When the population as a whole is aging because of historical changes in birth and mortality rates, meaning that an increasing percentage of people are older rather than younger with each passing year, it is perfectly possible to observe both a growth in the total number of cases of age-related disease and at the same time a reduction in the rate at which individuals develop age-related disease. Both of these trends are underway at the present time. In this context, the short article noted here reviews some of the epidemiological research that indicates the risk of suffering dementia is falling.

Numerous studies have reported a dip in dementia incidence in the developed world. When did this trend begin? Researchers analyzed birth cohort data from the Einstein Aging Study, which enrolls cognitively healthy older adults living in the Bronx. Surprisingly, people born after 1928 were 85 percent less likely to develop dementia than those born before that year. The reason for such a stark drop in incidence is unclear. Neither better education nor improved cardiovascular health accounted for the effect. "The birth cohort effect is intriguing but will need replication in other populations. This important insight compels us to search for novel social and environmental factors that may have impacted this birth cohort. Changes in nutrition, education, pollutants, and infections all occurred and would be worth examining."

A growing number of studies have reported a drop in dementia incidence in the U.S. and Europe over the last two or three decades. Researchers have speculated that this may be due to better public health, particularly cardiovascular health. The finding is not uniform, however, with a handful of studies reporting higher dementia incidence that may be due to greater recognition of the disease or a larger number of people reaching old age.

To try to clarify the picture, researchers examined data from participants who enrolled in the Einstein Aging Study between 1993 and 2015. The cohort comprised 1,348 participants who had completed at least one annual follow-up visit, with an average follow-up time of four years. All participants were older than 70, and about two-thirds were non-Hispanic white. The researchers diagnosed dementia by a clinical exam. A subset of participants donated their brains after death, and 96 percent of those with a dementia diagnosis had some type of extensive brain pathology. For example, in a subgroup diagnosed with Alzheimer's disease, 79 percent had plaques and tangles.

Within each age group, the researchers saw a steady drop in dementia incidence for those born in later years. Among people born before 1920 there were 5.09 cases per 100 person-years. This dropped to 3.11 for people born in the early 1920s, and 1.73 for those born in the late 1920s. The most dramatic shift occurred right at the turn of that decade, when the rate fell to 0.23. Mathematical modeling pegged the best estimate for the change point to July 1929. While the model suggests an abrupt change in dementia rates, the researchers noted that this might partly be the result of small sample size; the post-1929 cohorts totaled only 350 people, with just three cases of dementia among them. "If there were more people in the analysis, the trend might be smoother." Nonetheless, the findings were statistically significant, and the researchers believe the data are picking up a real decline in dementia risk at around this time point.

What might explain it? The researchers found marked decreases in the rates of heart attack and stroke in later birth cohorts, but after adjusting the model to account for this, the drop in dementia incidence in those born after 1929 remained unchanged. While previous epidemiological studies did not specifically examine birth years, those older findings are roughly congruent with the Einstein Aging Study data, reporting the greatest drop in dementia cases after 1990, the authors noted. People born after 1929 would have entered their 60s in that decade. Most cases of late-onset dementia occur after age 60. The Rotterdam Study found a 25 percent decrease in dementia incidence in the 1990s, while the Framingham Heart Study recently reported that incidence dropped starting in the late 1980s and continued to decline into the 2010s.

Link: http://www.alzforum.org/news/research-news/more-evidence-dementia-case-numbers-are-falling

The increasing number of senescent cells present in older tissues is one of the root causes of degenerative aging. It is also the closest to being effectively reversed. An open access paper describing the evidence for HSP90 inibitors to selectively destroy senescent cells was published earlier this month. I had half missed it in passing and half skipped over it in favor of a more general review of the current state of senolytic drug development, pharmaceuticals capable of clearing senescent cells, but on reflection I think it is worth pointing out. The number of senolytic drug candidates has not yet reached a count of twenty, and some of them are probably not all that great, such as quercetin and fisetin, while others are chemotherapeutics with enough in the way of ugly side-effects to be avoided if there is a choice in the matter. So new categories of potential senolytics are worth noting.

Like many classes of drug candidates, HSP90 inhibitors have been considered for use against cancer. There is a strong connection between the phenomenon of cellular senescence and cancer research, through scientists in that field have generally been interested in generating more senescent cells rather than fewer of them. They are trying to push tumor cells and potentially cancerous cells into becoming senescent rather than replicating rampantly, enhancing the natural function of of cellular senescence as a means to reduce cancer risk. Unfortunately, the fact that chemotherapeutics generate a high load of senescent cells in patients, either intentionally or because they are toxic to cells in general, is one of the reasons why chemotherapy is so damaging to long term health even when successful. There are other points of connection as well: cancer researchers are also interested in pushing abnormal cells into programmed cell death processes such as apoptosis, and selectively triggering apoptosis in senescent cells is the goal of all senolytic drug candidates to date. So we should certainly expect to see new senolytic pharmaceuticals to have been evaluated as cancer therapies at some point in the past.

Are HSP90 inhibitors any good in comparison to the other types of senolytic discovered to date? I'd say it is far too early to do any more than handwave this sort of comparison. The results from animal studies to date suggest that candidate senolytics fall into one of two broad categories: they either do little to senescent cells, or they clear up to 50% of these cells, that effectiveness varying by tissue type, drug candidate, and dosage. Different drugs in the same general category of senolytics can have very different outcomes. This sort of variation is in evidence in the data from progeroid mice in this study, which at least puts a few HSP90 inhibitors, geldanamycin and 17-AAG / tanespimycin, into the category of "clears senescent cells" rather than "does nothing" - the results in mice look something like 50% clearance in the kidney versus 25% in the liver, on a par with the best of the other present drug candidates with published animal data.

Identification of HSP90 inhibitors as a novel class of senolytics

Replicative senescence is a cellular program preventing further cell divisions once telomeres become critically short. Senescence also can be induced by cellular stress, including oxidative and genotoxic stresses, or by activation of certain oncogenes. Senescent cells secrete pro-inflammatory factors, metalloproteinases, and other proteins, collectively termed the senescence-associated secretory phenotype (SASP). With chronological aging, there is an accumulation of senescent cells in mammals. This is thought to drive senescence of neighboring cells via the SASP and the functional decline of tissues.

Clearance of senescent cells rodent models restored vascular reactivity, stabilized atherosclerotic plaques, improved pulmonary function, alleviated osteoarthritis, and improved fatty liver disease. Thus, the increase in cellular senescence that occurs with aging appears to play a major role in driving life-limiting age-related diseases. Therefore, therapeutic approaches to specifically kill senescent cells have the potential to extend healthspan and lifespan.

Using a bioinformatics approach, we recently identified several pro-survival pathways, including the Bcl-2/Bcl-XL, p53/p21, PI3K/AKT, and serpine anti-apoptotic pathways that, when inhibited, result in death of senescent murine and human cells. A combination of the drugs dasatinib and quercetin, which target several of these pro-survival pathways, induce death specifically in senescent murine and human cells. Similarly, we and others also demonstrated that several inhibitors of Bcl-2 family members like navitoclax (ABT263), A1331852 and A1155463 are senolytic in some, but not all cell types. In addition, a FOXO4-interacting peptide that blocks an association with p53 recently was demonstrated to induce apoptosis in senescent cells.

Here, we describe the development of a novel screening platform to identify senotherapeutics, drugs that either suppress senescence (senomorphics) or selectively kill senescent cells (senolytics). The screen utilizes DNA repair deficient Ercc1-/- primary murine embryonic fibroblasts (MEFs), which senesce rapidly when grown at atmospheric oxygen, and detection of senescence-associated β-galactosidase (SA-β-gal). Using this platform to screen a library of autophagy regulators, a process known to influence the senescence phenotype of different cell types, we identified HSP90 inhibitors as a novel class of senolytic agents, able to induce apoptosis of senescent cells specifically.

