A Rare Replication of a Human Longevity-Associated Gene Variant in Different Study Populations
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It isn't often at all that researchers find an association between longevity and genetic variants in humans that holds up in different study populations. This is quite the contrast with shorter-lived species such as mice, where significant effects on longevity via genetic variants are near commonplace. Nonetheless, here I point out a recent paper in which TXNRD1 variants show longevity associations in two European groups - it is a result of interest purely because of its rarity.

There are as of yet no human single gene manipulations that produce effects on longevity anywhere near as impressive as those achieved in laboratory species such as flies, worms, and mice. In one sense this is a part of a larger theme: approaches to altering the operation of metabolism in short-lived species produce sometimes dramatic extension of healthy life, and the shorter the normal life span the larger the gain. None of these have more than modestly beneficial short-term effects in humans, and nor are they expected to do better than adding just a few years to human life expectancy. Calorie restriction is a great example: it can extend life in mice by 40% or so, but certainly doesn't do that in humans. The rationale for this is that shorter-lived species tend to evolve a much greater plasticity of life span because events that might require a postponement of reproduction until later tend to take place over a much greater proportion of their life span. A seasonal famine is a large fraction of a mouse life span, but not so for humans - and hence only the mouse evolves a large extension of healthy life in response to reduced calorie intake.

It isn't just that there is an absence of large effects from human longevity-related genes, however. It is that there is a near absence of any human longevity-related genes backed by defensible data in multiple study populations. Many studies have found small effects and statistically significant associations between a wide variety of genetic variants and human longevity in one study population, but when following up in a different group of people, even in the same part of the world, researchers find that these correlations cannot be replicated. This strongly suggests that the genetic determinants of natural variations in humans longevity and health in later life are very complex, consisting of the interaction of hundreds or thousands of genes, each producing individually tiny effects, varying widely with environmental circumstances, and the whole network of interactions very different for different groups of people. At this point we probably shouldn't expect the study of genetics in aging to be a good path towards enhanced human longevity, and this simply because we're not finding the same sort of results in people, a plethora of defensible associations between specific genes and longevity, that easily fall out of the data in mice.

So all this said, here is one of the rare small effects and genetic associations with longevity that is replicated in different study populations. There are all too few of these beyond the well known APOE and FOXO3A associations. None have large effects. If you have the beneficial variant, you may have a slightly better chance of reaching extreme old age in the environment of today's medical technology - but in absolute terms your odds are still terrible, and something like three quarters of the people with these beneficial variants are still dead by 90. Improved understanding in biology is always a good thing, but this is not the road to rejuvenation and greatly extended healthy life spans:

Antioxidants and Quality of Aging: Further Evidences for a Major Role of TXNRD1 Gene Variability on Physical Performance at Old Age

The role of oxidative stress response in the susceptibility to longevity is a hot topic in aging research. Comparisons among species with different rates of aging suggested that long lived species tend to show reduced oxidative damage, reduced mitochondrial free radicals production, increased antioxidant defenses, and increased resistance to oxidative stress. Indeed, centenarians generally show a lower degree of oxidative stress. However, a direct cause-and-effect relationship between the accumulation of oxidative mediated damage and aging has not been strongly established. The overall cellular oxidative stress during aging is determined not only by ROS generation but also by a reduced defense capacity of antioxidant systems.

The thioredoxin system is a most important antioxidant frontier of the cell, able to regulate its reduction/oxidation (redox) status. Thioredoxin (Trx) plays an essential role in the antioxidant defense, both directly, acting as redox regulator of intra- and extracellular signalling pathways and transcription factors, and indirectly, by protein-protein interactions with key signaling molecules such as thioredoxin-interacting protein (TXNIP). Furthermore, Trx protects the cell against lipid and protein peroxidation by controlling the protein folding through the catalysis of sulfur-exchange reactions among protein complexes. Its endogenous regulator, TrxR1, is a key selenoprotein antioxidant enzyme as well, able to reduce Trx (its main substrate) and other compounds, thus detoxifying cells from oxidative injuries. Highly conserved along the evolution, the system has also a pivotal role in growth promotion, neuroprotection, inflammatory modulation, antiapoptosis, immune function, and atherosclerosis.

The variability of encoding gene (TXNRD1) was previously found associated with physical status at old age and extreme survival in a Danish cohort. To further investigate the influence of the gene variability on age-related physiological decline, we analyzed 9 tagging single nucleotide polymorphisms (SNPs) in relation to markers of physical and cognitive status, in a Southern-Italian cohort of 64-107 aged individuals. We replicated the association of TXNRD1 variability with physical performance, with three variants (rs4445711, rs1128446, and rs11111979) associated with physical functioning after 85 years of age. In addition, we found two SNPs borderline influencing longevity (rs4964728 and rs7310505) in our cohort, the last associated with health status and survival in Northern Europeans too. Overall, the evidences of association in a different population here reported extend the proposed role of TXNRD1 gene in modulating physical decline at extreme ages, further supporting the investigation of thioredoxin pathway in relation to the quality of human aging.

Cellular Senescence and Parkinson's Disease
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The Buck Institute here provides a popular science look at links between cellular senescence and the development of Parkinson's disease. The proximate cause of the symptoms of Parkinson's is the diminishing numbers and function of a small collection of dopamine generating neurons in the brain. This is a process that happens to all of us with aging, but Parkinson's patients have, for a variety of reasons, suffered more of the cell and tissue damage that leads to cell death and dysfunction in this population of neurons.

Parkinson's Disease (PD) is the second most common age-related neurological disorder in the US. Many genetic factors that contribute to an increased risk of developing PD have been identified over the years. These include mutations in the α-synuclein and Parkin genes. Additionally, epidemiology studies show increased risk of PD after exposure to pesticides and organic pollutants, as well as heavy metals. However, recent research shows that aging is a major player in the development of PD.

The motor issues present in PD patients are primarily caused by loss of dopaminergic neurons in the substantia nigra (SN) of the brain, which is a key regulator of motor movement and reward-seeking behavior. As a result, the most widely available PD treatments focus on replacing the neurotransmitter dopamine, which is produced by dopamingergic neurons, in various ways. These treatments do not halt disease progression, since dopaminergic neurons continue to degenerate even with these treatments. Instead, they only treat the symptoms of PD and make everyday life more manageable for PD patients.

Our brains possess the capability to replace lost cells through a process called neurogenesis, or the formation of new neurons. However, it turns out that the ability of the brain to produce new neurons is reduced both with age and in people who have a mutant version of α-synuclein (a major genetic risk factor for PD). This reduced capacity for neurogenesis extends to stem cell transplants in PD patients. Many groups have reported that healthy transplanted stem cells in PD patient brains show pathological characteristics over time. Thus it seems that there is something about the environment in the brain that causes healthy cells to develop the neurodegenerative characteristics of PD.

Here at the Buck Institute, we have found that cellular senescence may play a large role in the pathological neurodegeneration of PD. Cellular senescence is an anti-cancer mechanism intended to irreversibly prevent cell division when a cell is exposed to stress. Senescent cells show distinct biological markers, such as secretion of inflammatory compounds in a phenomenon also referred to as Senescence Associated Secretory Phenotype (SASP). Data suggests that cellular senescence in astrocytes may alter the brain environment to promote disease progression and inhibit neurogenesis. Astrocytes show increased levels of SASP factors, and manipulations that reduce cellular senescence also reduce Parkinsonian phenotypes in mouse models. Since cellular senescence is associated with age, astrocyte senescence may explain the age-dependency of PD onset. We are currently searching for potential treatments that can inhibit cellular senescence in the brain, thereby halting the progress of PD.

