Fight Aging! Newsletter, January 23rd 2017

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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  • Considering Pan-mTOR Inhibitors as Alternatives to Rapamycin
  • The Latest Analysis of Calorie Restriction in Primates: Benefits to Health and Longevity
  • Linking Inflammation, Immune Dysfunction, and Intestinal Aging
  • Correlating Activity Levels and Telomere Length as a Proxy for the Pace of Aging
  • A Future of Combination Therapies that Transform Cancer Cells into Senescent Cells, and then Suppress and Destroy Them
  • Latest Headlines from Fight Aging!
    • Fitness in Older Adults Correlates with Improved Brain Activity and Memory
    • A Profile of Craig Venter and Human Longevity Inc.
    • VCAM1 as a Potential Harmful Signal in Old Blood
    • Towards a Better Understanding of the Effects of Tiny Strokes on Cognitive Decline
    • Aging as the Evolutionary Cost of Complexity, Driven by Mitochondrial Dynamics
    • More Investigation of the 5q33.3 Locus in Human Longevity
    • The Case for Defeating Death by Aging
    • Aberrant Astrocytes as a Cause of Neurodegenerative Disease
    • TET2 Mutations and Atherosclerosis
    • Physical Activity Associated with Lower Heart Disease Mortality

Considering Pan-mTOR Inhibitors as Alternatives to Rapamycin

For a number of years now, mechanistic target of rapamycin (mTOR) has been the focus of a fair amount of research into aging. Goals include gaining a better understanding of the way in which metabolism determines natural variations in longevity, and also establishing means by which the pace of aging might be modestly slowed via long-term pharmaceutical alteration of metabolic processes. I don't consider this to be the most effective way forward for longevity science, but evidently a lot of people do. mTOR appears to be a factor in a range of genetic and other interventions shown to slow aging to varying degrees in laboratory animals, but for most of these so many changes take place in cellular biochemistry that it remains a challenge to talk definitively about root causes or most important mechanisms.

So far the search for drug candidates to target mTOR has produced few if any outstanding new leads. Rapamycin is the starting point, and has been shown to extend life span in mice, but it has side-effects that make it undesirable for widespread use in humans. Researchers have been exploring the expanding suite of rapalogs, drugs with similar structures and effects, but so far nothing has jumped to the fore by virtue of a large enough improvement to demand immediate clinical development. mTOR forms two complexes in the course of interactions relevant to aging, mTORC1 and mTORC2. There is a school of thought that suggests the problems inherent in rapamycin and similar compounds arise because they affect both of these complexes. There is evidence to suggest that targeting mTORC1 while leaving mTORC2 alone would capture beneficial outcomes without many of the problem side-effects - but easier said than done with pharmaceuticals given the tools to hand. The real issues in the biochemistry are also probably more complex than this simplistic view of the situation.

The paper linked below is characteristic of continued exploration of pharmaceutical databases in search of better options, as well as the increasing complexity of the underlying theory that steers this exploration. The biochemistry of aging, the intricacy with which it progresses from moment to moment, is enormously complex. The paper is also characteristic of an increasing interest in cellular senescence in all areas of the aging research community. With the proof that removal of senescence cells extends life in mice, and increasing evidence for the role of senescent cells in specific age-related diseases, researchers now have to fit these findings into the many and varied existing views of aging, or give senescence greater prominence where already present. In the case of mTOR, researchers demonstrated last year that mTOR inhibition appears to slow the approach of cells towards replicative senescence, the state that occurs at the Hayflick limit on cell replication, which is one of the reasons why it appears here as a yardstick for measuring the effects of alternatives to rapamycin.

Gerosuppression by pan-mTOR inhibitors

Rapamycin slows down aging in yeast, Drosophila, worms, and mice. It also delays age-related diseases in a variety of species including humans. Numerous studies have demonstrated life extension by rapamycin in rodent models of human diseases. The maximal lifespan extension is dose-dependent. One explanation is trivial: the higher the doses, the stronger inhibition of mTOR. There is another explanation: mTOR complex 1 (mTORC1) has different affinity for its substrates. For example, inhibition of phosphorylation of S6K is achieved at low concentrations of rapamycin, whereas phosphorylation of 4EBP1 is insensitive to pharmacological concentrations of rapamycin. Unlike rapalogs, ATP-competitive kinase inhibitors, also known as dual mTORC1/C2 or pan-mTOR inhibitors, directly inhibit the mTOR kinase in both mTORC1 and mTORC2 complexes.

In cell culture, induction of senescence requires two events: cell cycle arrest and mTOR-dependent geroconversion from arrest to senescence. In proliferating cells, mTOR is highly active, driving cellular mass growth. When the cell cycle gets arrested, then still active mTOR drives geroconversion: growth without division (hypertrophy) and a compensatory lysosomal hyperfunction (beta-Gal staining). So senescence can be caused by forced arrest in the presence of an active mTOR. Senescent cells lose re-proliferative potential (RPP): the ability to regenerate cell culture after cell cycle arrest is lifted. Quiescence or reversible arrest, in contrast, is caused by deactivation of mTOR. When arrest is released, quiescent cells re-proliferate. In one cellular model of senescence (cells with IPTG-inducible p21), IPTG forces cell cycle arrest without affecting mTOR. During IPTG-induced arrest, the cells become hypertrophic, flat, SA-beta-Gal positive and lose RPP. When IPTG is washed out, such cells cannot resume proliferation. Loss of RPP is a simple quantitative test of geroconversion. Treatment with rapamycin during IPTG-induced arrest preserves RPP. When IPTG and rapamycin are washed out, cells re-proliferate.

Recently, we have shown that Torin 1 and PP242 suppresses geroconversion, preventing senescent morphology and loss of RPP. In agreement, reversal of senescent phenotype was shown by another pan-mTOR inhibitor, AZD8085. Pan-mTOR inhibitors have been developed as cytostatics to inhibit cancer cell proliferation. Cytostatic side effects in normal cells are generally acceptable for anti-cancer drugs. However, cytostatic side effects may not be acceptable for anti-aging drugs. Gerosuppressive (anti-aging) effects at drug concentrations that are only mildly cytostatic are desirable. Pan-mTOR inhibitors differ by their affinity for mTOR complexes and other kinases. Here we studied 6 pan-mTOR inhibitors (in comparison with rapamycin) and investigated effects of 6 pan-mTOR inhibitors on rapamycin-sensitive and -insensitive activities of mTOR, cell proliferation and geroconversion: Torin 1, Torin 2, AZD8055, PP242, KU-006379 and GSK1059615.

As predicted by theory of TOR-driven aging, rapamycin extends life span and prevents age-related diseases. Yet, rapamycin (and other rapalogs such as everolimus) does not inhibit all functions of mTOR. Inhibition of both rapamycin-sensitive and -insensitive functions of mTOR may be translated in superior anti-aging effects. However, potential benefits may be limited by undesirable effects such as inhibition of cell proliferation (cytostatic effect) and cell death (cytotoxic effect). In fact, pan-mTOR inhibitors have been developed to treat cancer, so they are cytostatic and cytotoxic at intended anti-cancer concentrations. Yet, the window between gerosupressive and cytotoxic effects exists. At optimal gerosuppressive concentrations, pan-mTOR inhibitors caused only mild cytostatic effect. For Torin 1 and PP242, the ratio of gerosuppressive (measured by RPP) to cytostatic concentrations was the most favorable. The ratio of anti-hypertrophic to cytostatic concentration was similar for all pan-mTOR inhibitors. Gerosuppressive effect of pan-mTOR inhibitors (as measured by RPP) was equal to that of rapamycin because it is mostly associated with inhibition of the S6K/S6 axis. Yet anti-hypertrophic effect as well as prevention of SA-beta-Gal staining and large cell morphology was more pronounced with pan-mTOR inhibitors than with rapamycin. Also, at optimal concentrations, all pan-mTOR inhibitors extended loss of re-proliferative potential in stationary cell culture more potently than rapamycin.

At gerosuppressive concentrations, pan-mTOR inhibitors should be tested as anti-aging drugs. Life-long administration of pan-mTOR inhibitors to mice will take several years. Yet, administration of pan-mTOR inhibitors can be started late in life, thus shortening the experiment. In fact, rapamycin is effective when started late in life in mice. Optimal doses and schedules of administration could be selected by administration of pan-mTOR inhibitors to prevent obesity in mice on high fat diet (HFD). It was shown that high doses of rapamycin prevented obesity in mice on HFD even when administrated intermittently. Testing anti-obesity effects of pan-mTOR inhibitors will allow investigators to determine their effective doses and schedules within several months. It would be important to test both rapamycin-like agents such as Torin 1 and rapamycin-unlike agent such as Torin 2 or AZD8085. Selected doses and schedules can then be used to extend life-span in both short-lived mice, normal and heterogeneous mice as well as mice on high fat diet. These experiments will address questions of theoretical and practical importance: (a) role of rapamycin-insensitive functions of mTOR in aging. We would learn more about aging and age-related diseases. (b) can pan-mTOR inhibitors extend life span beyond the limits achievable by rapamycin.

