the observation that SKN-1 was also involved in regulation of extracellular matrix genes and the resulting collagen expression profiles that change as the organism ages. SKN-1 dependent extracellular matrix remodeling is critical for lifespan extension in C. elegans. Several longevity interventions that delay aging are, in part, successful due to enhancing the function of extracellular structures.

C. elegans is the simplest multicellular animal with tissues that can conceivably be compared to humans. It was originally chosen in the 1970s as a model organism. Some of its advantages are that it reproduces in a few days and it self-fertilizes, which can make genetic manipulation much easier. It is a great organism for studying aging, because you can do so much to it genetically, and you can see the effects of aging in a short amount of time. With respect to translatability, I think there is a tendency to always question that. But worms and humans share the most fundamental processes, and the most basic wiring is there. So for testing an idea or delving into the unknown, C. elegans is a great organism to start with.

Humans have a much more complex profile of collagens, so it is hard to draw direct comparisons literally. However, I think the remodeling of the extracellular matrix and collagen is important in human aging. As an example, collagen decreases in the skin with age, as does the elasticity, and as elasticity decreases this further drives a decrease in collagen levels. The extracellular matrix is certainly an area that could use further studies on the effects of aging on the matrices to evaluate what changes occur over time.

Link: http://sage.buckinstitute.org/?p=951

As we age, an increasing number of cells fall into a senescent state in which they cease dividing and begin to secrete all sorts of compounds that both harm surrounding tissue structure and raise the odds of nearby cells also becoming senescent. This seems to be a tool of embryonic development that now also acts to suppress cancer risk by removing the ability to divide from those cells most likely to become cancerous. Unfortunately it harms tissue function in doing so, and worse, only actually suppresses cancer risk when there are comparatively few senescent cells. Given a lot of these cells their activities cause chronic inflammation and other issues that in fact raise the risk of cancer, and help cancer cells to prosper where they do arise. By the time we reach old age, a high proportion of cells in many tissues are senescent.

The Strategies for Engineered Negligible Senescence, SENS, is a package of research programs based on repair of the known forms of cellular and molecular damage that cause aging. It is the path to true rejuvenation therapies, rather than merely slowing the progression of aging, and thus is worthy of far more attention and funding than it has at present. Some parts of the SENS research programs have gained more attention in recently years, however. It seems to me that I was on the ball a few years back when I suggested senescent cell clearance would be the first SENS technology to arrive. Since the 2011 demonstration of senescent cell clearance to slow down degenerative aging in a laboratory lineage of aging-accelerated mice, an increasing amount of attention has been given to removing senescent cells. A startup was funded early this year to work on one possible attempt, for example.

A few years ago I thought that meaningful progress here would be something along the lines of repurposing the targeted cell killing technologies under development in the cancer research community: identify a clear molecular signal for cellular senescence, assemble a treatment based on a sensor mechanism attached to a destructive payload, and introduce millions of them into the body. I still think that is the best way forward to obtain high degrees of cell clearance. However, the present research industry is very focused on drugs, and especially focused on the reuse of existing drugs even if the outcome is marginal. So it may very well be that the first senescent cell clearance therapies are (a) not all that great in terms of degree of clearance, and (b) based on drug candidates that already exist or are slight modifications of what already exists.

Still, as this news shows, senescent cell clearance is a part of the mainstream now. The people pursuing it are never going to mention SENS, but fifteen years of persistent advocacy and small-scale funding of early staging research for SENS goals has brought senescent cell clearance as a strategy to its present position. Let that not be forgotten. Let it also be noted that the effects of actually trying to repair some of the damage outlined in the SENS viewpoint are already more impressive than most of the efforts to slow aging over the past decade: drugs aiming to alter metabolism by targeting targeting sirtuins, mTOR, and so forth. This is what we should expect. Repair should always produce better results that simply tinkering with the mechanism to slightly slow the pace of damage. Full healthspan and lifespan studies in mice remain to be carried out for this approach, however, so the degree to which it affects the bottom line as well as other measures has yet to be determined.

Scripps Research, Mayo Clinic Scientists Find New Class of Drugs that Dramatically Increases Healthy Lifespan

The scientists coined the term "senolytics" for the new class of drugs. "We view this study as a big, first step toward developing treatments that can be given safely to patients to extend healthspan or to treat age-related diseases and disorders. When senolytic agents, like the combination we identified, are used clinically, the results could be transformative. The prototypes of these senolytic agents have more than proven their ability to alleviate multiple characteristics associated with aging. It may eventually become feasible to delay, prevent, alleviate or even reverse multiple chronic diseases and disabilities as a group, instead of just one at a time."

Senescent cells - cells that have stopped dividing - accumulate with age and accelerate the aging process. Since the "healthspan" (time free of disease) in mice is enhanced by killing off these cells, the scientists reasoned that finding treatments that accomplish this in humans could have tremendous potential. The scientists were faced with the question, though, of how to identify and target senescent cells without damaging other cells. The team suspected that senescent cells' resistance to death by stress and damage could provide a clue. Indeed, using transcript analysis, the researchers found that, like cancer cells, senescent cells have increased expression of "pro-survival networks" that help them resist apoptosis or programmed cell death. This finding provided key criteria to search for potential drug candidates.

Using these criteria, the team homed in on two available compounds - the cancer drug dasatinib and quercetin, a natural compound sold as a supplement that acts as an antihistamine and anti-inflammatory. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse bone marrow stem cells. A combination of the two was most effective overall.

Next, the team looked at how these drugs affected health and aging in mice. "In animal models, the compounds improved cardiovascular function and exercise endurance, reduced osteoporosis and frailty, and extended healthspan. Remarkably, in some cases, these drugs did so with only a single course of treatment." In old mice, cardiovascular function was improved within five days of a single dose of the drugs. A single dose of a combination of the drugs led to improved exercise capacity in animals weakened by radiation therapy used for cancer. The effect lasted for at least seven months following treatment with the drugs. Periodic drug administration of mice with accelerated aging extended the healthspan in the animals, delaying age-related symptoms, spine degeneration and osteoporosis.

The authors caution that more testing is needed before use in humans. They also note both drugs in the study have possible side effects, at least with long-term treatment. The researchers, however, remain upbeat about their findings' potential. "Senescence is involved in a number of diseases and pathologies so there could be any number of applications for these and similar compounds. Also, we anticipate that treatment with senolytic drugs to clear damaged cells would be infrequent, reducing the chance of side effects."

The Achilles' Heel of Senescent Cells: From Transcriptome to Senolytic Drugs

The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis.

Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose.

These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.

The cryonics industry conferences hosted by Alcor take place every three years. The last was in 2012, and if you take a look at the Alcor YouTube channel you'll find videos from the event. These conferences are well attended by scientists in various fields, and the presentations are always interesting. The next conference in the series will be held later this year: the date is October 9th and the place is Scottsdale, Arizona:

We hold the Alcor conferences only once every three years. We heard from many people who didn't make it to the 2012 conference who expressed regret after hearing about it from those who went. This will be a rare opportunity to network and hear about progress in numerous areas directly from those involved.