To validate the platform, HSP90 inhibitors were tested for senolytic activity in human cells in culture and in a progeroid mouse model of accelerated aging, where the intervention delayed multiple age-related comorbidities. These results demonstrate the utility of the screening platform for identifying novel classes of senotherapeutics. Furthermore, the results demonstrate that an HSP90 inhibitor used clinically is senolytic and could be potentially repurposed to extend healthspan.

Mitochondrial damage is important in aging, and many of the means shown to modestly slow aging in various species involve increased cellular maintenance activities directed towards mitochondria. One of these is mitophagy, a specialized form of autophagy that recycles damaged mitochondria. There is plenty of evidence to suggest that more efficient mitophagy is good for long-term health. There is also plenty of evidence for increased autophagy of all sorts to be one of the more important mediating mechanisms in many of the interventions shown to slow aging in laboratory species, including the long-studied and simple approaches of calorie restriction and exercise. In this paper, the authors review what is known of the effects of exercise on mitophagy and mitochondrial function in older individuals. We all know the rough boundaries of the benefits that can be produced by exercise; the open question for researchers is the degree to which various specific mechanisms contribute to those benefits.

The maintenance of mitochondrial structural integrity, biogenesis, and function is essential to cells, since mitochondrial dysfunction can induce disturbances in energy metabolism, increase reactive oxygen species (ROS) production and, consequently, trigger mechanisms of apoptotic cell death. Moreover, during the last decades, multiple lines of evidence in model organisms and humans have demonstrated that impaired mitochondrial function can contribute to the aging process, as well as age-associated diseases. In fact, it has been shown that decreased mitochondrial performance is a hallmark of aging possibly due to the central role of mitochondria in metabolism and cellular function. Thus, the potential toxicity of mitochondrial ROS (mtROS), originating from the mitochondrial respiratory chain, led to the formulation of the oxidative stress theory of aging, which suggested that the accumulation of oxidative damage to macromolecules is an important point in the aging process.

Mitochondrial DNA has two characteristics that make it a key target of mtROS: on the one hand, its proximity to the respiratory chain and, on the other, the lack of protective histones. Damaged mitochondrial DNA alters the respiratory chain, increasing the free radical generation and triggering a vicious cycle. These changes result in organic dysfunction and aging phenotype. Recently, however, in contrast to the original theory favoring oxidative damage as a cause for mtDNA mutations and corresponding declines in mitochondrial function, there are strong data arguing that most mammalian mtDNA mutations originate as replication errors made by the mitochondrial DNA polymerase.

Since mitochondria are involved in both adaptive metabolism and survival in response to cellular stress, it is necessary to maintain good mitochondrial functioning through a tight mitochondrial quality control. Recently, mitophagy has gained importance because the damage accumulated in the mitochondria may result in a large number of cell consequences. This process of dysfunctional mitochondria removal occurs by two major pathways, damage-induced mitophagy and developmental-induced mitophagy. Mitophagy not only clears dysfunctional mitochondria but also participates in adaptive response to nutrient deprivation, hypoxia, or developmental signals, promoting a reduction in the overall mitochondrial mass.

Physical exercise has been proposed as a nondrug treatment against different diseases for people of all ages. In addition, it is suggested that regular exercise could promote an increase in mitophagy capacity and produce effects on the mitochondrial life cycle. Theoretically, physical exercise could also have effects on the major signaling pathways that are involved in the quality and quantity control of mitochondria during the aging process, such as mitophagy. Mitochondria produce ROS that can act as signaling molecules, inducing a survival response or causing damage to cellular components. However, contraction of the skeletal muscle during physical exercise can activate a mitochondrial response that improves the quality of mitochondria in different ways: (1) increasing biogenesis; (2) enhancing the expression and action of the proteins involved in mitochondrial dynamics; (3) raising mitochondrial turnover by the action of mitophagy proteins; and (4) increasing the quality control of mitochondria through the degradation of damaged or dysfunctional mitochondria.

Although the studies analyzed do not exhibit a general consensus, it seems that aging impairs mitochondrial biogenesis and dynamics and decreases the mitophagic capacity of the organism. Several interventions, such as any type of physical exercise, are able to affect the activity and turnover of mitochondria by increasing biogenesis. In addition to the changes detected in the biogenesis, aerobic exercise or combined long-term training also seem to produce increases in several markers of mitochondrial dynamics and mitophagy.

Link: https://doi.org/10.1155/2017/2012798

The first, narrowly focused rejuvenation therapies based on repair of the cell and tissue damage that causes aging already exist. They are entering trials, they are under development in companies. Senolytic therapies to clear senescent cells will be a going concern in just a few years: the drug candidates are cheap, people are running small trials funded by philanthropists, and others are self-experimenting. The first forms of treatment capable of turning back numerous aspects of aging in humans to a large enough degree to be worth it are nearly here. Unless your remaining life expectancy is in fact only a few years, then you have every chance of being able to benefit from at least the first generation of these treatments. There is no excuse for turning away and shrugging, telling yourself that this is science fiction, the medicine of the next generation, out of reach and therefore not worth your support. That is all false.

Given that up to the beginning of the twentieth century many of us succumbed to disease at an early age, it should be no surprise that living a long life is still seen today as something akin to winning the lottery. Even when confronted with the galloping pace of scientific advances in human longevity, our historical sensibilities have led us to take a defeatist stance towards the subject: "Even if longevity interventions become available during my lifetime, I am already too late to take advantage of them, so why bother?" Indeed, for so long as tangible rejuvenation therapies do not become available, we will feel validated in our pragmatism.

Today, however, rejuvenation biotechnology is far from a fictional dream: it is a quickly growing field in which advances which may increase the lifespan of you and your children to well over a hundred years are already making their way to the clinic, and this is something we can no longer ignore. Every reality begins with a dream. Only 114 years ago, the Wright brothers made the first powered flight a reality, and since then we have taken to the skies, orbited the earth, and landed a man on the moon. Today, most of us will have flown in an airplane, and have ceased to see this as exceptional. It would be short-sighted to think that the same will not happen with new technologies such as cryonics or rejuvenation.

In the last year alone, we have seen a rapid rise in the number of senolytic drugs, that aim at clearing senescent cells, under development, with companies such as Unity Biotechnology recently raising more than 100 million dollars to push these therapies through the US regulatory process and into the clinic. Last year, scientists found a way to cheaply synthesize glucosepane, a key molecule thought to be a crucial factor in aging. A drug which clears glucosepane from the body is now being developed by the Spiegel Lab at Yale University, among others, and the first potential drug candidates are projected to be available within the next 10 years. And this is only the tip of the iceberg. At this point, it is indeed challenging to continue to pull the wool over our eyes. Not only are these therapies likely to become available in our lifetime, but it seems many of them will be reaching the market within the next decade.

However, reflecting on the feasibility and the desirability of bringing aging under comprehensive medical control inevitably demands us to question many of our preconceived assumptions regarding what is possible, what is or isn't good for us, and what is acceptable. Disputing what one had long thought to be true - or at least learned to accept - is never without effort or discomfort, and this is especially true when we consider that many of us still see aging as an inevitable, perhaps even necessary, fact of life. It should thus come as no surprise that one of the most common responses to the thought of robust rejuvenation is that of neglect; in other words: why concern ourselves with something that might come to pass only after we are long gone?