The Latest Analysis of Calorie Restriction in Primates: Benefits to Health and Longevity

The latest analysis of data on primate longevity under conditions of calorie restriction was published today, and sides with the claims of extended longevity and improved health made a few years ago. Two long-running studies of calorie restriction in rhesus macaques commenced in the late 1980s and early 1990s, and are currently in the phase at which survival data can be discussed rather than projected. Rhesus macaques are known to have lived for longer than 40 years in captivity, but most in these circumstances die by age 35, and the average age at death is 26. This is an exceptionally long time to run a study in the modern scientific community. The cost of such studies is large, and in the present environment they are unlikely to be repeated or expanded upon in the foreseeable future. Firstly because we are entering the era of rejuvenation therapies, in which methods of modestly slowing aging such as calorie restriction will soon become irrelevant. Secondly, because there has been considerable debate in the past few years over the design of these studies, whether the results to date in fact illustrate that longer-lived primates exhibit extension of life span under calorie restricted conditions, or indeed, whether or not the results are actually useful given the issues with the studies. Still, if we want the data we are unlikely to find other sources any time soon.

An important point to keep in mind while considering this topic is that short-lived species have a greater plasticity of longevity in response to environmental circumstances, such as a lower calorie intake, and most likely to any gene therapy or pharmaceutical that mimics aspects of those environment circumstances. We know this because the practice of calorie restriction does not reliably produce 110-year-old humans, while in mice calorie restriction reliably extends life by as much as 40%. Why does this difference exist? From a molecular biology perspective it is puzzling given that the short-term changes in metabolism that take place under conditions of calorie restriction are remarkably similar in mice and people. From an evolutionary perspective, on the other hand, there is a solid theoretical explanation: calorie restriction, which evolved very early in the development of life, is a response to seasonal famine. It is a way to increase the odds of survival in an environment of scarcity that tends to last only so long. A season is a lengthy fraction of a mouse life span, but not so for humans, and so only mice experience the evolutionary pressure that leads to a proportionally large extension of life in this scenario.

Running studies in primates that live for decades is a way to try to understand to what degree we should expect calorie restriction to extend life in humans, and perhaps also to understand something of the mechanisms that ensure the outcome is a lesser degree of life extension than in short-lived mammals. Were there large communities of human practitioners of calorie restriction, the studies would not have taken place: researchers would do exactly what they do for, say, the effects of exercise, and first turn to human epidemiological data. There are, however, very few people with the necessary decades of calorie restriction behind them, so it is hard to answer questions about human long-term outcomes. The biomarkers and human studies of a few years or less suggest large benefits in terms of resistance to age-related disease, but again, there is a noted absence of effects large enough and reliable enough to show up in established databases of mortality and disease. Given the small number of practitioners, it is not entirely unreasonable to expect an effect of five to ten years to be hard to find in existing data, but much larger than this and we must start to question the plausibility.

The open access paper quoted below is very readable, and actually goes into some detail regarding differences between the studies relevant to past disputes over results. If the topic interests you, then you should certainly look over the whole thing rather than just the summary here. Does this new study add good reasons to practice calorie restriction? I'd say probably not on the whole. If you are not already sold on the rapid and sizable beneficial effects to health that are produced via a calorie restricted diet, or at least sizable in comparison to what any widely available medical technology can do for basically healthy people today, then I can't imagine that the endorsement here will be much of an additional attraction. It is one more data point atop a large and compelling mountain of data points. Being healthy for the long term does require some effort, and that will continue to be the case for a while yet. Being rescued from aging and ill health by progress towards rejuvenation therapies may indeed happen, but when it will happen is a question mark. So why shorten the odds for your own future by letting things go today?

Caloric restriction improves health and survival of rhesus monkeys

A clear understanding of the biology of ageing, as opposed to the biology of individual age-related diseases, could be the critical turning point for novel approaches in preventative strategies to facilitate healthy human ageing. Caloric restriction (CR) offers a powerful paradigm to uncover the cellular and molecular basis for the age-related increase in overall disease vulnerability that is shared by all mammalian species. CR extends median and maximum lifespan in most strains of laboratory rodents and also delays the onset of age-related diseases and disorders. Lifespan is also extended by CR in most short-lived species, including the unicellular yeast, nematodes and invertebrates. There has been rapid progress in identifying potential mechanisms of CR utilizing these models. These short-lived species are well suited for the investigation of the underlying mechanisms of CR due to the relative ease in their genetic manipulation, extensive genetic and developmental characterization, low cost, and significantly reduced timeframe for completion of longevity studies. A key question underpinning this body of work is whether the biology of CR, and its ability to delay ageing and the onset of disease, applies to humans and human health.

To date three independent studies of rhesus monkeys (Macaca mulatta) have tackled the question of translatability of CR to primate species. The University of Maryland rhesus monkey study was the first to report a positive association of CR with survival with a 2.6-fold increased risk of death in control animals compared to restricted. The primary focus of the study was not CR however, and analysis was based on comparing 109 ad libitum fed males and females from colony records at that facility, including insulin resistant and diabetic animals, to only eight male CR monkeys. Two other studies focused specifically on the impact of CR in healthy male and female rhesus monkeys: one at the National Institute on Aging (NIA) involving 121 monkeys; and the other at the University of Wisconsin Madison (UW) with 76 monkeys. The same statistical team was engaged for analysis of data from both studies. The UW study has reported beneficial effects of CR, including significant improvements in health and age-related survival, and all-cause survival. In contrast, the NIA study reported no significant impact of CR on survival, although improvements in health were close to statistical significance. The basis for the contrasting outcomes from these two parallel studies has not been established. Analysis of limited published bodyweight data indicated that the controls were not equivalent between the two studies, pointing to fundamental differences in study design and implementation. Therefore, to more fully assess possible explanations for the discrepant findings between the two studies, we have conducted a comprehensive assessment of longitudinal data from both sites highlighting differences that may have contributed to the dissimilar outcomes.

Data from both study locations suggest that the CR paradigm is effective in delaying the effects of ageing in nonhuman primates but that the age of onset is an important factor in determining the extent to which beneficial effects of CR might be induced. In the UW study, reduced bodyweight, reduced adiposity and reduced food intake of the CR monkeys were associated with improved survival, with CR monkeys of both sexes surviving longer than controls, ∼28 and ∼30 years of age for males and females respectively, and longer than the median age for monkeys in captivity (∼26 years of age). Although an impact of CR on survival was not detected within the NIA old-onset cohort, comparison to the UW study shows that bodyweight was significantly lower in both control and CR groups of males and females than in their UW control counterparts, and was largely equivalent to that of UW CR. All males and females from the NIA old-onset groups consumed fewer calories than their counterpart controls from UW, instead both control and CR were closely aligned with food intake values of UW CR.

Importantly, the median survival estimates for old-onset males were very high, similar to what has been reported previously as the 90th percentile for this species (∼35 years of age). Six of the original 20 monkeys have lived beyond 40 years of age, the previous maximal lifespan recorded, and one old-onset CR male monkey is currently 43 years old, which is a longevity record for this species. Median survival estimates for old-onset females, ∼27 and ∼28 for controls and CR respectively, were also greater than national median lifespan estimates, with one remaining female currently 38 years of age. The clear benefit in survival estimates for monkeys within the old-onset cohort compared to UW controls suggests that food intake can and does influence survival. The lack of difference between control and CR old-onset monkeys suggests that a reduction in food intake beyond that of the controls brings no further advantage. The minimum degree of restriction that confers maximal benefit in rhesus monkeys has not yet been identified but is an active topic of investigation. Taken together, data from both UW and NIA studies support the concept that lower food intake in adult or advanced age is associated with improved survival in nonhuman primates.

The catalogue of pathologies identified in aged monkeys is shared with aged humans. The definitions used to identify morbidity were determined by veterinary staff and were essentially equivalent at both sites. A shared feature of both studies is the beneficial effect of CR in lowering the risk for age-related morbidity by more than two-fold. The beneficial effects extended to diseases that are among the most prevalent in human clinical care including cancer, cardiovascular disease and parameters associated with diabetes. A lower incidence of cancer was one of the first health benefits of CR documented and is considered to be a hallmark of CR in rodents. The incidence of cancer was lower in CR monkeys at both locations indicating that tumour suppression is a conserved feature of mammalian CR. CR also lowered the incidence of cardiovascular disorders at UW, and NIA monkeys from either diet group appear to have been protected compared to UW control monkeys.

Given the obvious parallels between human and rhesus monkey data, it seems highly likely that the beneficial effects of CR would also be observed in humans. Reports from the multicenter CALERIE study of short-term CR in humans document changes in bodyweight, body composition, glucoregulatory function and serum risk factors for cardiovascular disease in response to CR. These outcomes in humans align well with reports on rhesus monkey CR, confirming that the primary response to CR is conserved between these two species, and suggesting that the underlying mechanisms may also be conserved. In conclusion, the NIA and UW nonhuman primate ageing and CR studies address a central concept of relevance to human ageing and human health: that the age-related increase in disease vulnerability in primates is malleable and that ageing itself presents a reasonable target for intervention. The last two decades have seen considerable advances in ageing research in short-lived species and investigations of the mechanisms of CR have been prominent in this work. It will be particularly informative to determine the degree to which consensus hallmarks of ageing described in recent publications also manifest in primate ageing. The tissues and longitudinal data stored over the course of these two highly controlled monkey studies present a unique resource that can be used to identify key pathways responsive to CR in primates, to uncover primate-specific aspects of the basic biology of ageing, and to determine molecular basis for nutritional modulation of health and ageing. Processes impacted by CR would be prime targets for the development of clinical interventions to offset age-related morbidity, and identification of factors involved in the mechanisms of CR will be pivotal in bringing these ideas to clinical research and human health care.