We will very soon start announcing speakers and topics. For now, we plan to cover repair and revival scenarios, rehabilitation, and reintegration; the evidence supporting cryonics; how a regular person can afford cryonics and best plan for funding it and their own post-revival life; legal challenges and progress; multiple approaches to eliminating fracturing and other forms of damage; and much more!

This conference should be the largest cryonics conference yet, and we want the videos of sessions to serve a powerful educational and inspirational purpose for years to follow. There is already a substantial list of possible speakers and sessions but it is not too late to suggest your own ideas! Get your thoughts and suggestions in soon though, because the program will fill up over the next few weeks.

Link: http://www.alcor.org/blog/alcor-conference-2015-october-9-11/

One of the frustrating and probably incurable aspects of the popular press is that when a journalist reviews a field of work, he or she tends to paint every initiative as equal. So when it comes to efforts to extend human life span, no distinction is made between projects that have a good chance of achieving radical life extension or rejuvenation and those that can at best produce a slight slowing of aging, or those that are practical and supported by the present state of scientific knowledge versus highly speculative goals that may not be possible to achieve for a lifetime yet. To the journalist, these are all the same thing. It is something to think about whenever you read an article on an area of research or business with which you have no familiarity. You might not be learning as much as you think you are:

Peter Thiel, the billionaire co-founder of PayPal, plans to live to be 120. Compared with some other tech billionaires, he doesn't seem particularly ambitious. Dmitry Itskov, the "godfather" of the Russian Internet, says his goal is to live to 10,000; Larry Ellison, co-founder of Oracle, finds the notion of accepting mortality "incomprehensible," and Sergey Brin, co-founder of Google, hopes to someday "cure death." These titans of tech aren't being ridiculous, or even vainglorious; their quests are based on real, emerging science that could fundamentally change what we know about life and about death. It's hard to believe, though, since the human quest for immortality is both ancient and littered with catastrophic failures.

But historical precedent hasn't dissuaded some of the biggest names in Silicon Valley. Thiel, for example, has given $3.5 million to the Methuselah Foundation. Aubrey de Grey, Methuselah's co-founder, says the nonprofit's main research initiative, Strategies for Engineered Negligible Senescence (SENS), is devoted to finding drugs that cure seven types of age-related damage: "Loss of cells, excessive cell division, inadequate cell death, garbage inside the cell, garbage outside the cell, mutations in the mitochondria, and crosslinking of the extracellular matrix.... The idea is that the human body, being a machine, has a structure that determines all aspects of its function, including its chance of falling apart any time soon, so if we can restore that structure - at the molecular and cellular level - then we will restore function too, so we will have comprehensively rejuvenated the body."

But SENS, which has an annual operating budget of $5 million, is puny compared with the Brin-led Project Calico, Google's attempt to "cure death," which is planning to pump billions into a partnership with pharmaceutical giant AbbVie. Google is notoriously secretive, but it's rumored to be building a drug to mimic foxo3, a gene associated with exceptional life span. Then there's the Glenn Foundation for Medical Research, the granddaddy of modern antiaging initiatives, started by venture capitalist Paul F. Glenn in 1965. Since 2007, the foundation has distributed annual "Glenn Awards," $60,000 grants to independent researchers doing promising work on aging. The Glenn Foundation also works to kick-start antiaging initiatives within large institutions ("It began at Harvard, and then we sought out MIT and then the Salk Institute and then the Mayo Clinic," Mark R. Collins, spokesman for the Glenn Foundation, explains), and it puts more than $1 million per year toward grants by the American Federation for Aging Research, a charitable foundation dedicated to age-related disease.

Link: http://www.newsweek.com/2015/03/13/silicon-valley-trying-make-humans-immortal-and-finding-some-success-311402.html

Everything we know about the way in which people fall apart with age is based on what happened in the past. The research community has access to centuries of good epidemiological data to demonstrate what to expect in old age both with and without modern medicine. Though when you stop to think about the old today, bear in mind that the oldest old spent most of their old age in a time prior to genetic testing, highly effective heart therapies, and many other developments of the past twenty years. Those who are merely elderly still lived half their lives in a medical environment that would appear extremely primitive to anyone forced to cope with it today. We don't tend to think of the period from the 1940s to the 1960s as a backwards era of low-tech medicine, as little separates us culturally from those years, but the widely available medicine of the time was indeed lacking in comparison to today's technology.

Life expectancy is an odd and often misunderstood measure. It doesn't predict future life spans, but rather is a statistical measure of the average life span of a given birth year cohort if they relived the same life history as did the present population of old people. That means the same technologies, the same economic circumstances, the same pace of progress, and so forth. Obviously that won't happen: life expectancy is a useful statistical measure for comparing progress in medicine from year to year, and it does keep on going up, but it isn't a useful tool to inform you of how long you will live. That timeline remains to be determined, and we live in a time of very rapid improvement in biotechnology.

At the best of times there is a decade of lag between laboratory demonstrations and widespread availability in the clinic, and the present state of regulation is far from the best of times. There is a growing disconnect between the accelerating progress of cellular biotechnology and the ever heavier ball and chain shackled to clinical implementation of that research. The gap is widening now, but I think that in the future medical tourism and competition between regulatory regions will overcome this issue: there will be a sudden flood of pent up technology over a fairly short period of time, but who knows when the dam will finally break. The costs of medical development are falling to ever smaller fractions of the present cost of regulatory compliance: if development to the point of practical and reasonably safe usability costs $50 million while compliance costs $500 million, and that isn't too far from the actual state of affairs, then something has to give.

The modern upward trend in adult life expectancy has spanned centuries, created first by control over sanitation and infectious disease, and later by increasingly effective treatments for age-related conditions. We should not expect this to continue as it has been, however. This decade and the opening years of the next are an important transitional period, a shift between (a) the past age in which no attempt was made to treat the causes of aging as a medical condition and (b) the new era in which researchers are focused on aging itself rather than merely patching over its consequences. We should expect a great difference in the trendline of human longevity in the decades ahead precisely because there is a great difference between trying to treat aging and not trying to treat aging.

Thus this paper is not a roadmap for the future of those in their 30s and 40s today. Rather it is a look back at the results of the past for those who are old today:

Age-Related Variation in Health Status after Age 60

Disability, functionality, and morbidity are often used to describe the health of the elderly. Although particularly important when planning health and social services, knowledge about their distribution and aggregation at different ages is limited. The older population consists of an extremely heterogeneous group of persons; the older the age group, the greater the variation found in cognition, physical and sensory function, and social engagement, to mention just a few examples.