Yet our actions today have the possibility, for the first time in history, to bring a profound change to the number of people who may live long enough to benefit from rejuvenation. By acting to speed up the development of the first therapies in the coming years, we ensure that a large majority of people alive today are granted the opportunity to take advantage of them; conversely, our inaction will lead to a slowing down of the pace of progress, making the impossibility of robust rejuvenation a self-fulfilling prophecy.

Link: http://www.leafscience.org/not-in-my-lifetime/

Nothing in cellular biology is any way straightforward. All rules have exceptions, enormous complexity is the norm, and old understandings are consistently overturned with the arrival of new data: what was thought to be simple turns out to be anything but simple. Even something like the cellular maintenance processes of autophagy, universally demonstrated to be a good thing in laboratory species, to slow aging when more active, and to accelerate aging when disabled via genetic engineering, are no exception. As demonstrated here, researchers have found that selectively disabling autophagy can actually extend life in nematode worms, possibly because the operation of age-damaged autophagy in some important tissues is actually worse than the absence of running autophagy.

In the publicity materials, this is all wrapped in considerations of antagonistic pleiotropy in the evolution of aging, but I think the mechanics of the thing are more interesting in this case. In lower species like worms and flies there is a fair amount of evidence for some tissues to be especially influential over aging: the intestines, some groupings of neurons in the brain, for example. It is very unclear as to the degree to which this is still the case in mammals. Certainly most things demonstrated to slow aging in short-lived species have far less of an effect in long-lived species such as our own. Nonetheless, this research can be taken as an example of the importance of neurons in the pace of aging in nematodes.

Why we did not evolve to live forever: Unveiling the mystery of why we age

Natural selection results in the fittest individuals for a given environment surviving to breed and pass on their genes to the next generation. The more fruitful a trait is at promoting reproductive success, the stronger the selection for that trait will be. In theory, this should give rise to individuals with traits which prevent ageing as their genes could be passed on nearly continuously. Thus, despite the obvious facts to the contrary, from the point of evolution ageing should never have happened. This evolutionary contradiction has been debated and theorised on since the 1800s. It was only in 1953 with his hypothesis of antagonistic pleiotropy that George C. Williams gave us a rational explanation for how ageing can arise in a population through evolution.

Williams proposed that natural selection enriches genes promoting reproductive success but consequently ignores their negative effects on longevity. Importantly, this is only true when those negative effects occur after the onset of reproduction. Essentially, if a gene mutation results in more offspring but shortens life that's fine. This is because there can be more descendants carrying on the parent's genes in a shorter time to compensate. Accordingly, over time, these pro-fitness, pro-ageing mutations are actively selected for and the ageing process becomes hard-wired into our DNA. While this theory has been proven mathematically and its implications demonstrated in the real world, actual evidence for genes behaving in such as fashion has been lacking.

Now researchers have identified that genes belonging to a process called autophagy - one of the cells most critical survival processes - promote health and fitness in young worms but drive the process of ageing later in life. "These genes haven't been found before because it's incredibly difficult to work with already old animals, we were the first to figure out how to do this on a large scale. From a relatively small screen, we found a surprisingly large number of genes, 30, that seem to operate in an antagonistic fashion. Previous studies had found genes that encourage ageing while still being essential for development, but these 30 genes represent some of the first found promoting ageing specifically only in old worms. Considering we tested only 0.05% of all the genes in a worm this suggests there could be many more of these genes out there to find."

The researchers also found a series of genes involved in regulating autophagy which accelerate the ageing process. These results are surprising indeed, the process of autophagy is a critical recycling process in the cell, and is usually required to live a normal full lifetime. Autophagy is known to become slower with age and the authors of this paper show that it appears to completely deteriorate in older worms. They demonstrate that shutting down key genes in the initiation of the process allows the worms to live longer compared with leaving it running crippled. "Autophagy is nearly always thought of as beneficial even if it's barely working. We instead show that there are severe negative consequences when it breaks down and then you are better off bypassing it all together. It's classic antagonistic pleiotrophy. In young worms, autophagy is working properly and is essential to reach maturity but after reproduction, it starts to malfunction causing the worms to age."

In a final revelation, the team were able to track the source of the pro-longevity signals to a specific tissue, namely the neurons. By inactivating autophagy in the neurons of old worms they were not only able to prolong the worms life but they increased the total health of the worms dramatically. "We turn autophagy off only in one tissue and the whole animal gets a boost. The neurons are much healthier in the treated worms and we think this is what keeps the muscles and the rest of the body in good shape. The net result is a 50% extension of life."

Neuronal inhibition of the autophagy nucleation complex extends life span in post-reproductive C. elegans

Autophagy is a ubiquitous catabolic process that causes cellular bulk degradation of cytoplasmic components and is generally associated with positive effects on health and longevity. Inactivation of autophagy has been linked with detrimental effects on cells and organisms. The antagonistic pleiotropy theory postulates that some fitness-promoting genes during youth are harmful during aging. On this basis, we examined genes mediating post-reproductive longevity using an RNAi screen.

From this screen, we identified 30 novel regulators of post-reproductive longevity, including pha-4. Through downstream analysis of pha-4, we identified that the inactivation of genes governing the early stages of autophagy up until the stage of vesicle nucleation, such as bec-1, strongly extend both life span and health span. Furthermore, our data demonstrate that the improvements in health and longevity are mediated through the neurons, resulting in reduced neurodegeneration and sarcopenia. We propose that autophagy switches from advantageous to harmful in the context of an age-associated dysfunction.

The way to avoid the harms done to long-term health and life expectancy by excess visceral fat tissue is not to gain that fat, or to lose it if you have it. This is not the path pursued by that part of the research community interested following the large-scale funding associated with the metabolic diseases of obesity, of course. There is comparatively little profit to be made in telling people to lose weight, versus selling them compensatory pharmaceuticals for a lifetime. However, even with normal, healthy levels of fat tissue, as aging progresses that tissue starts to cause similar issues to those produced by excess fat in earlier life: chronic inflammation, metabolic disruption leading to type 2 diabetes, and so forth. The changes of aging include processes that introduce dysfunction into the relationship between fat and the immune system, one of which is examined here.

Adipose tissue inflammation has become widely accepted as a major contributor to metabolic dysfunction and disorders. Previous studies on diet induced obesity mice have shown that adipose tissue is primed for inflammatory changes prior to other metabolic organs. There is a plethora of research investigating factors in obese adipose tissue inflammation to identify valuable therapeutic targets for metabolic dysfunction. However, much less is understood about age-related adipose tissue inflammation and dysfunction. A better understanding of the cellular and molecular mechanisms of adipose tissue inflammation in aging will be crucial in the development of therapeutics for metabolic diseases beyond cases of diet-induced adipose tissue inflammation and insulin resistance.

Both age-related adiposity and diet-induced obesity are characterized by immune cell infiltration and a sustained inflammatory cycle. Among these various immune cells, adipose tissue macrophage (ATM) accumulation, proliferation, and polarization are major contributors to adipose tissue inflammation and dysfunction. Interestingly, recent studies suggest that changes in preadipocyte function during aging also lead to dysfunctional adipose tissue, eventually progressing to chronic inflammation. Our group have recently shown that elevated endoplasmic reticulum (ER) stress response in aging contributes to greater inflammatory responses, in part due to compromised autophagy activity in the aging adipose tissue. Recent studies have also indicated that with aging there is increased accumulation of senescent cells in many organs including fat depots, which contributes to aging pathologies. However, the detailed molecular mechanisms that lead to increased inflammation in aging adipose tissue are poorly defined.