While the field of cellular senescence is relatively young in the larger field of neurobiology, it is becoming more evident that cellular senescence is key to explaining age-related disorders. Cellular senescence in the brain may prove to be one of the underlying factors common to multiple age-related neurodegenerative diseases, which would make it an important therapeutic target to pursue.

Link: http://sage.buckinstitute.org/the-parkinsonian-brain-cellular-senescence-and-neurodegeneration/

The Latest Glenn Foundation Funding for Aging Research
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In past years the Glenn Foundation for Medical Research has reinforced the mainstream of the aging research community with grants of a few million dollars apiece to establish or expand laboratories in many major universities and research centers. Much of this supports work focused on cataloging and then attempting to safely alter the complex details of metabolic operation, such as through potential calorie restriction mimetic drugs, so as to slightly slow the aging process. Here is news of the latest round of grants:

Building on its previous gifts to MIT, the Glenn Foundation for Medical Research has pledged $2 million to establish a new center for the study of aging. The new Paul F. Glenn Center for Science of Aging Research at MIT will be directed by Novartis Professor of Biology Leonard Guarente. "With this generous gift, the Glenn Foundation will enable us to carry out a multitiered approach and leverage the strengths of all three labs to arrive at new and testable conclusions about what pathways and mechanisms govern aging. Behind all of our research is the drive to discover new therapeutic compounds that have the potential to improve the course of the aging process, and hopefully lead the way toward effective treatments for neurodegenerative diseases, like Alzheimer's disease and Parkinson's disease, as well as cancer."

The new center will build upon research that was formerly conducted within the Paul F. Glenn Laboratory for Science of Aging Research, which was established at MIT in 2008 with a $5 million gift from the foundation and expanded with an additional $1 million gift in 2013. These efforts were led by Guarente, a pioneer in the field of aging research who is known for his work to uncover the SIR2 gene, a key regulator of longevity in yeast and worms. Since then, Guarente and his colleagues have continued to explore aging, and key pathways and genes that govern aging in the human brain. A particular focus has been the role of sirtuin activation and nicotinamide adenine dinucleotide supplementation in slowing the aging process and diseases of aging. Their recent work involves the use of bioinformatics to advance their analysis.

Link: http://newsoffice.mit.edu/2015/glenn-foundation-gift-aging-research-initiatives-0625

Naked Mole Rats Retain Neural Plasticity Across a Life Span
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Two of the many topics of interest found in the study of longevity are (a) the long-lived naked mole rat and (b) the processes by which the mammalian brain generates new neurons and connections to maintain itself. Today I'll point out a paper that sits in the overlap between these two fields of study, in which researchers show that naked mole rats retain a very youthful-looking degree of neural plasticity, as well as other measures associated with younger, developing brains, all the way across their lengthy life spans.

The research community has put a great deal of time and money into the study of naked mole rat biology, and especially in recent years. This is an unusual species: very long-lived for its size, one of the very few eusocial higher animals, exhibiting negligible senescence over its considerable life span, and apparently immune to cancer. Given today's research priorities, with much more of a focus placed upon cancer than upon aging, it is the cancer resistance that really pulls in the funding and interest. Still, investigation of the underlying reasons for the exceptional longevity and healthspan of this species continues to produce a growing river of papers.

The brain changes over time, the connections between neurons altering in response to environment and circumstances. This remodeling occurs much more rapidly in youth than in adulthood, and further diminishes with age for reasons that are much debated: you can look at the state of research for any neurodegenerative condition to see the range of theorizing and discussion, coupled with the sheer amount of work left to be done in order to explore the full complexity of neural biochemistry. It is thought that some of the characteristic changes observed in the brain with age are a sort of compensatory remodeling, attempts to cope with rising levels of damage and dysfunction. It is more widely agreed that artificially increasing adult levels of neural plasticity could form the basis for therapies to partially alleviate at least some of the consequences of age-related neurodegeneration.

Here researchers argue that naked mole rats evolved a resilience to age-related degeneration in the brain by greatly extending the period over which the brain is developing. Processes that have diminished by adulthood in other mammals instead continue apace in naked mole rats. The argument ties in nicely with other aspects of the biochemistry of this species wherein it looks very much as though oxygen-poor underground environments were the evolutionary driver for changes that incidentally also happen to produce extended longevity with little degeneration until close to the end of life.

Protracted brain development in a rodent model of extreme longevity

In this study, we show that brain maturation, as indicated by molecular, morphological, and electrophysiological features, is extremely protracted in naked mole-rats. Embryonic and early postnatal (pre-weaning) neurogenesis apparently provides adequate neuronal populations for life-long brain function in naked mole-rats, since cell proliferation rates as measured by marker 5-ethynyl-2'-deoxyuridine (EdU) incorporation at postnatal dates, are not higher than in mice. This is also supported by the finding that markers of apoptosis are not elevated in the postnatal naked mole rat brain. Instead, we observed a prolonged retention of "immature" neuronal features including expression of PSA-NCAM, providing scaffolding for neurite outgrowth, delayed morphogenic maturation of hippocampal neurons, and incomplete synapse patterning as naked mole rats age. Therefore, we propose that while developmental neurogenesis provides adequate neuronal populations for adult brain functions, postnatal maturation of those neurons is greatly extended to provide much needed cellular dynamics to prevent structural damage and cell senescence in a low oxygen environment.

We found lower amounts of neurogenesis in the adult naked mole rat, as compared to the mouse. This suggests that the bulk of neurons is produced during fetal development, and remains physiologically active until senescence. In common laboratory rodents, particularly mice, neuronal apoptosis peaks during the neonatal period to prune redundancy during brain circuit formation. In our sample cohort, we did not find significant cleaved caspase-3 immunoreactivity during the period ranging from 7 days to 10 years postnatally, fuelling the provocative idea that cell production is tightly tuned by metabolic and/or oxygen restrictions, likely limiting otherwise metabolically demanding processes of cell elimination. Alternatively, some neuronal cohorts might not reach full maturity even during the extended life-span of naked mole rats, thus precluding their incentive to initiate apoptotic programs. Instead, we find elevated cleaved caspase-3 levels in the 21-year-old naked mole rat, reflecting the age-related increase of apoptosis found in common laboratory rodents.

In sum, we show that naked mole rats, a "treasure trove" for translational neurobiology, exhibit a very prolonged period of postnatal brain development consistent with a neotenous evolutionary mechanism. Protracted brain development may allow naked mole rat brain to cope with extremely low levels of O2 in their crowded subterranean burrows. Extended development may be accompanied by enhanced brain plasticity to preclude neurodegenerative processes during their extraordinary life-span. Thus, understanding the molecular basis of these processes warrants future research particularly aimed at expanding our tool kit to fight neurodegeneration and age-associated dementia.

The same question applies to naked mole rats as to salamanders and zebrafish: is it really practical from cost/benefit perspective to mine their biochemistry for the improvements we'd like to see in our own? That question can't be answered without doing most of the work, and the answer may be different in each case. Perhaps a useful therapy can result and is well within present medical capabilities if we only knew more. Equally perhaps integrating what is learned would require such sweeping, difficult changes to human biochemistry that we'd be far better off focusing on other types of therapy. We shall see.