We aim to characterize the variation of health status in 3080 adults 60+ living in Sweden between 2001 and 2004 and participating at the SNAC-K population-based cohort study using five indicators of health separately and in combination: number of chronic diseases, gait speed, Mini Mental State Examination (MMSE), disability in instrumental-activities of daily living (I-ADL), and in personal-ADL (P-ADL). Probability of multimorbidity and probability of slow gait speed were already above 60% and 20% among sexagenarians. Median MMSE and median I-ADL showed good performance range until age 84; median P-ADL was close to zero up to age 90. 30% of sexagenarians and 11% of septuagenarians had no morbidity and no impairment, 92% and 80% of them had no disability. 28% of octogenarians had multimorbidity but only 27% had some I-ADL disability. Among nonagenarians, 13% had severe disability and impaired functioning while 12% had multimorbidity and slow gait speed.

In this large cohort, we were able to capture the complexity and heterogeneity of health status in 60+ old adults. Until 80, most people do not have functional impairment or disability, despite the presence of morbidity or even multimorbidity. Disability is common only after age 90. The 80s are a transitional period when major health changes take place; often following the co-occurrence of more than one negative health event. If we consider good health as the absence of chronic diseases, functional impairment, and disability, good health is still the most prevalent pattern among sexagenarians. However, even among octogenarians, the most prevalent health state is characterized by presence of chronic disorders with impairment only in gait speed. In other words, morbidity and multimorbidity start early in late adulthood, but functional dependence becomes common only for people older than age 90.

One interesting correlation that has emerged fairly recently from very large epidemiological studies of health is that sitting time is associated with worse health and a shorter life expectancy independently of exercise. Explaining why this is the case is a still a fairly speculative process at this stage, but a first step is to try to pin down specific aspects of age-related disease and degeneration and associate those with sitting time.

Here researchers focus on the calcification of blood vessels, a part of the mineralization of connective tissues that occurs in aging. Along with cross-linking due to sugary metabolic waste, this process stiffens blood vessel walls. This in turn causes hypertension, contributes to atherosclerosis, and causes all sorts of further damage to tissues throughout the body due to structural failure in small blood vessels and inappropriate blood pressure. As for cross-links, there is a minimal amount of research taking place on how to demineralize tissues, but far from enough.

Sitting for many hours per day is associated with increased coronary artery calcification, a marker of subclinical heart disease that can increase the risk of a heart attack. The study found no association between coronary artery calcification and the amount of exercise a person gets, suggesting that too much sitting might have a greater impact than exercise on this particular measure of heart health. The results suggest that exercise may not entirely counteract the negative effects of a mostly sedentary lifestyle on coronary artery calcium. "It's clear that exercise is important to reduce your cardiovascular risk and improve your fitness level. But this study suggests that reducing how much you sit every day may represent a more novel, companion strategy (in addition to exercise) to help reduce your cardiovascular risk."

Coronary artery calcification, measured through a non-invasive CT heart scan, indicates the amount of calcium contained in plaques within the heart's arteries. Coronary artery disease occurs when such plaques accumulate over time, causing the arteries to narrow. Analyzing heart scans and physical activity records of more than 2,000 adults living in Dallas, the researchers found each hour of sedentary time per day on average was associated with a 14 percent increase in coronary artery calcification burden. The association was independent of exercise activity and other traditional heart disease risk factors. A particular strength of the study is that the researchers used a motion-tracking device called an accelerometer to measure how long participants were sedentary and how much they exercised, whereas most previous studies have relied on surveys.

Link: http://www.acc.org/about-acc/press-releases/2015/03/05/16/19/study-bolsters-link-between-heart-disease-excessive-sitting

Epidemiological studies of members of long-lived families are driving much of the interest in the genetics of longevity. While it is thought that genetic variations are much less important than lifestyle choices, they appear to become more influential in extreme old age, in the period of life when individuals are very damaged and frail. Investigating the root causes of such variations in human longevity is good science, but probably irrelevant to the future of longevity-enhancing medicine: effective therapies will repair damage and keep people young, indefinitely postponing the phase of life and loss of function in which genetic differences have any meaningful effect.

In this study, members of long-lived families are compared with age-matched individuals from families of ordinary longevity, and they are largely more healthy, as you'd expect. Aging is a global phenomenon of damage accumulation, and people who live longer tend to be less damaged and thus more healthy at a given age. Other studies have provided evidence for a genetic component to familial longevity, but note the spouse effect here however. That spouses marrying into long-lived families are also more healthy than the general population suggests that lifestyle choices continue to have a fairly strong influence on this data even in later ages:

The Long Life Family Study (LLFS) is a multicenter longitudinal study of exceptional survival among members of long-lived sibships (probands), their offspring, and spouses of either group. For these four "roles", we asked: Does membership in a long-lived family protect against disease? We used 2008-2010 Beneficiary Annual Summary Files from the Centers for Medicare & Medicaid Services (CMS) to compare prevalences of 17 conditions among 781 LLFS participants in Medicare with those of 3,227 non-LLFS matches from the general Medicare population.

Seven conditions were significantly less common among LLFS probands than their matches: Alzheimer's, hip fracture, diabetes, depression, prostate cancer, heart failure, and chronic kidney disease. Four diseases not strongly linked to mortality (arthritis, cataract, osteoporosis, glaucoma) were significantly more common for LLFS probands. Despite fewer people and less disease in those roles, LLFS offspring and LLFS spouses of either generation also had significantly lower risk for Alzheimer's, diabetes, and heart failure.

Common, severe mortality-associated diseases are less prevalent among LLFS probands and their offspring than in the general population of aging Americans. Quality-of-life-limiting diseases such as arthritis and cataract are more prevalent, potentially through more diagnosing of milder forms in otherwise healthy and active individuals. LLFS spouses are also relatively healthy. As the younger cohorts age into Medicare and develop more conditions, it will be important to see whether these tentative findings strengthen.

Link: http://dx.doi.org/10.1093/gerona/glv015

Age-related deterioration in blood vessels and the broader cardiovascular system generates damage in the brain. Blood vessel walls are elastic, a property that depends on the molecular structure of the proteins making up the extracellular matrix in that tissue. This structure is progressively degraded by the presence of sugary metabolic waste known as advanced glycation end-products (AGEs), which leads to the formation of cross-links between proteins and a consequent loss of elasticity. Stiffening of blood vessels causes hypertension and many of the cellular and molecular mechanisms involved overlap with those that speed the progression of atherosclerosis, a condition in which blood vessel walls become sources of chronic inflammation and are remodeled into fatty deposits by abnormal cellular activity. All of this causes a rising number of structural failures in the small blood vessels of the brain. Each one is effectively a tiny, unnoticed stroke, killing cells in a minuscule area of the brain. This harm adds up over time and is one of the contributing causes of age-related cognitive impairment.

