Fight Aging!

The liver is the most regenerative organ in adult mammals. Unlike any other organ, it is possible to cut out sections and the liver will regrow the lost tissue. The regrowth isn't perfect, unlike the case in highly regenerative species such as salamanders and zebrafish, but it does produce functional liver tissue. What makes the liver different? Despite a great deal of interest and activity in the research community, that question is nowhere near being comprehensively answered. Will practical regenerative therapies for the liver emerge before regenerative therapies for other organs? Maybe, maybe not. So far there is little sign that work on the liver is racing ahead of work on the rest of the portfolio of internal organs.

Today's open access paper is a recent output from just one line of investigation into liver regeneration, among the many lines that are presently ongoing. While the search for stem cell like populations in adult liver tissue is the focus here, with hybrid hepatocytes as the starting point, other research groups are looking into alternative splicing and the Hippo pathway that influences regeneration in a number of organs, or the subset of liver cells that express telomerase, behavior usually reserved for stem cells in the human body. It remains to be seen which lines of work will give rise to the next generation of regenerative medicine for the liver.

Liver transplants could be redundant with discovery of new liver cell

Scientists have identified a new type of cell called a hepatobiliary hybrid progenitor (HHyP), that forms during our early development in the womb. Surprisingly, HHyP also persists in small quantities in adults and these cells can grow into the two main cell types of the adult liver (Hepatocytes and Cholangiocytes) giving HHyPs stem cell-like properties. The team examined HHyPs and found that they resemble mouse stem cells which have been found to rapidly repair mice liver following major injury, such as occurs in cirrhosis.

"For the first time, we have found that cells with true stem cell-like properties may well exist in the human liver. This, in turn, could provide a wide range of regenerative medicine applications for treating liver disease, including the possibility of bypassing the need for liver transplants. We now need to work quickly to unlock the recipe for converting pluripotent stem cells into HHyPs so that we could transplant those cells into patients at will. In the longer term, we will also be working to see if we can reprogramme HHyPs within the body using traditional pharmacological drugs to repair diseased livers without either cell or organ transplantation."

Single cell analysis of human foetal liver captures the transcriptional profile of hepatobiliary hybrid progenitors

In rodents both hepatocytes and biliary epithelial cells (BECs) are derived from a common bi-potent hepatoblast population during liver development. In adult mice, conflicting evidence exists regarding the presence of a distinct bi-potent progenitor capable of regenerating both hepatocytes and BECs. The regenerative potential of the rodent liver has been attributed to hepatocytes, BECs, biliary-like progenitor cells or 'oval cells' arising in the ductal region, stem cells located around the central vein and hepatocyte or cholangiocyte de-differentiation into a hybrid bi-potent progenitor.

In comparison, the mechanisms of human liver regeneration are poorly characterised, and the existence of a bi-potent human liver 'progenitor' cell remains unclear. This issue is in part due to a substantial overlap in markers between potential progenitor populations, hepatic precursors and mature BECs, challenging the field to define the true transcriptional nature of a bi-potent progenitor phenotype that can be replicated for clinical use. Several recent studies have captured a bi-potent progenitor-like state via small molecule-reprogramming of primary hepatocytes, capable of in vitro hepatic and biliary maturation, imitating a process that has been observed during chronic mouse liver injury. Despite several well-established phenotypic criteria for liver progenitor cells, no benchmark exits that truly distinguishes them from other human hepatic and biliary cells. To facilitate the in vitro development of cell-based therapies for treating liver disease, it is critical to precisely define a liver progenitor cell that accurately captures the developmental origin of human liver parenchyma.

In this study we utilise single-cell RNA sequencing (scRNA-seq) to interrogate the transcriptome of human foetal and adult liver at single-cell resolution. In recent years scRNA-seq has helped identify unreported cell types within populations previously defined as homogenous. Here, we report the transcriptional signature of distinct hepatic cell types in foetal and adult human liver, including a foetal hepatobiliary hybrid progenitor (HHyP) population. We identify a gene expression profile that can distinguish between foetal HHyPs, foetal hepatocytes, and mature BECs. We further identify HHyP-like cells maintained in uninjured adult primary liver tissue. Finally, we sorted HHyPs from freshly isolated human foetal liver and show evidence of hepatic and biliary phenotypes in vivo. Our in depth profiling of previously undefined HHyPs finally provides an accurate template for the human liver progenitor phenotype that will be a valuable roadmap for translating ex vivo hepatic progenitor studies into successful cell-based liver disease therapies.

Stem cells support their tissues by generating daughter somatic cells and various forms of pro-regenerative signaling. Unfortunately, this activity declines with age. In the better studied stem cell populations, such as those in muscle tissue, this appears to be more a matter of signaling changes in the local environment than intrinsic damage to the stem cells themselves. The stem cells spend ever more time in a quiescent state, emerging ever more rarely to generate new daughter cells. At the high level, these changes must be a reaction to rising levels of molecular damage and its consequences such as chronic inflammation, but most of the research community is more interesting in finding proximate causes than in tackling root causes. The research here is an example of the type, in which scientists identify a specific epigenetic change that alters the muscle stem cell niche to suppress stem cell activity.

Muscle possesses remarkable regenerative capacity mediated by adult muscle stem cells, also called satellite cells (SCs) that reside in close association with individual myofibers, underneath the fiber's basal lamina. Responding to muscle injury, SCs will be activated and proliferate, differentiate, and fuse to existing damaged fibers or fuse with one another to form myofibers de novo. Meanwhile, a subpopulation of SCs returns to quiescence to replenish the stem cell pool. As we age, the mass, function, and regenerating capacity of muscle gradually decline, affecting mobility, voluntary function, and quality of life. It is thus imperative to investigate mechanisms accounting for the age-related muscle loss and functional decline.

Changes at all levels, including gene expression, histone modification, DNA methylation, and physical changes in muscle stem cell environment, or niche, have been found to be associated with aging. For instance, one of the studies of gene expression in aging muscle revealed that mitochondrial dysfunction is a major age-related phenomenon and highlighted the beneficial effects of maintaining a high physical capacity in the prevention of age-related muscle function decline. In another report, transcriptome-wide analysis demonstrated that the expression of extracellular matrix (ECM) genes is up-regulated during muscle aging. The myofiber basal lamina is comprised of an ECM network that is in direct contact with SCs and ECM plays an essential role in maintaining microenvironment homeostasis and SC function; the increased ECM levels in aging niche thus lead to deregulated behaviors of SCs. Specifically, SCs displayed decreased myogenic potential but increased expression of fibrogenic genes in aged muscle.

Alterations at epigenetic levels are also known to be associated with aging. For example, DNA hypermethylation at gene regions is associated with aging muscle. However, potential alterations of histone marks in aging muscle have not been investigated. For example, H3K27ac enrichment is a hallmark of enhancers. Several studies have shown the deregulation of H3K27ac and enhancers in aging tissues/cell types. In this study, we examined the changes of a panel of histone marks and found H3K27ac is markedly increased during aging in human skeletal muscle tissues. We next identified aging-related enhancer alterations and found them associated with the up-regulation of ECM genes. Furthermore, comparison of transcriptomes in young and aged SCs demonstrated that an age-related fibrogenic conversion of SCs. In mice, treatment of aging muscles with JQ1, an inhibitor of enhancer activation, reverted the ECM up-regulation and fibrogenic conversion of SCs, thus restored myogenic potential of SCs, suggesting that ECM increase in aging muscle is a result of enhancer activation and JQ1 can be a potential treatment approach for restoring SC function in aging muscle.

Link: https://doi.org/10.1111/acel.12996

Immune system dysfunction is an important component of age-related frailty, not just because of an increased vulnerability to infection and cancer, but also because the immune system falls into a state of chronic inflammation. It is overactive and ineffective at the same time, and this inflammation produces widespread dysfunction in tissues and processes throughout the body. This state has been given the name inflammaging. Here, researchers discuss inflammaging in the context of frailty in older individuals. It should go without saying that new therapeutic approaches that are able to restore correct immune function in the elderly will go a long way towards improving health and extending healthy life span. Developing such therapies, such as regrowth of the thymus, restoration of hematopoietic stem cells, regeneration of lymph nodes, and clearance of damaged immune cells, should be a higher priority than is presently the case.

Increasing attention has been paid to frailty as a potential explanation of the health diversity found in the elderly. Although a clear definition is still lacking, frailty is commonly understood as a geriatric state associated with increased vulnerability to internal and external stressors resulting from a significant loss of physiological reserve. Described as a disorder of multiple inter-related physiological systems, frailty is characterized by sedentariness, fatigue, weight loss, and poor muscle strength, and it increases the risk of adverse outcomes. However, frailty is a dynamic process that may be delayed or even reversed.

Several pathophysiological factors, including dysregulation of inflammatory processes, oxidative stress, mitochondrial dysfunction, and cellular senescence, underlie the frailty syndrome, and it is also influenced by many other factors, such as sociodemographic characteristics, psychological conditions, nutritional status, lack of physical activity, and comorbidities. However, is not clear what drives frailty and little is known about the risk factors that contribute to the development of the syndrome. Genetic differences together with environmental factors can contribute to the dysfunction of physiological mechanisms associated with frailty, leading, in turn, to the dysregulation of multiple systems, including the immune system. Furthermore, diet has been proposed to be a key element in the development frailty. Low intake of certain micronutrients and protein is associated with a higher risk of developing frailty.

Aging of the immune system leads to a low grade, chronic systemic inflammatory state, dubbed InflammAging, and it has been suggested that there exists a relationship between changes in inflammatory molecule levels and diseases and syndromes typical of old age. The InflammAging inflammatory phenotype is characterized by elevated inflammatory molecule levels, and associated with increased morbidity and mortality in older adults. It is suggested that InflammAging is a systemic physiological process that may involve one or several organs, leading to an increased risk of age-related chronic diseases and frailty. More recently it has been speculated that InflammAging is a dynamic auto-inflammatory process that can be amplified and propagated to neighbouring and distant cells and organs, thus accelerating and expanding aging processes both locally and systemically.

Furthermore, the concept of anti-inflammation, understood as an active phenomenon, has also been introduced. The rising levels of pro-inflammatory molecules in aging stimulate an increase in levels of anti-inflammatory mediators, serving to neutralize the dangerous inflammatory processes. The balance between inflammation and anti-inflammation has been suggested to determine the rate of aging, the onset and severity of age-associated disorders, and the individual's ability to achieve extreme longevity.

In conclusion, with study of the frailty syndrome still in its infancy, frailty analysis remains a major challenge. It is a challenge that needs to be overcome in order to shed light on the multiple mechanisms involved in the pathogenesis of this syndrome. Although several mechanisms contribute to frailty, immune system alteration seems to play a central role: this syndrome is characterized by increased levels of pro-inflammatory markers and the resulting pro-inflammatory status can have negative effects on various organs. Future studies should aim to better clarify the immune system alteration in frailty, and seek to establish exactly when the inflammation appears.

Link: https://doi.org/10.1016/j.arr.2019.100935

The proteasome is just one part of the extensive cellular maintenance apparatus, many systems operating to keep a cell functioning correctly in the face of inappropriate chemical reactions, broken molecules, damaged cellular structures, and the like. Each proteasome is a very complex assembly of proteins that, collectively, are responsible for shredding excess or damaged or otherwise unwanted proteins into component parts that will be recycled into new proteins. Cellular processes identify unwanted proteins and tag them with ubiquitin, and this chemical change allows the proteasome to engage with and break down the tagged protein.

As is the case for other cellular maintenance processes, particularly autophagy, changes in proteasomal activity can influence the pace of aging and length of life in short-lived species. Further, proteasomal activity declines with age, impairing cells. Cellular stress produced via a range of approaches, including the restricted nutrient availability of calorie restriction, causes increased and more efficient proteasomal activity. Cells become less cluttered with unwanted proteins, and are more efficient and functional as a result. Scaled up, this leads to slowed aging. Unfortunately this is nowhere near as effective as a strategy in long-lived species such as our own. While calorie restriction allows mice to live 40% longer, it only adds a few years at most to human life span. Nonetheless, the research community is interested in establishing ways to upregulate proteasomal activity as a potential basis for therapies.

In recent years, researchers have shown that causing cells to produce more of the proteasomal β5 subunit protein has the effect of improving proteasomal function and extending life in nematode worms and flies. In effect, a similar outcome to stress response is being produced without the actual stress response. A paper published earlier this year demonstrated that global overexpression of the β5 subunit can slow aging in flies. Here, a different research group shows that only overexpressing the β5 subunit in neurons also extends life in flies, but their data shows no effect on lifespan for global overexpression. This sort of conflicting data is often an issue with mechanisms producing modest effect sizes.