Linking Inflammation, Immune Dysfunction, and Intestinal Aging

Today I noticed a set of interesting research materials in which the authors report on their investigation of links between chronic inflammation and intestinal dysfunction in aging. Growing inflammation is characteristic of aging in an age in which near everyone puts on a great deal of weight as they get older. Visceral fat tissue produces excessive inflammation through a number of mechanisms, which is one of the ways in which its presence accelerates the onset of all of the common age-related diseases. But even putting fat tissue to one side, aging is still accompanied by ever greater levels of chronic inflammation, a consequence of the progressive failure of the immune system, hampered by the fundamental cell and tissue damage of aging on the one hand, and on the other by limits to capacity that are inherent in the way in which it is structured. Unregulated inflammation due to immune system malfunction, either in the innate or adaptive components, is called inflammaging and considered by some to be a distinct process from immunosenescence, the inability of the immune system to effectively combat pathogens and destroy unwanted cells.

Intestinal dysfunction is a central feature of aging in lower species such as flies, and measures of aging in the intestines can predict mortality in this species. Further, a number of the methods shown to slow aging in flies appear to work through improved stem cell activity in intestinal tissues. Flies are not people, however, and it isn't at all clear that the intestines have anywhere near the same degree of prominence in mammalian aging. If anything, that position should probably go to the cardiovascular system in our own species, given the distribution of proximate causes of human mortality, and the way in which cardiovascular aging correlates well with many other forms of ultimately fatal age-related disease. Still, there is an increasing interest these days among aging researchers in the microbiome that dwells within the gut, and the roles that this microbial ecosystem might play in aging, especially as tissue function begins to break down, and as the immune system becomes both more easily aggravated and less effective. Considered in the bigger picture, the open access paper here makes for interesting reading; you might just skip the publicity materials.

Research Team Identifies Mechanisms of Inflammation-induced Animal Aging

Researchers have identified the aging mechanisms of animals resulting from intestinal inflammation accumulation. So far, numerous hypotheses explaining animal aging have been published and one of them is inflammation-induced aging which proposes that accumulation of inflammation is the cause of animal aging. While inflammation-induced aging theory has been one of many hypotheses explaining the aging of animals, its substance has not been clearly proven. The research team has discovered that the pericytes surrounding the endothelial cells in the intestinal tissues decrease as an animal's biological age increases and thus the blood vessel function deteriorated, including the progress of vascular leakage. Through the experiment, this study has shown that this phenomenon is due to the increase of gut-resident inflammatory cells (macrophages) and the increase of TNF-α, cytokine secreted by these cells, as well as the entailed changes in the surrounding environment of blood vessel.

"This study is significant as we have newly identified the mechanisms of aging associated with inflammation increase and opened possibilities of applied researches on aging delay through inflammation control as well as anti-aging. We will conduct follow-up studies to find ways to extend human health life by controlling inflammatory cells and vascular leakage to delay aging." This study will open a new chapter in anti-aging, a long standing challenge for mankind. It is expected that the follow-up studies on intestinal inflammation control will make a great contribution to the development of various technologies that can practically delay aging. For these purposes, it is required to explore a variety of candidate substances that are able to control gut-resident inflammation and conduct clinical researches on them.

Microvasculature remodeling in the mouse lower gut during inflammaging

Of many proposed mechanisms underlying aging, inflammaging theory proposes that chronic low-grade inflammatory status caused by life-time exposure of animals to a variety of antigens contributes to age-associated morbidity and mortality. An hallmark of age-associated chronic inflammation would be macrophage infiltration. In intestine, the epithelial lining separates internal organs from the enteric environment loaded with various foreign substances including microbiota and its metabolic products as well as nutrients and wastes. The lamina propria (LP) lying beneath the enterocytes in the intestinal villi especially that in the lower part, houses a largest pool of macrophages for maintaining mucosal homeostasis against the gut microbiota and for the constant need of epithelial renewal. Age-associated deterioration of gastrointestinal function could be ascribed to inflammaging, although substantial evidence is yet to emerge.

In this study, we propose that the antigenic burden encountered in the intestine causes macrophage infiltration during the first few months after birth and that is sustained throughout life. Under the condition of chronic inflammation, it stands to reason to polarize macrophage toward the M2-like subtype to avoid tissue injury and eventual chaotic consequences caused by activated M1 macrophage. Consistently, it has been reported that total macrophages and myeloid derived suppressor cells cumulated in the spleens and bone marrow of aged mice were mostly anti-inflammatory M2 cells in aged mice. Macrophages are the sources of both pro-angiogenic and anti-angiogenic factors, which can differentially guide vascular network formation under many pathological conditions. We therefore propose that TNF-α derived from the macrophages in aged animals skews the angiopoetin-TIE-2 signaling in vascular endothelial cells to inflammatory settings that would facilitate recruitment of immune cells through endothelial cells. Such increase in vasculature permeability entails modulation of the endothelial cell network such as loss of VE-cadherin and pericyte, as demonstrated in this study. Together, our study demonstrates for the first time, to the best of our knowledge, that sustained aggravation of inflammation leads to age-related structural changes in organ.

Another item to consider here is a possible role for cellular senescence in these interactions, though this is not mentioned by the researchers. Senescent macrophages have been proposed to play a significant role in other inflammatory conditions, such as the development of atherosclerosis. Senescent cells produce inflammation in and of themselves, and so this might form the basis for a feedback loop of accelerated dysfunction in any situation in which macrophages accumulate over the course of aging. Senescent macrophages have been identified in other tissues, so this doesn't seem like a great leap, and possibly worth further investigation in the context of this research.

Correlating Activity Levels and Telomere Length as a Proxy for the Pace of Aging

There is considerable interest in the research community when it comes to answering questions about the effects of exercise and inactivity on long-term health, pace of aging, and mortality. Possibly more than the topic merits now that rejuvenation therapies and other advanced medical biotechnologies are plausible near future goals for development. Since the development of low-cost accelerometers of the sort now found in every mobile phone, the quality of data has improved to the point at which quite detailed questions on activity levels and health can be asked and potentially answered. For example, what is the dose-response curve for exercise, when measured in terms of outcomes such as incidence of age-related disease and mortality rates? Another topic that has attracted a lot of attention in the past few years is the degree to which sitting, or similar sedentary behavior, has a negative impact on health that is independent of exercise. The studies I've seen so far are divided on this question: is it the sitting or is it the overall inactivity that is harmful or correlated with harmful choices, such as a high calorie intake and putting on weight?

The challenge for many studies is that their datasets include only self-reported activity levels. As the accelerometer study linked below illustrates very well, there is enough of a difference between what people say they do and what they actually do when it comes to exercise, even given the best of intentions, to cause issues in statistical interpretation. One might go so far as to say that any study not using accelerometers should probably be treated with suspicion for anything other than the most general conclusions drawn from its data. We know that exercise is good, and we know that a completely sedentary life is about as bad as taking up smoking, but a self-reported study is no basis for establishing effects by dose, or more subtle relationships such as how the degree of periodic inactivity versus the degree of periodic activity affects health over the long term.

The study below uses average telomere length in white blood cells as a metric for age. This is on the whole a pretty terrible biomarker, with an age-related decline that only shows up in the statistics for large populations, and even there we find studies that fail to observe correlations in various groups. For individuals it is of a very dubious value. That said, it is probably passable for the purposes of this study, insofar as it can be used to make the primary point above about the problems of self-reported data. For preference I'd rather see researchers using DNA methylation biomarkers of physical age, but if that isn't in the dataset used, then not much can be done within the time and budget allotted other than to work with what you have.

It is worth recalling that what this telomere length measurement primarily reflects is immune system health, not aging. It only reflects age through the effects of age on the immune system and its constituent parts. New immune cells are created by stem cells with long telomeres, and lose a little of that length every time they divide. Average telomere length in this measurement is thus determined by (a) stem cell activity, which is known to decline with age, (b) the rate of division of immune cells, which depends on any number of factors, from infection to other forms of ill health to the age-related malfunctions of the immune system as a whole, and (c) the number of senescent immune cells lingering with very short telomeres instead of following their peers into self-destruction. Some of these latter factors are highly variable with circumstances and on a very short time frame, which is one of the reasons as to why this isn't such a great metric for individuals, and why one has to examine the data across a large number of people to observe declines over time.