A recently published paper suggests that more of the age-related changes observed in the brain may be due to vascular degeneration than previously thought. If so this implies that research aimed at removing cross-links has a greater importance, as do efforts to block the very early causes of atherosclerosis, such as the generation of oxidized lipids due to mitochondrial DNA damage. It also places a greater value on the basics of cardiovascular health in general: fitness, exercise, resilience, and so forth. When it comes to longevity and medicine, we must protect the brain: all other parts of the body could, in theory, be completely rebuilt or replaced if that becomes necessary, but the structure of the brain is the structure of the self. Lose that and there is nothing that can be done. Retain it and even if you must be cryopreserved as a last resort, there is still a chance at a future.

Human brains age less than previously thought

Older brains may be more similar to younger brains than previously thought. Researchers have demonstrated that previously reported changes in the ageing brain using functional magnetic resonance imaging (fMRI) may be due to vascular (or blood vessels) changes, rather than changes in neuronal activity itself. Given the large number of fMRI studies used to assess the ageing brain, this has important consequences for understanding how the brain changes with age and challenges current theories of ageing. A fundamental problem of fMRI is that it measures neural activity indirectly through changes in regional blood flow. Thus, without careful correction for age differences in vasculature reactivity, differences in fMRI signals can be erroneously regarded as neuronal differences. An important line of research focuses on controlling for noise in fMRI signals using additional baseline measures of vascular function. However, such methods have not been widely used, possibly because they are impractical to implement in studies of ageing.

An alternative candidate for correction makes use of resting state fMRI measurements, which is easy to acquire in most fMRI experiments. While this method has been difficult to validate in the past, the unique combination of an impressive data set across 335 healthy volunteers over the lifespan, as part of the CamCAN project, allowed researchers to probe the true nature of ageing effects on resting state fMRI signal amplitude. Their research showed that age differences in signal amplitude during a task are of a vascular, not neuronal, origin.

The effect of ageing on fMRI: Correction for the confounding effects of vascular reactivity evaluated by joint fMRI and MEG in 335 adults

In functional magnetic resonance imaging (fMRI) research one is typically interested in neural activity. However, the blood-oxygenation level-dependent (BOLD) signal is a composite of both neural and vascular activity. As factors such as age or medication may alter vascular function, it is essential to account for changes in neurovascular coupling when investigating neurocognitive functioning with fMRI. The resting-state fluctuation amplitude (RSFA) in the fMRI signal has been proposed as an index of vascular reactivity.

The use of RSFA is predicated on its sensitivity to vascular rather than neural factors. The effects of ageing on RSFA were significantly mediated by vascular factors, but importantly not by the variability in neuronal activity. The scaling analysis revealed that much of the effects of age on task-based activation studies with fMRI do not survive correction for changes in vascular reactivity, and are likely to have been overestimated in previous fMRI studies of ageing.

Many people believe that medical control over aging will be stunningly expensive, and thus indefinite extension of healthy life will only be available to a wealthy elite. This is far from the case. If you look at the SENS approach to repair therapies, treatments when realized will be mass-produced infusions of cells, proteins, and drugs. Everyone will get the same treatments because everyone ages due to the same underlying cellular and molecular damage. You'll need one round of treatments every ten to twenty years, and they will be given by a bored clinical assistant. No great attention will be needed by highly trained and expensive medical staff, as all of the complexity will be baked into the manufacturing process. Today's closest analogs are the comparatively new mass-produced biologics used to treat autoimmune conditions, and even in the wildly dysfunctional US medical system these cost less than ten thousand dollars for a treatment.

Rejuvenation won't cost millions, or even hundreds of thousands. It will likely cost less than many people spend on overpriced coffee over the course of two decades of life, and should fall far below that level. When the entire population is the marketplace for competing developers, costs will eventually plummet to those seen for decades-old generic drugs and similar items produced in factory settings: just a handful of dollars per dose. The poorest half of the world will gain access at that point, just as today they have access to drugs that were far beyond their reach when initially developed.

Nonetheless, many people believe that longevity enhancing therapies will only be available for the wealthy, and that this will be an important dynamic in the future. Inequality is something of a cultural fixation at the moment, and it is manufactured as a fantasy where it doesn't exist in reality. This is just another facet of the truth that most people don't really understand economics, either in the sense of predicting likely future changes, or in the sense of what is actually taking place in the world today:

The attitude now towards disease and old age and death is that they are basically technical problems. It is a huge revolution in human thinking. Throughout history, old age and death were always treated as metaphysical problems, as something that the gods decreed, as something fundamental to what defines humans, what defines the human condition and reality. Even a few years ago, very few doctors or scientists would seriously say that they are trying to overcome old age and death. They would say no, I am trying to overcome this particular disease, whether it's tuberculosis or cancer or Alzheimers. Defeating disease and death, this is nonsense, this is science fiction.

But, the new attitude is to treat old age and death as technical problems, no different in essence than any other disease. It's like cancer, it's like Alzheimers, it's like tuberculosis. Maybe we still don't know all the mechanisms and all the remedies, but in principle, people always die due to technical reasons, not metaphysical reasons. In the middle ages, you had an image of how does a person die? Suddenly, the Angel of Death appears, and touches you on the shoulder and says, "Come. Your time has come." And you say, "No, no, no. Give me some more time." And Death said, "No, you have to come." And that's it, that is how you die.

We don't think like that today. People never die because the Angel of Death comes, they die because their heart stops pumping, or because an artery is clogged, or because cancerous cells are spreading in the liver or somewhere. These are all technical problems, and in essence, they should have some technical solution. And this way of thinking is now becoming very dominant in scientific circles, and also among the ultra-rich who have come to understand that, wait a minute, something is happening here. For the first time in history, if I'm rich enough, maybe I don't have to die.

Death is optional. And if you think about it from the viewpoint of the poor, it looks terrible, because throughout history, death was the great equalizer. The big consolation of the poor throughout history was that okay, these rich people, they have it good, but they're going to die just like me. But think about the world, say, in 50 years, 100 years, where the poor people continue to die, but the rich people, in addition to all the other things they get, also get an exemption from death. That's going to bring a lot of anger.

And again, I don't want to give a prediction, 20 years, 50 years, 100 years, but what you do see is it's a bit like the boy who cried wolf, that, yes, you cry wolf once, twice, three times, and maybe people say yes, 50 years ago, they already predicted that computers will replace humans, and it didn't happen. But the thing is that with every generation, it is becoming closer, and predictions such as these fuel the process.

The same thing will happen with these promises to overcome death. My guess, which is only a guess, is that the people who live today, and who count on the ability to live forever, or to overcome death in 50 years, 60 years, are going to be hugely disappointed. It's one thing to accept that I'm going to die. It's another thing to think that you can cheat death and then die eventually. It's much harder. While they are in for a very big disappointment, in their efforts to defeat death, they will achieve great things. They will make it easier for the next generation to do it, and somewhere along the line, it will turn from science fiction to science, and the wolf will come.