Neuronal-specific proteasome augmentation via Prosβ5 overexpression extends lifespan and reduces age-related cognitive decline

With age, there is a progressive decline in 26S proteasome function in the nervous system of mammals as well as flies, with a corresponding increase in 20S proteasome levels but not activity, which either declines or is unchanged. These changes likely result from reduced capacity of the existing proteasome, diminished 26S assembly and disassembly of the 26S proteasome into free 20S to compensate for reduced 20S functionality. It has been shown that proteasome depletion and inhibition in mice can mirror brain aging phenotypes, producing neurodegeneration, cognitive deficits, and formation of Lewy-like bodies. The goal of this study is to establish whether age-related cognitive decline can be ameliorated by augmenting proteasome function.

The size and complexity of the proteasome has made manipulating its expression a challenge. Elevating the proteasome β5 subunit increases both expression of other subunits and whole proteasome assembly in mammalian cell cultures and Caenorhabditis elegans. We used the same approach in Drosophila melanogaster, utilizing UAS-Prosβ5 (fly ortholog of the β5 subunit). We used an inducible driver system to limit gene overexpression to adulthood, thereby removing developmental artifacts and allowing experiment and control animals to be genetically identical siblings.

We report that overexpression of the proteasome β5 subunit enhances proteasome assembly and function. Significantly, we go on to show that neuronal-specific proteasome augmentation slows age-related declines in measures of learning, memory, and circadian rhythmicity. Surprisingly, neuronal-specific augmentation of proteasome function also produces a robust increase of lifespan in Drosophila melanogaster. Our findings appear specific to the nervous system; ubiquitous proteasome overexpression increases oxidative stress resistance but does not impact lifespan and is detrimental to some healthspan measures. These findings demonstrate a key role of the proteasome system in brain aging.

The evidence from numerous studies of recent years makes it clear that resistance training produces significant benefits to the health and remaining life expectancy of older adults. To put it another way, most people do too little to maintain strength and their health suffers for it. The effects here seem to partially overlap with and partially be distinct from the benefits of aerobic exercise. But the benefits are broad, as indicated in this open access position paper on the subject.

Age-related loss of muscle mass (originally termed sarcopenia) has an estimated prevalence of 10% in adults older than 60 years (538), rising to greater than 50% in adults older than 80 years. Prevalence rates are lower in community-dwelling older adults than those residing in assisted living and skilled nursing facilities. Loss of muscle mass is generally gradual, beginning after age 30 and accelerating after age 60. Previous longitudinal studies have suggested that muscle mass decreases by 1.0-1.4% per year in the lower limbs, which is more than the rate of loss reported in upper-limb muscles. Sarcopenia is considered part of the causal pathway for strength loss, disability, and morbidity in older adult populations. Yet, muscle weakness is highly associated with both mortality and physical disability, even when adjusting for sarcopenia, indicating that muscle mass loss may be secondary to the effects of strength loss.

The rate of decline in muscle strength with age is two to five times greater than declines in muscle size. As such, thresholds of clinically relevant muscle weakness have been established as a biomarker of age-related disability and early mortality. These thresholds have been shown to be strongly related to incident mobility limitations and mortality. Given these links, grip strength (a robust proxy indicator of overall strength) has been labeled a "biomarker of aging". Losses in strength may translate to functional challenges because decreases in specific force and power are observed. Declines in muscle power have been shown to be more important than muscle strength in the ability to perform daily activities. Moreover, a large body of evidence links muscular weakness to a host of negative age-related health outcomes including type 2 diabetes, disability, cognitive decline, osteoporosis, and early all-cause mortality.

Resistance training is considered an important component of a complete exercise program to complement the widely known positive effects of aerobic training on health and physical capacities. There is strong evidence that resistance training can mitigate the effects of aging on neuromuscular function and functional capacity. Various forms of resistance training have potential to improve muscle strength, mass, and power output. Evidence reveals a dose-response relationship where volume and intensity are strongly associated with adaptations to resistance exercise.

Despite the known benefits of resistance training, only 8.7% of older adults (older than 75 years of age) in the United States participate in muscle-strengthening activities as part of their leisure time. When performed regularly (2-3 days per week), and achieving an adequate intensity and volume (2-3 sets per exercise) through periodization, resistance exercise results in favorable neuromuscular adaptations in both healthy older adults and those with chronic conditions. These adaptations translate to functional improvements of daily living activities, especially when power training exercise is included. In addition, resistance training may improve balance, preserve bone density, independence, and vitality, reduce risk of numerous chronic diseases such as heart disease, arthritis, type 2 diabetes, and osteoporosis, while also improving psychological and cognitive benefits.

Link: https://doi.org/10.1519/JSC.0000000000003230

Researchers have for many years demonstrated that short-lived organisms such as the nematode worms C. elegans live longer when there is some increase in damaging reactive oxygen species released by mitochondria. This is a hormetic mechanism: processes of cell maintenance are triggered into greater activity, and the net result is improved tissue function and increased longevity. Unfortunately we know that these mechanisms do not have the same sizable effect on life span in long-lived species such as our own, even though they appear quite beneficial to short term measures of health.

Establishing the fine details of exactly which stress responses are important, and to what degree, is a work in progress. Metabolism is enormously complex, and there are only so many scientists and so much funding for ongoing investigations. Researchers here identify xenobiotic detoxifying enzymes as an important component of stress responses, and in this context it is interesting to look back at other recent research showing correlation between genetic variants of xenobiotic metabolizing enzymes and human longevity.

Lifespan extension in different species can be achieved by various genetic manipulations and treatments, such as disruption of insulin/IGF1 signalling, decrease in mitochondrial respiration, suppression of translation or caloric restriction. Despite very different origins of these longevity programmes, they all warrant increased resistance to various stresses like heat, oxidative stress or radiation. Although the concept that lifespan might depend on the capacity to withstand external stress cues is very old, little is currently known about signalling pathways underlying these cytoprotective responses and their ability to affect lifespan. Furthermore, how much an individual cytoprotective mechanism contributes to the lifespan extension induced by different manipulations is a key question that remains to be answered.

Transcription profiling of many long-lived mutants from worm to mouse has recently revealed that upregulation of a number of genes involved in xenobiotic detoxification is common to longevity-assurance pathways across different phyla. Xenobiotic detoxification includes activation of drug-metabolizing enzymes (DMEs), which are classified in two main groups: phase I, mainly cytochrome P450 oxidases (CYPs), and phase II, mainly UDP-glucuronosyltransferases (UGTs), glutathione-S-transferases (GSTs), sulfotransferases, and acetyltransferases, coupled to the activity of phase III transporters that mediate the efflux of metabolic end products out of the cells after the completion of phase II.

Interestingly, analyses of expression profiles from long-lived mice, including calorically restricted mice, different dwarf mice, or mice treated with rapamycin, revealed that many CYPs are upregulated and positively correlate with increased longevity. Moreover, increased expression of multiple cyp genes was reported in diverse long-lived C. elegans models, including mitochondrial mutants. Although interesting, these findings provided just a correlative connection to longevity.

Here we identify Krüppel-like factor 1 (KLF-1) as a mediator of a cytoprotective response that dictates longevity induced by reduced mitochondrial function. A redox-regulated KLF-1 activation and transfer to the nucleus coincides with the peak of somatic mitochondrial biogenesis that occurs around a transition from larval stage. We further show that KLF-1 activates genes involved in the xenobiotic detoxification programme and identified cytochrome P450 oxidases, the KLF-1 main effectors, as longevity-assurance factors of mitochondrial mutants. Collectively, these findings underline the importance of the xenobiotic detoxification in the mitohormetic, longevity assurance pathway and identify KLF-1 as a central factor in orchestrating this response.

Link: https://doi.org/10.1038/s41467-019-11275-w

The innate immune cells called macrophages are vitally important to the health and function of tissues. They help to coordinate the intricate dance of stem cells, somatic cells, and immune cells that produces tissue regrowth and tissue maintenance. They destroy errant cells and pathogens. They have a variety of other roles as well. But where do macrophages come from? While some macrophages are generated within tissues, it is generally the case that in damaged or diseased tissues, most macrophages were originally monocytes. Circulating monocytes in the bloodstream enter tissues in response to chemical cues and then transform into macrophages that set to work to try to aid in repair and regeneration. Monocytes themselves are generated by cell populations in the bone marrow that descend from hematopoietic stem cells. At any given time about half of the monocytes in the body reside in the spleen, acting as a reserve that can leap into action when required.

Thus in any given situation of injury or disease in which the presence of macrophages would be beneficial, any process that prevents monocytes from arriving and transforming into macrophages will make things worse. Interestingly, it isn't always the case that more macrophages will improve the situation. Atherosclerosis, for example, is a condition in which fatty lesions that narrow and weaken blood vessels form because the macrophages responsible for repairing the problem become overwhelmed by cholesterol and die, adding their debris to the lesion. Adding more macrophages accelerates the process, which is why animal models of atherosclerosis often use angiotensin II to cause monocytes to leave the spleen and enter the bloodstream, to make lesions form faster.

In today's open access research materials, the authors report on a mechanism operating in heart tissue that impairs the ability of monocytes to become macrophages of a type and behavior suitable for tissue regeneration. Blocking this mechanism improves tissue maintenance, heart structure, and heart function. It is a recent example of many research results published over the past few years that, collectively, demonstrate the great importance of macrophage dynamics to normal tissue function. Macrophages have several phenotypes or polarizations, states distinguished by different markers and behaviors. The ones of interest are M1, inflammatory and aggressive, versus M2, anti-inflammatory and regenerative. A lot of issues in aging are marked by the presence of too many M1 macrophages, and there is considerable interest in the research community regarding the development of means to alter this balance.

Disrupting immune cell behavior may contribute to heart disease and failure

A new study provides evidence that when circulating anti-inflammatory white blood cells known as monocytes fail to properly differentiate into macrophages - the cells that engulf and digest cellular debris, bacteria and viruses - certain forms of heart disease may result. The research shows the presence of a specific protein prevents this monocyte-to-macrophage transition from occurring in the heart. This triggers a cascade of events that can cause heart muscle inflammation, or myocarditis; remodeling of the cardiac muscle structure; enlargement of the heart, or dilated cardiomyopathy; and weakening of the organ's ability to pump blood. Eventually, this can result in heart failure.

In previous live mouse and "test-tube" laboratory studies, researchers determined that IL-17A stimulates spindle-shaped cardiac cells called fibroblasts to release a mediator that causes one type of monocyte, an inflammatory cell known as Ly6Chi to accumulate in greater numbers in the heart than the anti-inflammatory type known as Ly6Clo.

"The good news, also shown by our study, is that blocking a key protein, known as interleukin-17A or IL-17A, permits the differentiation of anti-inflammatory monocytes, promotes healthy cardiac function, and allows the newly created macrophages to protect, rather than attack, cardiac muscle. We knew that cardiac fibroblasts stimulated by IL-17A are potent producers of a protein, granulocyte-macrophage colony-stimulating factor, or GM-CSF, that is a cytokine, a molecule that evokes an immune response and inflammation in tissues. So, thinking that GM-CSF might be the key to why differentiation is disrupted, we added antibodies against GM-CSF to a mix of cardiac fibroblasts, IL-17A, and Ly6Clo and found that we could counter IL-17A's influence on the fibroblasts, and in turn, restore normal Ly6Clo monocyte-to-macrophage differentiation,"

The Cardiac Microenvironment Instructs Divergent Monocyte Fates and Functions in Myocarditis

Two types of monocytes, Ly6Chi and Ly6Clo, infiltrate the heart in murine experimental autoimmune myocarditis (EAM). We discovered a role for cardiac fibroblasts in facilitating monocyte-to-macrophage differentiation of both Ly6Chi and Ly6Clo cells, allowing these macrophages to perform divergent functions in myocarditis progression. During the acute phase of EAM, IL-17A is highly abundant. It signals through cardiac fibroblasts to attenuate efferocytosis of Ly6Chi monocyte-derived macrophages (MDMs) and simultaneously prevents Ly6Clo monocyte-to-macrophage differentiation.

We demonstrated an inverse clinical correlation between heart IL-17A levels and efferocytic receptor expressions in humans with heart failure (HF). In the absence of IL-17A signaling, Ly6Chi MDMs act as robust phagocytes and are less pro-inflammatory, whereas Ly6Clo monocytes resume their differentiation into MHCII+ macrophages. We propose that MHCII+Ly6Clo MDMs are associated with the reduction of cardiac fibrosis and prevention of the myocarditis sequalae.