Population Life Expectancy Inversely Correlated with Childhood Autoimmune Disease Incidence
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A researcher here runs the numbers to demonstrate an inverse correlation between autoimmune disease incidence and life expectancy. It is interesting to speculate on the mechanisms here, which are probably not going to turn out to be a straightforward matter of (a) declining immune function being important in the progression of aging, and (b) more autoimmunity indicating a greater tendency to subclinical immune dysfunction over the course of aging in a population:

The autoimmune diseases are among the ten leading causes of death for women and the number two cause of chronic illness in America. They are a predisposing factor for cardiovascular diseases and cancer. Patients of some autoimmune diseases have shown a shorter lifespan and are a model of accelerated immunosenescence. Centenarians from the other side, are used as a model of successful aging and have shown better preserved several immune parameters and lower levels of autoantibodies. My study is focused on clarifying the connection between longevity and some autoimmune and allergic diseases in 29 developed OECD countries as the multidisciplinary analyses of the accelerated or delayed aging data could show a distinct relation pattern, help to identify common factors and determine new important ones that contribute to longevity and healthy aging.

I have assessed the relations between the mortality rates data of Multiple Sclerosis MS, Rheumatoid arthritis RA, Asthma, the incidence of Type 1 diabetes T1D from one side and Centenarian Rates (two sets) as well as Life Expectancy data from the other side. The obtained data correspond to an inverse linear correlation with different degrees of linearity. I have been the first to observe a clear tendency of diminishing Centenarian Rates or Life Expectancy in countries having higher death rates of Asthma, MS and RA and a higher incidence of T1D in children. I have therefore concluded that most probably there are common mechanistic pathways and factors, affecting the above diseases and in the same time but in the opposite direction the processes of longevity. Further study, comparing genetic data, mechanistic pathways and other factors connected to autoimmune diseases with those of longevity, could clarify the processes involved, in order to promote the longevity and limit the expanding of those diseases in the younger and older population.

Link: http://dx.doi.org/10.1089/rej.2015.1690

The Prospects for Stem Cells to Treat Chronic Wounds
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Based on the evidence to date, stem cell transplants could be used to treat chronic, non-healing wounds that occur in older patients, though work to be accomplished in order to achieve this goal. Here is an open access review paper on that topic:

Wound healing is an elaborate process that occurs in three distinct, yet overlapping, phases: inflammation, cell proliferation, and remodeling. Adult cutaneous wound repair is characterized by a highly evolved fibroproliferative response to injury that quickly restores the skin barrier, thereby reducing the risk of infection and further injury. The inflammatory phase is characterized by influx of polymorphonuclear cells followed by monocytes/macrophages. Macrophages secrete the growth factors and cytokines necessary for wound healing. Stimulated by these growth factors, healing proceeds to the proliferative phase, made up of fibroplasia, matrix deposition, angiogenesis, and reepithelialization. Remodeling is a dynamic phase during which various collagens are continuously deposited and degrade.

Chronic wounds occur when there is a failure of injured skin to proceed through an orderly and timely process to produce anatomic and functional integrity. Causative factors include malnutrition and immunosuppression, and chronic wounds are commonly seen as a consequence of diabetes mellitus and vascular compromise. Current techniques to manage chronic wounds typically focus on modification of controllable causative factors. The advent of skin substitutes has increased our armamentarium for treating this difficult condition, but to date no ideal therapy is available to treat troublesome, chronic wounds.

New therapies in this area are required to optimize outcomes for our patients. Stem cells, with their unique properties to self-renew and undergo differentiation, are emerging as a promising candidate for cell-based therapy for the treatment of chronic wounds. Mesenchymal stem cells (MSC), a progenitor cell population of the mesoderm lineage, have been shown to be significant mediators in inflammatory environments. Preclinical studies of MSC in various animal wound healing models point towards a putative therapy. This review examines the body of evidence suggesting that MSC accelerate wound healing in both clinical and preclinical studies and also the possible mechanisms controlling its efficacy.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461792/

Investigations of the INDY Gene Illustrate that "Very Slow" is the Default Speed of Aging Research
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Here I point out a recent review on the topic of INDY gene manipulations and consequent increased longevity via altered metabolic processes. Given just how long ago this gene was discovered, and how similar at a high level the research reviews on this topic are today in comparison to those of a decade ago, this line of work well illustrates that even in the more mainstream reaches of science, with better prospects for funding, early stage research into aging and longevity is really very, very slow.

INDY stands for "I'm not dead yet" and was named after it was discovered that reducing levels of the protein that this gene encodes has the effect of extending life in flies. That discovery was made fifteen years ago, almost a different era in the life sciences relevant to aging, back when longevity genes were a new and amazing thing, it wasn't the case that new ways to tinker with metabolism to modestly extend healthy life were being discovered and published on a near monthly basis, as is the situation today, and researchers were very reluctant to talk in public about the prospects for treating aging in humans because it would likely sabotage their careers. How things have changed.

There is no necessary reason for aging research to very, very slow, as opposed to merely slow, or at least no necessary reason that cannot be corrected. Yes, it is the case that getting things done in life science research is painfully slow in comparison to, say, starting a business selling shoes. A great deal of available funding passes through very bureaucratic channels, there is not enough funding to avoid long delays between phases of a research program in order to seek new grants, and then it takes a few years in the middle to actually get anything meaningful accomplished in the lab. In aging research the situation is made worse if you want to run life span studies in species that live for a few years, such as mice. The need for life span studies as the bottom line of "did it work?" in longevity science is something that everyone in the research community would like to do away with. That seems feasible given progress towards markers for biological age, but there is a way to go yet on that front before researchers can make quick measurements before and after a prospective rejuvenation therapy and feel confident that the data will be useful in place of years of running a life span study.

But as for the rest of it, given more money the aging research community could be just as dynamic and productive as, say, the stem cell research community. Still slower than starting up a shoe business, but moving about as rapidly as you can expect from the life sciences. To speed things up further would require, at the least, radical surgery on the regulatory framework of the FDA, or an enormous influx of funding akin to the Apollo program or similar. At the end of the day it comes down to being a reasonable expectation that you should wait five to ten years to see how any particular program turns out, and absent a lot of funding you might still be waiting around fifteen or twenty years later. Five years is about long enough to get one thing accomplished in a life science program, or to figure out that whatever it was you were trying doesn't really work.

So back to INDY as our illustration of this point. The association with increased longevity was established in 2000, and establishing proximate mechanisms and deciding that the alterations to metabolism from lack of INDY looked a lot like calorie restriction was accomplished within a few more years. After that there was something of a hiatus of meaningful progress as judging by a review from 2013, with intervening years dotted with replication of INDY effects in other species such as mice and nematode worms, and more methodical exploration of the chains of biochemical connections leading into and out of the proximate mechanisms. Just last year researchers had come far enough to decide that intestinal stem cell populations had a lot to do with the longevity effect, but then this seems to be generally important in flies, and so any mechanism that extends life probably does much the same.