Link: http://edge.org/conversation/yuval_noah_harari-daniel_kahneman-death-is-optional

Researchers have put some numbers to the life expectancy lost to obesity and its most common associated conditions. The message, as always, is that it is a bad idea to let yourself accumulate excess fat tissue. It is easy to let things slide in that direction in this modern age of comparative wealth and plenty, but there are consequences, even for being just moderately overweight:

Obesity, hypertension and diabetes are known risk factors for heart failure, a chronic condition in which the heart cannot pump enough blood to meet the body's needs. For the first time, scientists have quantified the average number of heart failure-free years a person gains by not developing those risk factors by age 45. The study found that people who had obesity, hypertension and diabetes by age 45 were diagnosed with heart failure 11 to 13 years earlier, on average, than people who had none of those risk factors by age 45. People who had only one or two of the risk factors, but not all three, developed heart failure an average of three to 11 years earlier than people with none of the risk factors. Despite advances in heart disease treatment and prevention, the pattern was consistent across data collected over the past 40 years. "The associations between these risk factors and heart failure has been remarkably stable over time. Although the prevalence of some of these risk factors has changed, the association remains the same."

"The message from this study is that you really want to prevent or delay the onset of these risk factors for as long as possible. Doing so can significantly increase the number of years you are likely to live free of heart failure. In the clinic, we often give patients metrics of risk that are relative and abstract. It's a much more powerful message, when you're talking to patients in their 30s or 40s, to say that they will be able to live 11 to 13 years longer without heart failure if they can avoid developing these three risk factors now."

Link: http://www.eurekalert.org/pub_releases/2015-03/acoc-sqh030315.php

The immune system is enormously complex and has many jobs. It isn't just a matter of destroying invading pathogens, but also clearing senescent, precancerous, and other unwanted cells. The decline of the immune system in old age is a major contribution to frailty, as not only are the old threatened by infections that the young can shrug off, but the immune system falters in destroying damaged cells that threaten health. The aged immune system falls into a state of ineffectiveness combined with constant overactivity that causes chronic inflammation. Systematic inflammation in turn contributes to the progression of many ultimately fatal age-related conditions. If the immune system could be even partially restored to a more youthful profile, that would go a long way towards improving health in old age.

There are a range of approaches to the problem of immune system aging, not least because there are numerous different contributions to the degeneration of immune function. The supply of new immune cells dries up in later life, leading researchers to propose stem cell therapies, introduction of new immune cells by infusion, or regeneration of the thymus tissues where immune cells mature. Equally the immune system becomes badly misconfigured due to the influence of persistent herpesviruses like cytomegalovirus (CMV). Ever more cells are devoted to uselessly fighting CMV rather than reacting to new threats. Here the direct path to a therapy is to work on ways to selectively destroy the unwanted immune cells, which should prompt the creation of replacements lacking the CMV fixation.

There are plenty of other points at which researchers could intervene by manipulating the processes of immune cell depletion and production, though the effects will probably be less impressive than a sweeping clearance of most unwanted cells. Even fairly simple interventions such as extended fasting have been shown to have some impact, clearing out and then repopulating sections of the immune system for a net benefit. The open access research linked below focuses on tinkering with the regulatory processes that steer creation of immune cells by hematopoietic stem cells in bone marrow, processes called lymphopoiesis and myelopoiesis that are balanced in youth but shift towards increasing myelopoiesis with aging. Like much of this research it is presented in the context of cancer treatments, as the most widely used therapies are hard on the immune system and the cancer community is in search of ways to compensate, but it may have broader implications over the long term for the treatment of immune system decline in aging:

Enhanced Hematopoietic Stem Cell Function Mediates Immune Regeneration following Sex Steroid Blockade

One key etiological factor underlying a wide range of diseases is the progressive decline in immune function with age. At its core is a reduction in lymphopoiesis within the bone marrow (BM) and thymus, attributed in part to a decrease in the number and function of lymphoid progenitors. Increasing evidence suggests that intrinsic changes to the earliest hematopoietic stem cells (HSCs) also contribute toward age-related immune degeneration. Deficiency in DNA repair, altered DNA methylation patterns, aberrant metabolism and reactive oxygen species, and skewed upregulation of myeloid- (at the expense of lymphoid-) associated genes all contribute to altered HSC function with age. However, in addition to intrinsic functional changes, extrinsic alterations to the HSC niche also likely to contribute toward the degeneration of HSC function with age.

Evidence suggests that sex steroids play at least some role in age-related degeneration of lymphopoiesis, and we, and others, have previously shown that sex steroid ablation (SSA) is able to rejuvenate aged and immunodepleted BM and thymus, enhance peripheral T and B cell function, and promote immune recovery following hematopoietic stem cell transplantation. However, the mechanisms underlying SSA-mediated immune regeneration are still unresolved. In this study, we sought to examine the events upstream of SSA-mediated lymphoid regeneration, focusing on the earliest HSPCs.

We herein show that, mechanistically, SSA induces hematopoietic and lymphoid recovery by functionally enhancing both HSC self-renewal and propensity for lymphoid differentiation through intrinsic molecular changes. Our transcriptome analysis revealed further hematopoietic support through rejuvenation of the bone marrow (BM) microenvironment, with upregulation of key hematopoietic factors and master regulatory factors associated with aging such as Foxo1. These studies provide important cellular and molecular insights into understanding how SSA-induced regeneration of the hematopoietic compartment can underpin recovery of the immune system following cell-damaging cancer therapies. These findings support a short-term strategy for clinical use of SSA to enhance the production of lymphoid cells and HSC engraftment, leading to improved outcomes in adult patients undergoing HSCT and immune depletion in general.

The quality of cartilage tissue depends upon its mechanical properties. In past years getting that right has proven to be challenging: growing cartilage cells is one thing, but forming the correct three-dimensional structures and extracellular matrix so that the resulting tissue can bear load is quite another. Nonetheless, progress has been made. To follow on from a recent demonstration of cartilage regeneration using induced pluripotent stem cells, here another group is using embryonic stem cells to regrow cartilage in situ:

Researchers have developed a protocol under strict laboratory conditions to grow and transform embryonic stem cells into cartilage cells (also known as chondrocytes). "This work represents an important step forward in treating cartilage damage by using embryonic stem cells to form new tissue, although it's still in its early experimental stages." During the study, the team analysed the ability of embryonic stems cells to become precursor cartilage cells. They were then implanted into cartilage defects in the knee joints of rats. After four weeks cartilage was partially repaired and following 12 weeks a smooth surface, which appeared similar to normal cartilage, was observed. Further study of this newly regenerated cartilage showed that cartilage cells from embryonic stem cells were still present and active within the tissue.