Regular exercise has many beneficial effects on health because it triggers stress response mechanisms that work to maintain cell quality and function. It is worth noting that it isn't as good at this as the practice of calorie restriction, however. This might be expected from the differing effects of exercise and calorie restriction on life span in short lived species such as laboratory mice. Calorie restriction can improve maximum life span by as much as 40%, while exercise can only improve healthy life span. This isn't a case of do one or the other, of course. Do both.

Age is associated with rising levels of chronic inflammation, and in the brain this correlates with the dysfunction of microglia, supporting immune cells with a range of important roles. They don't just clear up debris, but also participate in many of the functions of neurons and neural connections. Needless to say, when they start to be inflammatory and overactive, this is not good for brain health. It is connected to the progression of all of the most common neurodegenerative conditions. Exercise is well known to reduce inflammation, and the research here adds to the existing mountain of data on this front.

Exercise impacts our body at multiple levels, including the central nervous system (CNS). In responding to exercise-related stress (e.g., hypoxia, heat, free radicals, etc.) and injuries, the body launches multiple endogenous protective and repair systems by altering gene expression and releasing a range of factors that prepare the body for the next challenge. These factors, amongst others, involve trophic effects, anti-oxidation, energy metabolism, and anti-inflammation.

Some of these factors enhance brain function and ameliorate brain disorders by inducing neuroplasticity, increasing metabolic efficiency, and improving anti-oxidative capacity. Others maintain brain homeostasis and protect brain from pathological insults by regulating glial activation and neuroinflammation. Activated microglia and several pro-inflammatory cytokines play active roles in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). It has been well-documented that although acute, high-intensity exercise may cause muscle injury and induce inflammation, long-term exercise at low-to-moderate intensity negatively regulates the inflammatory response.

Considerable evidence also suggests that exercise may inhibit microglial activation by downregulation of the levels of pro-inflammatory factors. However, the mechanism for the exercise-related downregulation of pro-inflammatory factors is less clear, as pro-inflammatory cytokines can be secreted from various sources (e.g., injured neurons, astrocytes, and microglia). Thus, the anti-microglial activation effect of exercise can be interpreted indirectly by upregulating the levels of trophic factors, which then lead to reduced neuronal injury and degrees of microglial activation.

Furthermore, there are a few reports suggesting that physical exercise can shift the composition of the gut microbiome, which then affects both peripheral and central inflammation, including microglial activation in the CNS. Although some mechanisms are still waiting to be determined, it should be emphasized that physical activity represents a natural strong anti-inflammatory strategy to improve brain function.

Link: https://doi.org/10.3390/cells8070691

Does carrying excess body weight, meaning inflammatory visceral fat tissue that distorts metabolism in many ways, actually accelerate the processes of aging, or just make all later life health issues worse and shorten life expectancy via unrelated mechanisms? The evidence leans in the direction of actually accelerating aging. Regardless, by now we should all be used to the headlines announcing that yet another aspect of age-related degeneration proceeds faster in overweight individuals.

Having a bigger waistline and a high body mass index (BMI) in your 60s may be linked with greater signs of brain aging years later, according to a new study that suggests that these factors may accelerate brain aging by at least a decade. "People with bigger waists and higher BMI were more likely to have thinning in the cortex area of the brain, which implies that obesity is associated with reduced gray matter of the brain. These associations were especially strong in those who were younger than 65, which adds weight to the theory that having poor health indicators in mid-life may increase the risk for brain aging and problems with memory and thinking skills in later life."

The study involved 1,289 people with an average age of 64. Participants' BMI and waist circumference were measured at the beginning of the study. An average of six years later, participants had MRI brain scans to measure the thickness of the cortex area of the brain, overall brain volume and other factors. Having a higher BMI was associated with having a thinner cortex, even after researchers adjusted for other factors that could affect the cortex, such as high blood pressure, alcohol use, and smoking. In overweight people, every unit increase in BMI was associated with a 0.098 millimeter thinner cortex and in obese people with a 0.207 mm thinner cortex. Having a thinner cortex has been tied to an increased risk of Alzheimer's disease. Having a bigger waist was also associated with a thinner cortex after adjusting for other factors.

"In normal aging adults, the overall thinning rate of the cortical mantle is between 0.01 and 0.10 mm per decade, and our results would indicate that being overweight or obese may accelerate aging in the brain by at least a decade. These results are exciting because they raise the possibility that by losing weight, people may be able to stave off aging of their brains and potentially the memory and thinking problems that can come along with brain aging. However, with the rising number of people globally who are overweight or obese and the difficulty many experience with losing weight, obviously this is a concern for public health in the future as these people age."

Link: http://med.miami.edu/news/study-shows-extra-weight-in-60s-may-be-linked-to-brain-thinning

One option for patient advocacy for the treatment of aging as a medical condition is to petition governments and large international organizations such as the World Health Organization to adjust their positions on research funding and goals in medicine. This a fairly popular path, for all that I think it not terribly effective at speeding up the cutting edge of research and development. Large organizations of any sort are inherently conservative, and tend to get meaningfully involved in new fields of human endeavor only long after their support would have been truly influential.

Nonetheless, numerous examples of government focused initiatives have emerged from our community over the past decade. They include the Longevity Dividend initiative, petitioning the US government for greater public funding for translational aging research; the small single issue political parties focused on longevity in Germany, Russia, and elsewhere; efforts to influence the contents of the International Classification of Diseases produced by the World Health Organization, in order to classify aging as a disease; and so forth. In recent years, an informal collaboration between advocates, investors, and others in the UK has been making inroads into influencing thinking on aging and longevity in government circles in that country. One of their successes is noted here.

Success, yes, and somewhat more than has been achieved elsewhere. Nonetheless, progress in these efforts in any part of the world tends to be painfully slow and incremental. Persuading bureaucrats to think about making a formal goal of the addition of just a few years to life expectancy over the next few decades is considered a victory. But this is far too little. We live now in an era of biotechnology in which much larger gains in life expectancy are possible and plausible given sufficient investment in research and development. The implementation of rejuvenation therapies, of which senolytic treatments to clear senescent cells are only the first, will up-end all these minor expectations of a few years here and a few years there. That should be the goal.

UK Government Prioritizes Healthy Longevity as a Major National Priority in New Green Paper

This week the UK Government published the green paper of its Preventive Medicine National Strategy, entitled "Advancing our health: prevention in the 2020s - consultation document". In practice, this indicates that the UK will be the first country to officially implement P4 (Personalized, Preventive, Precision and Participatory) medicine into its national healthcare system.

This is the newest development in a series of large steps that the UK government has made in recent years towards the development of a proactive, progressive and technology-driven national Healthy Longevity development strategy, beginning with the formation of the Ageing Industrial Grand Challenge (prioritizing the problem of ageing population as one of four key national industrial development challenges for the nation) in 2017, followed by the launch of the £98 million Government-led Healthy Ageing Industrial Strategy Challenge Fund in 2018, and the launch of the All-Party Parliamentary Group for Longevity in 2019.

These are some of the major factors that led to the UK being ranked first in Aging Analytics Agency's National Longevity Development Plans analytical report, which used quantitative metrics to rank the strength, proactivity and relevance of various nations' Longevity development projects and initiatives.

Advancing our health: prevention in the 2020s - consultation document

Thanks to developments in public health and healthcare, we've made great progress in helping people to live longer lives. For example, life expectancy has increased by almost 30 years over the past century. Cancer survival rates are up and mortality rates from heart disease and stroke are down. However, these improvements in life expectancy are beginning to slow, and over 20% of years lived are expected to be spent in poor health.

Last year, the government set a mission as part of the Ageing Society Grand Challenge to "ensure that people can enjoy at least 5 extra healthy, independent years of life by 2035, while narrowing the gap between the experience of the richest and poorest". The green paper proposals will not deliver the whole '5 years'. But they will help us towards achieving this mission. Further details on this will be provided later in the year, through a government response to the green paper.

Somatic mosiacism is the tendency for aged tissues to display a mix of mutations, spread through cell lineages from an original mutation in a stem cell or progenitor cell. The consensus in the research community is that this degrades tissue function, contributing to the aging process, but there is a lack of evidence for whether or not this is significant across the present human life span. Clearly eventually it has to become a problem, given ways to deal with all of the other aspects of aging, but without a grasp of the size of the effect, it is hard to say whether or not this issue should be targeted now or later.

How does one go about repairing somatic mosiacism in any case? This is a tough question. Repairing diverse mutations in living tissue is possible in the grand scheme of things, given sufficiently advanced molecular nanotechnology, but it is possible with the tools of the next twenty years or so? That would likely mean programmable, highly efficient gene therapies, but in the open access paper here researchers demonstrate that, in the case of at least one gene, there may be other, simpler possibilities.

Normal tissues progressively accumulate cells carrying somatic mutations, some of which are linked to neoplasia and other diseases. This process is exemplified by human esophageal epithelium (EE), in which mutations generated by cell-intrinsic processes colonize the majority of normal epithelium by middle age. The most common mutations are under strong positive selection, meaning that there is an excess of protein altering over silent mutations within each gene. This indicates that these mutations confer a competitive advantage over wild-type cells and drive clonal expansions in normal tissue.

We speculated that, as in other systems of competitive selection, altering the tissue environment may change the relative fitness of particular mutations and their prevalence in the tissue. In this study, we focused on p53 mutations because these are the most enriched during malignant transformation. p53 is mutated in 5%-10% of normal EE but in almost all esophageal squamous cell carcinomas (ESCCs). This argues that ESCC emerges from the p53 mutant cell population in normal epithelium and that mutation of p53 is required for cancer development.

We speculated that altering the selective pressure on mutant cell populations may cause them to expand or contract. We tested this hypothesis by examining the effect of oxidative stress from low-dose ionizing radiation (LDIR) on wild-type and p53 mutant cells in the mouse esophagus. We found that LDIR drives wild-type cells to stop proliferating and differentiate. p53 mutant cells are insensitive to LDIR and outcompete wild-type cells following exposure. Remarkably, combining antioxidant treatment and LDIR reverses this effect, promoting wild-type cell proliferation and p53 mutant differentiation, reducing the p53 mutant population. Thus, p53-mutant cells can be depleted from the normal esophagus by redox manipulation, showing that external interventions may be used to alter the mutational landscape of an aging tissue.

Link: https://doi.org/10.1016/j.stem.2019.06.011

Impaired drainage of cerebrospinal fluid (CSF) with age is a hot topic in the field of neurodegeneration at the moment. In younger individuals, passage of CSF out of the brain via a number of routes is thought to provide a way to maintain normally low levels of metabolic waste, such as the amyloid-β associated with Alzheimer's disease. Reduced fluid flow due to the damage and dysfunction of aging then contributes to the raised levels and aggregation of these waste products, and thus to neurodegenerative conditions. A number of companies are developing therapies based on this vision of brain aging, such as Leucadia Therapeutics. Thus we should expect to see impaired CSF drainage decisively proven or disproven as a major cause of neurodegeneration in clinical trials over the next few years. Even in advance of those trials, the evidence to date is quite compelling, however.

Though the brain drains its waste via the cerebrospinal fluid (CSF), little has been understood about an accurate route for the brain's cleansing mechanism. Scientists have now reported the basal side of the skull as the major route, so called "hotspot" for CSF drainage. They found that basal meningeal lymphatic vessels (mLVs) function as the main plumbing pipes for CSF. They confirmed macromolecules in the CSF mainly runs through the basal mLVs. Notably, the team also revealed that the brain's major drainage system, specifically basal mLVs are impaired with aging.

Throughout our body, excess fluids and waste products are removed from tissues via lymphatic vessels. It was only recently discovered that the brain also has a lymphatic drainage system. mLVs are supposed to carry waste from the brain tissue fluid and the CSF down the deep cervical lymph nodes for disposal. Still scientist are left with one perplexing question - where is the main exit for the CSF? Though mLVs in the upper part of the skull were reported as the brain's clearance pathways in 2014, no substantial drainage mechanism was observed in that section.

The researchers used several techniques to characterize the basal mLVs in detail and verified that specialized morphologic characteristics of basal mLVs indeed facilitate the CSF uptake and drainage. Using CSF contrast-enhanced magnetic resonance imaging in a rat model, they found that CSF is drained preferentially through the basal mLVs. They also utilized a lymphatic-reporter mouse model and discovered that fluorescence-tagged tracer injected into the brain itself or the CSF is cleared mainly through the basal mLVs.