This year, the paper linked below finally comes to the point at which it is suggested that perhaps INDY is a drug target that someone should look into vis a vis treating aging and the diseases of aging. That can be taken as the starting point for a pretty long process of thought and work and delay. Perhaps something will come of it in some lab somewhere, perhaps not. You might, by analogy, look at the situation for heat shock proteins or other ways to trigger greater cell maintenance via autophagy as potential drug targets to modestly slow aging. That has been seriously suggested for years now, but I've yet to see any meaningful movement in that direction. Bear in mind that I'm not talking about SENS rejuvenation research here, that is still in the process of becoming a large concern, I'm talking about the core mainstream focus of the research community, which is at present to build drugs that might slightly slow down aging - not something we should expect to produce useful results any time soon, but comparatively well funded and supported. That these and many similar projects move erratically if at all is, I think, one symptom of an underfunded and divided field of research, in which many researchers are not at all interested in treating aging, and there is far too little money for all that should be done or could be done to build a better future.

The role of INDY in metabolism, health and longevity

The Drosophila I'm Not Dead Yet (Indy) gene encodes a plasma membrane transporter of Krebs cycle intermediates with highest affinity for citrate. In flies INDY is predominantly expressed in the midgut, which is important for food absorption; the fat body, which modules glycogen and fat storage, and oenocytes (fly liver), which is the site of lipid mobilization and storage. Thus, reduction in INDY reduces uptake, synthesis and storage of nutrients and affects metabolic activity. Reduction of Indy expression in both flies and worms extends longevity by a mechanism that is reminiscent of calorie restriction (CR), which is an environmental manipulation that extends longevity in a variety of species. Flies with reduced INDY levels experience many of the physiological changes that are commonly observed in CR flies. Such changes include altered lipid metabolism and insulin signaling, as well as enhanced mitochondrial biogenesis and spontaneous activity

Studies investigating the function of mammalian Indy (mIndy) show the highest levels of expression in the liver and brain. Similar to the trend of Indy expression in flies, mRNA levels were found to change during starvation in rat hepatocytes and mice liver. Furthermore, studies in mIndy-/- mice show similar effects in mitochondrial function, as well as lipid and glucose metabolism in the liver as those previously described in less complex organisms and in mice on CR. Together, these data suggest that the level and location of INDY serves to regulate and possibly mediate metabolic responses to nutrient availability during aging.

It is thought that these physiological changes are due to altered levels of cytoplasmic citrate, which directly impacts Krebs cycle energy production as a result of shifts in substrate availability. Citrate cleavage is a key event during lipid and glucose metabolism; thus, reduction of citrate due to Indy reduction alters these processes. With regards to mammals, mice with reduced Indy (mIndy-/-) also exhibit changes in glucose metabolism, mitochondrial biogenesis and are protected from the negative effects of a high calorie diet.

The recent work completed by our lab and others support a role for INDY as a regulator of metabolism whose transcriptional levels change in response to calorie content of the food, as well as in response to energetic requirements of the organism. The similar effects of INDY reduction on metabolism in flies, worms, and mice suggest an evolutionary conserved and universal role of INDY in metabolism. Together, these findings suggest that INDY could be potentially used as a drug target for treatment of obesity and Type II Diabetes in humans. Further investigation on the mechanism of INDY reduction could provide valuable information regarding the means to a healthier and more productive life.

An Early Attempt to Work Around Immunosenescence
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Researchers have recently demonstrated a partial restoration of immune response in aged mice using a combination of existing Toll-like receptor agonists. This might be seen as a first step on the road to ways to reverse those aspects of immune system failure with age that depend more on misconfiguration rather than cellular damage.

The immune system declines with age for a variety of reasons, and this decline accounts for a great deal of the frailty of the elderly, vulnerable to infections that the young shrug off, and less able to eliminate precancerous cells. Some of these reasons involve the rising levels of damage to all tissues and cells that occurs with aging, while others are structural and inevitable due to the way in which the immune system works. Even absent cellular damage it would fail over the course of a lifetime. For example, the slow pace of immune cell replacement in adults means that the population of these cells is effectively limited, and in the adaptive immune system ever more of that population consists of memory T cells devoted to past threats rather than naive T cells needed to meet new threats. Most of those memory T cells are not even particularly helpful, being duplicates of one another that exist because of the recurring presence of viruses that cannot be cleared from the body, such as cytomegalovirus. Some form of targeted cell clearance should be a useful approach here, to free up space for new immune cells, and has in fact been demonstrated to produce benefits in the laboratory for other immune cell types.

At base this sort of thing is a programming and configuration problem. Cells are machines that operate according to their state and the chemical signals they receive. Removing the misconfigured cells is one way to deal with the problem, and only requires the ability to reliably identify and target the cells to be destroyed. Given better understanding of cells and their signals in any given tissue type or system in the body, it should also be possible to change cell behaviors for the better, however. This more complex strategy may be particularly applicable to the immune system, given that so much of its age-related dysfunction is a matter of misconfiguration rather than damage. So in this research, you might see the seeds of more complex and comprehensive reprogramming efforts in the future:

Immunosenescence is characterised by decline in both adaptive and innate immune functions. Innate immune responses are activated, mainly, by stimulation of Toll-like receptors (TLRs), the expression and function of which declines with age. Dendritic cells (DCs) from both young and aged individuals exhibit comparable activation in response to most TLR ligands, and are equally capable of direct and cross-presentation of antigens to T cells in vitro, underscoring the likely importance of TLR-induced DC activation in promoting adaptive immunity. TLR stimulation is therefore a promising strategy to enhance vaccine efficacy in the elderly. Combinations of TLR agonists may be especially effective, as demonstrated in animal models and clinical trials.

We previously showed that triggering of multiple TLRs, using a combined adjuvant for synergistic activation of cellular immunity (CASAC), incorporating polyI:C, interferon (IFN)-γ and MHC-class I and II peptides, results in potent cytotoxic T cell-mediated immunity in young mice. Optimization of the adjuvant formulation and investigation of mechanism of action were also performed. We now report the ability of CASAC to improve vaccination-induced responses in aged mice by promoting induction of antigen-specific cellular immunity to both foreign and self tumour-associated peptide antigens.

We have demonstrated that our combined molecular adjuvant CASAC effectively promotes functional antigen-specific CD8+ T cell responses to vaccination with peptides in aged mice, despite their immunosenescent phenotype. CASAC improved responses in aged mice not only to a highly immunogenic foreign antigen, but also to the tumour-associated self-antigen TRP-2 whose immunogenicity is being evaluated in clinical trials. Restoration of response to vaccination in immunosenescent aged mice by CASAC likely reflects the benefits of multiple TLR triggering on DC function and provision of IFN-γ could substitute for lack of IFN-γ from CD8+ memory cells during the early phase of immune response. Since CASAC comprises a combination of agents that individually are approved for human use, our findings suggest that a CASAC-based vaccination strategy may be amenable to rapid clinical translation, particularly against chronically experienced antigens such as persistent infections or tumour-associated antigens in older people.