Developing and testing this protocol in rats is the first step in generating the information needed to run a study in people with arthritis. Before this will be possible more data will need to be collected to check that this protocol is effective and that there are no toxic side-effects. But researchers say that this study is very promising as not only did this protocol generate new, healthy-looking cartilage but also importantly there were no signs of any side-effects such as growing abnormal or disorganised, joint tissue or tumours. Further work will build on this finding and demonstrate that this could be a safe and effective treatment for people with joint damage.

Link: http://www.eurekalert.org/pub_releases/2015-03/uom-usm030315.php

Regular moderate exercise is correlated with greater life expectancy in humans and shown to cause greater life expectancy in animal studies. It definitely improves health. Thus now that more of the mechanisms of exercise are understood, researchers are interested in uncovering molecular targets and drugs that can reproduce some of those effects:

Scientists have discovered a new hormone that fights the weight gain caused by a high-fat Western diet and normalizes the metabolism - effects commonly associated with exercising. Hormones are molecules that act as the body's signals, triggering various physiological responses. The newly discovered hormone, dubbed "MOTS-c," primarily targets muscle tissue, where it restores insulin sensitivity, counteracting diet-induced and age-dependent insulin resistance.

To test the effects of MOTS-c, the team injected the hormone into mice fed a high-fat diet, which typically causes them to grow obese and develop a resistance to insulin. The injections not only suppressed both effects in mice, they also reversed age-dependent insulin-resistance, a condition that precedes diabetes. "This discovery sheds new light on mitochondria and positions them as active regulators of metabolism." MOTS-c is unique among hormones in that it is encoded in the DNA of mitochondria - the "powerhouses" of cells that convert food into energy. Other hormones are encoded in DNA in the nucleus.

While all of the experiments on MOTS-c to date have been performed on lab mice, the molecular mechanisms that make it function in mice exist in all mammals, including humans. The MOTS-c intellectual property has been licensed to a biotechnology company, and clinical trials in humans could begin within the next three years.

Link: http://pressroom.usc.edu/newly-discovered-hormone-mimics-the-effects-of-exercise/

If surveying what is known of the pathology of age-related conditions, we find an array of cellular damage and metabolic waste accumulation that happens in everyone. The people with age-related medical conditions have a lot more of one or more types of this damage and waste, however. That is the root cause of their dysfunction and frailty. Aging isn't a linear process and damage causes further damage, so small differences early on can always snowball into large differences later. Accumulating damage and waste byproducts as the result of the normal operation of metabolism is common to all of us, and this makes it a good place to look for therapeutic targets. If spending billions and decades on medical research, better to emerge with a treatment that can benefit everyone.

Alzheimer's disease progresses hand in hand with the accumulation of amyloid-β (Aβ) in brain tissues. Much of the comparatively well funded field of Alzheimer's research is focused on clearing amyloid or interfering in the mechanisms thought to link it to cell death and neurodegeneration. There are plenty of other opinions in the field on the relevance of this approach, given that it is proving harder than expected to produce meaningful results in clinical trials, but for now that is where most of the funding goes. This will hopefully produce a technology platform for amyloid clearance, such as via immunotherapies, that can be generalized to clear the other score or so forms of amyloid that accumulate in tissues with advancing age. In some cases it isn't so clear as to exactly what harm they are causing, but they are not present in young tissues in significant amounts, so the prudent course of action is to remove them anyway. Clearance followed by observing the results will probably teach us more about their role in aging than the same amount of time and money spent on more conventional studies.

Amyloid accumulation takes place in everyone, not just those with enough resulting damage to officially qualify as an Alzheimer's patient. The dividing line isn't sharp at all: more amyloid correlates with more cognitive dysfunction, and at some point that tips over the margin. It isn't a road that anyone really wants to be on at all, of course, but nonetheless here we all are until new applications of medical science arrive to rescue us. That will require large amounts of funding and public support, both of which are presently far smaller in scale than they might be. Ours is a society that likes circuses and bonfires in preference to science and progress. When does the damage of aging start? It starts in youth, but takes decades to rise to the point at which it is noticeable. Here are two recent reports of research on this topic:

Alzheimer amyloid clumps found in young adult brains

Scientists examined basal forebrain cholinergic neurons to try to understand why they are damaged early and are among the first to die in normal aging and in Alzheimer's. These vulnerable neurons are closely involved in memory and attention. Researchers examined these neurons from the brains of three groups of deceased individuals: 13 cognitively normal young individuals, ages 20 to 66; 16 non-demented old individuals, ages 70 to 99; and 21 individuals with Alzheimer's ages 60 to 95.

Scientists found amyloid molecules began accumulating inside these neurons in young adulthood and continued throughout the lifespan. Nerve cells in other areas of the brain did not show the same extent of amyloid accumulation. The amyloid molecules in these cells formed small toxic clumps, amyloid oligomers, which were present even in individuals in their 20's and other normal young individuals. The size of the clumps grew larger in older individuals and those with Alzheimer's. "This points to why these neurons die early. The small clumps of amyloid may be a key reason. The lifelong accumulation of amyloid in these neurons likely contributes to the vulnerability of these cells to pathology in aging and loss in Alzheimer's."

Brain Amyloid-β Burden Is Associated with Disruption of Intrinsic Functional Connectivity within the Medial Temporal Lobe in Cognitively Normal Elderly

The medial temporal lobe is implicated as a key brain region involved in the pathogenesis of Alzheimer's disease (AD) and consequent memory loss. Tau tangle aggregation in this region may develop concurrently with cortical Aβ deposition in preclinical AD, but the pathological relationship between tau and Aβ remains unclear.

We used task-free fMRI with a focus on the medical temporal lobe, together with Aβ PET imaging, in cognitively normal elderly human participants. We found that cortical Aβ load was related to disrupted intrinsic functional connectivity of the perirhinal cortex, which is typically the first brain region affected by tauopathies in AD. There was no concurrent association of cortical Aβ load with cognitive performance or brain atrophy. These findings suggest that dysfunction in the medial temporal lobe may represent a very early sign of preclinical AD and may predict future memory loss.

Nitric oxide is present in many areas of metabolism that change with aging or that influence the pace of aging. Calorie restriction results in increased nitric oxide levels, for example, though as always researchers are far from putting all the pieces of the calorie restriction response together in a neat arrangement of cause and effect. Nitric oxide levels are thought to influence mitochondrial activity and stem cell populations as well, and both of those are important in aging. There is interest in trying to manipulate nitric oxide mechanisms in efforts to slow the progression of aging:

Nutrition and medical advancements leading to increased lifespan are not adequately translating into improved healthspan. Present-day gerontology research suggests that, unlike traditional approaches that focus on specific diseases, deciphering, and targeting the aging process itself could be the most clever approach toward increased healthspan.

