Fight Aging! Newsletter, July 6th 2015

July 6th 2015

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • Investigations of the INDY Gene Illustrate that "Very Slow" is the Default Speed of Aging Research
  • Naked Mole Rats Retain Neural Plasticity Across a Life Span
  • A Rare Replication of a Human Longevity-Associated Gene Variant in Different Study Populations
  • Recent Papers on Energy Metabolism and Longevity
  • Inflammation is Still Poorly Understood in Comparison to its Importance in Aging
  • Latest Headlines from Fight Aging!
    • Are Mitochondrial Mutations Really All That Important?
    • An Early Attempt to Work Around Immunosenescence
    • The Prospects for Stem Cells to Treat Chronic Wounds
    • Population Life Expectancy Inversely Correlated with Childhood Autoimmune Disease Incidence
    • The Latest Glenn Foundation Funding for Aging Research
    • Cellular Senescence and Parkinson's Disease
    • So: At What Age Do You Want to Become Diseased and Die?
    • Stem Cells Age as Well
    • A Report on the Second International Symposium on the Genetics of Aging and Life History
    • Prions Involved in Long Term Memory Maintenance


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.


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.


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.


Here I'll point out a couple of papers on the topic of energy, metabolism, and natural variations in longevity. One of the many ways of looking at the operation of metabolism is from the point of view of energy consumption and expenditure: how does energy flow around the system, how do these flows vary in different circumstances and between different species, and what can that tell us about the way in which our biology breaks down over the course of aging, or even why we age at all?

It is quite possible to measure a living being in the same way as one can measure an engine as a black box, assessing energy in, energy stored, energy expended. You can put an individual in an enclosed room and measure calorie intake, changes in gas fractions in the air, and so forth. Separately, within cells and tissues it is possible to catalog chemical reactions and the transfers of energy that accompany them, to build a picture of how the energy is ported from, say, food to movement of limbs, at both the high level and the very low level. Some types of model are pretty good and some are pretty sketchy since they depend on incomplete knowledge, but researchers have been working on aspects of this field of research for quite a long time, and both understanding and the quality of the models continues to improve.

One of the other fields tied in to considerations of energy metabolism is the study of calorie restriction, well known to extend healthy life span and improve health in near every species measured to date. Lowered intake of calories causes sweeping changes in the operation of cellular biology, and of course all of that can be considered in terms of energy. The two open access papers linked below both touch upon calorie restriction in the course of their discussion. This first is written from the minority programmed aging point of view, the second from the majority opposition viewpoint of aging as accumulated cell and tissue damage - though of course even with each of these factions there is a great deal of debate and many different theories of aging.

Energy excess is the main cause of accelerated aging of mammals

To date, over 300 theories explaining aging were put forward. Some of them, like the uncritically accepted free radical theory of aging, do not find unequivocal experimental support. Others, like theories focused on the distinction between mortal somatic cells and immortal germ line, can explain only general rules of aging, but are restricted to animals. Those, like antagonistic pleiotropy theory, are informative, but cannot explain the details of mechanisms of senescence and longevity. The closest to ideas presented in this paper is the postulate of hyperfunction.

The analysis of cases of unusually high longevity of naked mole rats and an alternative explanation of the phenomenon of calorie restriction effects in monkeys allowed for postulating that any factor preventing an excess of energy consumed, leads to increased lifespan, both in evolutionary and an individual lifetime scale. It is postulated that in mammals the most destructive processes resulting in shortening of life are not restricted to the phenomena explained by the hyperfunction theory. Hyperfunction, understood as unnecessary or even adverse syntheses of cell components, can be to some extent prevented by lowered intake of nutrients when body growth ceases. We postulate also the contribution of glyco/lipotoxicity to aging, resulting from the excess of energy.