Link: http://dx.doi.org/10.1186/s12979-015-0033-0

Are Mitochondrial Mutations Really All That Important?
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Prompted by attention given to a recent study claiming to cast doubt on the primary role of damaged mitochondria in aging, here is a lengthy and detailed article from the SENS Research Foundation on what is known of mitochondrial DNA damage and aging. It is worth bearing in mind when reading the scientific literature that any single study, especially if claiming to overthrow the consensus, should always be weighed against the rest of the recent literature in a given field:

The study was of fibroblasts, which are a kind of skin cell. It is interesting and contributes to a long-standing debate in this field about the frequency of specific mitochondrial DNA mutations with age and tissue type, and whether they contribute to specific diseases. It is clear at this point that mitochondrial dysfunction occurs with age and that damage in the form of mutations to mitochondria contributes to the diseases and disabilities of aging. We don't believe that this particular study is actually a challenge to scientists' existing understanding about how changes in mitochondria with age both drive and are driven by cellular and molecular damage, and the diseases and disabilities of aging.

What is actually known about the frequency and impact of specifically age-related mitochondrial mutations? First, in line with the ability of dividing cells to dilute out structural damage, multiple studies in aging rodents and humans report that the mutations in mitochondria that persist in cells and thus accumulate with age are confined almost entirely to cell types that don't divide during adulthood (e.g., brain neurons, heart muscle cells, and skeletal muscle). Second, those mutations are quite surprisingly rare: even in tissues that are actually affected by mitochondrial mutations with age, fewer than 1% - and perhaps as few as 0.1% - of cells are found to be affected.

Still, the evidence suggesting that this damage drives degenerative aging is powerful. The level of oxidative damage to mitochondrial DNA, the rate of accumulation of mitochondrial DNA mutations with age, and the structural vulnerability to such mutations are collectively robustly correlated with species maximum lifespan (the strongest integrative measure of the overall rate of aging in a species). Remarkably, this has recently been demonstrated even in rockfish, whose senescence is nearly negligible: lifespan in rockfish species was found to correlate negatively with the rate of mutation of their mitochondrial, but not nuclear, genomes - a relationship that the investigators' analysis suggested was not likely to be an artifact of tradeoffs with fecundity or the rate of germline DNA replication.

Calorie restriction (the most robust intervention that slows the rate of aging in mammals) lowers the rate of accumulation of mitochondrial deletion mutations with age. And when mice are given a transgene that directs a form of the antioxidant catalase directly to their mitochondria - an enzyme that complements the existing antioxidant machinery in the mitochondria in a way that reduces total mitochondrial DNA oxidative damage, including but not limited to deletion mutations - it extends their mean and maximal lifespan and ameliorates multiple pathologies of aging. Yet no such effects are observed when the same enzyme is directed to sites outside of the mitochondria, or when other antioxidant enzymes are expressed elsewhere in the cell, or even when non-complementary enzymes are sent to the mitochondria.

The apparent paradox in all of this is the strong link between mitochondrial DNA deletions and the rate of degenerative aging in the face of the rarity of such mutations. There are two broad kinds of resolution to this paradox. The first is the tissue-specific one. Although cells overtaken by mitochondria bearing DNA deletions are rare, they can have powerful effects on health in tissues where they are unusually enriched in critical cell types, particularly if relatively few of those cells exist in the first place. Such is the case for the key dopamine-producing neurons in an area of the brain known as the substantia nigra pars compacta (SNc). SNc dopaminergic neurons are much more vulnerable to being overtaken by mitochondria bearing large deletions in their DNA than are other cell types in the brain, and such mutations clearly drive dysfunction, including being tightly liked to Parkinson's disease. The same high regional vulnerability to mitochondrial DNA deletions occurs in people suffering with non-Parkinson movement disorders and even in "normal" aging brains, albeit at a lower rate and yet the finding has no parallel in the smaller and less harmful point mutations.

The other kind of tissue-specific effect relates more to the unique properties of the affected cell type itself, with the cardinal case in this category being skeletal muscle. Unlike most cell types, skeletal muscle "cells" are not isolated from all of their neighbors by a membrane. Instead, the long stretches of skeletal muscle fibers are comprised of multiple segments, each of which contains its own nucleus, which is in turn supported by a local population of mitochondria, with additional mitochondria in the membrane-bound space outside the fiber itself. Mitochondrial DNA deletions not only accumulate with age at a faster pace in skeletal muscle than in many other aging tissues, but because of that structure their effects are much more catastrophic. When a local nucleus' mitochondrial population is overtaken by deletion mutations, the segment first atrophies at that point, and then fails, leading the fiber to split or break locally and ultimately causing the loss of the entire fiber. These processes - loss of energy production and the splitting and loss of fibers - are a key driver of sarcopenia, the age-related loss of skeletal muscle mass and function that occurs even in lifelong master athletes.

Because deletion mutations in mitochondrial DNA are core molecular lesions driving these diseases, repair of these mutations will be central to their prevention, arrest, and reversal. But you can't tell that from a study of skin cells.

Link: http://sens.org/research/research-blog/question-month-11-are-mitochondrial-mutations-really-all-important

2015 Summer Scholars at the SENS Research Foundation
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In this post you'll find pointers to the profiles of some of the SENS Research Foundation summer scholars for 2015. These talented young scientists are placed in influential labs for the summer to work on research relevant to the goal of treating aging and age-related disease. Cultivating today's young academics is the starting point for building the dedicated, enthusiastic research community of tomorrow, the people who will usher in the rejuvenation therapies of the 2030s and beyond.

At the very best possible pace of development, a pace that would require considerably more funding for the relevant research than is presently the case, it will likely be another twenty years before the first comprehensive package of rejuvenation therapies are in the final stages of development, on the way to the clinic. Unless the funding situation dramatically improves in the next few years, the likely timeline is longer: most of today's research interest in the treatment of aging as a medical condition goes towards research programs that cannot possibly produce actual rejuvenation, and can at best only modestly slow the pace of aging. Yet the cost in time and money for that course will likely be much greater than for attempts to create rejuvenation by repairing the causes of aging. It is frustrating, one of many things that must change if we are to see meaningful progress towards an end to aging.

The people who will lead laboratories and found startups at the time of the first commercial rejuvenation treatments are in the final years of their academic biotechnology studies today. Whether or not tomorrow's leaders choose to enter the aging research field is something that we can influence today. For many decades aging research has been the poor cousin in medicine, thought of as a dead-end, ill-funded area of research. Yet this is far from the case: aging research today is a hotbed of cutting-edge molecular biology, rich with potential, and I think it no great exaggeration to say that medical control over degenerative aging will grow to become the principal pillar of medicine in the later decades of this century. There are names and fortunes to be made in the years ahead, but that all starts with education: showing the students of today that work on aging is a great choice for a life science career, and helping them to make connections in the research community and related industries that will serve them well in the years ahead.

As for any human endeavor, a research community doesn't just spontaneously emerge from nothing. It must be cultivated. This is an important aspect of the work of organizations like the SENS Research Foundation. It's not just a matter of funding and coordinating the right research today, but also ensuring that a community of enthusiastic scientists exists to carry that work through to completion in the decades ahead. Thus the SENS Research Foundation runs a yearly placement of talented young scientists in their Summer Scholars program, sending them out to some of the most noted laboratories in the US. Some of this year's crop are profiled:

2015 Summer Scholar Profile: Amanda Paraluppi Bueno

I am very excited to work for SENS Research Foundation because I will have the chance to learn and contribute to research centered around the diseases of aging at the Wake Forest Institute for Regenerative Medicine (WFIRM), which is an extraordinary place for this field. This summer, my Principal Investigator is Dr. Graça Almeida-Porada and my mentors are Saloomeh Mokhtari and Steven Greenberg. Our goal is to develop novel cell-based therapies that could provide a curative treatment for Inflammatory Bowel Disease (IBD).