It has long been suggested that CSF turnover and drainage declines with ageing. However, alteration of mLVs associated with ageing is poorly understood. In this study, the researchers observed changes of mLVs in young (3-month-old) and aged (24~27-months-old) mice. They found that the structure of the basal mLVs and their lymphatic valves in aged mice become severely flawed, thus hampering CSF clearance. By mapping out a precise route for the brain's waste clearance system, this study may be able to help find ways to improve the brain's cleansing function, enabling a new strategy for eliminating the buildup of aging-related toxic proteins.

Link: https://www.eurekalert.org/pub_releases/2019-07/ifbs-nim072319.php

Carrying excess visceral fat tissue, the fat packed around organs in the abdomen, accelerates all of the common conditions of aging. This is most likely largely mediated by chronic inflammation, the overactivation of the immune system that fat tissue produces. Numerous mechanisms contribute to this inflammation: fat tissue generates an outsized number of lingering senescent cells that secrete inflammatory signals; dying fat cells produce DNA debris that triggers an immune response; fat cells burdened by a lot of lipids generate similar signals to those released by infected cells; and so forth.

Chronic inflammation is particularly important in the progression of atherosclerosis. Cholesterols in the bloodstream find their way into blood vessel walls, and must be removed by the innate immune cells known as macrophages, which hand off the cholesterol to high-density lipoprotein (HDL) particles for it to be carried back to the liver for excretion. With age, rising levels of inflammation and oxidative stress generate ever more oxidized cholesterols, and these damaged molecules, particularly 7-ketocholesterol, cause macrophages to become dysfunctional. Further, chronic inflammation causes macrophages to act inappropriately, becoming inflammatory themselves rather than usefully engaging in removing cholesterol from blood vessel tissue. The result is fatty lesions, formed of cholesterols and the debris of dead macrophages, overwhelmed trying to help. The more inflammatory signaling there is, the more macrophages are called in to their doom.

In the research results I'll point out today, scientists have found another way in which fat tissue can degrade the ability of macrophages to remove cholesterol from blood vessel walls, operating independently of inflammatory mechanisms. Exosomes, a form of membrane-bound extracellular vesicle packed with signal molecules, are released by fat cells and, when taken up by macrophages, impair the ability of those macrophages to carry out the action of passing a cholesterol molecule to an HDL particle. While the study was carried out in young people, I would expect the mechanism to operate in older individuals as well. There are already countless very good reasons to avoid becoming fat: it is arguably the case that being overweight literally accelerates the aging process. Nonetheless, here is another one.

MicroRNAs from human fat cells can impair macrophage ability to eliminate cholesterol

In atherosclerosis, blood vessels that carry oxygen-rich blood throughout the body become inflamed, and macrophages settle in the vessel wall and become overloaded with cholesterol. A plaque forms that restricts blood flow. But it remains a mystery how fat cells residing in one place in the body can trigger mayhem in cells and tissues located far away. Extracellular vesicles (EVs) seemed likely troublemakers since they enable intercellular communication. "We found that seven specific small sequences of RNA (microRNA) carried within the extracellular vesicles from human fat tissue impaired the ability of white blood cells called macrophages to eliminate cholesterol. Fat isn't just tissue. It can be thought of as a metabolic organ capable of communicating with types of cells that predispose someone to develop atherosclerotic cardiovascular disease, the leading cause of death around the world."

Because heart disease can have its roots in adolescence, the researchers enrolled 93 kids aged 12 to 19 with a range of body mass indices (BMIs), including the "lean" group, 15 youth whose BMI was lower than 22 and the "obese" group, 78 youths whose BMI was in the 99th percentile for their age. Their median age was 17. Seventy-one were young women. The researchers collected visceral adipose tissue during abdominal surgeries. "We were surprised to find that EVs could hobble the macrophage cholesterol outflow system in adolescents of any weight. It's still an open question whether young people who are healthy can tolerate obesity - or whether there are specific differences in fat tissue composition that up kids' risk for heart disease."

Cholesterol efflux alterations in adolescent obesity: role of adipose-derived extracellular vesical microRNAs

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality worldwide. Although primarily a disease of adults, youth with obesity show evidence of subclinical ASCVD which places them at increased risk as adults for coronary heart disease and stroke. The mechanisms by which obesity confers cardiovascular risk are not fully understood, but inflammation within visceral adipose tissue (VAT) is thought to be contributory. Further, the impact of excess adipose tissue on distal sites such as arterial wall monocytes/macrophages, direct participants in ASCVD, are also thought to contribute to disease pathogenesis.

In this study we show, for the first time, significant alterations in cholesterol efflux capacity in adolescents throughout the range of BMI, a relationship between six circulating adipocyte-derived EVs microRNAs targeting ABCA1 and cholesterol efflux capacity, and in vitro alterations of cholesterol efflux in macrophages exposed to visceral adipose tissue adipocyte-derived EVs acquired from human subjects. These results suggest that adipocyte-derived EVs, and their microRNA content, may play a critical role in the early pathological development of ASCVD.

Parkinson's disease, like most other neurodegenerative conditions, is characterized not just by chronic inflammation and cell death, but also by protein aggregation. Solid deposits of α-synuclein form in the brain, bringing with them a halo of toxic biochemistry that harms and kills neurons. It is expected that finding ways to clear these aggregates will prove to be an effective treatment for the condition, though there remain questions about the ordering of cause and effect. Does chronic inflammation or mitochondrial dysfunction lead to protein aggregation, or vice versa? As is usually the case, the easiest way to answer these questions is to clear the aggregates in a good disease model, or in the real thing in human patients, and see what happens.

Scientists have investigated the therapeutic potential of GM1 in Parkinson's disease for nearly 30 years. Previous research showed that Parkinson's patients have less GM1 than healthy patients in the part of the brain most affected by Parkinson's, the substantia nigra. Other researchers followed this work to show in cell culture models that GM1 interacts with a protein called alpha-synuclein. In Parkinson's disease, alpha-synuclein can form clumps, which can become toxic to brain cells in the substantia nigra and lead to cell death.

In new work, researchers have shown that giving daily GM1 doses to animals that overproduce alpha-synuclein inhibits the toxic effects of the protein. "When we looked in the brains of these animals, not only did we find we could partially protect their dopamine neurons from the toxic effects of alpha synuclein accumulation, we had some evidence that these animals had smaller and fewer aggregates of alpha-synuclein than animals that received saline injection instead of GM1." In addition to protecting brain cells from death, the treatment also reversed some early motor symptoms.

The researchers suspect that less GM1 in the brains of Parkinson's disease patients may facilitate the aggregation of alpha-synuclein and increase its toxicity. "By increasing GM1 levels in the brains of these patients, it would make sense that we could potentially provide a slowing of that pathological process and a slowing of the disease progression, which is what we found previously in a clinical trial of GM1 in Parkinson's disease patients." The team is now following up on their results to find out what other effects GM1 might have on alpha-synuclein.

Link: https://www.jefferson.edu/about/news-and-events/2019/7/molecule-reduces-accumulation-of-toxic-protein-in-parkinsons.html

The Life Extension Advocacy Foundation (LEAF) volunteers recently interviewed María Blasco, on the occasion of her presentation at the Ending Age-Related Diseases conference in New York earlier this month. Blasco is one of the leading researchers in the field of telomere biology, particularly the role of telomerase and the prospects for developing telomerase gene therapies to slow aging by lengthening telomeres globally throughout the body. This should have the effect of putting damaged cells back to work, resulting in better tissue maintenance and function, but quite possibly at the cost of increased cancer risk.

Telomerase gene therapy works to achieve this goal in mice, extending life and actually reducing cancer risk, possibly because of improved immune suppression of cancer overwhelming any increased generation of cancerous cells. There is some debate over whether or not the same approach will be safe in humans. Humans and mice have very different telomere dynamics, and the balance of effects may or may not be similar. It seems likely that we'll find out the direct way as human trials and clinical therapies become more widespread over the next decade.

You and your team recently showed that it is the rate of telomere shortening that predicts the lifespan of a species rather than the total length of telomeres. Does this discovery confirm the role of telomere attrition as a primary cause of aging rather than a consequence?

I think this study that means that telomeres are important in determining a species' longevity. It's not something that happens only in humans, where it's already clear that in humans, telomere length matters, because there are humans that have mutations in telomerase, and they are going to have diseases associated with telomere shortening, which means that telomere shortening rates are very limiting for humans. We didn't know whether this was general to other species or only something particular to humans. In this study, we see that telomeres seem to matter across evolution in different species, from birds to mammals. It's not the telomere length that matters but the rate of telomere shortening. So, we see that the rate of telomere shortening actually fits into a power law curve, and this predicts the longevity of a given species.

Could it mean that telomere shortening rate could be a suitable aging biomarker to test interventions against aging with?

I think so; telomere shortening rate is important in humans in order to determine if anyone is at risk of prematurely developing diseases associated with short telomeres. It's not as important to measure telomeres once, because this probably is not going to be very informative, but the rate at which telomeres shorten may be more informative of the risk of developing any disease related to short telomeres.

Telomerase has many effects that are independent of telomeres. Can you see that they matter in aging?

Well, it is interesting because we have, in the past, demonstrated that we can extend the lifespan of mice by using telomerase, but it must be wild-type telomerase; if we use catalytically dead telomerase, then we don't see this lifespan extension. So I would say that in order to see effects of telomerase in lifespan, you need it to be catalytically active telomerase, and this is the canonical pathway of telomerase, which is elongating the telomeres. At least in our hands, this is the mechanism by which telomerase can increase longevity: by extending short telomeres.

Would you say that the telomere mechanisms and the dynamics are really that different between mice and people?

I think humans and mice are not that different. What is very different is the rate at which mice experience shortening telomeres, or in other words, mice are much worse than humans at maintaining their telomeres. So, I think this makes a difference. So mice shorten their telomeres really fast, we still don't understand why compared to humans, but now we also know that different species shorten their telomeres at different rates, and I think it's very interesting to study that. We don't know why. For example, the elephant and the flamingo have the same rate of telomere shortening and they have similar longevity; why is that? Then a mouse has a much faster rate of telomere shortening and a shorter longevity. I think this is a very interesting question to solve in the future.

Link: https://www.leafscience.org/an-interview-with-dr-maria-blasco/

Senescent cells are a mechanism of aging, but also a mechanism of regeneration. When entering a senescent state, a cell shuts down replication and begins to secrete a mix of inflammatory and other signals, rousing the immune system and altering the behavior of surrounding cells. In addition to the other ways in which cells become senescent, in response to the Hayflick limit on cellular replication, or to potentially cancerous DNA damage, senescent cells also arise in response to injury. Their secretions help to guide the complicated dance of immune cells, stem cells, and somatic cells that takes place during the consequent regeneration. Afterwards, the senescent cells self-destruct via apoptosis, or are destroyed by the immune system.

Unfortunately, it is never the case that all senescent cells are destroyed. Those resulting from injury are a tiny fraction of the somatic cells that become senescent on reaching the Hayflick limit, but we can still hypothesize that cellular senescence is important in, say, the way in which joint injuries can become lasting disabilities, or bring on early arthritis. As lingering senescent cells accumulate in tissues, secreted signals that are beneficial in the short term become instead the cause of chronic inflammation and disruption of normal tissue function. Senescent cells are thus a cause of aging, and we will all benefit from therapies capable of removing those that linger in our bodies.

Today's open access paper is an example of the widespread and ongoing deeper investigations of the biochemistry of senescent cells. The present growth of a biotechnology development community focused on producing therapies to destroy senescent cells helps to ensure that ever more funding is provided for fundamental research. In the present environment any novel examination of cellular senescence might turn up mechanisms that can give rise to startup biotechnology companies, which tends to encourage more such research. In this case the focus is on one of the many protein interactions underlying the behavior of senescent cells in muscle regeneration and aging.

Hsp90β interacts with MDM2 to suppress p53-dependent senescence during skeletal muscle regeneration

Skeletal muscle acts as a key regulator of systemic aging in humans. The negative effects of senescence on skeletal muscle were recognized since loss of muscle mass during aging results in frailty and decrease in life qualify. Reduction of quiescent muscle stem cells through senescence leads to the decline in muscle regeneration in aged mice. It is noteworthy that the senescence-associated secretory phenotype (SASP) plays a key role in regulating the beneficial action of senescence during tissue regeneration.

Notably, transient, but not aberrant or prolonged, exposure to the SASP enhances stemness and induces cell plasticity, both of which are beneficial for regeneration. However, a p53-dependent persistent senescence impairs muscle repair, indicating that the accurate temporal regulation of p53-induced senescence is pivotal for ensuring accomplishment of muscle regeneration. Interestingly, a recent report showed that activated Notch-p53 is important for the expansion of muscle stem cell in aged animal. Moreover, p53 also regulates the balance between myoblast differentiation and quiescence. These findings indicate that the roles of p53 in modulating muscle homeostasis are complicated.