During the last decade, major advances were made in identifying the molecular mechanisms by which lipid-derived products promote inflammation in different cell types. One type of lipid-derived product, non-esterified fatty acids (NEFA), elevates tissue inflammation through interaction with the pattern recognition receptor Toll-like receptor 4 (TLR4) via its endogenous ligand Fetuin-A (Fet A), a liver derived glycoprotein. Fet A is considered a biomarker of chronic inflammation due to its ability to stimulate the production of inflammatory mediators from both adipocytes and macrophages. Interestingly, Fet-A null mice were protected against obesity and insulin resistance with aging.

The involvement of Fet A-mediated activation of TLR4 pathway in adipose tissue inflammation in diet-induced obesity is well explored. However, the role of this pathway in age-associated adipose tissue inflammation is unknown. We undertook this study to test the hypothesis that age-related adipose tissue inflammation is dependent on the Fet A-mediated TLR4 signaling pathway. We first evaluated the expression of Tlr4 and Fet A gene products in adipose tissue, liver, and plasma samples derived from young and old mice. We then exploited the TLR4-deficient mice to investigate the role of TLR4 in age-associated adipose tissue inflammation, ER stress response, autophagy activity, cellular senescence, and metabolic status (glucose tolerance).

We found that, in contrast to data from diet-induced obesity models, adipose tissue from aged mice have normal Fet A and TLR4 expression. Interestingly, aged TLR4-deficient mice have diminished adipose tissue inflammation compared to normal controls. We further demonstrated that reduced adipose tissue inflammation in old TLR4-deficient mice is linked to impaired ER stress, augmented autophagy activity, and diminished cellular senescence. Importantly, old TLR4-deficient mice have improved glucose tolerance compared to age-matched wild type mice, suggesting that the observed reduced adipose tissue inflammation in aged TLR4-deficient mice has important physiological consequences. Taken together, our present study establishes novel aspect of aging-associated adipose tissue inflammation that is distinct from diet-induced adipose tissue inflammation. Our results also provide strong evidence that TLR4 plays a significant role in promoting aging adipose tissue inflammation.

Link: https://doi.org/10.18632/aging.101288

This very readable review paper walks through what is known of modifications to proteins that occur after their creation, and the role these modifications play in aging. If you are familiar with the SENS view of aging as an accumulation of damage, you'll recall that this damage includes the buildup of numerous forms of metabolic waste, and many of these items are modified proteins. Equally, the vast majority of other age-related changes in modified proteins are downstream consequences of the damage of aging or reactions to the damage of aging, not root causes - the details matter on a case by case, per-protein and per-modification basis.

From a biodemographic point of view, aging is defined as an exponential increase in mortality with time, sometimes accompanied by a deceleration or plateau at later ages. Although the changes that underlie aging are complex, it is characterized by the gradual accumulation of a wide variety of molecular and cellular damage throughout the lifespan. The nine proposed hallmarks of aging in mammals are genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. However, the connections between these hallmarks, their contributions to aging, and their links with frailty and disease remain incompletely understood. In fact, uncovering the biological basis of aging is one of the greatest contemporary challenges in science.

Interestingly, epigenetics plays a crucial role in aging. While there are several different types of epigenetic mechanisms, protein posttranslational modifications (PTM) are intriguing contributors in regulating aging. Proteins are the basis of cellular and physiological functioning in living organisms, and the physical and chemical properties of proteins dictate their activities and functions. The primary sequence of a protein is a main determinant of protein folding and final conformation as well as biochemical activity, stability, and half-life. However, at any given moment in the life of an individual, its proteome is up to two or three orders of magnitude more complex than the encoding genomes would predict. One of the main routes of proteome expansion is through posttranslational modifications (PTM) of proteins.

Protein PTM results from enzymatic or nonenzymatic attachment of specific chemical groups to amino acid side chains. Such modifications occur either following protein translation or concomitant with translation. PTM influences both protein structure and physiological and cellular functions. Examples of enzymatic PTMs include phosphorylation, glycosylation, acetylation, methylation, sumoylation, palmitoylation, biotinylation, ubiquitination, nitration, chlorination, and oxidation/reduction. Nonenzymatic PTMs include glycation, nitrosylation, oxidation/reduction, acetylation, and succination. Some rare and unconventional PTMs, such as glypiation, neddylation, siderophorylation, AMPylation, and cholesteroylation, are also known to influence protein structure and function.

Generally, protein PTMs occur as a result of either modifying enzymes related to posttranslational processing (such as glycosylation) or signaling pathway activation (such as phosphorylation). Moreover, PTM patterns are known to be affected by disease conditions. Similarly, the dysregulation of PTM is associated with the aging process. In this context, both enzymatic and nonenzymatic PTMs can undergo age-related alterations. Alteration in the pattern of nonenzymatic PTMs depends mainly on the nature of the modifying substances, such as metabolites and free radicals. For instance, reactive oxygen species can lead to oxidation of amino acid side chains (oxidation of thiols to different forms, oxidation of methionine, formation of carbonyl groups, etc.), modification by-products of glycoxidation and lipoxidation, and formation of protein-protein cross-links as well as oxidation of the protein backbone, resulting in protein fragmentation. In contrast, changes in the nature of enzymatic PTMs rely primarily on the activities of modifying enzymes.

As awareness of the role of PTMs in aging and aging-related diseases grows, there is an urgent need for the development of methods to detect protein PTMs more rapidly and accurately. Furthermore, the recent finding of rare and unconventional modifications in age-related pathologies calls for the development of more specific and sensitive methods to detect such modifications. The recent rapid progress in large-scale genomics and proteomics technologies is likely to be a catalyzing factor for such studies. Drugs that target PTMs, such as phosphorylation, acetylation, methylation, and ubiquitination, will serve as useful tools in exploring the basic mechanism of PTM modulation and provide a pharmacological platform to combat the detrimental effects of aging.

Link: https://doi.org/10.1155/2017/5716409

If you spend much time scanning through papers of interest to the field of aging research, one of the things that may strike you about the past few years of work on senescent cells is the way in which it dovetails so well with past research of all sorts. A great deal of life science work in many parts of the broader field makes a whole lot more sense given the context of senescent cell accumulation as both (a) an important contributing cause of aging, and (b) an important source of chronic inflammation.

Yet this context wasn't missing a decade go or more - there was more than enough evidence to place senescent cell clearance into the first SENS rejuvenation research proposals, for example. It was there for anyone to recognize. But it wasn't given the weight it deserved, and too many researchers let the biochemistry of cellular senescence fade into the background, failing to consider it as a matter of importance for the mechanisms they happened to be focused upon. This is a problem, because, put simply, any condition or change in aging with a strong inflammatory component is fundamentally linked to cellular senescence. It cannot be ignored.

The paper noted here is a good example of this snug fit between older research and modern, more widespread realizations of the importance of cellular senescence. Researchers have long investigated links between cancer cells, inflammation, and platelet regulation. Platelets are a form of small cell-like structure that are primarily responsible for clotting as a way to control bleeding. They are manufactured by a fascinating process of shedding from cells known as megakaryocytes. But in this context, you might think of platelets as an abstract bundle of mechanisms by which cells can amplify inflammatory signaling to generate much larger effects on surrounding tissues and bodily systems, though that is perhaps an oversimplification.

Like all systems in cellular metabolism, the behavior of platelets runs awry in older people. Blood clotting can run amok or proceed incorrectly and fail to resolve. It turns out that the inflammatory signals from tumor cells and their relationship with platelets, categorized by interested cancer researchers over the years without giving all that much thought to cellular senescence, are probably very relevant to the activities of senescent cells as well. Senescent cells are the missing third leg for the stool portrayed in this picture, and platelets may be an important part of the bigger picture for cellular senescence and cancer risk in aging.