Too Much Sitting, Too Little Exercise May Accelerate Biological Aging

Researchers report that elderly women who sit for more than 10 hours a day with low physical activity have cells that are biologically older by eight years compared to women who are less sedentary. The study found elderly women with less than 40 minutes of moderate-to-vigorous physical activity per day and who remain sedentary for more than 10 hours per day have shorter telomeres - tiny caps found on the ends of DNA strands, like the plastic tips of shoelaces, that protect chromosomes from deterioration and progressively shorten with age. As a cell ages, its telomeres naturally shorten and fray, but health and lifestyle factors, such as obesity and smoking, may accelerate that process. Shortened telomeres are associated with cardiovascular disease, diabetes and major cancers. "Our study found cells age faster with a sedentary lifestyle. Chronological age doesn't always match biological age."

Nearly 1,500 women, ages 64 to 95, participated in the study. The women are part of the larger Women's Health Initiative (WHI), a national, longitudinal study investigating the determinants of chronic diseases in postmenopausal women. The participants completed questionnaires and wore an accelerometer on their right hip for seven consecutive days during waking and sleeping hours to track their movements. "We found that women who sat longer did not have shorter telomere length if they exercised for at least 30 minutes a day, the national recommended guideline. Discussions about the benefits of exercise should start when we are young, and physical activity should continue to be part of our daily lives as we get older, even at 80 years old."

Associations of Accelerometer-Measured and Self-Reported Sedentary Time With Leukocyte Telomere Length in Older Women

Emerging evidence has linked leukocyte telomere length (LTL) to modifiable factors such as smoking, body mass index, and physical activity. Sedentary behavior has also been studied in relation to LTL, but with mixed findings. In the Nurses' Health Study, there was no association of total sedentary time or specific sedentary behaviors with LTL, but in 2 recent studies, reduced sedentary time was associated with longer LTL. However, these studies were limited by several factors, including failure to measure sedentary time objectively (i.e., by accelerometer). Accelerometer-measured sedentary time is not highly correlated with self-reported time, the latter of which often underestimates actual time spent in sedentary behaviors. In a cross-sectional study, we assessed associations of accelerometer-measured and self-reported sedentary time with LTL in older white and African-American women from the Objective Physical Activity and Cardiovascular Health (OPACH) Study, an ancillary study of the Women's Health Initiative (WHI).

In the overall sample, there were 863 (58.3%) white and 618 (41.7%) African-American women. Women were aged 79.2 years, on average, ranging in age from 64 years to 95 years. Women wore the accelerometer for an average of 14.7 hours/day over an average of 6.3 days. The mean amounts of accelerometer-measured and self-reported sedentary time were 9.2 hours/day and 8.6 hours/day, respectively. The mean amounts of accelerometer-measured and self-reported moderate- to vigorous-intensity physical activity (MVPA) were 0.8 hours/day and 0.5 hours/day, respectively. Accelerometer-measured and self-reported sedentary time were weakly correlated; accelerometer-measured and self-reported MVPA were similarly weakly correlated. Women with greater amounts of accelerometer-measured sedentary time were more likely to be older, white, and obese. They were also more likely to have high blood pressure, a history of chronic diseases, a lower physical performance score, and fewer hours/day of MVPA and to have experienced a fall in the past 12 months. Women with higher self-reported sedentary time were more likely to be older, white, and obese and to have a history of chronic diseases. They also had a lower physical performance score and lower levels of self-reported MVPA, and they were less likely to be in excellent or very good health.

Among older women who were less physically active as measured by accelerometry, a greater amount of accelerometer-measured sedentary time was significantly associated with shorter LTL. Findings persisted after adjustment for demographic characteristics, lifestyle behaviors, and body mass index but were attenuated after adjustment for a history of chronic diseases and use of hormone therapy. In the full-adjustment model, LTL was on average 170 base pairs shorter in the most sedentary women compared with the least sedentary women. Since women may lose on average 21 base pairs/year, this suggests that the most sedentary women were biologically older by 8 years. Our findings have important implications for an aging population, in which greater time spent sedentary and less physical activity tends to be the norm

Although we did not observe a significant statistical interaction between sedentary time and MVPA, several studies examining joint associations of sedentary time and physical activity with adverse health outcomes have observed that disease and mortality incidence risks associated with higher sedentary time were either attenuated or eliminated among persons engaging in greater amounts of physical activity and were stronger in those with lower levels of physical activity. In our study, accelerometer-measured sedentary time was not associated with LTL among women who were more physically active. Additionally, sedentary time was not associated with LTL among women meeting current public health recommendations of ≥30 minutes/day of MVPA; in those not meeting this recommendation, higher sedentary time was associated with shorter LTL.

A Future of Combination Therapies that Transform Cancer Cells into Senescent Cells, and then Suppress and Destroy Them

The research community is presently expanding the understanding of the biochemistry and role of senescent cells in aging and age-related disease. This is happening in the wake of a series of landmark animal studies demonstrating extension of life and reversal of markers of tissue aging through selective destruction of senescent cells, events that have attracted the attention of many research groups and funding organizations. There is considerably increased investment in the field when compared to even as recently as five years ago, a time at which it was a real struggle for even prestigious research groups to raise the funds needed for animal studies of senescent cell removal. This is an object lesson for anyone who thinks science moves on the shortest path towards important gains. Significant evidence for the role of senescent cells in aging and disease has existed for decades, and the SENS proposals have included their removal as a potential rejuvenation therapy since the turn of the century. In any case, I predict that this ongoing gain in knowledge will accelerate as senolytic therapies, treatments based on the targeted removal of senescent cells, continue to prove effective on their way to the clinic. The size of the field and its funding will increase greatly.

This is going to produce interesting outcomes as researchers involved in other areas of medicine assimilate the new findings and come to appreciate the importance of senescent cells. In the cancer research community, for example, there are already established programs aiming to use the induction of senescence as a form of therapy. Cellular senescence acts as a form of defense against cancer, a way to make cells irreversibly halt replication and then largely self-destruct, or attract immune cells to destroy them. Since preventing replication and destroying cells is exactly the goal of cancer therapies, this seems a potentially viable approach. The challenge here, as researchers are now realizing, is that those newly formed senescent cells that are not destroyed go on to cause a lot of harm. Arguably this is visible in the long-term damage caused by even successful chemotherapy. Senescent cells generate a potent mix of signals, the senescence-associated secretory phenotype (SASP) that disrupts tissue structure, changes the behavior of other cells for the worse, and generates high levels of chronic inflammation.

The present state of knowledge is, however, enough to clearly envisage a class of near future cancer therapies made up of the combination of treatments to (a) induce senescence in cancer cells, (b) attempt to reduce the SASP by altering the internal processes of senescent cells, and (c) to destroy as many of these newly senescent cells as possible. I'm not convinced that trying to modulate SASP signaling is a cost-effective path forward in comparison to destruction of senescent cells, given the current state of the field, but a fair number of research groups are undertaking work in that direction. I think it to be the most complex option, requiring much more new knowledge, and with a lower chance of success for any given research group and project. Further, sufficiently good senolytic therapies should render it unnecessary: just deliver them alongside the therapy that induces senescence in cancer cells. In any case, this open access paper outlines the vision for combination therapies along these lines:

Aging tumour cells to cure cancer: "pro-senescence" therapy for cancer

In contrast to normal cells, one of the hallmarks of cancer cells is the capability to escape senescence, thus acquiring a limitless replicative potential that is the prelude to invasion, metastasis and additional features of malignancy. However, cancer cells can undergo senescence if subjected to certain insults such as oncogenic stress, DNA damage and metabolic changes. This type of senescence response occurs immediately and also independently of telomere shortening, a phenomenon known as "premature" senescence. For instance, several anticancer chemotherapies and radiotherapies are known to induce senescence in both normal and cancer cells. Senescence can also occur in tumour cells in vivo as a consequence of overexpression of oncogenes or loss of tumour suppressor genes, demonstrating for the first time that senescence acts as a barrier against tumorigenesis. Analysis of tumour samples from patients demonstrated that, whereas benign tumours accumulate markers of senescence, invasive cancers lack senescence. Subsequent publications validated these findings in different types of tumour. Given the surprising discovery that senescence limits the development of cancer, we and others envisioned targeted therapies that selectively enhanced senescence in cancer cells used for the therapy of various tumours. This approach, named "pro-senescence" therapy for cancer, differs from the chemotherapy-induced senescence that affects both normal and cancer cells.

Several small molecule inhibitors that are currently in clinical development have been reported to induce senescence in cancer. Among these compounds, inhibitors of the cyclin-dependent kinases CDK4/6 have been associated with a high percentage of responses in patients affected by breast cancer and are the most promising pro-senescence compounds currently being tested in the clinic. Compounds that enhance the level of the tumour suppressor gene p53, such as MDM2 inhibitors and PRIMA-1 analogues, have been reported to enhance senescence in tumour cells with normal and mutant p53 and are currently being tested in the clinic. Many compounds that are currently being tested at the preclinical level are also promising pro-senescence therapies. Inhibitors of SirT1, a protein deacetylase that negatively regulates p53 function in cancer, induced senescence in preclinical tumour models. MYC inhibitors can also drive a cellular senescence response.