Here, we found that Hsp90β, but not Hsp90α isoform, was significantly upregulated during muscle regeneration. RNA-seq analysis disclosed a transcriptional elevation of p21 in Hsp90β-depleted myoblasts, which is due to the upregulation of p53. Moreover, knockdown of Hsp90β in myoblasts resulted in p53-dependent cellular senescence. In contrast to the notion that Hsp90 interacts with and protects mutant p53 in cancer, Hsp90β preferentially bound to wild-type p53 and modulated its degradation via a proteasome-dependent manner. Moreover, Hsp90β interacted with MDM2, the chief E3 ligase of p53, to regulate the stability of p53. In line with these in vitro studies, the expression level of p53-p21 axis was negatively correlated with Hsp90β in aged mice muscle. Consistently, administration of 17-AAG, a Hsp90 inhibitor under clinical trial, impaired muscle regeneration by enhancing injury-induced senescence in vivo. Taken together, our finding revealed a previously unappreciated role of Hsp90β in regulating p53 stability to suppress senescence both in vitro and in vivo.

As numerous senolytic therapies to clear senescent cells continue their progress towards the clinic, the research and development communities find themselves in ever greater need of better biomarkers for cellular senescence. Those that presently exist, such as staining tissue samples for senescence-associated β-galactosidase, are good enough for much of the present scope of research use, but not a suitable basis for either clinical assays or more sophisticated investigation of the mechanisms of senescence. As (a) there are numerous paths by which cells become senescent, prompted by different circumstances, and (b) senescence may vary in other ways between tissue types, and (c) different senolytics have different degrees of effectiveness across these varied classes and cells, it is the case that better and more consistent biomarkers would help to speed progress in this field.

Senescence is a state of indefinite growth arrest. It can be induced by various sublethal stresses, including telomere shortening, genomic injury, epigenomic damage and signaling from oncoproteins. Senescence is also characterized by a senescence-associated secretory phenotype (SASP) whereby cells produce and secrete pro-inflammatory cytokines. Senescence is beneficial for tissue remodeling, embryonic development, wound healing, and tumor suppression in young individuals. However, in old individuals it promotes aging-associated declines and diseases.

Progress to identify senescent cells in order to exploit them therapeutically has been hampered by a lack of robust and universal measurable traits. Thus far, senescence has been studied in a range of cell types induced by diverse triggers such as replicative exhaustion, DNA damage, oxidation and other stress conditions like signaling through oncoproteins. Due to this heterogeneity, finding broad biomarkers of senescence has been challenging and senescent cells are currently found through the combined detection of multiple biochemical markers such as p16, p53, p21 and SA-βGal, despite the fact that they are not exclusively nor consistently induced in senescence.

In this study, we sought to identify universally expressed transcripts across various senescent cell models. We performed RNA sequencing (RNA-seq) analysis after triggering senescence in human WI-38 and IMR-90 fibroblasts, human umbilical vein endothelial cells (HUVECs) and human alveolar endothelial cells (HAECs) through replicative exhaustion (WI-38, IMR-90), exposure to ionizing radiation (WI-38, IMR-90, HUVEC, HAEC) or doxorubicin (WI-38) or expression of an oncogene (oncogene-induced senescence, OIS) (WI-38). Comparisons of all the patterns of expressed transcripts revealed 68 RNAs that were increased (50 RNAs) or decreased (18 RNAs) across all senescence models, although a mimimum of 5 RNAs were sufficient to identify senescent cells bioinformatically. Most RNAs altered during senescence were protein-coding transcripts, but the long non-coding RNA PURPL (p53-upregulated regulator of p53 levels) was one of the most strikingly elevated transcripts.

Link: https://doi.org/10.1093/nar/gkz555

The relationship between normal genetic variations and consequence differences in life expectancy is enormously complex. Countless genetic variations have tiny, contingent, interacting effects on health and late life resilience to the damage of aging. Correlations found in epidemiological studies are rarely replicated between study populations. FOXO3 is one of the very small number of genes for which effects on longevity are found in multiple species and human populations. These effects are not large: a modestly increased chance of living longer. It is also worth noting recent research that downgraded the expected size of effect for FOXO3 based on more rigorous assessment of data. Here, researchers discuss some of the low-level mechanisms that might explain this association.

Health span is driven by a precise interplay between genes and the environment. Cell response to environmental cues is mediated by signaling cascades and genetic variants that affect gene expression by regulating chromatin plasticity. Indeed, they can promote the interaction of promoters with regulatory elements by forming active chromatin hubs.

FOXO3 encodes a transcription factor with a strong impact on aging and age-related phenotypes, as it regulates stress response, therefore affecting lifespan. A significant association has been shown between human longevity and several FOXO3 variants located in intron 2. This haplotype block forms a putative aging chromatin hub in which FOXO3 has a central role, as it modulates the physical connection and activity of neighboring genes involved in age-related processes.

Here we describe the role of FOXO3 and its single-nucleotide polymorphisms (SNPs) in healthy aging, with a focus on the enhancer region encompassing the SNP rs2802292, which upregulates FOXO3 expression and can promote the activity of the aging hub in response to different stress stimuli. FOXO3 protective effect on lifespan may be due to the accessibility of this region to transcription factors promoting its expression. This could in part explain the differences in FOXO3 association with longevity between genders, as its activity in females may be modulated by estrogens through estrogen receptor response elements located in the rs2802292-encompassing region. Altogether, the molecular mechanisms described here may help establish whether the rs2802292 SNP can be taken advantage of in predictive medicine and define the potential of targeting FOXO3 for age-related diseases.

Link: https://doi.org/10.1016/j.csbj.2019.06.011

The mTOR gene is deeply involved in the regulation of cellular activities in response to nutrient sensing. It is also implicated in the many, many changes that occur to slow aging in response to a restricted calorie intake, including processes known to be important to aging such as mitochondrial function and cellular senescence. Given that most research to date on intervention in the aging process has focused on the calorie restriction response and related upregulation of stress response mechanisms, it is no surprise that mTOR has attracted a lot of attention. The first mTOR inhibitor drugs are already going through clinical trials, developed by companies such as resTORbio and Navitor Pharmaceuticals.

It is unfortunate that this strategy for modulating the pace of aging has far larger effects on life span in short-lived species than in long-lived species such as our own: calorie restriction extends life by 40% in mice, but by no more than a few years for us. This is thought to be a consequence of the seasonal nature of famine. A famine lasts a large fraction of a mouse life span, but very little of a human life span, so only the mouse has the evolutionary pressure to develop a large plasticity of life span in response to calorie restriction.

The end result of these factors is that upregulation of stress response mechanisms just doesn't do as much in our species as it does in mice, or in any other short-lived laboratory species. Thus we shouldn't expect therapies targeting mTOR to do much more than can already be achieved via the practice of calorie restriction. That means some degree of improved health, as illustrated in clinical trials for immune function in later life, for example, but no great extension of life span.

mTOR as a central regulator of lifespan and aging

Consistent with its role in coordinating protein synthesis, energy metabolism, and autophagy in cancer, emerging evidence suggests that mTOR may act as a central node that orchestrates many aspects of cellular and organismal biology related to aging phenotypes. Inhibition of the mTOR pathway by rapamycin or genetic means has profound effects on life span and age-associated phenotypes across a wide array of organisms. However, the underlying mechanisms are still unclear as it has been reported that during aging mTOR activity is both increased and decreased, depending on, for example, tissue or sex. It was suggested that, in spite of these variations, overall aging does not result in a generalized increase in mTOR signaling. If this is the case, it is possible that mTOR activity aligns with the antagonistic pleiotropy theory of aging, whereby its levels are beneficial during development but limit the health span in adult life.

Owing to its central role in age-related processes, mTOR represents an appealing target to ameliorate age-related pathologies. Despite its capacity to expand life span, the function of rapamycin (and of rapalogs) as an immunosuppressant might be of concern, as a decline in immune function (immunosenescence) already occurs in the elderly, leading to infection-related morbidity and mortality. Intriguingly, several studies in both mice and humans suggest that mTOR inhibitors could reduce immunosenescence. In mice, rapamycin can restore the self-renewal and hematopoiesis of hematopoietic stem cells and enable effective vaccination against the influenza virus. A randomized trial testing the effects of rapalog RAD001 in a cohort of healthy elderly patients also showed an enhanced response to the influenza vaccination.

Another limitation of rapamycin is that its chronic exposure in mice leads to mTORC2 inhibition in, for example, hepatocytes. Active-site mTOR inhibitors also inhibit mTORC2. Strikingly, selective suppression of mTORC2 reduces life span and is associated with changes in endocrinology and metabolism (for example, insulin resistance), which have a negative impact on health span. Thus, developing specific inhibitors which effectively suppress all mTORC1 outputs, but do not exert a major effect on mTORC2, appears to be warranted as a strategy to target age-related pathologies and improve health span. Interestingly, in a recent trial of healthy elderly patients, the combination of low-dose RAD001 (rapalog) and BEZ235 (dual mTOR/PI3K catalytic inhibitor) was proposed to selectively inhibit mTORC1 and not mTORC2 and led to enhanced immune function and a reduction in infections. However, it is important to note that complete inhibition of mTORC1 can be deleterious.

Biguanides (for example, metformin) are pharmaceuticals which are thought to have a beneficiary effect (in aging) that indirectly impinges on mTOR. Metformin is a first-line anti-diabetic drug which has been used for more than 60 years in the clinic and has very few side effects. It was shown to modulate life span in model organisms, to affect several processes dysregulated in aging (for example, cellular senescence, inflammation, autophagy, and protein synthesis), and to improve cognitive function and neurodegeneration in humans. By inhibiting mitochondrial complex I, metformin causes energetic stress which results in mTORC1 inhibition through AMPK-dependent and independent mechanisms.

Although many studies have uncovered possible targets of metformin action in the cell in the context of aging, the full extent of metformin's mechanism of action at the cellular and organismal levels is still incompletely understood. Nonetheless, clinical trials in which metformin is used to improve health span or aging-related conditions are being proposed. For instance, in the TAME (targeting aging with metformin) clinical trial, a placebo-controlled multi-center study of about 3000 elderly patients who are 65 to 79 years old, the effects of metformin on the development of age-associated outcomes like cardiovascular events, cancer, dementia, and mortality will be monitored.

In at least some portions of the brain, new neurons are created throughout life in a process called neurogenesis. This is vital to memory and learning, but declines with age. Faltering neurogenesis is arguably implicated in the development of some neurodegenerative conditions. As most of the evidence for neurogenesis in adult individuals has been established in mice, and in recent years there has been some debate over whether or not these same processes do in fact operate in humans. So far, the most recent evidence leans towards supporting the existence of human adult neurogenesis. Given this, the research community remains interested in developing means of increasing the pace of neurogenesis as a basis for therapies to enhance cognitive function in the old, but progress towards this goal remains slow.

Adult hippocampal neurogenesis has been proposed to be a key element in ensuring and maintaining functional hippocampal integrity in old age. Neurodegenerative diseases due to the age-dependent rapid and continuous loss of neurons (such as Parkinson's disease and Huntington's disease) have been suggested to reflect the contraposition of the neurogenic process such that under homoeostatic conditions a fine balance between neurodegeneration and neuroregeneration exists, and under pathological conditions, the balance is disturbed and a disease manifests. Even though little evidence has accumulated in support of this theory, if it proves correct, it in combination with findings regarding the high potential of stem-cell-based strategies for the treatment of age-related neurodegenerative disorders, make the hypothesis that adult neurogenesis holds a key to novel therapeutic approaches in the treatment of age-related neurodegenerative disorders rather attractive.

Decreased hippocampal neurogenesis is proposed as an important mechanism underlying age-related cognitive decline as well as neurodegenerative disorders such as Alzheimer's disease (AD) and various types of dementia. Evidence in this regard was recently published in two separate recent studies examining hippocampal neurogenesis in human tissue from people suffering mild cognitive impairment and AD. Both studies demonstrated a dramatic decrease in the number of neural progenitor cells and neuroblasts in hippocampal tissue from AD patients which was related to the stage of the disease. Interestingly, a decrease in the number of newborn neurons was observed in AD patients at the very early stage of the disease when the characteristic neurofibrillary tangles and senile plaques had not become prevalent. This suggests a potential for using neurogenesis levels as an early biomarker of the disease.