Besides two other factors seem to participate in aging. One of them is lack of telomerase activity in some somatic cells. The second factor concerns epigenetic phenomena. Excessive activity of epigenetic maintenance system probably turns off some crucial organismal functions. Another epigenetic factor playing important role could be the microRNA system deciding on expression of numerous age-related diseases. However, low extrinsic mortality from predation is a conditio sine qua non of the expression of all longevity phenotypes in animals. Among all long-lived animals, naked mole rats are unique in the elimination of neoplasia, which is accompanied by delayed functional symptoms of senescence. The question whether simultaneous disappearance of neoplasia and delayed senescence is accidental or not remains open.

On the complex relationship between energy expenditure and longevity: Reconciling the contradictory empirical results with a simple theoretical model

The relationship between energy expenditure and longevity has been a central theme in aging studies. The oldest theory in the field - the rate of living theory (RLT) suggests that the rate of mass-specific energy expenditure (metabolic rate) is negatively correlated with longevity. The predicted correlation between energy expenditure and lifespan does not hold when comparisons are made across taxons, however. A typical example is that birds have higher metabolic rate than mammals with the same body mass, yet live much longer. The oxidative stress theory of aging (OST), another theory that links energy metabolism and longevity, suggests that the deleterious productions of oxidative metabolism (e.g., reactive oxygen species, ROS) cause various forms of molecular and cellular damage, and the accumulation of the damage is associated with the process of aging. Widely considered by many researchers as a modern version of the RLT at the molecular and cellular level, this theory shares all the supports and challenges of the RLT, as well as a few of its own.

In this paper, we present a simple theoretical model based on first principles of energy conservation and allometric scaling laws. We show that oxidative metabolism can affect cellular damage and longevity in different ways in animals with different life histories and under different experimental conditions. Qualitative data and the linearity between energy expenditure, cellular damage, and lifespan assumed in previous studies are not sufficient to understand the complexity of the relationships. Our model provides a theoretical framework for quantitative analyses and predictions. The model is supported by a variety of empirical studies, including studies on the cellular damage profile during ontogeny; the intra- and inter-specific correlations between body mass, metabolic rate, and lifespan; and the effects on lifespan of (1) diet restriction and genetic modification of growth hormone, (2) the cold and exercise stresses, and (3) manipulations of antioxidant.

The oxidative damage producing process starts from the overall energy expenditure (measured as oxygen consumption rate). Under many circumstances, energy expenditure is proportional to the production rate of ROS, which is in turn proportional to the net oxidative damage. Assuming that the net oxidative damage is the cause of aging and the determinant of lifespan, in these cases there is a direct and simple link between lifespan and metabolic rate. However, two factors, namely antioxidant scavenging and damage repair mechanisms, can alter the damage level (the output of the process) while keeping the energy expenditure rate (the input) roughly unchanged. Enhancing or weakening these two factors can result in a nonlinear correlation between net cellular damage level and oxygen consumption, and therefore a complex relationship between energy expenditure and longevity. The nonlinearity between damage and oxygen consumption may also be partially attributed to the incomplete mitochondrial coupling due to proton leak and electron leak, which causes a fraction of consumed oxygen not to produce ROS.

We need to emphasize that the protective mechanisms of anti-oxidative scavenging and damage repair require energy. So, the overall protective efficacy depends on the amount of energy allocated to these mechanisms and the efficiency of energy utilization for this purpose. Thus, we hypothesize that there are two ways to enhance the protection. The first way is to allocate more energy to protection. More energy for protection does not necessarily require an increase in overall energy expenditure. Some lifespan extension interventions can reshuffle the energy allocation and induce tradeoffs between protection and other life history traits. One of the most important traits that is often manipulated to tradeoff with protection is biosynthesis during growth. For example, when growth is retarded by diet restriction or genetic modification of growth hormone, the energy requirement for biosynthesis is reduced accordingly. The second way is to enhance the protective efficiency, so that one unit of the energy is associated with less molecular damage. Protective efficiency can be altered by experimental manipulations, such as down- or up-regulating genes for antioxidant enzymes, or altering the structures of molecules, such as the fatty acid composition of membranes, to change their vulnerability to oxidative insults.