Another challenge in the field of senescence therapy for cancer is the lack of clinically validated biomarkers for the identification of senescence in human tumours. The prognostic use of senescence-associated-β-galactosidase (SA-β-galactosidase), a well characterised in vitro marker for senescence, has been tested in small trials evaluating the efficacy of neo-adjuvant chemotherapies. Results from these trials demonstrate that this marker increases upon treatment and predicts patient outcome. However, the use of SA-β-galactosidase alone as a unique marker of senescence has been criticised since it can lead to many false positives. Recent findings have identified of new markers of senescence with prognostic relevance. However, neither SA-β-galactosidase staining nor additional markers have been used so far in large clinical trials to evaluate the efficacy of pro-senescence compounds. Thus, development of novel biomarkers that can accurately assess the occurrence of senescence in cancer patients is the need of the hour. This would help improve the stratification of patients who may respond to therapies that enhance senescence in cancer.

SASP has profound effects on the surrounding tumour microenvironment and it represents a promising target for cancer therapy. Several groups have recently proposed therapies that reprogram the SASP to enhance the tumour-suppressive role of senescence in cancer and restrain the negative effects of the SASP. For instance, we have recently shown that Stat3 regulates the SASP of Pten-loss induced cellular senescence (PICS). In Pten null senescent tumours, Stat3 activation promotes an immunosuppressive tumour microenvironment that impairs senescence surveillance. However, pharmacological inhibition of Janus kinase 2 (JAK2) in these tumours induces the reprogramming of the SASP, thus leading to an antitumour immune response that promotes the clearance of senescence tumour cells. The SASP is also controlled by mTOR (mechanistic target of rapamycin). Indeed, mTOR inhibitors reduced SASP.

The use of senolytic therapies may also enhance the efficacy of pro-senescence therapies by removing senescence cells from the tumour. Senolytic therapies may be administered concomitantly with or after pro-senescence compounds to decrease potential negative side effects of the SASP in tumours where the tumour immune clearance does not take place. As recently reported, senescent tumour cells rely on pro-survival networks and are therefore more susceptible to the inhibition of these pathways. For instance, Bcl-2/Bcl-x inhibitors may be used in combination with pro-senescence compounds to enhance the efficacy of pro-senescence therapy. Since senescent tumour cells also undergo to metabolic reprogramming, pharmacological inhibition of specific metabolic demands may be used to promote the clearance of senescent cells in tumours treated with pro-senescence therapies. Such an approach has been successfully tested in a model of lymphoma but it still remains to be validated in additional tumour models. In conclusion, we believe that pro-senescence therapy for cancer is a promising new therapeutic strategy and that in the future novel, therapies based on senescence induction in cancer will be the standard of care for the treatment of cancer patients.

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Fitness in Older Adults Correlates with Improved Brain Activity and Memory

Researchers here add more data to the known correlations between specific measures of fitness and cognitive function in later life. There are any number of potential mechanisms linked to exercise that might explain a slower age-related decline in memory and learning capacity in people who better maintain physical fitness, such as the state and activity of the immune system in the brain, as well as mitochondrial function, and vascular integrity. Pinning down specific contributions and the relative importance between mechanisms is, of course, a challenge.

Older adults who experience good cardiac fitness may be also keeping their brains in good shape as well. In what is believed to be the first study of its kind, older adults who scored high on cardiorespiratory fitness (CRF) tests performed better on memory tasks than those who had low CRF. Further, the more fit older adults were, the more active their brain was during learning. Healthy young (18-31 years) and older adults (55-74 years) with a wide range of fitness levels walked and jogged on a treadmill while researchers assessed their cardiorespiratory fitness by measuring the ratio of inhaled and exhaled oxygen and carbon dioxide. These participants also underwent MRI scans which collected images of their brain while they learned and remembered names that were associated with pictures of unfamiliar faces.

The researchers found that older adults, when compared to younger adults, had more difficulty learning and remembering the correct name that was associated with each face. Age differences in brain activation were observed during the learning of the face-name pairs, with older adults showing decreased brain activation in some regions and increased brain activation in others. However, the degree to which older adults demonstrated these age-related changes in memory performance and brain activity largely depended on their fitness level. In particular, high fitness older adults showed better memory performance and increased brain activity patterns compared to their low fitness peers. The increased brain activation in the high fitness older adults was observed in brain regions that show typical age-related decline, suggesting fitness may contribute to brain maintenance. Higher fitness older adults also had greater activation than young adults in some brain regions, suggesting that fitness may also serve a compensatory role in age-related memory and brain decline.

A Profile of Craig Venter and Human Longevity Inc.

Despite all the publicity, Human Longevity Inc. is a personalized medicine company rather than a longevity science company, intended to be the seed for a new industry that provides an incremental advance on present day customization of medicine through use of genetics. As I've said for a while now, this sort of application of genetics is not the path to significant enhancement of human longevity. All that this industry can do in the near term is inform us more accurately as to why the natural variations in human longevity exist, and provide ways to move someone from a slightly lower life expectancy bracket into a slightly higher life expectancy bracket. The latter is something that you can do for yourself today by undertaking exercise or calorie restriction. This is fiddling small change in the bigger picture. In that bigger picture, it is clear that we all age for the same underlying reasons: exactly the same forms of accumulated cell and tissue damage drive aging in all of us. Effective therapies to treat the causes of aging - and thereby produce radical life extension of decades at first and centuries later - will repair this damage, and will thus be exactly the same for everyone, with a massive scale of production to drive down the costs. The expensive undertaking of highly personalized medicine is simply not all that important when it comes to rejuvenation and the future of human longevity.

Craig Venter's latest venture, Human Longevity, Inc., or HLI, creates a realistic avatar of each of its customers - they call the first batch 'voyagers' - to provide an intimate, friendly interface for them to navigate the terabytes of medical information being gleaned about their genes, bodies and abilities. Venter wants HLI to create the world's most important database for interpreting the genetic code, so he can make healthcare more proactive, preventative and predictive. Such data marks the start of a decisive shift in medicine, from treatment to prevention. Venter believes we have entered the digital age of biology. And he is the first to embark on this ultimate journey of self-discovery. HLI has now submitted an analysis of its first 10,000 human genomes for publication, passing a milestone in creating what Venter hopes will be the world's largest, most comprehensive database of information to help transform healthcare and find answers to one of the oldest questions of all: is it possible to defy the ravages of ageing?

In 1998 Venter unveiled the privately funded Celera Genomics, which incurred the wrath of his peers in the public genome programme. He found himself battling with some of the world's biggest scientific institutions. The race propelled him onto front pages around the world when Celera unveiled its first human genome alongside the publicly funded version. Today, everybody in the field wants genomics to be part of medicine, he says. When it came to deciding where to bring about that merger, and finish the job that he started with Celera, Venter returned to the West Coast. On the coast, occupying land owned by the university, Venter has built the Californian campus of his not-for-profit J. Craig Venter Institute. He also set up Synthetic Genomics. This company is trying to understand the basic software of life and rewrite it to create novel organisms that can produce fuel, chemicals and medicines.

To synthesise the insights from these ventures, Venter founded HLI with stem cell pioneer Robert Hariri and technology entrepreneur Peter Diamandis, founder of the XPRIZE Foundation. Venter regards HLI as Celera on steroids. "The whole idea behind this is to identify the risk, then modify that risk so that you end up with longer periods of normal health. That is what the patient wants too. The patient does not want just more years but quality years." HLI started out stockpiling human genomes by sequencing them for partners that needed the data for research. This is only one ingredient of what Venter hopes will become the biggest genotype-phenotype database in the world. "Right now, we know less than 1 per cent of the genome in terms of how to really interpret it. Even with that, that's extremely valuable in being able to start this new preventative medicine paradigm where this information can help people understand their own health risk and hopefully save a lot of lives." So far, HLI has amassed the sequences of around 20,000 whole genomes, says Venter. But, of course, he wants even more. The company has room for more sequencing facilities on its third floor and is considering a second centre in Singapore, planning to rapidly scale to sequencing the genomes of 100,000 people per year - whether children, adults or centenarians, and including both those with disease and those who are healthy. By 2020, Venter aims to have sequenced a million genomes.

Venter wants to move from basic genetics to impacting individual lives "very directly. The most important part of that is nothing to do with the genome directly, but measuring phenotype and physiology and understanding their medical risk. That is what the Health Nucleus is all about." Although the focus is on understanding the genome, HLI will gather more than just human DNA, studying the microbiomes of its patients too - their cargo of gut microbes, which play a key role in health. Most valuable of all, Venter wants to link these various -omes to patients' phenotypes: their anatomy, physiology and behaviour. To do this, standard body measurements, online cognitive tests and blood samples are taken. The Health Nucleus adds yet more data using non-invasive tests. My tour begins with the room where HLI conducts a total body scan to create the avatars that inhabit its app. We pass through a succession of white rooms. There's one where magnetic resonance imaging (MRI) scans are shown, revealing visceral fat (which is linked to type 2 diabetes and cardiovascular disease) muscle volume, grey matter, white matter and more.

"We will be developing the evidence around this to make the case for preventive medicine." HLI has more work to do, such as organise a randomised controlled trial to compare the outcomes of people who get the tests with those who do not. Not everyone is convinced that HLI's testing will translate into improved health. Venter says that criticisms stem from the conservative nature of the medical community, notably when it comes to keeping the costs of screening under control. "That is the medical establishment saying: we want to keep doing what we do, we want to see people after they develop symptoms and have something wrong with them. The 'human longevity approach' is the exact opposite."