The mechanisms underlying the age-related decline in hippocampal neurogenesis remain poorly understood. It has been proposed that within the senescent brain the neurogenic niche may be deprived of the extrinsic signals regulating the neurogenic process or that the aged neural progenitor cells are less responsive to normal signalling within the niche, or both. The evidence accumulated thus far points to changes in the properties of the neurogenic niche with age, rather than changes in the phenotype of the stem cells or progenitor cells themselves. For instance, it has been reported that the numbers of neural stem cells and neural progenitor cells as well as the proportion of astrocytes to neurons in the hippocampus of young and aged rats remained the same; however, there was a decrease in the number of cells actively undergoing mitosis in the aged animals.

Link: https://doi.org/10.1111/acel.13007

The research reviewed here is a great example of the presently dominant paradigm in efforts to treat age-related disease. Scientists analyze the disease state, find regulator proteins that are differently expressed in normal and diseased tissue, and look for ways to force expression in diseased tissue to look more like that of normal tissue. There is no consideration of trying to fix the underlying molecular damage that caused this change. It is a little like pressing the accelerator harder in a car with a failing engine. This strategy is why most efforts to treat age-related disease in the past have either failed or produce only minor benefits. Without fixing the underlying damage, it will continue to cause all of the downstream consequences that lead inexorably to failure of tissue function and death.

Aging is a progressive disruption of the homeostasis of physiological systems with age. It results in structural destruction, organ dysfunction, and increased susceptibility to injuries and diseases. The kidney is one of the most susceptible organs to aging. Aging-associated complications can lead to kidney dysfunction, including a decreased glomerular filtration rate, tubular dysfunction, and glomerulosclerosis. Furthermore, kidney aging has important implications for aging-associated comorbidities, especially cardiovascular diseases.

While the molecular mechanism underlying kidney aging remains unclear, chronic kidney disease (CKD) shares many phenotypic similarities with aging, including cellular senescence, fibrosis, vascular rarefaction, loss of glomeruli, and tubular dysfunction. The pathogenic mechanisms involved in CKD may thus provide insight into the molecular pathways leading to kidney aging. They might also provide potential targets against kidney aging.

Recent efforts to overcome aging have shifted from the identification of risk factors to the determination of endogenous protective factors that might neutralize the adverse effects of aging. Among the various endogenous protective factors reported are AMP-activated protein kinase (AMPK), fibroblast growth factor 21 (FGF21), insulin, and vascular endothelial growth factor (VEGF).

Recent studies have shown that aging-related kidney dysfunction is highly associated with metabolic changes in the kidney. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), a transcriptional coactivator, plays a major role in the regulation of mitochondrial biogenesis, peroxisomal biogenesis, and glucose metabolism and lipid metabolism. PGC-1α is abundant in tissues, including kidney proximal tubular epithelial cells, which demand high energy. Many in vitro and in vivo studies have demonstrated that the activation of PGC-1α by genetic or pharmacological intervention prevents telomere shortening and aging-related changes in the skeletal muscle, heart, and brain. The activation of PGC-1α can also prevent kidney dysfunction in various kidney diseases. Therefore, a better understanding of the effect of PGC-1α activation in various organs on aging and kidney diseases may unveil a potential therapeutic strategy against kidney aging.

Link: https://doi.org/10.1111/acel.12994

Autophagy is a collection of cellular maintenance processes that act to recycle damaged structures in the cell, thereby maintaining cell health and function. On the one hand, the efficiency of autophagy declines with age, and this loss of function is associated with numerous age-related diseases, particularly of the central nervous system and its population of very long-lived neurons. On the other hand, increased autophagy is an important component of many of the interventions shown to slow aging in short-lived species, such as via calorie restriction. A fair number of research groups are working on ways to upregulate autophagy in our species, but this has been going on for a while with little concrete movement towards the clinic.

Autophagy is a complicated process of multiple steps, and at every step there are plausible proximate causes for a faltering of the system with age. The formation of autophagosomes to encapsulate materials to be recycled can break down, as is the case in today's open access paper. The mechanisms by which autophagosomes are transported to a lysosome for deconstruction of their contents are degraded. The lysosome itself becomes filled with metabolic waste that it struggles to break down, making it bloated and inefficient.

In the case of defects relating to autophagosomes it is unclear as to why the breakage happens, how it relates to the underlying molecular damage that causes aging. Given this, approaches to therapy tend to focus on overriding proximate changes. Researchers find regulatory systems that can be adjusted in order to force the relevant mechanism to work despite its normal reaction to systemic damage in and around cells. In principle this should always be worse as a strategy than identifying and repairing the damage, but it can produce benefits in some cases. In the example here, researchers find a way to override the failure to form autophagosomes that is observed in old neurons.

Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons

Unlike most of the cells in our body, our neurons are as old as we are: while other cell types are replaced as they wear out, our neurons must last our entire lifetime. The symptoms of disorders such as Alzheimer's disease and ALS result from neurons in the brain or spinal cord degenerating or dying. But why do neurons sometimes die?

One reason may be that elderly neurons struggle to remove waste products. Cells get rid of worn out or damaged components through a process called autophagy. A membranous structure known as the autophagosome engulfs waste materials, before it fuses with another structure, the lysosome, which contains enzymes that break down and recycle the waste. If any part of this process fails, waste products instead build up inside cells. This prevents the cells from working properly and eventually kills them.

Aging is the major shared risk factor for many diseases in which brain cells slowly die. Could this be because autophagy becomes less effective with age? Researcher isolated neurons from young adult, aging and aged mice, and used live cell microscopy to follow autophagy in real time. The results determined that autophagy does indeed work less efficiently in elderly neurons. The reason is that the formation of the autophagosome stalls halfway through. However, increasing the amount of one specific protein, WIPI2B, rescues this defect and enables the cells to produce normal autophagosomes again.

As long-lived cells, neurons depend on autophagy to stay healthy. Without this trash disposal system, neurons accumulate clumps of damaged proteins and eventually start to break down. The results identify one way of overcoming this aging-related problem. As well as providing insights into neuronal biology, the results suggest a new therapeutic approach to be developed and tested in the future.

Hematopoietic stem cells (HSCs) resident in bone marrow generate immune cells, and their activity is thus vital to the correct function of the immune system. Like all stem cell populations, HSCs are sustained by a niche of supporting cells. One of the interesting questions relating to the aging of stem cells and the decline of stem cell activity in later life is whether this is a problem inherent to the stem cells themselves, or it arises from change and damage in the niche. There is evidence for both to be the case, but it is possible to argue that, until extreme old age, the loss of activity is more a matter of the niche than actual incapacity on the part of stem cells.

One of the ways in which HSC behavior changes with age, and that alters the immune system for the worse, is that ever more myeloid and ever fewer lymphoid daughter cells are created. This myeloid skew is a well studied phenomenon, but as for all complex systems in the body, the causes and their relations to one another are much debated. Here, researchers discuss some specific mechanisms in the HSC niches in the bone marrow that may contribute to this phenomenon.

Hematopoietic aging is characterized by expansion of hematopoietic stem cells (HSCs) with impaired function, such as reduced engraftment, quiescence, self-renewal, unfolded protein response, and lymphoid differentiation potential, leading to myeloid-biased output both in mice and humans. Myeloid malignancies are more frequent in the elderly, but whether changes in the aged HSCs and/or their microenvironment predispose to these malignancies remains unclear.

Megakaryocytes promote quiescence of neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change during pathological or natural aging is unclear. Premature aging in Hutchinson-Gilford progeria syndrome recapitulates physiological aging features, but whether these arise from altered stem or niche cells is unknown. Here, we show that the bone marrow microenvironment promotes myelopoiesis in premature and physiological aging.

During physiological aging, HSC-supporting niches decrease near bone but expand further from bone. Increased bone marrow noradrenergic innervation promotes β2-adrenergic-receptor(AR)-interleukin-6-dependent megakaryopoiesis. Reduced β3-AR-Nos1 activity correlates with decreased endosteal niches and megakaryocyte apposition to sinusoids. However, chronic treatment of progeroid mice with β3-AR agonist decreases premature myeloid and HSC expansion and restores the proximal association of HSCs to megakaryocytes. Therefore, normal or premature aging of BM niches promotes myeloid expansion and can be improved by targeting the microenvironment.

Link: https://doi.org/10.1016/j.stem.2019.06.007

Parkinson's disease, like many neurodegenerative conditions, is associated with the age-related aggregation of a specific protein, in this case α-synuclein. The protein aggregates have a halo of harmful biochemistry, causing dysfunction and cell death in neurons. Researchers here propose that the increased levels of oxidative stress observed in old tissues spur the spread of α-synuclein protein aggregates from cell to cell as the disease progresses. Oxidative stress can arise from mitochondrial dysfunction, as mitochondria produce oxidative molecules as a byproduct of their normal operation, but is also associated with chronic inflammation. Both are also features of aging and thought to be important in the progression of neurodegenerative conditions.

At the microscopic and pathological levels, Parkinson's disease is characterized by accumulation of abnormal intraneuronal inclusions. They are formed as a result of aggregation of a protein called α-synuclein. In the course of the disease, these inclusions progressively appear in various brain regions, contributing to the gradual exacerbation of disease severity. The mechanisms behind this advancing pathology are poorly understood. Research now indicates that oxidative stress, i.e. an excessive and uncontrolled production of reactive oxygen species, could play an important role in the pathological spreading of α-synuclein.

In a series of experiments, researchers studied mice that overproduced α-synuclein in a specific brain region, namely the dorsal medulla oblongata, known to be a primary target of α-synuclein pathology in Parkinson's disease. Under this condition, the researchers were able to show oxidative stress, formation of small α-synuclein aggregates (so called oligomers) and neuronal damage. Increased production of α-synuclein also led to its "jump" from donor neurons in the medulla oblongata into recipient neurons in neighboring brain regions that became affected by progressive α-synuclein accumulation and aggregation.

Interestingly, treatment of mice with paraquat, a chemical agent that generates substantial amounts of reactive oxygen species and thus triggers an oxidative stress, exacerbated α-synuclein pathology and resulted in its more pronounced spreading throughout the brain. "Our findings support the hypothesis that a vicious cycle may be triggered by increased alpha-synuclein burden and oxidative stress. Oxidative stress could promote the formation of alpha-synuclein aggregates which, in turn, may exacerbate oxidative stress. Jumping from neuron to neuron, this toxic process could affect more and more brain regions and contribute to progressive pathology and neuronal demise."

Link: https://www.dzne.de/en/news/public-relations/press-releases/press/detail/parkinsons-a-new-study-associates-oxidative-stress-with-the-spreading-of-aberrant-proteins/

With the continued failure of clinical trials of therapies for Alzheimer's disease, largely immunotherapies, that aim to clear amyloid-β, a growing faction of researchers are rejecting the amyloid hypothesis. In that mainstream view of the condition, the accumulation of amyloid-β causes the early stages of Alzheimer's, but in addition to disrupting the function of neurons, it also causes immune cells in the brain to become inflammatory, dysfunctional, and senescent. This in turn sets the stage for the aggregation of tau protein into neurofibrillary tangles, which causes widespread cell death and the much more severe manifestations of later stage Alzheimer's disease.

Why do only some old people exhibit the condition? In the mainstream view, this is equivalent to asking why only some old people have significantly raised levels of amyloid-β in the brain. This might be due to different rates at which drainage of cerebrospinal fluid becomes impaired with aging, preventing molecular waste from leaving the brain. But many researchers are starting to consider that infectious pathogens are the most important cause, as amyloid-β has now been shown to be an antimicrobial peptide, a part of the innate immune system. The more infection, the more amyloid-β. There is good evidence for persistent infections such as forms of herpesvirus to be associated with Alzheimer's risk.

In today's open access paper, the infection hypothesis is extended further to bypass amyloid-β. The authors suggest that infection leads directly to the stage of chronic inflammation and senescent immune cells in the brain. Amyloid-β accumulation is not necessary for the progression of Alzheimer's in this view of the condition, and may be just a side-effect. As is usually the case in such matters, the best way to find out what is actually going on is to repair or block one mechanism in isolation of all of the others and see what happens. This is quite challenging in the case of Alzheimer's disease, as the animal models are all highly artificial: mice don't naturally suffer Alzheimer's or any similar condition. Thus one can reverse a mechanism or pathology that was introduced into the model, but that doesn't say much about what happens in the human condition, as it has quite different origins and progression.