The Potential Role of Senescence as a Modulator of Platelets and Tumorigenesis

The functional connection between cancer and platelets has been recognized since the late nineteenth century, when an association between the occurrence of certain solid tumors and the development of venous thrombosis and blood hypercoagulability was first described. Accordingly, defects in platelet function or reduced platelet counts have both been associated with a reduced ability of tumors to metastasize. We now know that platelets may contribute to the establishment of various hallmarks of cancer, including the ability of cancer cells to sustain proliferation, to resist apoptosis and to promote angiogenesis and metastasis. It is presently unclear, however, to what extent these contributions are the result of a direct action of platelets on tumor cells or, alternatively, may be part of an underlying inflammatory process inherent to many tumors. Inflammatory cells and soluble mediators of inflammation are important constituents of the tumor microenvironment.

Typical hallmarks of physiological aging include impaired tissue regeneration and repair, a functional impairment of progenitor cellsalterations of the immune system. While the specific cellular changes associated with each one of these hallmarks will vary depending on the tissue analyzed, cellular senescence is rapidly emerging as an underlying process that may help explain some of these changes. In keeping with this idea, senescent cells accumulate in several tissues derived from aged animals. In addition to cell cycle arrest, the establishment of a mature senescent phenotype involves extensive metabolic reprograming, as well as the implementation of complex traits such as the senescence-associated secretory phenotype (SASP). The SASP refers to the almost universal capacity of senescent cells to produce and secrete a variety of soluble and insoluble factors, including extracellular proteases, cytokines, chemokines, and growth factors.

A common feature of aging and age-related diseases is chronic inflammation. The term "inflammaging" has been coined to describe a low-grade, chronic, and systemic inflammation associated with aging and aging phenotypes in the absence of evidence of infection. In line with this concept, many of the factors secreted by senescent cells are also well-known pro-inflammatory molecules with the potential to induce chronic inflammation in certain biological contexts. More recently, a unique type of inflammation triggered by senescent cells, the senescence-inflammatory response, has been identified.

Based on the emerging physiological and pathological processes in which the SASP might be involved, it is conceivable that senescent cells may also affect hemostasis through mechanisms that include, but are not limited to, changes in the production and functional status of platelets. As mentioned elsewhere in this review, IL-6 is one of the most prominent pro-inflammatory cytokines present in the SASP. Moreover, IL-6 upregulates the synthesis of hemostatic factors, such as fibrinogen, and may also directly activate platelets.

Thus, it is tempting to speculate that the high levels of IL-6 (and other pro-inflammatory factors, such as IL-1β and TNF-α) detected in aged individuals could reflect, at least in part, an increased rate of secretion of this cytokine by senescent cells - or by other cells responding to senescent cells - in the context of a senescence-induced chronic inflammation. An age-dependent increase of pro-inflammatory factors would, in turn, contribute to platelet activation and a higher proclivity to thrombus formation. Therefore, we postulate that cellular senescence (as a result of physiological aging or secondary to therapeutic stress) might play an important role in the regulation of platelet function. By regulating the activation of platelets, senescent cells could provide yet another mechanism contributing to the higher prevalence of chronic inflammation (and cancer) in aged individuals.

The functional interaction between cancer cells and platelets has been well established. Most of the efforts aimed to clarify these interactions have been focused on the ability of tumor cells (or tumor-associated stromal cells) to produce and secrete pro-inflammatory factors that can result in the activation of platelets. Active platelets - acting synergistically with other components of the tumor stroma - can then promote or enhance tumor progression and metastasis. Paradoxically, many of the factors secreted by tumor cells or tumor-associated inflammatory cells with a known effect on platelet activity are also produced and secreted by cells undergoing senescence, a process originally regarded as tumor suppressive. Indeed, the evidence indicates that cellular senescence may also play an active role in driving, rather than suppressing, tumor formation, a non-cell autonomous role that seems to be largely dependent on the SASP. Accordingly, factors released by senescent cells may help create a pro-tumorigenic microenvironment that enhances proliferation and migration of neighbor cells. Although still controversial, this model would be in line with the observation that the prevalence of most cancers increases with age.

Alterations in hemostasis involving platelet dysfunction or alterations in the process of fibrinolysis are at the core of thrombogenesis. As with cancer, thrombogenesis is most commonly observed in older individuals, who presumably harbor a higher proportion of senescent cells in their tissues. We, therefore, postulate that cellular senescence, either as a result of normal aging or secondary to stress, could play an important role in the regulation of platelet function. According to this model, senescent cells have the ability to modify the microenvironment in ways that may enhance tumorigenesis. Similarly, senescent cells might also regulate the activity of platelets, the process of fibrinolysis, or both. By regulating the activation of platelets, senescent cells may provide yet another mechanism to enhance tumorigenesis. Whether or not these circuits are relevant to tumorigenesis and/or thrombogenesis remains to be fully elucidated.

Join the circulatory systems of two mice, one young and one old, a procedure known as heterochronic parabiosis, and the young one suffers some of the impact of aging while the old one loses some of that same impact. Regenerative capacity and stem cell activity are affected, for example. Researchers continue to search for factors in the blood that might explain this, but this work is still in its comparatively early stages. The question of the degree to which the mechanisms involve beneficial factors in young blood or harmful factors in old blood remains to be settled, with a range of interesting evidence on both sides. The "bad old blood" view seems to have the more compelling demonstration so far, I feel. If this is the case, benefits in the old mice are realized because the harmful factors in old blood are diluted by young blood, not because the young blood is providing beneficial signals.

Aging is a gradual biological process characterized by a decrease in cell and organism functions. Gingival wound healing is one of the impaired processes found in old rats. Here, we studied the in vivo wound healing process using a gingival repair rat model and an in vitro model using human gingival fibroblasts for cellular responses associated to wound healing. To do that, we evaluated cell proliferation of both epithelial and connective tissue cells in gingival wounds and found decreased of Ki67 nuclear staining in old rats when compared to their young counterparts.

We next evaluated cellular responses of primary gingival fibroblast obtained from young subjects in the presence of human blood serum of individuals of different ages. Eighteen to sixty five years old masculine donors were classified into 3 groups: "young" from 18 to 22 years old, "middle-aged" from 30 to 48 years old and "aged" over 50 years old. Cell proliferation, measured through immunofluorescence for Ki67 and flow cytometry for DNA content, was decreased when middle-aged and aged serum was added to gingival fibroblasts compared to young serum. Myofibroblastic differentiation, measured through alpha-smooth muscle actin (α-SMA), was stimulated with young but not middle-aged or aged serum both the protein levels and incorporation of α-SMA into actin stress fibers. High levels of PDGF, VEGF, IL-6R were detected in blood serum from young subjects when compared to middle-aged and aged donors. In addition, the pro-inflammatory cytokines MCP-1 and TNF were increased in the serum of aged donors.

In wounds in old rats there is an increased of staining for TNF compared to young rat wounds. Moreover, healthy gingiva (non injury) shows less staining compared to a wound site, suggesting a role in wound healing. Moreover, serum from middle-aged and aged donors was able to stimulate cellular senescence in young cells as determined by the expression of senescence associated beta-galactosidase and histone H2A.X phosphorylated at Ser139. Further, we detected an increased frequency of γ-H2A.X-positive cells in aged rat gingival tissues. The present study suggests that serum factors present in middle-aged and aged individuals may be responsible, at least in part, for the altered responses observed during wound healing in aging.

Link: https://doi.org/10.1371/journal.pone.0184189

The results noted here are unsurprising, a confirmation of what was expected by most in the field. The practice of calorie restriction has been shown to extend healthy life span and slow near all measures of aging in a range of species. Now that the research community has established a number of epigenetic clocks, characteristic patterns of DNA methylation that change in fairly predictable ways over the course of aging, it was only a matter of time before those too were shown to be slowed by calorie restriction. If, as is the consensus, calorie restriction does in fact slow the causes of aging, and slow aging as a process overall, then it should also slow all consequent measures of aging.