VCAM1 as a Potential Harmful Signal in Old Blood

Heterochronic parabiosis, linking the circulatory systems of an old and a young mouse, benefits the old mouse in that it reduces some measures of aging. Researchers initially focused on possible beneficial signals in young tissues and blood, but more recent research suggests that the outcome may occur because harmful signals present in old tissues and blood are diluted. If this is the primary mechanism, it would explain why transfusion of young blood to old individuals does not appear produce similar effects in animal studies. Here researchers claim evidence for one such harmful signal:

The effects of blood on ageing were first discovered in experiments that stitched young and old mice together so that they shared circulating blood. Older mice seem to benefit from such an arrangement, developing healthier organs and becoming protected from age-related disease. But young mice aged prematurely. Such experiments suggest that, while young blood can be restorative, there is something in old blood that is actively harmful. Now researchers seem to have identified a protein that is causing some of the damage, and have developed a way to block it.

The researchers found that the amount of a protein called VCAM1 in the blood increases with age. In people over the age of 65, the levels of this protein are 30 per cent higher than in under-25s. To test the effect of VCAM1, researchers injected young mice with blood plasma taken from older mice. Sure enough, they showed signs of ageing: more inflammation in the brain, and fewer new brain cells being generated, which happens in a process called neurogenesis. Blood plasma from old people had the same effect on mice. When researchers injected plasma from people in their late 60s into the bodies of 3-month-old mice - about 20 years in human terms - the mice's brains showed signs of ageing. These effects were prevented when researchers injected a compound that blocks VCAM1. When the mice were given this antibody before or at the same time as old blood, they were protected from its harmful effects.

Some teams have begun giving plasma from young donors to older people, to see if it can improve their health, or even reduce the effect of Alzheimer's disease. But for the best chances of success, we'll also need to neutralise the damaging effects of old blood. Other researchers comment that it is "surprising that a single protein seems to have such a huge effect," but the results need to be replicated by another lab. A drug that protects people from the effects of old blood would be preferable to plasma injections. Should transfusions from young donors turn out to be effective, it would be difficult to scale this up as a treatment for all. Drugs that block harmful proteins in our own blood would be cheaper, safer and more accessible.

Towards a Better Understanding of the Effects of Tiny Strokes on Cognitive Decline

In recent years it has become clear that we all suffer many tiny, unnoticed strokes as we age. These involve the rupture or blockage of small blood vessels in the brain and resulting damage and cell death in a very small area of tissue. Hypertension, the age-related increase in blood pressure, and consequences of other forms of cell and tissue damage on blood vessel integrity speed up this process, and the aggregate effect of these microstrokes explains some of the correlation between cardiovascular aging and neurodegeneration. Here, researchers make a start on understanding the scale of this effect in living brains:

Evidence overwhelmingly supports a link between cognitive decline and cerebrovascular diseases. Not only do individuals with cerebrovascular diseases have a much higher incidence of cortical microinfarcts (mini-strokes), but post-mortem histological and in vivo radiological studies also find that the burden of microinfarcts is significantly greater among people with vascular cognitive impairment and dementia (VCID) than in age-matched, non-demented individuals. Until now, the mechanisms by which these miniscule lesions (~0.05 to 3 millimeters in diameter) contribute to cognitive deficits including dementia have been poorly understood. Findings from a recent study provide crucial information for better understanding the impact of microinfarcts, showing that the functional deficits caused by a single microinfarct can affect a larger area of brain tissue and last longer than was previously thought to be the case.

The functional effects of microinfarcts are extremely difficult to study. Not only are most microinfarcts difficult to detect with standard neuroimaging techniques, mismatches between in vivo functional data and post-mortem histological evidence make it nearly impossible to connect microinfarcts to the timeline of cognitive decline. "These infarcts are so small and unpredictable, we just haven't had good tools to detect them while the person was still alive. So, until now, we basically just had post-mortem snapshots of these infarcts at the end of the dementia battle as well as measures of the person's cognitive decline, which might have been taken years before the brain became available for study. Even though a person may experience hundreds of thousands of microinfarcts in their lifetime, each event is extremely small and thought to resolve in a matter of days. It's been estimated that, overall, microinfarcts affect less than 2% of the entire human brain. But those estimates of tissue loss are based only on the 'core' of the microinfarct, the area of dead or dying tissue that we can see in routine, post-mortem, histological stains."

To investigate their theory of broader impacts, the team developed a mouse model so that they could examine the effects of individual cortical microinfarcts on surrounding tissue function in vivo over several weeks post-event. The team used photothrombosis to occlude a single arteriole in the barrel cortex of mice fitted with cranial windows. They then compared functional readouts of sensory-evoked brain activity, indicated by activity-dependent c-Fos expression or in vivo two-photon imaging of single vessel hemodynamic responses, to the location of the microinfarct core. Post-mortem, c-Fos immunostaining revealed that an area estimated to be at least 12-times greater in volume than the microinfarct core had been affected by the event. Furthermore, in vivo, two-photon imaging of single vessel, sensory-evoked hemodynamics found that neuronal activity across the affected tissue area remained partially depressed for 14 to 17 days after the microinfarct. Together, these data indicate that functional deficits caused by a single microinfarct occur across a much larger area of viable peri-lesional tissue than was previously understood and that the resulting deficits are much longer-lasting.

Aging as the Evolutionary Cost of Complexity, Driven by Mitochondrial Dynamics

This popular science article walks through a new interpretation of one class of evolutionary theory of aging, envisaging the existence of aging as being necessary for the formation of complex life forms with active metabolism and high energy demands. While there are higher species that exhibit negligible senescence for much of their lifespans, such as naked mole rats and lobsters, the only definitively immortal animals are lower species such as hydra, and even then only in optimal conditions. It isn't necessary for aging to be essential for it to dominate, however: it would only need to be significantly advantageous in evolutionary competition to reach the situation we see today, in which aging is near ubiquitous in the animal world. This is nonetheless an interesting take on the current body of theory regarding the origins of aging, and dovetails nicely with the significance of mitochondria to aging today:

Life's ever-repeating cycles of birth and death are among the most fundamental principles of nature. An organism starts out as a single cell that grows and divides, develops into an embryo, matures and reaches adulthood, but then ages, deteriorates, and eventually succumbs to death. But why does life have to be cyclic, and why does it have to end in senescence and death? After all, animals like corals and marine sponges live for thousands of years and are capable of virtually infinite regeneration and cell repair. Even in more complex animals, offspring do not inherit their parents' age: every new generation starts with cells in a pristine state, with no trace of aging. If senescence is somehow suppressed in reproductive cells, why do the rest of the organism's tissues end up deteriorating and dying?

At the end of the 19th century, the German biologist August Weismann realized that complex organisms consist of two cell types: the "immortal" germline - eternally young cells that give rise to sperm and eggs - and the "disposable" somatic cells that form the rest of the body. More recently, Weismann's ideas were given an overhaul by Thomas Kirkwood in his disposability theory of aging. Kirkwood argued that the force of natural selection declines with age, as most organisms in their natural environments die due to external hazards such as predators, parasites and starvation. At the same time, organisms must invest resources into both the reproductive effort and the maintenance and repair of their somatic cells. But because the probability of surviving external threats declines with time, the optimal strategy is to allocate less and less resources into somatic maintenance as time goes by. Lack of cell repair in the later stages of the life cycle results in the progressive loss of function and gradual decay - aging.

The real-world picture turned out to be more complex than Weismann's model could have predicted. In complex animals like mammals, birds and insects, Weismann's assumption of the rigid germline-somatic cell distinction holds true: only a relatively small group of cells in an adult retain reproductive potential, while the rest become irreversibly differentiated into somatic tissue cells - liver, skin, muscle - that cannot give rise to a new organism. But this is not the case in the most ancient members of the kingdom, such as hydrae, corals and sponges. Even in their adult forms, these organisms maintain large populations of universal stem cells that can generate both somatic and reproductive cells, that is, germline and somatic cells never really segregate. It is the lack of germline sequestration that gives corals and their relatives the power of regeneration and vegetative plant-like reproduction.

Rather than being universal to all animals, the Weismann barrier appears to be a relatively recent innovation of complex organisms, evolving together with somatic aging and death. What drove the evolution of this separation is not clear, but the answer will also shed light on the origin of mortality in complex animals. There are signs that the evolution of both the germline and mortal somatic cells is related to cellular energetics. Animal cells produce energy through respiration in their mitochondria - the organelles of bacterial origin that retain their own tiny genomes, distinct from the chromosomes housed within the nucleus. Each cell contains tens and hundreds of mitochondria, and each mitochondrion has several DNA molecules. This tiny genome regulates mitochondrial function; its integrity is crucial to cellular respiration, as defective mitochondrial genes often lead to debilitating diseases, neuromuscular degeneration and early death. A large part of mitochondrial gene defects arise from random copying errors in imprecise DNA replication.