The Post-amyloid Era in Alzheimer's Disease: Trust Your Gut Feeling

Advanced age is a major Alzheimer's disease (AD) risk factor; therefore, understanding cellular senescence and its impact on endothelial cells (ECs), neurons, glia, and immune cells is an essential prerequisite for elucidating the pathogenesis of this condition. Brain accumulation of extracellular β-amyloid and intracellular hyperphosphorylated tau are the pathological hallmarks of AD. Both neurons and astrocytes synthesize β-amyloid from amyloid precursor protein (APP), while phagocytic microglia prevent its accumulation by removing it via the triggering receptor expressed on myeloid cells-2 (TREM-2).

The amyloid hypothesis postulates that accumulation and deposition of β-amyloid are the primary causes of AD, which promotes tau aggregation into neurofibrillary tangles (NFTs), ultimately triggering neuronal death. Although never universally accepted, the amyloid hypothesis drove AD research for at least two decades. Lately, however, many researchers and clinicians have questioned this model as amyloid removal failed to improve memory in numerous clinical trials. With the same token, neuroimaging studies detected significant β-amyloid deposits in 20-30% of healthy older individuals, while in many AD patients, this marker was not observed.

Moreover, β-amyloid was recently characterized as an antimicrobial peptide (AMP), and its accumulation in AD brains may be a reflection of increased microbial burden. AMPs are defensive biomolecules secreted by the innate immune system, including microglia and astrocytes, in response to a variety of microorganisms and malignant cells. The β-amyloid-AMP connection is further supported by the observation that central nervous system (CNS) infections were diagnosed in some clinical trials, following the administration of anti-amyloid vaccines.

Recent studies have reported co-localization of microorganisms with senescent neurons and glial cells in the brains of both AD patients and healthy older individuals, reviving the infectious hypothesis. CNS infectious agents have been detected previously in AD patients; however, it was difficult to assess if they represented the cause or effect of this condition. A recent study may have settled this issue as it detected gingipain, a Porphyromonas gingivalis antigen, linked to AD, in the brains of healthy older persons, suggesting that they would have developed the disease if they lived longer. As P. gingivalis is a major cause of gum disease and a modifiable AD risk factor, treatment of periodontal infection must be considered a clinical priority.

It has been well-established that inflammation and cellular senescence are closely related, but the role of pathogens in this process has been less emphasized. Astrocytes are the most numerous brain cells. Recent studies report that astrocytes are innate immune cells that, along with microglia, play a key role in the phagocytic removal of molecular waste, dead, or dying cells. Preclinical studies have reported that astrocytes undergo both replicative senescence and stress-induced senescence, however, the difference between senescent and reactive astrocytes is not entirely clear at this time. Recent studies seem to indicate that these phenotypes may be closely related or even identical as upregulated inflammatory and synapse-eliminating genes were found in both senescent and reactive astrocytes.

Dystrophic microglia with growth arrest and senescent markers have been demonstrated in AD patients, but the difference between the reactive and dystrophic phenotype is unclear at this time. Taken together, senescent microglia, incapable of proper immunosurveillance and phagocytosis, contribute to the accumulation of molecular waste, dead or dying cells, inducing inflammaging and immunosenescence. Astrocytes may respond to these microenvironmental changes by converting to a phenotype marked by aberrant elimination of healthy synapses and neurons, a possible pathogenetic mechanism of AD.

Thus, microbiota-induced senescence is a gradually emerging concept promoted by the discovery of pathogens and their products in Alzheimer's disease brains associated with senescent neurons, glia, and endothelial cells. We take the position that gut and other microbes from the body periphery reach the brain by triggering intestinal and blood-brain barrier senescence and disruption. Commensal gut microbes live in symbiosis with the human host as long as they reside in the GI tract where they can be kept under control. Cellular senescence alters the integrity of biological barriers, allowing translocation and dissemination of gut microorganisms throughout the body tissues, including the brain. Operating "behind enemy lines," pathogens can gain control of host immune defenses and metabolism, triggering senescence and neurodegenerative pathology.

Both genders lose muscle mass and strength with age, leading to sarcopenia and frailty. Why do women undergo age-related muscle loss more rapidly following menopause, however? Researchers here suggest that the sex hormone estradiol is necessary to support the activity of muscle stem cells, and thus falling levels of estrogen following menopause is the mechanism driving this outcome. Loss of stem cell function in muscle tissue is also the most credible cause for the onset of sarcopenia without considering gender, so this all fits together quite nicely.

Over the course of an individual's life, skeletal muscle undergoes numerous injurious insults that require repairs in order for function to be maintained. The maintenance and injury repair of skeletal muscle is dependent on its resident stem cell (i.e., the satellite cell). With proliferation, satellite cells undergo asymmetric division through which a subpopulation of the daughter satellite cells do not differentiate, but instead return to quiescence, repopulating the satellite cell pool (i.e., self-renewal). The balance of this asymmetric division process is critical and necessary to ensure the life-long preservation of satellite cells in skeletal muscle.

Aging diminishes the satellite cell pool and, as a result, the regenerative capacity of skeletal muscle in aged males is impaired compared to that of younger males, but such age-induced impairments in females is less studied. Similarly, age-associated changes in the satellite cell environment, in combination with cell-intrinsic alterations, disrupt quiescence and the balance of asymmetric division, ultimately impacting satellite cell maintenance and muscle regenerative potential. Such results support the concept that circulatory factors, including hormones that differ between the young and old systemic environments and the activity of their subsequent signaling pathways, contribute to age-associated decrements in satellite cell maintenance and overall muscle regenerative capacity.

A well-known hormone that changes with age is estradiol, the main circulating sex hormone in adult females. Serum estradiol concentration declines dramatically at the average age of 51 in women, corresponding to the time of menopause. Estradiol deficiency reduces skeletal muscle mass and force generation in women and prevents the recovery of strength following contraction-induced muscle injury and traumatic muscle injury in female mice. However, evidence that this regenerative phenotype involves effects of estradiol directly on satellite cells is lacking.

In this study, we use rigorous and unbiased approaches to demonstrate the in vivo necessity of estradiol to maintain the satellite cell number in females. Further, we use mouse genetics to show that the molecular mechanism of estradiol action is cell-autonomous signaling through estrogen receptor α (ERα). Specifically, we show the functional consequence of estradiol-ERα ablated signaling in satellite cells including impaired self-renewal, engraftment, and muscle regeneration, and the activation of satellite cell mitochondrial caspase-dependent apoptosis. Together, these results demonstrate an important role for estrogen in satellite cell maintenance and muscle regeneration in females.

Link: https://doi.org/10.1016/j.celrep.2019.06.025

Yet another sizable study has shown that common dietary supplements have little to no effect on late life mortality. This finding of course has to compete with the wall to wall marketing deployed by the supplement market. Researchers have been presenting data on the ineffectiveness of near all supplements of years, but it doesn't seem to reduce the enthusiasm for these products. In the past it was fairly easy to dismiss all supplements as nonsense, or at the very least causing only marginal effects that were in no way comparable to the benefits of exercise and calorie restriction, but matters are now becoming more complex. New supplements based on altered mitochondrial biochemistry or senolytic activity, such as nicotinamide riboside, mitoQ, and fisetin, might well have effect sizes that are worth it as an addition to calorie restriction and exercise; we shall see as human studies progress.

In a massive new analysis of findings from 277 clinical trials using 24 different interventions, researchers say they have found that almost all vitamin, mineral, and other nutrient supplements or diets cannot be linked to longer life or protection from heart disease. Although they found that most of the supplements or diets were not associated with any harm, the analysis showed possible health benefits only from a low-salt diet, omega-3 fatty acid supplements and possibly folic acid supplements for some people. Researchers also found that supplements combining calcium and vitamin D may in fact be linked to a slightly increased stroke risk.

Surveys show that 52% of Americans take a least one vitamin or other dietary/nutritional supplement daily. An increasing number of studies have failed to prove health benefits from most of them. "The panacea or magic bullet that people keep searching for in dietary supplements isn't there. People should focus on getting their nutrients from a heart-healthy diet, because the data increasingly show that the majority of healthy adults don't need to take supplements."

The vitamin and other supplements reviewed included: antioxidants, β-carotene, vitamin B-complex, multivitamins, selenium, vitamin A, vitamin B3/niacin, vitamin B6, vitamin C, vitamin E, vitamin D alone, calcium alone, calcium and vitamin D together, folic acid, iron and omega-3 fatty acid (fish oil). The diets reviewed were a Mediterranean diet, a reduced saturated fat (less fats from meat and dairy) diet, modified dietary fat intake (less saturated fat or replacing calories with more unsaturated fats or carbohydrates), a reduced fat diet, a reduced salt diet in healthy people and those with high blood pressure, increased alpha linolenic acid (ALA) diet (nuts, seeds and vegetable oils), and increased omega-6 fatty acid diet (nuts, seeds and vegetable oils). Each intervention was also ranked by the strength of the evidence as high, moderate, low or very low risk impact.

The majority of the supplements including multivitamins, selenium, vitamin A, vitamin B6, vitamin C, vitamin E, vitamin D alone, calcium alone and iron showed no link to increased or decreased risk of death or heart health. "Our analysis carries a simple message that although there may be some evidence that a few interventions have an impact on death and cardiovascular health, the vast majority of multivitamins, minerals and different types of diets had no measurable effect on survival or cardiovascular disease risk reduction."

Link: https://www.hopkinsmedicine.org/news/newsroom/news-releases/save-your-money-vast-majority-of-dietary-supplements-dont-improve-heart-health-or-put-off-death

Accumulation of senescent cells with age is one of the causes of aging. In recent years, the broader scientific community has become convinced of this point, and thus funding is now directed towards many varied investigations of cellular senescence and what to do about it. A young industry has emerged, made up of biotech companies focused on the selective destruction of senescent cells, mostly using small molecule drugs. Since these drugs operate through different mechanisms, tend to be tissue specific, only clear a fraction of senescent cells that varies by tissue, and will thus probably be more effective when combined together, research continues to find ever more senolytic compounds.

Senescent cells are created constantly, either in response to damage or a toxic local environment, or more commonly as the result of a somatic cell reaching the Hayflick limit on cell replication. Senescence is an irreversible state in which cell replication shuts down, and a potent mix of inflammatory signals is secreted. This can be useful in the short term, such as during wound healing, or to put a halt to potentially cancerous cells. Near all senescent cells either self-destruct or are destroyed by the immune system quite quickly. It is the tiny minority to linger that contribute to the aging process, such as by generating an environment of chronic inflammation.

The open access paper here is representative of numerous projects presently underway in the research and development communities, performing screening of small molecules from established databases in search of new senolytics. Some of these searches are more informed by prior investigation of plausible mechanisms than others, but at the end of the day the output is compounds that are then evaluated in detail for their ability to selectively destroy senescent cells. The best of the compounds noted here, fenofibrate, is on a par with navitoclax for selectivity, which is about at the lower level of what might be tolerable as a human therapy. The more off-target cells that are destroyed, the worse the side-effects. This is a starting point, however: other compounds in this category will no doubt be better, or might be engineered to be better.

Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy

Increasing evidence about the molecular mechanisms of ageing suggests that many chronic diseases such as osteoarthritis (OA) are associated with the hallmarks of ageing, including cellular senescence and defective autophagy. Accumulation of senescent cells in tissues contributes to age-related diseases. Articular cartilage of patients with OA shows features of senescence. Senescence-associated secretory phenotype (SASP) factors released from chondrocytes, such as pro-inflammatory cytokines and extracellular matrix degrading enzymes, have been identified as major mediators contributing to the development and progression of OA. Similarly, intra-articular injection of senescent cells in mice results in OA-like pathology.

Cartilage ageing can be modified by selective elimination of senescent chondrocytes to prevent the detrimental microenvironment changes occurring in joint dysfunction. A major step into the translation of senolytic treatments for OA was demonstrated by the beneficial effects of selective clearance of senescence chondrocytes using the Bcl-2 family inhibitor Navitoclax in animal models. The broad impact of senolytic treatment is also highlighted by the efficacy of dasatinib and quercetin combination in several models of age-related disease, which results in an extension of healthspan and lifespan in mice.

Cellular senescence and autophagy are not only essential for homeostasis but are potential therapeutic targets for age-related diseases. We aim to test this therapeutic hypothesis in preclinical models of OA, where senescence and autophagy play a relevant role. A novel cell-based dual imaging screening assay was developed to identify both senotherapeutics, able to either suppress markers of senescence (senomorphics) or to induce apoptosis of senescent cells (senolytics), and autophagy modulators.

Senotherapeutic molecules with pro-autophagic activity were identified. Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and OA chondrocytes whereas PPARα knockdown conferred the opposite effect. Moreover, PPARα expression was reduced through both ageing and OA in mice and also in blood and cartilage from knees of OA patients.

