Measuring the Processes of Aging in Younger Adults
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A recent open access paper describing efforts to measure degenerative aging in people in their twenties and thirties age bracket has been doing the rounds in the media. It is interesting to see people making an effort to create definitive measurements of aging in earlier age groups. The signs should certainly be there to see, given discriminating enough biotechnologies: the underlying damage that causes aging occurs at all ages. I'm also very much in favor of anything that might make the younger people in the audience feel more like they have skin in the game. In my experience one of the great ironies in persuading people to care about aging, to speak out for the cause and help fund research, is that the young think it isn't their problem, and the old think that there is no point in helping given that meaningful results will only arrive in the decades ahead. Everyone looks to their own lawn and little beyond.

Nonetheless, the young age too. Aging is a process of damage accumulation, accelerating to greater obvious results in later life due to interactions between damage that cause problems greater than the sum of the parts, and also due to declining repair and maintenance mechanisms. Damage feeds on damage in any machine: the more of it there is, the faster it arrives, and old, damaged machines see a rapid decline in mean time to failure. There are numerous types of cellular and molecular damage at the roots of aging, some of which can be repaired by our cells, were they operating at best capacity, and others that cannot. Aging is thus caused by a mix of two types of harm. On the one hand there is a slow and relentless accumulation of some types of defect: consider cross-links in the extracellular matrix that cannot be broken down by any of the enzymes we produce, generated as comparatively rare byproducts of metabolic operation, or mitochondrial mutations that can evade cellular quality control mechanisms and result in a growing population of dysfunctional cells packed with dysfunctional mitochondria. On the other hand there is a constant, ongoing, rapid creation of other types of defect that is matched by an equally rapid and capable set of repair processes. Unfortunately that repair effort itself winds down over time, allowing damage to get ever further ahead. Here you might think of plain old tissue maintenance by stem cell populations, as the decline of stem cell activity in aging is an important concern in medical research these days.

I think that much further work would need to be done in order to validate that the methods of measuring aging used by these researchers hold up well enough, and in fact correlate usefully with outcomes. Telomere length in particular is very flaky as usually measured in white blood cells, prone to all sorts of interesting and apparently contradictory outcomes in various different studies.

Researchers learn to measure aging process in young adults

Researchers introduced a panel of 18 biological measures that may be combined to determine whether people are aging faster or slower than their peers. The data comes from the Dunedin Study, a landmark longitudinal study that has tracked more than a thousand people born in 1972-73 in the same town from birth to the present. Health measures like blood pressure and liver function have been taken regularly, along with interviews and other assessments. "We set out to measure aging in these relatively young people. Most studies of aging look at seniors, but if we want to be able to prevent age-related disease, we're going to have to start studying aging in young people."

The progress of aging shows in human organs just as it does in eyes, joints and hair, but sooner. So as part of their regular reassessment of the study population at age 38 in 2011, the team measured the functions of kidneys, liver, lungs, metabolic and immune systems. They also measured HDL cholesterol, cardiorespiratory fitness, lung function and the length of the telomeres -- protective caps at the end of chromosomes that have been found to shorten with age. The study also measures dental health and the condition of the tiny blood vessels at the back of the eyes, which are a proxy for the brain's blood vessels.

Based on a subset of these biomarkers, the research team set a "biological age" for each participant, which ranged from under 30 to nearly 60 in the 38-year-olds. The researchers then went back into the archival data for each subject and looked at 18 biomarkers that were measured when the participants were age 26, and again when they were 32 and 38. From this, they drew a slope for each variable, and then the 18 slopes were added for each study subject to determine that individual's pace of aging.

Most participants clustered around an aging rate of one year per year, but others were found to be aging as fast as three years per chronological year. Many were aging at zero years per year, in effect staying younger than their age. As the team expected, those who were biologically older at age 38 also appeared to have been aging at a faster pace. A biological age of 40, for example, meant that person was aging at a rate of 1.2 years per year over the 12 years the study examined.

Quantification of biological aging in young adults

At present, much research on aging is being carried out with animals and older humans. Paradoxically, these seemingly sensible strategies pose translational difficulties. The difficulty with studying aging in old humans is that many of them already have age-related diseases. Age-related changes to physiology accumulate from early life, affecting organ systems years before disease diagnosis. Thus, intervention to reverse or delay the march toward age-related diseases must be scheduled while people are still young. Early interventions to slow aging can be tested in model organisms. The difficulty with these nonhuman models is that they do not typically capture the complex multifactorial risks and exposures that shape human aging. Moreover, whereas animals' brief lives make it feasible to study animal aging in the laboratory, humans' lives span many years. A solution is to study human aging in the first half of the life course, when individuals are starting to diverge in their aging trajectories, before most diseases (and regimens to manage them) become established. The main obstacle to studying aging before old age - and before the onset of age-related diseases - is the absence of methods to quantify the Pace of Aging in young humans.

We studied aging in a population-representative 1972-1973 birth cohort of 1,037 young adults followed from birth to age 38 y with 95% retention: the Dunedin Study. When they were 38 y old, we examined their physiologies to test whether this young population would show evidence of individual variation in aging despite remaining free of age-related disease. We next tested the hypothesis that cohort members with "older" physiologies at age 38 had actually been aging faster than their same chronologically aged peers who retained "younger" physiologies; specifically, we tested whether indicators of the integrity of their cardiovascular, metabolic, and immune systems, their kidneys, livers, gums, and lungs, and their DNA had deteriorated more rapidly according to measurements taken repeatedly since a baseline 12 y earlier at age 26. We further tested whether, by midlife, young adults who were aging more rapidly already exhibited deficits in their physical functioning, showed signs of early cognitive decline, and looked older to independent observers.