Where these publicity materials run awry is to paint epigenetic changes as a cause of aging. There is certainly a faction in the research community whose members consider aging to be a selected, evolved program, and place epigenetic changes as a root cause of aging. However I think they continue to have an uphill struggle to try to prove that case in the face of the overwhelming evidence for aging to be caused by accumulations of molecular damage, with epigenetic changes a downstream consequence of that damage: cells reacting to increased damage in the surrounding environment and themselves. The complexity of cellular biochemistry in a living individual means that this debate is unlikely be resolved through inspection before it is resolved by observing the results of different approaches to rejuvenation therapies. For example, clearance of senescent cells is a form of damage repair that extends life in mice: if that also turns back epigenetic changes of aging, something that has yet to be established in a published paper, then this would be strong evidence against epigenetic change as a cause of aging.

New research is the first to show that the speed at which the epigenome changes with age is associated with lifespan across species and that calorie restriction slows this process of change, potentially explaining its effects on longevity. "Our study shows that epigenetic drift, which is characterized by gains and losses in DNA methylation in the genome over time, occurs more rapidly in mice than in monkeys and more rapidly in monkeys than in humans." The findings help to explain why mice live only about two to three years on average, rhesus monkeys about 25 years, and humans 70 or 80 years.

Chemical modifications such as DNA methylation control mammalian genes, serving as bookmarks for when a gene should be used - a phenomenon known as epigenetics. Previous studies had shown that these changes occur with age, but whether they were also related to lifespan was unknown. The researchers made their discovery after first examining methylation patterns on DNA in blood collected from individuals of different ages for each of three species - mouse, monkey, and human. Mice ranged in age from a few months to almost three years, monkeys from less than one year to 30 years, and humans from age zero to 86 years (cord blood was used to represent age zero). Age-related variations in DNA methylation were analyzed by deep sequencing technology, which revealed distinct patterns, with gains in methylation in older individuals occurring at genomic sites that were unmethylated in young individuals, and vice versa.

In subsequent analyses, striking losses in gene expression were observed in genomic regions that had become increasingly methylated with age, whereas regions that had become less methylated showed increases in gene expression. Investigation of a subset of genes affected by age-related changes in methylation revealed an inverse relationship between methylation drift and longevity. In other words, the greater the amount of epigenetic change - and the more quickly it occurred - the shorter the species' lifespan.

One of the strongest factors known to increase lifespan in animals is calorie restriction, in which calories in the diet are reduced while still maintaining intake of essential nutrients. To examine its effects, the researchers cut calorie intake by 40 percent in young mice and by 30 percent in middle-aged monkeys. In both species, significant reductions in epigenetic drift were observed, such that age-related changes in methylation in old animals on the calorie-restricted diets were comparable to those of young animals. With the latest findings, the researchers were able to propose a new mechanism - the slowing of epigenetic drift - to explain how calorie restriction prolongs life in animals. "The impacts of calorie restriction on lifespan have been known for decades, but thanks to modern quantitative techniques, we are able to show for the first time a striking slowing down of epigenetic drift as lifespan increases."

Link: https://www.eurekalert.org/pub_releases/2017-09/tuhs-tru091317.php

Therapies such as statins, that aim to reduce circulating levels of low-density lipoprotein (LDL) cholesterol, are perhaps the most prevalent medical approach to cardiovascular disease. Indeed, when measured against the low bar set for past attempts to treat age-related conditions, they are one of the most successful forms of treatment to date. A sizable fraction of the reduction in cardiovascular mortality over the past few decades is attributed to the widespread use of statins and similar treatments. Still, this is only a delaying action, it is not a fix for the underlying problems.

How do reductions in LDL cholesterol slow the consequences of cardiovascular aging? The processes of interest involve damaged cholesterol molecules and cellular reactions to their presence. As the various causes of aging progress, there is ever greater inflammation and oxidative stress to produce damaged, oxidized cholesterols that find their way into the bloodstream. Once there, this mix of damaged molecules irritates blood vessel walls. In most cases unwanted metabolic waste of this sort is promptly cleaned up, consumed by the immune cells called macrophages, and disposed of. In some cases, however, there is an overreaction, or macrophages become overwhelmed by the damaged forms of cholesterol. A feedback loop is created in which the blood vessel wall becomes inflammatory, drawing in ever more macrophages that become dysfunction and die to add their mass to the creation of the characteristic fatty lesions of atherosclerosis. These masses narrow blood vessels and disrupt the structure of the blood vessel wall. They reduce critical blood flow, and eventually, as blood pressure rises due to other age-related issues, these fatty plaques rupture to kill or seriously injure the individual.

All of this can be slowed by interfering in any of the critical steps, even without preventing the underlying causes. It can't be reversed without forms of repair, however. So researchers could aim to make macrophages more resilient, could reduce the flux of damaged cholesterol by reducing the overall level of cholesterol, could dampen inflammation by attempting to adjust the regulation of the immune system, and so forth. All of these will slow down atherosclerosis to the degree that any particular implementation can produce change. But to turn it back, themedical community would need means of safely breaking down the problem compounds that irritate blood vessels and kill macrophages. Researchers associated with the SENS Research Foundation have investigated this class of treatment over the years, as their budget has permitted, and made some progress in targeting the problem compound of 7-ketocholesterol via adaptation of baterial enzymes.

Just how low can LDL cholesterol go, however? If less is consistently better, because it slows down atherosclerosis, does less ever stop being better? At some point, one has to presume that running out of LDL cholesterol has to be a bad thing, or else we wouldn't evolved to have it to begin with. With the advent of new and far more effective approaches such as PCSK9 inhibitors, a considerably more powerful intervention than statins, it is possible to reduce cholesterol levels to a fraction of what they would otherwise be. Normal healthy adults have LDL cholesterol measures somewhere below 100 mg/dL. The most severely impacted older people can be nearing or passing 200 mg/dL. The latest therapies can push LDL cholesterol in older people down below 10 mg/dL, far beneath that of normal, young, healthy individuals. The evidence suggests that this is beneficial, and for exactly the same reasons that smaller reductions are beneficial: it reduces the pace at which atherosclerosis progresses. This leads to a number of questions that researchers seem generally unwilling to state in print at this point in time, such as whether or not all adults should be lowering cholesterol throughout their lives, or whether to focus on gene therapies that can achieve this effect across the entire life span without the need for drugs.

How Low Should LDL Cholesterol Go?

A newer class of cholesterol lowering drugs known as PCSK9 inhibitors has emerged as an effective treatment for drastically lowering LDL cholesterol beyond current treatment targets. In a new analysis, researchers sought to explore whether there was "floor effect" in the lowering of LDL cholesterol - essentially, is there a threshold below which there would be no added clinical benefit? Additionally, researchers explored whether ultra-low LDL cholesterol levels would have any negative impact.

Using data from the FOURIER trial (Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk), which found that patients treated with the PCSK9 inhibitor evolocumab and statin therapy had a 20 percent reduction in the risk of cardiovascular death, myocardial infarction, or stroke, researchers examined the efficacy and safety of very low levels of LDL cholesterol among 25,982 patients per the degree of LDL-C reduction following one month of treatment. Researchers found that the risk for cardiovascular events (including cardiovascular death, heart attack, and stroke) over 2.2 years progressively declined as LDL cholesterol levels decreased to below 20 mg/dL (0.5 mmol/L), and participants who achieved an LDL-C of less than 10 mg/dL (0.26 mmol/L) had a more than 40 percent lower risk of cardiovascular events than those with an LDL cholesterol equal to or greater than 100 mg/dL (2.6 mmol/L).