The Almeida-Porada lab has already shown that increasing the expression of immunomodulatory molecules on mesenchymal stem cells (MSC) leads to better immunosuppression and improvement of IBD in a murine model. Other cells that could help in the treatment of the gut inflammation are endothelial progenitor cells (EPC). These cells are known to increase the vascularization in ischemic tissues. Therefore, EPC could help normalize vascularization in the intestinal submucosa of IBD patients. Hence, I plan to treat IBD in mice using MSC and EPC as cell therapy to promote the modulation of the immune system and increase the vascularization in the intestine.

2015 Summer Scholar Profile: Blake Johnson

I first became interested in the field of regenerative medicine after viewing Dr. Anthony Atala's TED Talk on his 3-D kidney printing work. The ability of regenerative medicine to be applied to a vast array of cells, tissues, and organs and the possibility of making patients truly well again, as opposed to managing symptoms, is inspiring. WFIRM is an outstanding research institution, and it is an honor to have been selected to spend the summer learning and growing here.

This summer, I am working under the direction of Dr. John Jackson to generate thymus organoids capable of producing functional T-cells. The thymus serves an important function as the site of T-cell development. Interestingly, as we age, the thymus undergoes involution, or decreases in size, leading to a decrease in naïve T-cells. The ability to generate a functional thymus outside the body would have a number of clinical applications, including rejuvenation of an aging thymus to boost the immune response in older individuals and development of tolerance in organ transplantation.

2015 Summer Scholar Profile: Le Zhang

This summer, I will be conducting my research project in Dr. Jeanne Loring's laboratory at the Center for Regenerative Medicine in the Scripps Research Institute. The Loring lab has derived dermal fibroblasts from 10 patients with Parkinson's disease. These fibroblasts have been reprogrammed to induced pluripotent stem cell (iPSCs), which have been differentiated into midbrain-specific neural progenitor cells. These cells will later develop into dopaminergic neurons after transplantation. The Loring lab is the first lab conducting iPSC transplantation on Parkinson's disease patients, so it is essential to ensure genomic stability of the cells being transplanted. An important method to determine genomic integrity of patients' iPSC lines is single nucleotide polymorphism (SNP) genotyping, which can be used to examine millions of single base pair differences at genomic sites specific to humans.

SNP analysis will enable me to determine if the cell populations are suitable for transplantation or whether they have too much genetic change and, hence, potential risk for tumorigenesis. My research this summer will generate and analyze genomic SNP profiles from patient-specific dermal fibroblasts, iPSCs, and neuronal progenitors. SNP patterns from the three cell types will be compared to determine whether genomic instability has occurred from fibroblasts to iPSCs then to neuronal progenitors. Hopefully, with efforts from other scientists and me, the Loring Lab will successfully identify some cell lines that are suitable for transplantation and pass the FDA approval.

2015 Summer Scholar Profile: Zeeshaan Arshad

Under the mentorship of Professor Chas Bountra and Dr. David Brindley, my project will propose a model of open innovation in the translation process to address the problem of developing Alzheimer's disease drugs. To do this, I will use a model to compare open innovation to more conventional drug development strategies by measuring certain metrics to determine the effect open innovation has on each stage of the translation process. These metrics can give us an insight into the rate and effectiveness of the process at each stage and, therefore, an idea about how open innovation can improve the translation process.

We are all familiar with Alzheimer's disease. Not only is it a disease that causes significant morbidity and mortality, it is also one of the most costly. So, why haven't we cured it already? There are numerous reasons why this is a difficult problem to solve. The main problem being the lack of understanding of the disease itself, including potential drug targets. This leads to drug discovery being very risky and inefficient. For example, in the last few decades, extensive research has explored targeting amyloid plaques and neurofibrillary tangles as potential drug targets to treat Alzheimer's disease with little success. Furthermore, in the conventional drug development process, organizations work in isolation, creating an environment in which similar compounds are sometimes studied in parallel. So, how can we fix this problem? The answer lies in making the translation process between research and healthcare implementation more effective.

2015 Summer Scholar Profile: Ryan Louer

This summer, I will be working in Dr. Anthony Atala and Dr. James Yoo's lab under Drs. Myung Jae Jeon and Young Sik Choi studying ovarian cell therapies that will be able to produce natural levels of sex steroids that can be controlled by feedback mechanisms and, hopefully, produce viable oocytes. The importance of this research is providing effective therapies for hormone and egg replacement that do not have the potential harmful side effects, such as increased risk for heart disease and certain cancers, that current replacement methods pose. Cell-based therapies can be used in post-menopausal women, women who have had ovarian cancer, and women who have experienced damage to their ovaries from other sources.

Currently, we are characterizing a 3D collagen matrix and structure that closely mimics the natural environment within the ovary. My specific role in the project will be to test and define the importance of the ratio of granulosa cells to theca cells as well as find the optimum total number of cells in each follicle construct. I will be analyzing each ratio and follicle size for the ability to produce a physiologically normal level of estrogen and progesterone as well as assessing overall cell viability.

2015 Summer Scholar Profile: Jonah Simon

At the SRF Research Center, I am working on the Oncology team with Dr. Haroldo Silva. My project is to develop new high-throughput assays for quantifying activity of the Alternative Lengthening of Telomeres (ALT) pathway in human cells. Cancer cells must be able to proliferate without limit - something that normal cells can't do. Telomeres are repetitive noncoding DNA strands at the ends of eukaryotic (plants, animals, etc.) chromosomes. Every time a cell divides, telomeres shorten, protecting the genetic material from being damaged and limiting the proliferation of the cell. Some cells, such as stem cells and cancer cells, are able to lengthen their telomeres to be able to divide without limit. 85% of cancer cells use the enzyme telomerase to lengthen telomeres. The remainder maintain telomere length with ALT, a pathway based on homologous recombination (a mechanism used for DNA repair).

The current assays for ALT activity rely on characteristics of ALT cells: heterogeneous telomere length, the presence of ALT-associated PML bodies (APBs), and the presence of extrachromosomal circular C-strand telomeric DNA (C-Circles, or CCs). All of the current assays have problems, and none of them are high-throughput. One of the assays I'll be developing is a high-throughput version of the APB assay. Classically, this assay measures colocalization of PML protein with TRF2, a telomere binding protein (drug treatment can lower TRF2 expression, making the APB assay unreliable). I will bypass TRF2 and look for colocalization of PML with telomeric DNA directly. I'll accomplish this by using immunofluorescence to detect PML protein and FISH (fluorescent in situ hybridization) to detect telomeric DNA with a complementary fluorescent DNA probe.

Changing the View of Aging: Are We Winning Yet?
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Peter Thiel, who has invested millions into the SENS rejuvenation research programs over the past decade, has of late been talking much more in public on the topic of treating aging. Having wealth gives you a soapbox, and it is good that he is now using it to help the cause of treating aging as a medical condition. One of Thiel's recent public appearances was a discussion on death and religion in this context.

In the struggle to produce meaningful progress in rejuvenation research, the tipping point can come from either a very large amount of money, hundreds of millions of dollars at least, dedicated to something very similar to the SENS research programs, or from a widespread shift in the commonplace view of aging. At the large scale and over the long term medical research priorities reflect the common wisdom, and it is my view that public support is needed to bring in very large contributions to research. The wealthiest philanthropists and largest institutional funding bodies follow the crowd as a rule, they only rarely lead it. They presently give to cancer and stem cell research precisely because the average fellow in the street thinks that both of these are a good idea.