We developed and validated two methods by which aging can be measured in young adults, one cross-sectional and one longitudinal. Our longitudinal measure allows quantification of the pace of coordinated physiological deterioration across multiple organ systems (e.g., pulmonary, periodontal, cardiovascular, renal, hepatic, and immune function). We applied these methods to assess biological aging in young humans who had not yet developed age-related diseases. Young individuals of the same chronological age varied in their "biological aging" (declining integrity of multiple organ systems). Already, before midlife, individuals who were aging more rapidly were less physically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biological aging in young adults can be used to identify causes of aging and evaluate rejuvenation therapies.

I absolutely disagree with the author's position that intervention to reverse aging and age-related disease must happen while people are young. It will be certainly be much easier to achieve medical control of aging when people are young, as therapies will then have to successfully repair far less damage and a much smaller variety of damage. But, and this is crucial, the whole point of developing methods of repair for the causes of aging rather than methods of merely slowing it down is so that the old can be rescued - so that we create rejuvenation. This is no small point: it is a core part of the plan for SENS and other repair-based rejuvenation strategies.

More on Beta-2 Microglobulin Blood Levels and Aging, Resulting From Parabiosis Research
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Over the past couple of years, researchers have been involved in cataloging differences in signaling molecules in the blood when comparing old and young mice. This is an outgrowth of heterochronic parabiosis studies, in which an old and a young individual have their circulatory systems joined and the results observed. The effects are improved health, regeneration, and aspects of cell biology such as stem cell activity in the old individual, and opposing negative impacts on the young individual. This was in the news recently with a focus on TGF-β signaling and stem cell activity in the brain, but the other part of that research involves β2 microglobulin (B2M), which is front and center in the publicity materials linked below.

The orthodox theory is that stem cell activity declines with age in reaction to growing levels of tissue damage, and this happens because it reduces cancer risk, with life span emerging from the processes of natural selection as a balance between death by cancer on the one hand and death by loss of tissue maintenance and organ function on the other. The evidence to date suggests that in mammals at least this is far from a finely balanced outcome and that there is a in fact a fair amount of room to boost cell activity and regeneration in old age without greatly increasing cancer incidence.

Thus researchers are greatly interested in finding ways to restore stem cell activity in the old, and turn back loss of tissue maintenance. There is a good chance that much of this declining activity is caused, proximately at least, by changes in cell signaling over the course of aging, and especially in levels of signal molecules carried in the blood stream - which comes back to parabiosis as an investigative tool. If specific signals important in age-related decline of function can be identified, then changing their levels can form the basis for therapies.

The root cause of loss of function with age is still cell and tissue damage, however, and the best goal is to repair that damage and thus have the signaling changes revert themselves, not interfere at a higher level, even if it happens to turn out that there are benefits to be had. Even if you can improve greatly on today's medicine by restoring stem cell activity, with a backup provided by next generation targeted cancer therapies, then there is still the harm caused by forms of damage such as mitochondrial dysfunction and waste products such as cross-links and amyloid. That will still kill us if left untreated, stem cells or no stem cells.

Age-related cognitive decline tied to immune-system molecule

Connecting the circulatory system of a young mouse to that of an old mouse can reverse the declines in learning ability that typically emerge as mice age. Over the course of their long-term research on so-called young blood, however, the researchers had noted an opposite effect: blood from older animals appears to contain "pro-aging factors" that suppress neurogenesis - the sprouting of new brain cells in regions important for memory - which in turn can contribute to cognitive decline.

Beta-2 microglobulin, or B2M, levels steadily rise with age in mice, and are also higher in young mice in which the circulatory system is joined to that of an older mouse. B2M is a component of a larger molecule called MHC I (major histocompatibility complex class I), which plays a major role in the adaptive immune system. These findings were confirmed in humans, in whom B2M levels rose with age in both blood and in the cerebrospinal fluid (CSF) that bathes the brain. When B2M was administered to young mice, either via the circulatory system or directly into the brain, the mice performed poorly on tests of learning and memory compared to untreated mice, and neurogenesis was also suppressed in these mice.

These experiments were complemented by genetic manipulations in which some mice were engineered to lack a gene known as Tap1, which is crucial for the MHC I complex to make its way to the cell surface. In these mice, administration of B2M in young mice had no significant effect, either in tests of learning or in assessments of neurogenesis. The group also bred mice missing the gene for B2M itself. These mice performed better than their normal counterparts on learning tests well into old age, and their brains did not exhibit the decline in neurogenesis typically seen in aged mice.

The effects on learning observed in the B2M-administration experiments were reversible: 30 days after the B2M injections, the treated mice performed as well on tests as untreated mice, indicating that B2M-induced cognitive decline in humans could potentially be treated with targeted drugs. "From a translational perspective, we are interested in developing antibodies or small molecules to target this protein late in life. Since B2M goes up with age in blood, CSF, and also in the brain itself, this allows us multiple avenues in which to target this protein therapeutically."

β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis

Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain. Here we identify β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner.

B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.

Inflammation is Still Poorly Understood in Comparison to its Importance in Aging
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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.

Recent Papers on Energy Metabolism and Longevity
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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 the distinction between mortal soma and immortal germ line or disposable soma theory, 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.

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.