Multiple cell effectors work together to cause the senescent cell phenotype. Particularly, two cellular organelles - nucleus and mitochondrion - have been implicated in the "wear and tear" aspects of aging. Nitric oxide (NO) generated through the endothelial nitric oxide synthase (eNOS) acts to promote mitochondrial biogenesis and bioenergetics, with a favorable impact in diverse chronic diseases of the elderly. Obesity, diabetes and aging share common pathophysiological mechanisms, including mitochondrial impairment and dysfunctional eNOS. Here we review the evidences that eNOS-dependent mitochondrial biogenesis and quality control, and possibly the complex interplay among cellular organelles, may be affected by metabolic diseases and the aging processes, contributing to reduce healthspan and lifespan.

Though still in its infancy, research on the role of the eNOS-NO system in the control of cell organelle connections and quality control might reveal exciting avenues for disease treatment in the coming years. The development of novel therapies aiming to preserve eNOS-NO signaling will benefit from the identification of site-specific interaction with the eNOS structure. Drugs or nutrients able to sustain the eNOS-NO generating system might contribute to maintain organelle homeostasis and represent novel preventive and/or therapeutic approaches to chronic age-related diseases. Efforts to identify druggable eNOS sites are ongoing, although our knowledge about the therapeutic usability of the proposed eNOS-targeting molecules in the long-term is limited.

Link: http://journal.frontiersin.org/article/10.3389/fcell.2015.00006/full

This article goes into some detail on recent research into whether retrotransposons in the genome play a meaningful role in aging. This is analogous to the debate over whether stochastic nuclear DNA damage has a role in aging beyond causing cancer, and the sort of studies you'd need to introduce clear proof one way or another are much the same:

Retrotransposons, often referred to as jumping genes, are mobile genetic elements that parasitize host machinery to replicate themselves across the genome. Since their emergence more than 100 million years ago, retrotransposons have been enormously successful. Modern mammalian genomes, for example, are riddled with the scars of these copy-and-paste events, with retrotransposon-derived DNA now accounting for nearly 50 percent of the human genome.

The most dangerous retrotransposon in mammalian genomes is the long interspersed nuclear element-1 (LINE-1 or L1). L1 retrotransposons are a little more than 6 kilobases long and encode an RNA-binding protein and an endonuclease with reverse-transcriptase activity that allow the element to autonomously replicate in the host genome via an RNA intermediate. The human genome contains more than 500,000 copies of L1s. Although the vast majority of these have been inactivated as a result of truncation, mutation, and internal rearrangement, it is estimated that approximately 100 of these L1s per nuclear genome still retain their replication activity. Despite their abundance, however, L1s are not benign. Rather, their activity, and even their presence, represents a real danger to the host, increasing the risk of DNA damage, cancer, and other maladies. Given the consequences of L1 activity, it is unsurprising that host genomes devote considerable resources to suppressing these retrotransposons. Indeed, every step of the L1 life cycle is impeded in some way by host factors such as gene silencing, antiviral defense machinery, small RNAs, and autophagy.

Historically, little attention has been given to retrotransposition in somatic tissue, because this was thought of as an evolutionary dead end. In recent years, however, evidence has accumulated that L1 elements can become active in a variety of somatic tissues in humans and mice, including in the brain, skeletal muscle, heart, and liver. Intriguingly, some of the highest L1 activity has been observed in aging tissues, particularly those affected by age-related pathologies such as cancer. This raises the interesting possibility that L1 activity may contribute to the aging process. Increased DNA damage and mutagenesis are prevalent in aging tissues, and L1 activity is known to increase following such damage. In addition, a small number of studies have shown that overexpression of L1 can cause cells to senesce, a hallmark of aging tissues. The role of L1 in driving age-related processes is now a topic ripe for study.

Link: http://www.the-scientist.com/?articles.view/articleNo/42274/title/Wrangling-Retrotransposons/

The Movement for Indefinite Life Extension (MILE) is one of a number of grassroots initiatives in which ordinary folk like you or I are doing their part to help raise awareness and funding for rejuvenation research. Every great journey is made one small step at a time, and the tipping point at which the public at large begins to accept and supports longevity science in the same way as is the case for cancer research today will be crossed by one such modest effort among many. The community of people who understand and support efforts to bring an end to degenerative aging through medical science grows and diversifies as the years pass. The more of us there are the more that we can do to help advance research and educate the public. There is a role for everyone in this, and at all levels of effort, whether it is donating millions to establish a new research program or persuading a few of your friends that it's pretty silly to be for cancer research but against a cure for all age-related frailty and disease.

MILE is organizing an online demonstration on March 21st to coincide with live meetups in Chicago, Los Angeles, and Washington D.C. I was asked to provide a poster or two, and so bearing in mind that this is a demonstration I ran up something very simple that should be legible at distance. Less is more for this sort of thing, and it is easy enough to cut and paste other taglines and URLs. The font is Liberation Sans Bold, but any generic sans-serif font works just fine at this size.

Support Rejuvenation Research Poster: 4200 x 2800px

Fund More Research Poster: 4200 x 2800px

The liver is the most regenerative of organs in mammals, capable of regrowing much of its mass. That is arguably less important than the ability of a complete liver to regenerate the damage of aging and disease, such as growing fibrosis and dysfunction in cell populations necessary for organ function. Deployment of therapies to reliably achieve this goal still lies ahead, but researchers are making slow progress in the right direction:

The liver possesses extraordinary regenerative capacity in response to injury. However, liver regeneration is often impaired in disease conditions. Wild-type p53-induced phosphatase 1 (Wip1) is known as a tumor promoter and enhances cell proliferation mainly by deactivating anti-oncogenes. However, in this work, we identified an unexpected role of Wip1 in liver regeneration. In contrast to its known role in promoting cell proliferation in extra-hepatic tissue, we found that Wip1 suppressed hepatocyte proliferation after partial hepatectomy (PH). Deletion of Wip1 increased the rate of liver regeneration following partial hepatectomy.

The enhanced liver regeneration in Wip1 deficient mice was due to the activation of mammalian target of rapamycin complex 1 (mTORC1) pathway. Furthermore, we showed that Wip1 physically interacted with and dephosphorylated mammalian target of rapamycin (mTOR). Interestingly, inhibition of Wip1 also activated p53 pathway during liver regeneration. Disruption of the p53 pathway further enhanced the liver regeneration in Wip1 deficient mice. Therefore, inhibition of Wip1 has a dual role in liver regeneration, i.e. promoting hepatocyte proliferation via activation of mTORC1 pathway, meanwhile suppressing liver regeneration through activation of p53 pathway.

For the first time we demonstrate that mTOR is a new direct target of Wip1. Wip1 inhibition can activate the mTORC1 pathway and enhance hepatocyte proliferation after hepatectomy. Therefore, our findings have clinical applications in cases where liver regeneration is critical, including acute liver failure, cirrhosis or small-for-size liver transplantations.