In the RLT, the overall energy expenditure is the determinant of longevity, whereas in the OST, the determinant is the net cellular damage. As discussed above, because energy allocation and protective efficiency can both change in a variety of situations, these two determinants are not simply proportional to each other, and the link between longevity and energy expenditure is far more complex. Thus, we argue that the OST is not merely the modern version of the RLT at the cellular and molecular level.


Many researchers investigate inflammation, but like everything involving the immune system it is a very complex collection of processes, yet to be fully understood, and especially in the role it plays in degenerative aging. The greater the capabilities of modern biotechnology, the more details of molecular biology become visible for scientists to catalog and puzzle over: the deeper they look, the more there is to find. Here I pick one paper out of many - a look at the JAK-STAT signaling pathway in the context of inflammation in nervous system tissues - to illustrate this point.

Numerous age-related diseases count chronic inflammation as a factor contributing to pathology: think of it as a source of cell and tissue damage, even where the link isn't as direct and well understood as is the case for atherosclerosis, to pick an example. Even if you manage to evade all of the common ways to inflict significant additional unnecessary inflammation upon yourself - smoking, chronic injury, a sedentary lifestyle, and perhaps most significantly excess visceral fat tissue - your immune system still steadily malfunctions with advancing age. You're better off for being a fit, thin, non-smoker, but only better off, not immune. Your immune system falls into a state in which it is both ineffective and chronically overactive, and this and its consequences are given the name inflammaging.

If you read around the subject you'll see that enough is known to paint defensible summaries regarding inflammation and the activity of the immune system, but you don't have to wander far beyond the outline to find yourself off the maps and into unknown or hotly debated territory. This is one of the reasons why I favor work on comparatively simple engineering approaches to near-future treatments for immune aging, such as targeted destruction of memory T cells, or complete destruction and recreation of the immune cell population, or regeneration of the thymus. These strategies avoid the need to gain a far greater knowledge of immune system organization before producing new therapies. Gaining that knowledge is proving to be costly and slow, and while it will be needed for meaningful progress in the treatment of some autoimmune conditions such rheumatoid arthritis, the the more direct approaches noted above offer an alternative path with a shorter time to clinical application.

It is interesting that this team has focused on the JAK-STAT pathway in the context of nerve tissue and inflammation, as their research must have overlapped that of another comparatively recent discovery related to this pathway. In that other work, scientists showed that interfering in the JAK-STAT pathways can restore stem cell activity in aged muscle tissue, and via processes that don't immediately seem to be much related to inflammation.

Control of Inflammatory Responses: a New Paradigm for the Treatment of Chronic Neuronal Diseases

The term 'inflammation' was first introduced by Celsus almost 2000 years ago. Biological and medical researchers have shown increasing interest in inflammation over the past few decades, in part due to the emerging burden of chronic and degenerative diseases resulting from the increased longevity that has arisen thanks to modern medicine. Inflammation is believed to play critical roles in the pathogenesis of degenerative brain diseases, including Alzheimer's disease and Parkinson's disease. Accordingly, researchers have sought to combat such diseases by controlling inflammatory responses.

We identified Janus kinase-signal transducer and activators of transcription (JAK-STAT) as a new inflammatory signal in the brain and showed that its inflammatory signals can be activated by LPS, IFN-γ, gangliosides and thrombin. The receptor activated by these ligands or cytokines phosphorylates JAKs, leading to the phosphorylation (i.e. activation) of STAT molecules. Activated STATs form dimers and translocate to the nucleus, where they act as transcription factors; they induce the expression of inflammatory genes that have STAT-binding sites in their promoter regions, thereby activating subsequent inflammatory responses. Because the JAK-STAT pathways mediate the actions of numerous growth factors and cytokines, their negative feedback pathways are well developed and tightly regulated. The endogenous negative feedback molecules include phosphatases and inhibitory proteins, such as the suppressor of cytokine signaling (SOCS) proteins. Because the individual SOCS family proteins regulate different molecules of the JAK-STAT signaling pathways, we could possibly use them to specifically or synergistically control different JAK-STAT pathways. Indeed, the anti-inflammatory properties of many clinically available drugs, including aspirin, are mediated via SOCS proteins. Thus, it is particularly interesting to consider the development of additional SOCS-targeting drugs.