Since a large part of mitochondrial gene defects arise from random copying errors in imprecise DNA replication, as cells in a developing organism divide, their mitochondria replicate too, each time introducing new DNA mutations. In our recent scientific paper, we show that in organisms with fast mitochondrial defect accumulation, natural selection favors segregation of an isolated germline with a lower number of cell replication cycles, as it minimizes the damage to the energy-producing organelles that could potentially be transmitted to the next generation. If the pace of error accumulation is slow, however, the strict germline-somatic cell barrier should not evolve. Our model therefore suggests that "disposable" somatic cells, that gave rise to aging and mortality, has evolved as a strategy to maintain mitochondrial quality in complex organisms with multiple tissues and high energy requirements, in which mitochondrial defects accumulate relatively fast.

More Investigation of the 5q33.3 Locus in Human Longevity

The search for gene variants associated with human longevity has turned up only two reliable correlations to date, with a couple more in the tentative bucket awaiting further confirmation. The effects of all of these are not large; individually, each represents only a small increase in the odds of a longer life. The emerging picture of the genetics of longevity is one of thousands of tiny influences, near all of which are highly conditional on circumstances and other variants. The vast majority of correlations observed in any one study population are not seen in others. One of the variants still in the tentative bucket is 5q33.3, first noted a couple of years ago, and this paper is illustrative of the sort of work required in the ongoing investigation of such correlations:

The search for major longevity genes in humans has so far had limited success and only the APOE and FOXO3A genes have been found to consistently associate with human longevity. Recently, however, a third longevity locus was proposed based on the results of a genome-wide association meta-analysis including 12,736 long-lived individuals older than 85 years and 76,268 controls younger than 65 years of European descent. In this study, the single nucleotide polymorphism (SNP) rs2149954 on chromosome 5q33.3 was found to associate with survival to beyond 90 years of age. This association has afterwards been confirmed in a genome-wide association study of exceptional longevity in Han Chinese centenarians. Investigation of the effect of rs2149954 on prospective survival in the meta-analysis showed a significant association with lower all-cause mortality as well. Further investigation of cause-specific mortality in a sub-group analysis revealed that the lower mortality seen in rs2149954 minor allele carriers was partly conferred by a decreased mortality risk for cardiovascular disease, primarily due to protection from stroke. However, a protective effect of the rs2149954 minor allele on mortality independent of cardiovascular disease was also found.

Previous studies in middle-aged individuals have revealed a significant association between the rs2149954 minor allele and a decreased risk for coronary artery disease, and lower diastolic and systolic blood pressure. Also, two SNPs on chromosome 5q33.3 in high linkage disequilibrium with rs2149954, rs9313772 and rs11953630, have been reported to be associated with blood pressure and hypertension. In individuals older than 75 years the association between rs2149954 and all-cause mortality was, however, not found to be influenced by blood pressure. So, although there is an established connection between rs2149954 and different cardiovascular phenotypes, there also seems to be an effect of the variant in mechanisms other than those associated with cardiovascular disease and blood pressure regulation, at least in long-lived individuals. The role of the 5q33.3 locus in survival and longevity is therefore still partly unknown.

To further explore this, we investigated the influence of rs2149954 on age-related phenotypes previously shown to predict survival in the oldest-old: cognitive function (evaluated by a 5-item cognitive composite score and the Mini-Mental State Examination (MMSE)), physical function (evaluated by an activity of daily living (ADL) strength score, hand grip strength, gait speed, and chair stand), ADL disability, depression symptomatology, and self-rated health. In addition, self-reported diseases related to cancer and cardiovascular disease, which are among the leading causes of death, were explored. The apparent age-dependent pleiotropy in the role of the 5q33.3 locus was addressed by analyzing long-lived as well as middle-aged and elderly individuals.

In the middle-aged and elderly individuals, we found a nominally significant association between the minor allele of rs2149954 and a lower risk of hypertension. This is supported by an analysis of the diastolic and systolic blood pressure measured in the middle-aged individuals at a later follow-up assessment. Here we find that homozygous carriers of the rs2149954 minor allele have lower diastolic and systolic blood pressure, which is in line with the previously found association between rs2149954 and lower diastolic and systolic blood pressure in middle-aged individuals. Overall, our results support a role of rs2149954 in cardiovascular health, and we confirm the previously found association between rs2149954 and a lower risk of hypertension in middle-aged as well as in elderly individuals. The 5q33.3 locus thus appears to play a persistent role in cardiovascular health throughout the entire age-span investigated here, although we see a shift with age from a role in hypertension to a role in heart attack and heart failure. This shift is supported by a number of studies indicating that while high blood pressure is disadvantageous in midlife it appears to be advantageous at higher ages where it is associated with better physical and cognitive health and lower all-cause mortality. This reversal of risk has been suggested to take place around the age of 75 to 85 years and it is thus consistent with the age-related attenuation that we see for the association between rs2149954 and hypertension.

The Case for Defeating Death by Aging

This flashy popular press article in the modern style of scrolling illustrates an important point: that it is actually quite difficult for newcomers to build a coherent picture from the varied claims and lines of research taking place in the field of longevity science. The thing that they are missing, and which takes some time to put together for yourself, is enough of an understanding of the underlying biology to make estimates of likelihood of success for given project versus the plausible scale of the outcome. Will it produce a lengthening of life or postponement of age-related disease, and for how long? Absent this understanding, most journalists tend to put all of the various work at the same level of priority and interest, and thus assemble an article from a more or less random sampling of the field, but this simply isn't the case. For example, the work on developing metformin as a way to slow aging is both unlikely to produce reliable outcomes, based on the animal data, and those outcomes will be small even if successful. The same could be said of pretty much all of the current pharmaceutical approaches that aim to alter the operation of metabolism to slow down the progression of aging - but even in that category, some, like mTOR inhibitors, are far more plausible than others. In comparison, methods of repair that remove damage and waste in tissues, like senescent cell clearance, should be a much more reliable and effective means of turning back aging, producing actual rejuvenation. These are very different things, but few journalists will have the necessary background to explore this point.

The most outspoken opponent of death by aging in the scientific community is probably Aubrey de Grey. In his mind, aging is unhealthy; a collection of undesirable side effects of being alive. He likens aging to malaria because it kills a lot of people. If you could cure it, wouldn't you? There is a growing cohort of well-credentialed scientists investigating radical life extension: geneticist Craig Venter, one of the first to sequence the human genome; biochemist Cynthia Kenyon, who discovered that a mutation in a single gene doubled a worm's lifespan and is now vice president of aging research at Google sister company Calico; and molecular biologist Bill Andrews, who led the team that discovered the human gene for telomerase, an enzyme considered critical in aging. Their promises include keeping 90-year-olds as healthy as 50-year-olds, as the Virginia-based Methuselah Foundation says; extending life to 150 years, as Andrews says; and being biologically 25 years old indefinitely, as de Grey says. We're taught that death is natural and that trying to escape it is wishful lunacy. However, these researchers have made tangible discoveries. They've published studies in highly respected journals and attracted serious amounts of funding. When they say it's possible to live longer, and maybe forever, it's tempting to believe them.

Every few months, scientists will come out with a new finding that shows how a very specific set of changes slowed down some aspects of aging in animals. Of course, each study is more insightful when viewed as part of the body of anti-aging research as a whole. To understand what researchers have accomplished in this area, it's helpful to understand what "aging" means in a scientific context. Specifically, aging refers to the time-related degradation or decline of the bodily functions necessary for survival. As we age, changes occur in our bodies on a cellular level that affect not just our heart and lungs but also our muscles and our nervous system. These changes affect all of the different systems in our bodies. And each of these systems individually begins to work a little less well as we get older, and gradually that produces the burden of dysfunction that ultimately results in disease, disability, and eventually death. We also now understand that biological age doesn't always correspond to clock age. Imagine a pair of twins: One drinks too much, eats poorly, rarely gets enough sleep, and never exercises, while the other does the opposite. The first twin is likely to age faster and develop more of those age-related diseases.

The key lies with what scientists call signaling, or how cells communicate to govern basic functions like cell repair and immune response. While errors in cell signaling can cause autoimmune diseases, diabetes, and cancer, it also turns out that modifying signaling pathways can also slow aging, at least in animals. Researchers have identified two age-related signaling pathways: the Insulin/IGF-1 signaling pathway, which is linked to growth and metabolization, and the Target for Rapamycin or TOR, which in addition to growth regulates how cells move, and replicate. The deeper you get into anti-aging science, the more you'll see these acronyms. If we can slow down that biological clock enough, the thinking goes, we could delay the onset of old age and the diseases that come with it. Centenarians, humans that manage to live to 100 years and beyond, are more likely to carry mutations that reduce the activity of the IGF-1 receptors than those who die younger. At the same time, similar studies in yeast have shown that if you genetically alter TOR signaling pathways so that they communicate less, the yeast also lived longer. In total, the research suggests if you can find ways of calming down these signaling pathways you might be able to slow down aging.

One way of reducing signal TOR pathways is unpleasant if you enjoy eating. Studies have shown that mice fed 65 percent less food lived up to 60 percent longer. Thankfully, researchers have found other interventions, that work on the same pathway. Rapamycin, an anti-rejection drug used by kidney transplant patients, has increased lifespan in mice by up to 14 percent; low-dose Aspirin increased worm lifespan by 23 percent. A national clinical trial called Targeting Aging with Metformin, or TAME, to test Metformin's anti-aging effects in humans has received FDA approval. "What we want to show is that if we delay aging, that's the best way to delay disease."