So it is very important that we reach a point at which research into treating degenerative aging is regarded as a sensible course of action, not something to be ridiculed and rejected. Over the past decade or two a great deal of work has gone into this goal on the part of a small community advocates and researchers. It is paying off; the culture of science and the media's output on aging research is a far cry from what it was ten years ago. When ever more authorities and talking heads are soberly discussing the prospects of extended healthy life and research into the medical control of aging, it is to be hoped that the public will follow. Inevitably religion is drawn in as a topic in these discussions once you start moving beyond the scientific community:

The Venn diagram showing the overlap of people who are familiar with both Peter Thiel and N.T. Wright is probably quite small. And I think it is indicative of a broader gap between those doing technology and those doing theology. It is a surprise that a large concert hall in San Francisco would be packed with techies eager to hear a priest and an investor talk about death and Christian faith, even if that investor is Peter Thiel.

Thiel has spoken elsewhere about the source of his optimism about stopping and even reversing aging. The idea is to do what we are doing in every other area of life: apply powerful computers and big data to unlock insights to which, before this era, we've never had access. Almost everyone I talk with about these ideas has the same reaction. First there is skepticism  - that can't really happen, right? Second, there is consideration  - well those Silicon Valley guys are weird, but if anyone has the brains and the money to do it, it's probably them. Finally comes reflection, which often has two parts - 1. I would like to live longer. 2. But I still feel a little uneasy about the whole idea.

The concept of indefinite life extension feels uncomfortable to people, thinks Thiel, because we have become acculturated to the idea that death, like taxes, is inevitable. But, he says, "it's not like one day you'll wake up and be offered a pill that makes you immortal." What will happen instead is a gradual and increasingly fast march of scientific discovery and progress. Scientists will discover a cure for Alzheimer's and will say, "Do you want that?" Of course our answer will be "Yes!" They will find a cure for cancer and say, "Do you want that?" And again, of course, our answer will be "Yes!" What seems foreign and frightening in the abstract will likely seem obvious and wonderful in the specific. "It seems," Thiel said, "that in every particular instance the only moral answer is to be in favor of it."

One of Wright's objections was to articulate a skepticism about whether the project of life extension really is all that good, either for the individual or for the world. "If [I] say, okay I'll live to be 150. I'll still be a sinner. I'll still be conflicted. I'll still have wrong emotions. Do I really want to go on having all that stuff that much longer? Will that be helpful to the world if I do?" This roused Thiel. "I really have to disagree with that last formulation...it strikes me as very Epicurean in a way." For Peter Thiel, Epicureanism is akin to deep pessimism. It means basically giving up. One gets the sense he finds the philosophy not just disagreeable but offensive to his deepest entrepreneurial instincts and life experience. "We are setting our sights low," he argued, "if we say everyone is condemned to a life of death and suffering."

Link: http://www.forbes.com/sites/valleyvoices/2015/06/24/peter-thiel-n-t-wright-on-technology-hope-and-the-end-of-death/

Trametinib Modestly Extends Healthy Life Spans in Flies
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Researchers have found that the MEK inhibitor trametinib, used as a cancer treatment, modestly extends life in flies. This is of interest for researchers involved in mapping the relationships between metabolism and natural variations in longevity, but otherwise not all that significant in the grand scheme of things. The plasticity of life span in response to drug treatments that alter the operation of metabolism is much greater in short-lived creatures, and it should be expected that a small extension of life such as this one would map to next to nothing in humans, even assuming that the underlying mechanism of action is in fact shared. I believe that efforts to develop drug treatments to slow aging in humans based on this sort of result are doomed to lengthy and expensive failure, or at best result in very marginal therapies that will do no more than add a couple of years to life expectancy - something that can already be achieved through exercise or calorie restriction.

Adult fruit flies given a cancer drug live 12% longer than average, according to a study researching healthy ageing. Trametinib is used to treat skin cancer and was chosen for its ability to inhibit Ras signalling as part of the Ras-Erk-ETS cell pathway. The role of Ras has been well characterised in cancer but it is also known to affect the ageing process. Previously, the DNA of yeast was changed to reduce Ras activity, which extended lifespan, so the team wanted to explore inhibitors of this pathway in an animal. "Our aim is to understand the mechanisms of ageing and alter the processes that lead to loss of function and to disease. We studied this molecular pathway in flies because they are reasonably complex and yet age more quickly than mammals. We were able to extend their lifespan both genetically and by using a cancer drug to target the Ras pathway, which provides us with the first evidence for the anti-ageing potential of drugs developed to dampen this pathway."

Female fruit flies were given trametinib as an additive in their food. A small dose of 1.56 µM, which is approximately equivalent to a daily dose of the drug in a human cancer patients, increased the fruit flies' average life expectancy by 8%. With a higher dose of 15.6 µM, the flies lived 12% longer on average. To test the anti-ageing properties of the drug in later life, fruit flies over 30 days old that had almost all stopped laying eggs were given the same moderate dose of 15.6 µM, and still had an increased life expectancy of 4%. Flies exposed continuously to the drug from an earlier stage in life lived longer than those who began dosing later in life, possibly indicating a cumulative effect of the drug. "Identifying the importance of the Ras-Erk-ETS pathway in animal ageing is a significant step on the way to developing treatments that delay the onset of ageing. The pathway is the same in humans as it is in flies and, because the Ras protein plays a key role in cancer, many small molecule drugs already exist, some of which have been approved for clinical use. With support from pharma, we can refine these molecules over the next 10-20 years to develop anti-ageing treatments which don't have the adverse effects of cancer drugs."

Link: https://www.ucl.ac.uk/news/news-articles/0615/250615-fruit-flies-live-longer/

Longevity Drives Economic Growth
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Economic growth is fetishized in modern society, an idol and a yardstick. This shouldn't be surprising given the benefits that accompany the wealth of a society, amply demonstrated within the span of a lifetime for many countries in Asia and Africa, as entire populations moved rapidly from a state of agrarian poverty to build far wealthier industrial societies. It is argued here that rising life expectancy is a principal driver of economic growth, not just a benefit of increased wealth, and given this we should expect to see interesting times ahead of us.

It is arguably the case that the Industrial Revolution happened where it did and when it did in part due to a few generations of small but steady increases in life expectancy. This drove a slowly compounded increase in wealth and technology, which in turn fed back into further increases in life expectancy, and over time this small difference between England and the rest of Europe grew large enough to be the economic basis for a suddenly rapid expansion in technology and prosperity. Progress is the consequence of investment, and investment requires wealth. The growth curve is exponential, a bootstrapped grind from nothing that accelerates and feeds on itself as progress produces wealth that drives progress.

But why does longevity improve economic growth? Firstly because people who expect to be around for longer have more of an incentive to invest in improving the state of their property over the long term, and that happens to coincide with what should be going on if the goal is to create greater wealth for all. Short term thinking is the great destroyer of prosperity. Secondly age-related disease and disability imposes huge costs, both direct and opportunity costs: the sick must be cared for, and the productive work they could have carried out now goes undone. When people die, their knowledge and their contributions are lost. The cost of this lost human capital is staggering, should you actually sit down to run the numbers.