Despite years of research, inflammatory responses and the mechanisms underlying the actions of anti-inflammatory drugs remain to be clarified. Current studies in the field of immunology are expected to provide new insights into inflammation responses, inflammation-regulating drugs, and the relevant control mechanisms. Some antibodies and drugs used in clinical practice are capable of directly targeting specific signaling molecules/receptors. In the case of anti-inflammatory drugs, however, most such specific targeting therapeutics have been used only casually or experimentally.

Detailed information is now being obtained regarding the pharmacological actions of typical non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and steroids. If we hope to effectively regulate inflammation for the treatment of diseases, the mechanisms responsible for controlling the inflammatory response need to be firmly established. We should also seek to better understand the cause-and-effect relationships between inflammatory responses and the progression of related human diseases. Given that inflammatory/immune responses are physiological phenomena that can provide protection or cause damage, their therapeutic modulation must be precisely controlled in quantitative, qualitative and temporal terms. Improper control could compound the disease processes or cause a new disease. Thus, additional research is warranted to improve our understanding of the inflammatory response.


Monday, June 29, 2015

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.

Monday, June 29, 2015

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 CpG, 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.

Tuesday, June 30, 2015

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.

Tuesday, June 30, 2015

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.

Wednesday, July 1, 2015

In past years the Glenn Foundation for Medical Research has reinforced the mainstream of the aging research community with grants of a few million 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 two 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 five million gift from the foundation and expanded with an additional one 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.

Wednesday, July 1, 2015

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.

Thursday, July 2, 2015

Here are a few thoughts on the need for advocacy in longevity science from Rejuvenaction:

People don't think that ageing is a disease because they're used to thinking that it's just a stage of life. They will start to finally accept that this is not the case only when a sufficiently large number of other people in positions of authority, scientists and organizations, will come out and say it out loud. That's one sad truth: people accept things far more quickly than they understand them, and if, at some point, news from the anti-ageing world will frequently populate their TV screens, social media feeds, newspaper articles, and even casual discussions, they will stop ignoring the problem of ageing and cease to oppose its resolution. Nobody likes to advocate for an unpopular cause: it doesn't feel good to be the only person in a group to support a certain claim while being fiercely opposed by all the others, but it does feel nice to be on the winning side of an argument.

Unfortunately, with the exception of the SENS Research Foundation and a few others, researchers of the field are quite hesitant about their goals. I don't see anything wrong with looking for a "fountain of youth". Actually, I don't see how can you want to just "increase health span" without looking for a fountain of youth or eternal life. If they want to increase the current health span it's clearly because they think that the current one isn't enough. So they're not okay with getting sick of the diseases of old age at 80. Now just how much do they want to increase this health span? Till you're 100? 120? When is it okay to get age-related diseases? Unless you increase health-span indefinitely, at some point you are going to get age-related diseases, and they will kill you.

And say that one day they manage to extend health span so that you don't start experiencing age-related decay until you're 120. Then some other researchers come along and say that "they just want to extend health span" so that age-related diseases are delayed until you're 140. Are we saying no to that? Extending your health span up to when you're 120 is fine but up to when you're 140 is not? Why? This game is rather silly, particularly when you think about the obvious fact that unless you have a health problem of some sort, you do not die: yes, being shot, poisoned, electrocuted, eaten by a shark and whatever violent death you can think of counts too, because they all cause you health issues that eventually (rather fast, in fact) kill you. So, if you're not looking for eternal life, it means you're explicitly and intentionally leaving around some health problem of which people can die. In the case of age-related diseases, which ones should we leave around? Which age-related diseases are okay to die of? Alzheimer's? Cancer? Cardiovascular disease? Make your pick - I'm okay without any of those, thank you.