"Our findings demonstrate that there is essentially no floor effect, and that lower levels translated to a greater reduction in risk. Among high-risk patients, achieving a LDL cholesterol level far below the most common treatment target of 70 mg/dL (1.8 mmol/L) can further reduce the risk for an adverse cardiovascular event, with no major safety concerns."

Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial

27,564 patients were randomly assigned a treatment in the FOURIER study. 1025 (4%) patients did not have an LDL cholesterol measured at 4 weeks and 557 (2%) had already had a primary endpoint event or one of the ten prespecified safety events before the week-4 visit. From the remaining 25,982 patients (94% of those randomly assigned) 13,013 were assigned evolocumab and 12,969 were assigned placebo. 2,669 (10%) of 25,982 patients achieved LDL-cholesterol concentrations of less than 0.5 mmol/L, 8,003 (31%) patients achieved concentrations between 0.5 and less than 1.3 mmol/L, 3,444 (13%) patients achieved concentrations between 1.3 and less than 1.8 mmol/L, 7471 (29%) patients achieved concentrations between 1.8 to less than 2.6 mmol/L, and 4,395 (17%) patients achieved concentrations of 2.6 mmol/L or higher.

There was a highly significant monotonic relationship between low LDL-cholesterol concentrations and lower risk of the primary and secondary efficacy composite endpoints extending to the bottom first percentile (LDL-cholesterol concentrations of less than 0.2 mmol/L). Conversely, no significant association was observed between achieved LDL cholesterol and safety outcomes, either for all serious adverse events or any of the other nine prespecified safety events. These data support further LDL-cholesterol lowering in patients with cardiovascular disease to well below current recommendations.

This is an interesting experiment, though note that the DOI link goes straight to a PDF at the time of writing. It is carried out in cell culture, so don't take the results too seriously: they would have to be replicated in at least an organoid tissue structure that better matched natural brain tissue. Nonetheless, the researchers show that brain cells in this more artificial environment are capable of recovering from some of the damage done by the presence of amyloid-β, the protein aggregate associated with Alzheimer's disease. The present consensus is that it isn't the amyloid itself that causes the harm, but rather the surrounding halo of related proteins and fragments. Still, get rid of the amyloid, and that halo vanishes as well.

Patients with Alzheimer's disease (AD) chiefly suffer from impairment of memory and other cognitive functions. AD is neuropathologically characterized by senile plaques and neurofibrillary tangles, which are composed of amyloid β-protein (Aβ) and phosphorylated tau proteins, respectively. Recently, a new concept has emerged: that soluble oligomeric forms of Aβ (Aβ oligomers), but not Aβ fibrils, play a primary pathogenic role in the pathological cascade of AD. This idea is based on findings that soluble forms of Aβ provoke neurotoxic effects, including tau abnormalities (especially hyperphosphorylation), functional and structural abnormalities of synapses, and induction of neuronal death. This concept is supported by numerous studies that have employed a variety of experimental systems, including cell culture, brain slices, and animal models, as well as the fact that Aβ oligomers are abundant in post-mortem AD brains. Thus, oligomeric Aβ is considered a major culprit in the molecular pathology of AD.

To investigate the pathological roles of Aβ oligomers, we have established a neuron culture model system, in which rat primary neurons are exposed to relatively low concentrations of Aβ42 oligomers (Aβ-O) for relatively long periods (2-3 days). We observed that Aβ-O induces neurotoxic insults with limited cell death under these conditions. Because these changes are reflective of characteristic pathological features of AD, this neuron model is considered a useful system for investigating the neurotoxic mechanisms triggered by Aβ oligomers.

We were interested in the question of whether the neurotoxicity of Aβ oligomers is reversible and abates upon their removal, an issue that has remained largely unexplored. To investigate this possibility, we designed the following experimental paradigm: Rat primary cultured neurons were treated with Aβ-O for 2 days, at which point cells were deprived of Aβ-O by replacing the medium with fresh medium lacking Aβ-O, or were re-provided Aβ-O and cultured for an additional 2 days; untreated neurons were used as controls. Neurons continuously treated with Aβ-O showed greater activation of caspase-3 and eIF2α, and exhibited persistent, abnormal alterations of tau and β-catenin. In contrast, upon Aβ deprivation, caspase-3 and eIF2α activation were considerably attenuated, aberrant phosphorylation and caspase-mediated cleavage of tau recovered for the most part, and abnormal alterations of β-catenin were partially reversed.

These results indicate that removal of extracellular Aβ-O can fully or partially reverse Aβ-O-induced neurotoxic and synaptotoxic alterations in our neuron model. Our findings suggest that Aβ oligomer-associated neurotoxicity is a reversible process in that neurons are capable of recovering from moderate neurotoxic insults. These data also support the idea that Aβ oligomers act on the cell surface of neurons to transmit aberrant signals, resulting in various abnormal cellular responses; upon Aβ oligomer removal, the aberrant signals subside, resulting in reversal of all abnormal responses.

Link: https://doi.org/10.18632/oncotarget.19083

The evidence has been in place for some years to show that low calorie diets can reverse type 2 diabetes even in comparatively late stages. For the vast majority of patients, this is a disease of choice: they chose to become fat enough to suffer sufficient metabolic disruption to produce the condition, as well as to accelerate the aging process, and they choose to remain fat enough to maintain this level of damage. Yes, eating less and exercising more is harder than it used to be, in this environment of low-cost calories, comfort, and convenience, but "harder" is not "I have no choice in this."

A body of research putting people with type 2 diabetes on a low calorie diet has confirmed the underlying causes of the condition and established that it is reversible. Research has revealed that for people with type 2 diabetes: (a) excess calories leads to excess fat in the liver; (b) as a result, the liver responds poorly to insulin and produces too much glucose; (c) excess fat in the liver is passed on to the pancreas, causing the insulin producing cells to fail; (d) losing less than 1 gram of fat from the pancreas through diet can re-start the normal production of insulin, reversing type 2 diabetes; (e) this reversal of diabetes remains possible for at least 10 years after the onset of the condition.

"I think the real importance of this work is for the patients themselves. Many have described to me how embarking on the low calorie diet has been the only option to prevent what they thought - or had been told - was an inevitable decline into further medication and further ill health because of their diabetes. By studying the underlying mechanisms we have been able to demonstrate the simplicity of type 2 diabetes." A body of research now confirms the Twin Cycle Hypothesis - that Type 2 diabetes is caused by excess fat actually within both liver and pancreas. This causes the liver to respond poorly to insulin. As insulin controls the normal process of making glucose, the liver then produces too much glucose. Simultaneously, excess fat in the liver increases the normal process of export of fat to all tissues. In the pancreas, this excess fat causes the insulin producing cells to fail.

The Counterpoint study, which was published in 2011, confirmed that if excess food intake was sharply decreased through a very low calorie diet, all these abnormal factors would be reversed. The study showed a profound fall in liver fat content resulting in normalisation of hepatic insulin sensitivity within 7 days of starting a very low calorie diet in people with type 2 diabetes. Fasting plasma glucose became normal in 7 days. Over 8 weeks, the raised pancreas fat content fell and normal first phase insulin secretion became re-established, with normal plasma glucose control. "The good news for people with Type 2 diabetes is that our work shows that even if you have had the condition for 10 years, you are likely to be able to reverse it by moving that all-important tiny amount of fat out of the pancreas. At present, this can only be done through substantial weight loss." The Counterbalance study published in 2016, demonstrated that type 2 diabetes remains reversible for up to 10 years in most people, and also that the normal metabolism persists long term, as long as the person doesn't regain the weight.