Increased life expectancy in past centuries was largely a matter of raising the average age at death through better nutrition and control of infectious disease, as well as other improvements in the provision of medicine, such as greater availability of any sort of worthwhile medical services. This was a matter of reducing mortality rates in childhood and early adulthood more than anything else. The future will be quite the opposite, and indeed even today the causes of the upward trend in life expectancy are quite different from those of the 17th and 18th centuries. We will live to see large gains in life expectancy arriving in later life, produced by addressing the causes of aging so as to create rejuvenation and extended vigor.

The effects on economic growth should still be just as profound over time. If stewardship of property is greatly improved by life expectancy at birth growing from 40 to 80, and the costs of aging and disease reduced, then the economic outlook improve again when the expectancy for health life span pushes towards 200 and beyond. I say beyond because if anyone alive today makes it that far, then so much technological progress will have occurred that the state of biotechnology should enable indefinite health by that time. There is no upper limit on human life span given sufficiently capable therapies to repair the causes of aging, and we are now moving into an era in which researchers are just starting to look at doing this, as opposed to patching over the consequences and hoping for the best.

The Longevity Dividend from an Aging Population

Indeed, a central issue with America's aging population - driven by longer lives, lower birth rates and the graying of 78 million baby boomers - is the question of how to manage a society with as many old as young. This is fundamentally a question of economics. The question for all of us is how to square 21st century aging populations with misaligned 20th century policies. Investing giant BlackRock recently addressed this challenge in a white paper and related panel discussion in New York. BlackRock, which manages $4.77 trillion in assets and serves 89% of the largest U.S. retirement plans, brings a compelling set of new ideas to the table.

The most remarkable thing about the new BlackRock report, "Unlocking the Longevity Dividend: How Longer Lives Are Changing Retirement, Investing and the Economy," is that it's not another woe-is-us lamentation on how demographics are going to doom America and the world. Instead, the report argues that if we get things right, longevity and population aging can be a lever of growth for individuals, families, businesses and nations - essentially, everyone on the planet.

BlackRock gets it right by focusing on the fundamentals of human capital: "Longer lives have created a vast pool of experience, capability and wealth that can become a driver for 21st century economic growth. Indeed, the transformative power of the generation now entering retirement should come as no surprise: Baby Boomers, born in the two decades following World War II, have reinvented every phase of life they have entered, often by design and sometimes through sheer force of numbers and economic clout."

To What Degree is Behavioral Change in Aging Driven by Specific Forms of Neurodegeneration?
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To what degree should we expect characteristic changes in behavior observed in the old to have a physical basis in neurodegeneration rather than being an outcome of living in our present cultures for a long time? If the neurodegeneration was prevented or repaired, what behavioral patterns would change, and why? Obviously researchers are a long way from providing defensible answers to those questions, but in this published research the authors provide evidence to suggest that behavioral flexibility is eroded in old age by a physical process, the destruction of a specific class of neuron:

Cholinergic interneurons are rare - they make up just one to two percent of the neurons in the striatum, a key part of the brain involved with higher-level decision-making. Scientists have suspected they play a role in behavioral flexibility, the ability to change strategy when the rules change, and researchers recently confirmed this with experiments. Previous studies tried to identify the role of cholinergic interneurons by recording brain wave activity during behavioral tasks. While that can strongly indicate specific neurons are correlated with a particular behavior, it is not definitive. In this study, researchers killed cholinergic interneurons with a toxin that directly targets them, and then observed how rats reacted to rule changes compared with normal rats with intact neurons. "Our experiments show direct causation, not correlation."

Rats with and without damaged neurons were given tasks for several weeks - they had to press either lever A or B to get a sugar pellet reward. During the first few days, Lever A always resulted in a reward. Both groups of rats had no problem learning the initial strategy to get the sugar pellet - press Lever A. But then, the rules of the game changed. A novel stimulus was introduced - a light flashed above the correct lever, which oscillated between Lever A and B. To get their sugar fix, the rats had to shift strategy and pay attention to this new information. While normal rats quickly responded to the light, rats with damaged neurons could not. The latter group continued to repeat the strategy they had already learned, and were disinclined to explore what the light meant.

"This indicates that cholinergic interneurons throughout the striatum play a common role, namely inhibiting old rules and encouraging exploration, but different regions of the striatum are activated depending on the situation and type of stimulus. Since cholinergic interneurons degenerate with age, this work may provide a clue for understanding the decline in mental flexibility that occurs with advancing age."

Link: http://www.oist.jp/news-center/press-releases/rare-neurons-enable-mental-flexibility

Evidence for Memory to be Stored in Synapses
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Understanding the storage model for human memory will enable a range of medical technologies relevant to repair and augmentation of the brain, but at present there is only a general consensus on the online of that model. Researchers believe that the data of memory is stored in the architecture of synapses, and here researchers provide more evidence that synapses are indeed the relevant location in mammals. This is perhaps of interest due to recent research in lower animals that seemed to rule out synaptic structures as the location of memory.

Our memories are as fleeting as the brain structures that store them, or so the theory goes. When the connections - called synapses - between neurons break, the memories they hold are thought to evaporate along with them. The idea seemed good, but has been hard to test. Now a team has taken on the challenge, studying a brain region called the hippocampus, which stores "episodic" memories. These are the memories of events or conversations that might be forgotten over time if the memories aren't used. The challenge to studying synapses in this region is that the hippocampus is so deep and the connections so densely packed that no microscope could easily monitor the synapses' longevity.

When mice experience a new episode or learn a new task that requires spatial navigation, the memory is stored for about a month in a structure at the center of the brain called the hippocampus (it is stored slightly longer in people). If mice have hippocampus-disrupting surgery within a month of forming a memory - a memory of meeting a new cage-mate or navigating a maze - that memory is lost. If the disruption occurs after more than a month, then the mouse still retains the memory of a new friend or location of food. That's because the memory had been relocated to a different region of the brain, the neocortex, and is no longer susceptible to disruption in the hippocampus.

In the past, scientists had monitored connections between neurons in the neocortex, nearer the brain's surface and therefore visible with little disruption to the brain. They watched not the connections themselves, but the bulbous projections called spines that form connections at their tips. Watching the spines come and go serves as a proxy for knowing when excitatory connections between neurons are created and broken. Those scientists found that about half of the spines in the neocortex were permanent and the rest turned over approximately every five to 15 days. "The interpretation was that about half the spines in the neocortex are long-term repositories for memories while others retain malleability for new memories or forgetting."

If the same line of thinking held true for the hippocampus as it did for the neocortex, spines in the hippocampus should turn over roughly every 30 days along with the memories they hold. Verifying that idea had been challenging, however, because the hippocampus is deeply buried in the brain and the spines in that region are so densely packed that multiple spines can appear to merge into one. The team overcame that problem with new techniques that allow stable imaging of a single neuron in a living mouse over long time periods, an optical needle, called a microendoscope, that provides high-resolution images of structures deep within the brain, and a mathematical model that took into account the limitations of the optical resolution and how that would affect the image datasets depicting the appearances and disappearances of spines. The researchers found that the region of the hippocampus that stores episodic memories contains spines that all turn over every three to six weeks - roughly the duration of episodic memory in mice.

Link: http://news.stanford.edu/pr/2015/pr-memory-monitor-biox-061715.html