I'm willing to concede that, perhaps, the researchers are playing it safe: they know that if you dare saying that you want to get rid of biological ageing altogether then people will jump down your throat, and thus it's better to slowly get them used to anti-ageing research before making bolder claims. However, I disagree: curing ageing is an urgent humanitarian problem, and there's no time to fool around to please the masses. We need to educate people, get them understand that curing ageing and immortality aren't the same thing at all, that age-related diseases are an extremely serious and compelling problem that needs to be addressed right now, before it goes from bad to worse, and that all the objections to the defeat of ageing make no sense whatsoever.

Thursday, July 2, 2015

Today I thought I'd point out an interesting post from the Buck Institute team on the topic of stem cell aging. The good news here is that the characteristic age-related decline of stem cell function is an issue that the research community has to engage with on the way to developing effective treatments based on their work. It is unavoidable: the majority of regenerative medicine based on the use of stem cells is most applicable to age-related diseases, yet the old and damaged tissue environment disrupts stem cell activity.

What happens to adult stem cells as a person ages? Can they always maintain their regenerative capacity? The answer is no. Adult stem cells maintain tissue homeostasis and differentiate into the cell types that make up the tissue in which they reside, however these processes become less efficient over time. Adult stem cell dysfunction caused by aging has been reported in many organ systems including the heart, muscle, and bone marrow. Some adult stem cell populations like neural stem cells in the brain and melanocyte stem cells in hair follicles actually decline with age. Both adult stem cell dysfunction and a decline in number translate to a reduced regenerative response to tissue or age-related damage.

A few of the culprits: DNA damage occurs in aging stem cells over time because of factors present inside and outside of the cells and because of exposure to genotoxic stress (chemical factors that cause genetic mutations). The machinery that repairs DNA in older stem cells does not function as precisely, and this can cause genomic instability, cell death, or even cancer if a person is really unlucky. Cellular senescence is a term that refers to cells that have entered a state where they can no longer proliferate and divide. Senescence occurs in older stem cells because of elevated cellular stress. Senescent stem cells are bad news because they secrete factors that can cause inflammation and stem cell dysfunction, which further exacerbates symptoms of aging and disease. Then there is mitochondrial dysfunction. Mitochondria are the batteries that power our cells. Mitochondria have their own genome, and in aging stem cells, mitochondrial DNA can be damaged, which impairs mitochondrial function and consequently, adult stem cell function.

So how do we solve the problem of aging stem cells? One obvious approach is to rejuvenate adult stem cells by preventing DNA damage, cellular senescence, and mitochondrial dysfunction. Another strategy is to transplant healthy adult stem cells from a donor into a patient with disease or damaged tissue. However, the issue with adult stem cell transplantation is that the environment (called the niche) into which you transplant healthy stem cells may contain toxic factors (caused by disease or damage) that will kill off the newly transplanted stem cells or impair their function. Thus, a better approach would be to fix or reverse aging phenotypes in the surviving stem cells and other mature cells in that niche, and then transplant healthy donor stem cells into a rejuvenated, healthy environment.

One last thing to consider as one addresses the aging adult stem cell issue is when to intervene therapeutically. Trying to restore adult stem cell function in already diseased or older tissue might not be as effective as preventing damage from accumulating in the same stem cells earlier in life. Prevention of stem cell aging would be a promising strategy to fight aging itself, but that would require the ability to predict or diagnose disease onset in healthy people, which is a huge and complicated endeavor.