Link: http://dx.doi.org/10.1002/hep.27755

Regular readers know that significant progress towards human rejuvenation, ending frailty and disease in aging, requires that SENS research, or something very like it, disrupts the present status quo to become the scientific mainstream in this field. SENS is focused on periodic repair of the fundamental damage to cells and macromolecules that occurs as a side-effect of the ordinary operation of metabolism. A strong focus here is on the accumulation of metabolic byproducts such as amyloids, lipofuscin and cross-links, while in comparison age-related changes in telomere biochemistry and epigenetic patterns are not all that important as targets: changes there are secondary effects, and thus should be reversed if the underlying damage is repaired.

In comparison the mainstream high level research strategy for aging and longevity is the other way around for these areas; there is comparatively little concern with metabolic byproducts as a target for treatment outside of the Alzheimer's field, and a great deal of interest in targeting telomeres and epigenetic changes. In general this is driven by a philosophy of metabolic alteration: the guiding principles are to (a) find ways to change the operation of metabolism to slow down the accumulation of damage and thus slow aging, or (b) force metabolic control processes back into a youthful configuration. This is a far worse approach than damage repair; it cannot produce rejuvenation, and in many cases ignores the root causes of aging while trying to force damaged biochemistry to behave as though it were not damaged and aged. We should expect only marginal outcomes from such efforts.

Both SENS and the present mainstream overlap in their concern for cancer and stem cell function. Both consider mitochondrial function important in aging, but with important differences in the present consensus of how and why it is important, and what should be done as a result. In the SENS vision, stochastic nuclear DNA damage is probably not all that important outside of cancer, but the mainstream consensus is that it probably is a cause of age-related disregulation of cellular activities and tissue function. This article reflects the mainstream view:

Age is the number one risk factor for myriad diseases, including Alzheimer's, cancer, cataracts, and macular degeneration. And while researchers are making progress in understanding and treating each of these ailments, huge gaps remain in our understanding of the aging process itself. The aging process can be traced down to the level of cells, which themselves die or enter senescence as they age, and even to the genomic level. Accumulation of mutations and impairments in DNA repair processes are highly associated with symptoms of aging. In fact, disorders that cause premature aging are typically caused by mutations in genes involved in the maintenance of our DNA. And at the cellular level, decreases in stem cells' proliferative abilities, impairments in mitochondrial function, and proneness to protein misfolding can all contribute to aging. As scientists continue to detail these various processes, the big question is, "At what step along all these pathways is the best place to intervene to try to promote healthy aging? The therapeutic goal would be to increase health span, not life span. There's nothing fun about living to be really old if your health diminishes to the point that it's no longer fun to be alive."

As DNA replicates, the cellular machinery involved in the process makes mistakes, leading to changes in the DNA sequence. While it's unclear exactly how DNA damage contributes to aging, what's certain is that the damage and mutations contribute to cancer, "There is this exponential increase in cancer risk during aging, so it's not at all unlikely . . . that accumulation of damage to the genome is really a major factor here." Premature-aging diseases in humans also point to the role of DNA repair and stabilization mechanisms in the aging process. But how DNA damage leads to aging in normal adults remains an open question.

Epigenetic marks shift over time in a variety of healthy cells. Indeed, mapping of DNA methylation in human cells has shown that some areas of the genome become hypermethylated with age, while others show reduced methylation. Histone modifications, another type of epigenetic mark, have also been shown to change with age in some human tissues. The question now is whether these epigenetic changes influence aging. "Is this an epiphenomenon that happens just because we age, or is it actually causing symptoms or diseases of aging and limiting life span?"

A particularly influential form of DNA damage occurs at telomeres, the repetitive sequences that cap chromosomes and shorten with age. While germ and stem cells express an enzyme called telomerase that replenishes telomeres, most cells' telomeres shrink with every division, due to the fact that DNA polymerase cannot fully replicate the ends of chromosomes. If the telomeres shrink too much or are damaged, cells undergo apoptosis or enter senescence. Telomere damage has clear effects on aging. Mice with short telomeres have diminished life spans and reduced stem-cell and organ function, while mice whose telomerase is enhanced in adulthood age more slowly.

Life depends on proper protein function. And proper protein function is all about proper protein folding. Misshapen proteins are often rendered useless and can clump together with other misfolded proteins inside cells. It is not yet clear whether protein misfolding leads to aging, but it appears that it is an almost inevitable physiological reality that the two coincide. To add insult to injury, advancing age also brings about the decline of molecular chaperones that aid in the folding process and of protective pathways that normally help clear misfolded proteins from cells. "The big open question is whether the accumulation of misfolded protein aggregates is the cause or consequence of the aging process. The hypothesis is that maybe there is a widespread accumulation of misfolded protein aggregates affecting all cells in the body, and that produces progressive dysfunction of cells in the body that leads to aging."

There is a new view of oxidative damage to mitochondria. "If damage is not too severe, there's some sort of protective response. What won't kill you makes you stronger." There is a limit to how much damage the organelle can handle, however, and mitochondrial dysfunction may well contribute to aging. "It's consistent with this idea that maybe from metabolism you get oxidative stress, you then get DNA damage, then that decline in mitochondrial function makes us age." Mitochondria's role in aging is likely not limited to oxidative or even DNA damage. Given the organelles' broad-reaching involvement in metabolism, inflammation, and epigenetic regulation of nuclear DNA. "They may be central integrators of many of the pathways we've implicated in aging."

Healthy adults produce about 200 billion new red blood cells each day to replace the same number removed from circulation every 24 hours. But the rate of blood-cell production declines with age. "It's a bit of a mystery as to why these self-renewing cells in different tissues stop working. The nature of molecular aging at the cellular level is not fully known." Researchers have also linked epigenetic alterations, such as locus-specific changes in DNA methylation, to the reduced regenerative capacity of stem cells with age. And age-related shifts in the environment in which stem cells divide and differentiate, dubbed the stem-cell niche, may also contribute to stem-cell aging. Exactly why and how stem cells slow down with age is still a mystery.

Stem cells and other cells that undergo damage and decline do not age in isolation. Researchers are finding that some processes of aging influence the release of regulators that circulate in the blood. "At one time, everybody thought, well, cells just get old and die. But the cells do more than just die. They do negative things, and they persist." One such regulator is growth differentiation factor 11 (GDF11), which measurably decreases with age. Researchers found that young blood can restore some lost functions in the hearts, brains, and skeletal muscles of older mice, and that these effects can be replicated by treating old mice with GDF11. The researchers are now working to pinpoint the sources of circulating GDF11, as well as to understand the mechanisms by which it remodels aging tissues.

Many of the questions voiced in the article could be answered most cost-effectively by implementing the SENS research programs to the point of demonstrating all of the repair biotechnologies in mice, and then observing the results. At this time it is estimated that the cost of doing so is about a decade of time and perhaps a billion dollars; this is about the same cost as is incurred in the development of a single new drug. It seems well worth doing.

Link: http://www.the-scientist.com/?articles.view/articleNo/42280/title/How-We-Age/