Aberrant Astrocytes as a Cause of Neurodegenerative Disease

Astrocytes are an important class of support cell in the brain, and one of the most common cell types in brain tissue. They carry out a wide range of tasks, most of which are absolutely essential to the functions performed by neurons. A few years ago, researchers suggested that senescent astrocytes may be responsible for a sizable portion of the progression of neurodegenerative conditions, a proposal expanded and further investigated since then, with a great deal more evidence gathered. Astrocyte behavior in the brain appears to change for the worse with age in a number of ways, not all of which may be connected to cellular senescence, and some of which might be preventable in the near term. The publicity materials here outline some of the most recent findings on this topic, in which the researchers propose that transformed astrocytes are producing some form of signal that results in the death of nearby neurons, and show that these astrocytes are present in neurodegenerative conditions where such cell death occurs:

While most of us haven't heard of astrocytes, these cells are four times as plentiful in the human brain as nerve cells. Now, a team has found that astrocytes, which perform many indispensable functions in the brain, can take on a villainous character, destroying nerve cells and likely driving many neurodegenerative diseases. "We've learned astrocytes aren't always the good guys. An aberrant version of them turns up in suspicious abundance in all the wrong places in brain-tissue samples from patients with brain injuries and major neurological disorders from Alzheimer's and Parkinson's to multiple sclerosis. The implications for treating these diseases are profound." Up to now, the pharmaceutical industry has mostly targeted nerve cells, also known as neurons. But a broad range of brain disorders may be treatable by blocking astrocytes' metamorphosis into toxic cells, or by pharmaceutically countering the neuron-killing toxin those harmful cells almost certainly secrete.

Once thought of as mere packing peanuts whose job it was to keep neurons from jiggling when we jog, astrocytes are now understood to provide critical hands-on support and guidance to neurons, enhancing their survival and shaping the shared connections between them that define the brain's labyrinthine circuitry. It's also known that traumatic brain injury, stroke, infection and disease can transform benign "resting astrocytes" into "reactive astrocytes" with altered features and behaviors. But until recently, whether reactive astrocytes were up to good or evil was an open question. In 2012, researchers resolved that ambiguity when they identified two distinct types of reactive astrocytes, which they called A1 and A2. In the presence of LPS, a component found in the cell walls of bacteria, they observed that resting astrocytes somehow wind up getting transformed into A1s, which are primed to produce large volumes of pro-inflammatory substances. A2s, on the other hand, are induced by oxygen deprivation in the brain, which occurs during strokes. A2s produce substances supporting neuron growth, health and survival near the stroke site.

In a series of experiments using laboratory mice, the scientists identified three pro-inflammatory factors whose production was ramped up after LPS exposure: TNF-alpha, IL-1-alpha and C1q. In the brain, all three of these substances are secreted exclusively by microglia. Each, by itself, had a partial A1-inducing effect on resting astrocytes. Combined, they propelled resting astrocytes into a full-fledged A1 state. Next, the researchers confirmed that A1s jettison the nurturing qualities they'd had as resting astrocytes. Further experiments showed that A1s lose resting astrocytes' capacity to prune synapses that are no longer needed or no longer functional and whose continued existence undermines efficient brain function. Indeed, when the researchers cultured healthy neurons with increasingly stronger concentrations of the broth in which A1s had been bathing, almost all the neurons eventually died. This and other experiments showed that A1s secrete a powerful, neuron-killing toxin.

Finally, the researchers analyzed samples of human brain tissue from patients with Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and multiple sclerosis. In every case, they observed large numbers of A1s preferentially clustering where the disease was most active. For example, in the samples from Alzheimer's patients, nearly 60 percent of the astrocytes present in the prefrontal cortex, a region where the disease takes a great toll, were of the A1 variety. Because A1s are highly toxic to both neurons and oligodendrocytes, these findings strongly imply that A1 formation is helping to drive neurodegeneration in these diseases. An effort to identify the neurotoxin secreted by A1 astrocytes is underway. "We're very excited by the discovery of neurotoxic reactive astrocytes, because our findings imply that acute injuries of the retina, brain and spinal cord and neurodegenerative diseases may all be much more highly treatable than has been thought."

TET2 Mutations and Atherosclerosis

There is some debate over whether accumulated stochastic nuclear DNA damage is significant in aging over the present human life span in ways other than increased cancer risk, and a lack of good studies that provide evidence to support theoretical arguments in either direction. Stochastic DNA damage is observed, different in every cell, but like many of the changes of aging this cannot yet be effectively repaired, and thus it is very challenging to distinguish its effects in isolation. On the side of arguing for significance, the mechanism by which it contributes to aging is assumed to be a growing level of general dysfunction in cellular populations. This conjecture is supported by work such as that shown here, in which specific mutations are pointed out as problematic for the normal function of tissues, but the challenge here is still that there is no good demonstration of its significance in normal aging over and above other mechanisms, such as those outlined in the SENS vision of aging. It might only be a problem if ten times as many cells are mutated than normally happens. Or a hundred times. One possible next step would be gene therapy to repair mutated instances of the gene where they occur in order to assess the size of the effect, but that sort of study hasn't taken place yet.

Though cardiovascular disease, which is characterized in part by atherosclerosis, or plaque build-up, is a leading cause of death in the elderly, almost 60 percent of elderly patients with atherosclerotic cardiovascular disease (CVD) exhibit no conventional risk factors, or just one. This and other data suggest that age-dependent risk factors that haven't yet been identified may contribute to CVD. Scientists know that accumulation of somatic DNA mutations is a feature of aging, though little data exists on the role of such mutations in age-associated disorders beyond cancer. Meanwhile, recent human studies indicate that aging is associated with an increase in somatic mutations in the hematopoietic system, which gives rise to blood cells; these mutations provide a competitive growth advantage to the mutant hematopoietic cells, allowing for their clonal expansion - a process that has been shown to be associated with a greater incidence of atherosclerosis, though specifically how remains unclear.

In this study, researchers investigated whether there is a direct relationship between such mutations and atherosclerosis. They generated an experimental model to investigate how one of the genes commonly mutated in blood cells of elderly humans, TET2, affects plaque development. Plaque formation accelerated in the models transplanted with Tet2-deficient bone marrow cells, likely through increasing macrophage-driven inflammation in the artery wall. The results strengthen support for the hypothesis that hematopoietic mutations play a causal role in atherosclerosis. "Our studies show that mutations in our white blood cells, that we acquire as we age, may cause cardiovascular disease. Understanding this new mechanism of cardiovascular disease could lead to the development of new therapies to treat individuals who suffer from heart and blood vessel ailments due to these mutations. Furthermore, because these mutations become prevalent starting at middle age, these studies suggest that genetic analyses of blood samples could add to the predictive value of traditional risk factors - high cholesterol, hypertension, diabetes, and smoking - that are currently monitored."

Physical Activity Associated with Lower Heart Disease Mortality

In the past few weeks a fair number of papers have been published on the very straightforward relationship between exercise and cardiovascular mortality, and here is another of them. A mountain of past data demonstrates the association between greater activity and lower mortality in later life, but in human studies it is usually difficult to prove causation. For that we can turn to the equally large mountain of animal data, where experiments can be constructed to prove that differences in mortality are caused by differences in physical activity. Given all of this evidence, it would be foolish not to try to lead a more active life, and thereby suffer less in the years ahead.

Being physically inactive - sitting for long periods of time - can be so harmful to your health that experts sometimes call it "sitting disease." In fact, worldwide, physical inactivity is estimated to cause some 3.2 million deaths a year. Medical experts know that regular physical activity lessens death from all causes and death from heart disease specifically for middle-aged people. However, until now, little has been known about the benefits of exercise for older people when it comes to deaths associated with heart disease.

A new study examined whether regular leisure-time physical activity could reduce deaths from all causes, and whether it also could reduce deaths from cardiovascular disease. To study this association, researchers examined information taken from 2,465 men and women aged 65 to 74 who participated in a national health study conducted between 1997 and 2007 in Finland. The participants answered a questionnaire that assessed their lifestyle habits, including whether they smoked or engaged in exercise. Researchers also knew the participants' level of education, height and weight, blood pressure, and cholesterol levels. The research team followed the participants through the end of 2013. Then, they consulted the Finnish mortality register to determine how many of the participants had died (and what caused their deaths).

The researchers discovered that moderate- as well as high-levels of physical activity were associated with a decreased risk of heart disease and death from all causes, including from events such as strokes or heart attacks. Physical activity works in several ways to improve your heart's health. Exercise helps people maintain a healthy body weight, lowers blood pressure, reduces the risk of blood clots, helps stabilize blood sugar levels, and improves the ratio of unhealthy LDL to healthy HDL cholesterol in your body. If you are already moderately active, that is enough to make a positive impact on your health. If you're sedentary and become more active - even by taking several short walks around your home each day - you can improve your health significantly, and lower your risk of heart disease.


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