Link: http://www.ncl.ac.uk/press/news/2017/09/type2diabetesisreversible/

In the past few years, a number of epidemiological studies have suggested a correlation between more time spent sitting and a greater risk of mortality and age-related disease. Intriguingly, the claim is that this correlation persists even in people who do in fact exercise sufficiently. This should be considered in the context that statistical studies of human health and activities are notoriously challenging, given the degree to which data must be massaged into shape. Seemingly small differences in choice of metric can produce opposing outcomes: for example, differences in assessing the trajectory of weight over a lifetime, as well as whether to measure body mass index or waist circumference, have at times in the recent past produced quite distorted views of the degree to which excess fat tissue is harmful.

So the matter is far from settled as to whether lengthy periods of sedentary behavior - such as sitting - are a cause of harm even in people who meet guidelines for activity and exercise. There is no good mechanism, beyond that this might reflect an association with any number of other behaviors or conditions or choices or states of life that are themselves correlated with shorter life expectancy. Sitting time correlates with vascular calcification, for example, but that doesn't say anything about why this might be the case in people who do exercise in between their seated periods. The most obvious suggestion is that this is a question of overall activity levels in life, and length of time spent sitting is just a good proxy for overall activity levels. If the past fifty years are any guide, researchers will keep turning out this sort of study to argue subtle points of statistical interpretation well into the era of functional rejuvenation therapies - by which point the whole exercise becomes somewhat irrelevant.

Long Sitting Periods May Be Just as Harmful as Daily Total

A new study finds that it isn't just the amount of time spent sitting, but also the way in which sitting time is accumulated during the day that can affect risk of early death. Adults who sit for one to two hours at a time without moving have a higher mortality rate than adults who accrue the same amount of sedentary time in shorter bouts. "We tend to think of sedentary behavior as just the sheer volume of how much we sit around each day. But previous studies have suggested that sedentary patterns - whether an individual accrues sedentary time through several short stretches or fewer long stretches of time - may have an impact on health."

The researchers used hip-mounted activity monitors to objectively measure inactivity during waking time over a period of seven days in 7,985 black and white adults over age 45. (The participants were taking part in the REGARDS study, a national investigation of racial and regional disparities in stroke.) On average, sedentary behavior accounted for 77 percent of the participants' waking hours, equivalent to more than 12 hours per day. Over a median follow-up period of four years, 340 of the participants died. Mortality risk was calculated for those with various amounts of total sedentary time and various sedentary patterns. Those with the greatest amount of sedentary time - more than 13 hours per day - and who frequently had sedentary bouts of at least 60 to 90 consecutive minutes had a nearly two-fold increase in death risk compared with those who had the least total sedentary time and the shortest sedentary bouts.

Patterns of Sedentary Behavior and Mortality in U.S. Middle-Aged and Older Adults: A National Cohort Study

Excessive sedentary time is ubiquitous in Western societies. Previous studies have relied on self-reporting to evaluate the total volume of sedentary time as a prognostic risk factor for mortality and have not examined whether the manner in which sedentary time is accrued (in short or long bouts) carries prognostic relevance. Sedentary time was measured using a hip-mounted accelerometer. Prolonged, uninterrupted sedentariness was expressed as mean sedentary bout length. Hazard ratios (HRs) were calculated comparing quartiles 2 through 4 to quartile 1 for each exposure (quartile cut points: 689.7, 746.5, and 799.4 min/d for total sedentary time; 7.7, 9.6, and 12.4 min/bout for sedentary bout duration) in models that included moderate to vigorous physical activity.

Over a median follow-up of 4.0 years, 340 participants died. In multivariable-adjusted models, greater total sedentary time (HR, 1.22; HR, 1.61; and HR, 2.63) and longer sedentary bout duration (HR, 1.03; HR, 1.22; and HR, 1.96) were both associated with a higher risk for all-cause mortality. Evaluation of their joint association showed that participants classified as high for both sedentary characteristics (high sedentary time [≥12.5 h/d] and high bout duration [≥10 min/bout]) had the greatest risk for death.

These findings highlight the importance of the total volume of sedentary time and its accumulation in prolonged bouts as important health risk behaviors. Meta-analyses have shown that total sedentary time is associated with cardiovascular disease and mortality, independent of moderate physical exercise. However, these findings are largely based on self-reported sedentary time, data that may underestimate the magnitude of the relationship between sedentariness and health risk. Use of accelerometers reduces potential biases and measurement error inherent in self-reported data. To our knowledge, this is the largest study to date with objective measures of sedentary behavior and prospective health outcomes. The magnitude of the association between total sedentary time and all-cause mortality (2.6-fold greater risk for quartile 4 vs. quartile 1) is notably higher than that reported in meta-analyses (HR 1.22).

A key finding of our study, which we believe is the first to report, is that patterns of sedentary time accumulation are associated with mortality. Previous cross-sectional studies have reported associations between the total number of breaks in sedentary time per day (the reciprocal to mean sedentary bout length) and cardiometabolic biomarkers. These findings led to the "prolonger" versus "breaker" hypothesis, which postulates that it is not only the amount of sedentary time that is important to cardiometabolic health, but also the manner in which it is accumulated.

Areas of China can act as a laboratory for the impact of particulate air pollution on long-term health. There are good reasons to think that the established correlations between air pollution and life expectancy are due to physical and biochemical mechanisms such as increased chronic inflammation. It has been equally possible to argue that that the relationship has more to do with relative wealth of populations, however, as wealthier regions tend to have lower levels of pollution. In this study, researchers put some numbers to the correlation, and improve on previous attempts to rule out wealth and other effects as significant contributing causes.

A study finds that a Chinese policy is unintentionally causing people in northern China to live 3.1 years less than people in the south, due to air pollution concentrations that are 46 percent higher. These findings imply that every additional 10 micrograms per cubic meter of particulate matter pollution reduces life expectancy by 0.6 years. The elevated mortality is entirely due to an increase in cardiorespiratory deaths, indicating that air pollution is the cause of reduced life expectancies to the north. "These results greatly strengthen the case that long-term exposure to particulates air pollution causes substantial reductions in life expectancy."

The study exploits China's Huai River policy, which provided free coal to power boilers for winter heating to people living north of the river and provided almost no resources toward heating south of the river. The policy's partial provision of heating was implemented because China did not have enough resources to provide free coal nationwide. Additionally, since migration was greatly restricted, people exposed to pollution were generally not able to migrate to less polluted areas. Together, the discrete change in policy at the river's edge and the migration restrictions provide the basis for a powerful natural experiment that offers an opportunity to isolate the impact of sustained exposure to particulates air pollution from other factors that affect health.

Overall, the study provides solutions to several challenges that have plagued previous research. In particular, prior studies rely on research designs that may be unlikely to isolate the causal effects of air pollution; measure the effect of pollution exposure for relatively short periods of time (e.g., weekly or annually), failing to shed light on the effect of sustained exposure; examine settings with much lower pollution concentrations than those currently faced by billions of people in countries, including China and India, leaving questions about their applicability unanswered; measure effects on mortality rates but leave the full loss of life expectancy unanswered.

The study follows on an earlier study, conducted by some of the same researchers, which also utilized the unique Huai River design. Despite using data from two separate time periods, both studies revealed the same basic relationship between pollution and life expectancy. However, the new study's more recent data covers a population eight times greater than the previous one. It also provides direct evidence on smaller pollution particles that are more often the subject of environmental regulations.

Link: https://news.uchicago.edu/article/2017/09/11/air-pollution-cuts-three-years-lifespans-northern-china