Friday, July 3, 2015

The number of scientific conferences covering the molecular biology of aging seems to be growing. Here is a recently published report from a conference held last year, for example:

Aging is a fundamental problem that the world is currently facing. The population of elderly people is higher than it has ever been before and continues to increase at an even higher rate. Although life expectancy has been dramatically increased in industrialized countries, many elderly people still suffer from serious age-related diseases, and the burden of healthcare costs is increasing steadily because aging is directly related to many illnesses, including cancer, diabetes, and cardiac dysfunction. Therefore, delaying the onset of age-related diseases, improving quality of life, and providing humans with a healthy aging strategy are among the main goals of research on aging. Model organisms have proven to be reliable tools for studying aging and have revealed promising biological foundations for delaying the onset and the progress of age-related human diseases. To address and discuss emerging issues on various aspects of the biology of aging, the International Symposium on the Genetics of Aging and Life History II was held at the campus of the Daegu Gyeongbuk Institute of Science and Technology (DGIST), South Korea, from May 14 to 16, 2014.

Many leading scientists from all over the world attended the symposium to share their ideas. The scientists at the meeting presented their work, which aims to identify solutions for aging and age-associated diseases. Pharmacological strategies and bioinformatics approaches to understand aging, cellular senescence, sensory and mitochondrial signaling, and the role of microRNAs in the regulation of lifespan were among the wide range of topics covered at the meeting. Interventions that slow aging and delay the onset of age-associated diseases were discussed thoroughly.

There is no doubt that the importance of research on aging has been emphasized in the last few decades. The increasing interest in and demand for aging research is also felt in East Asian countries, including South Korea. Many notable meetings on aging research have been successfully held in Asia, including the Symposium on the Genetics of Aging and Life History (South Korea), the Trinations Aging Symposium (China), a conference on the Molecular Basis of Aging and Disease, Cold Spring Harbor Laboratory Asia (China), and others. Leading scientists in the field are invited from throughout the world, and the number of participants has been increasing at each meeting. We believe that these meetings, including the Symposium on the Genetics of Aging and Life History, substantially bridge different areas of aging research and bring opportunities for collaborations.

Friday, July 3, 2015

If verified by other laboratories, this seems like a meaningful step forward in understanding the physical structure of memory. A greater knowledge of the biological basis for memory storage has important applications in many fields, not just the obvious ones in medicine:

Researchers have shown how how prion-like proteins are critical for maintaining long-term memories in mice, and probably in other mammals. When long-term memories are created in the brain, new connections are made between neurons to store the memory. But those physical connections must be maintained for a memory to persist, or else they will disintegrate and the memory will disappear within days. Many researchers have searched for molecules that maintain long-term memory, but their identity has remained elusive.

Prions - a name derived from the words protein infectious particles - are a unique class of proteins. Unlike other proteins, they are not only able to self-propagate but also to induce other proteins to take on their alternative shape. When prions form in a cell, notably in a neuron, they cause damage by grouping together in sticky aggregates that disrupt cellular processes. In contrast, functional prion proteins can play a physiological role in the cell and do not contribute to disease.

Researchers first identified functional prions in the giant sea slug (Aplysia) and found they contribute to the maintenance of memory storage. More recently, they searched for and found a similar protein in mice, called CPEB3. In one of many experiments, the researchers challenged mice to repeatedly navigate a maze, allowing the animals to create a long-term memory. But when the researchers knocked out the animal's CPEB3 gene two weeks after the memory was made, the memory disappeared.

The researchers then discovered how CPEB3 works inside the neurons to maintain long-term memories. "Like disease-causing prions, functional prions come in two varieties, a soluble form and a form that creates aggregates. When we learn something and form long-term memories, new synaptic connections are made, the soluble prions in those synapses are converted into aggregated prions. The aggregated prions turn on protein synthesis necessary to maintain the memory." As long as these aggregates are present long-term memories persist. Prion aggregates renew themselves by continually recruiting newly made soluble prions into the aggregates. "This ongoing maintenance is crucial."

A similar protein exists in humans, suggesting that the same mechanism is at work in the human brain, but more research is needed. "It's possible that it has the same role in memory, but until this has been examined, we won't know. There are probably other regulatory components involved. Long-term memory is a complicated process, so I doubt this is the only important factor."


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