Remarkably, in a retrospective study, fibrate treatment improved OA clinical conditions in human patients from the Osteoarthritis Initiative (OAI) Cohort. Blood from the PROspective Osteoarthritis Cohort of A Coruña (PROCOAC) and human cartilage from non-OA and knee OA patients were employed. Levels of PPARα were lower in OA patients compared to non-OA controls. The potential efficacy of PPARα agonists was also evaluated using the Osteoarthritis Initiative (OAI) Cohort. In this cohort, there were 35 fibrate users and 3322 participants not taking fibrates in the selected sample. Using a genetic matching, 35 fibrate users were matched to 35 participants in the control group. Interestingly, the results indicate that fibrate use by time interaction was associated with a statistically significant improvement of self-reported Western Ontario McMaster Osteoarthritis Index (WOMAC) function and WOMAC total scores. There was also a trend towards a decrease in WOMAC pain score. The results suggest that the fibrate use, when compared with non-use, was associated with a yearly decrease in WOMAC.

Stem cells perform the vital function of supporting surrounding tissue by providing new daughter somatic cells to make up losses and take their place to maintain tissue function. This stem cell activity declines with age, however, due to a combination of intrinsic damage to these cell populations, and increasing inactivity. The latter is an evolved reaction to rising levels of damage, one that serves to reduce cancer risk in earlier old age, but at the cost of a lengthy decline into incapacity. Pick near any dysfunction of aging and it is likely that loss of stem cell activity is to some degree contributing to the outcome.

Successful fracture healing requires the simultaneous regeneration of both the bone and vasculature; mesenchymal stem cells (MSCs) are directed to replace the bone tissue, while endothelial progenitor cells (EPCs) form the new vasculature that supplies blood to the fracture site. In the elderly, the healing process is slowed, partly due to decreased regenerative function of these stem and progenitor cells.

MSCs from older individuals are impaired with regard to cell number, proliferative capacity, ability to migrate, and osteochondrogenic differentiation potential. The proliferation, migration and function of EPCs are also compromised with advanced age. Although the reasons for cellular dysfunction with age are complex and multidimensional, reduced expression of growth factors, accumulation of oxidative damage from reactive oxygen species, and altered signaling of the Sirtuin-1 pathway are contributing factors to aging at the cellular level of both MSCs and EPCs.

Because of these geriatric-specific issues, effective treatment for fracture repair may require new therapeutic techniques to restore cellular function. The causes of cellular aging and the concomitant decline in functionality are wide-ranging, but provide some intriguing indications of potential targets for speeding fracture healing in older individuals. In the future, cell therapies that supplement the inadequate native cellular response with MSCs or endothelial colony forming cells (ECFCs); bone anabolic pharmacological agents, particularly in combination with strategies to localize their delivery to the bone fracture; drugs that reduce oxidative stress, cellular senescence, or activate SIRT1; and/or physical therapeutics may prove effective in promoting fracture healing in the elderly.

Advanced age is the primary risk factor for a fracture, due to the low bone mass and inferior bone quality associated with aging; a better understanding of the dysfunctional behavior of the aging cell will provide a foundation for new treatments to decrease healing time and reduce the development of complications during the extended recovery from fracture healing in the elderly.

Link: https://doi.org/10.4252/wjsc.v11.i6.281

Cellular senescence is a cause of aging. Cells become senescent in response to a variety of circumstances: damage, a toxic environment, reaching the Hayflick limit on replication, and so forth. In all cell populations, older individuals exhibit increasing numbers of senescent cells, perhaps largely due to the progressive decline of the immune system and its growing failure to clear out unwanted or harmful cells. Lingering senescent cells secrete a potent mix of signals that rouse the immune system into a state of chronic inflammation, and degrade tissue function and structure. The more of them there are, the worse the outcome.

Mesenchymal stem cells (MSCs) are located in specific areas of tissues, called "niches", and are characterized as being in a state of relative quietness, from which they can exit under the proper conditions to obtain the proliferative potential necessary for tissue regeneration. MSCs have sustained interest among researchers by contributing to tissue homeostasis and modulating inflammatory response, all activities accomplished primarily by the secretion of cytokines and growth factors, because their paracrine action is the main mechanism explaining their effects, regardless of source.

Senescence is defined as a mechanism for limiting the regenerative potential of stem cells. It is now evident that senescent cells secrete dozens of molecules, for which the terms "senescence-associated secretory phenotype (SASP)" and "senescence-messaging secretome (SMS) factors" have been proposed. The secreted factors contribute to cellular proliferative arrest through autocrine/paracrine pathways as well as in vivo and in vitro. SMS factors released by senescent cells play a key role in cellular senescence and physiological aging by activation of cytoplasmic signalling circuitry.

The population of mesenchymal stem cells, also known as mesenchymal stromal cells, contributes directly to the homeostatic maintenance of organs; hence, their senescence could be very deleterious for human bodily functions. The milestone in MSC investigation will be discovering senescence markers to determine the quality of the in vitro cells for cell-based therapies. Researchers have proposed TRAIL receptor CD264 as the first cellular senescence mesenchymal marker in bone marrow-derived MSCs, because it has the same expression profile of p21 during culture passage.

Link: https://doi.org/10.4252/wjsc.v11.i6.337

I recently attended the second Ending Age-Related Diseases conference in New York, hosted by the Life Extension Advocacy Foundation (LEAF). The mix of attendees was much the same as last year: an even split between scientists, entrepreneurs, investors, patient advocates, and interested onlookers, all focused on the treatment of aging as a medical condition. The presentations were similarly a mix of scientists talking about their research programs, entrepreneurs presenting on the data produced by their companies, and investors discussing the state of the industry.

For my part, I have already presented several times this year on the work taking place at Repair Biotechnologies, while we were raising our seed round. So rather talk again on a familiar topic, I chose instead to discuss the terrible state of clinical translation in the life science industry - the institutional, widespread, ongoing failure to develop promising research programs into therapies. This is particularly the case for the treatment of aging, given that translational research in gerontology was actively suppressed by leading scientists for much of the last 40 years. This was an overreaction to the "anti-aging" industry of fraud, supplements, and false hope established in the 1970s, and probably set us back decades.

Even now there is a great gulf between academia and industry, into which projects vanish. This gulf is built of many factors: scientists rarely have good connections to the people who could carry forward their projects; academic funding tends to stop once projects get close to the point at which they could be translated; universities do far too little to nurture new companies, and instead focus on being toll collectors; most investors sit around waiting for companies to form and come to them, rather than devoting their resources to helping companies form; and so forth. The result is that the research community is littered with credible projects in a dormant state, just waiting for someone to champion their development.

A number of fellow entrepreneurs in the longevity industry presented their latest data at the conference. Doug Ethell of Leucadia Therapeutics noted the proof of principle of his thesis on the roots of Alzheimer's disease, data obtained in ferrets. Partially occluding the cribriform plate in the skull, to mimic the process of ossification that occurs with age in humans, blocks drainage of cerebrospinal fluid, thus allowing amyloid and other molecular waste to build up in the brain and cause neurodegeneration and cognitive decline.

Greg Fahy of Intervene Immune presented quite a lot of data on what six to twelve months of treatment with growth hormone and DHEA does to the thymus and measures of immune system composition in older individuals. It makes for a compelling story, given their evidence for thymic regrowth and improvement in the immune system, for all that I remain dubious about growth hormone as a mode of treatment for aging. There is a lot of evidence to suggest that it isn't such a great plan. But perhaps undergoing a year of such treatment to have a somewhat larger, somewhat more active thymus going forward is a sensible trade-off, should these results hold up in larger patient groups.

John Lewis of Entos Pharmaceuticals gave a great presentation on the lipid nanoparticle (LNP) platform used by Oisin Biotechnologies to destroy senescent cells and by OncoSenX to destroy cancer cells. This platform is one of the candidate technologies to power all of the next generation of gene therapies, ensuring that most implementations can just work, comparatively simply, and with far less effort than is presently required. The presentation included the final study results from the mouse lifespan study run by Oisin Biotechnologies in which LNPs were set to target cells that expressed p16, p53, or both p16 and p53. That last group lived significantly longer, and had their first death at the point at which half of the control group had died.

Kelsey Moody presented on LysoClear, one of the ever growing number of subsidiary companies generated by the Ichor Therapeutics team. The company is developing an approach to treat macular degeneration by using compounds derived from bacterial enzymes to break down molecular waste that builds up in the lysosome, impairing cell function. His emphasis was on the need to be careful, conservative, and methodical in preclinical development, using LysoClear development as an example of always proving each step before moving on, building on well-proven existing work.

From the scientific community, Maria Blasco discussed at length her work on telomeres and telomerase gene therapy in mouse models. Her group sees loss of telomere length in tissues as a significant contributing cause of aging, with wide-ranging downstream effects, rather than a marker of aging that results from loss of stem cell function. Amutha Boominathan presented on her work at the SENS Research Foundation, moving mitochondrial genes into the cell nucleus in order to prevent the consequences of damage to mitochondrial DNA. In principle this can stop inevitable mitochondrial DNA damage from causing aging. Morgan Levine discussed epigenetic clocks based on DNA methylation, and what lies ahead in getting them to be useful to speed up development of rejuvenation therapies. The clocks and the therapies must develop in parallel, and many different clocks will likely be needed. The biggest task ahead is to understand exactly what it is that these epigenetic clocks are measuring.

From the investment community, Joe Betts-Lacroix noted that of the 1000 or so biotech startups out there, maybe 70 or so are credibly involved in working on aging and longevity. This industry is in its very earliest stages. One of the worthies in our community is presently assembling a database of those aging-focused startups, which I hope will be made publicly available fairly soon. There is a lot more that our community needs to do in order to help newly arriving entrepreneurs and investors become knowledgeable and productive quickly, and a database of companies is a good idea in this context.

Both James Peyer of the newly founded Kronos BioVentures and Sree Kant of Life Biosciences discussed how to invest in longevity, given the nature of the industry and its present constraints and peculiarities. James Peyer, as always, brought a very interesting set of ideas to the conference, and Life Biosciences is itself a sensible strategic response to the twin challenges of (a) a lack of entrepreneurs and (b) researchers who really don't want to leave academia. Life Biosciences wraps subsidiary companies around research teams, providing an environment that still feels like academia, and in which much of the trouble of running a company is abstracted away into the larger parent organization.

I have of course omitted mention of a number of other presentations and panels, and no offense is intended to the speakers. The above is really just a list of things that caught my attention, or that I happened to be there for rather than being caught up in meetings. All in all it was a good event, as was the case last year. The LEAF volunteers did a great job, and I encourage you to add this conference series to your 2020 agenda.

This popular science article from the AARP is representative of the sort of outsider's view of the longevity industry that is presently dominant. On the one hand, it is good that the media and advocacy organizations such as AARP are finally talking seriously about treating aging as a medical condition. On the other hand, the author looks at two of the most popular areas of development, mTOR inhibitors and senolytics, in a way that makes them seem more or less equivalent, and then further adds diet and exercise as another equivalent strategy. This will be continuing issue, I fear. People, as a rule, don't think about size of effect and quality of therapy when discussing present initiatives.

These strategies are in fact very different, and the differences are important. Clearance of senescent cells via senolytic treatments is a radically different and better class of therapy than mTOR inhibition. Senolytics remove a cause of aging in one treatment, improving all aspects of health in later life in consequence, while mTOR inhibitors must be taken continually and only encourage the aging metabolism into a state that is somewhat more resistant to the underlying damage that causes aging. Tackling underlying causes will always be more effective than trying to cope with those causes without repairing them.

"We've reached the perfect storm in aging science," says physician Nir Barzilai. "Everything is happening. We have the foundation from decades of animal studies. We're ready to move on to people." The ultimate goal: to put the brakes on aging itself - preventing the pileup of chronic health problems, dementia and frailty that slam most of us late in life. "I want 85 to be the new 65," says Joan Mannick, the chief medical officer and cofounder of resTORbio.

The need is enormous. In a decade, nearly 1 in 5 Americans will be 65 or older. Three out of 4 will have two or more serious health conditions. At least 1 in 4 can expect memory lapses and fuzzy thinking, while 1 in 10 will develop dementia. "Right now doctors play whack-a-mole with chronic diseases in older adults. You treat one, another pops up. The goal instead is to tackle aging itself, the major risk factor for almost every major disease. Our society, our drug companies and medical profession aren't addressing all this suffering that happens as people grow old. But the older people in my life are beloved to me. If we can do something about aging, we shouldn't ignore it."

Older people who took the mTOR inhibitor RAD001, a similar drug to resTORbo's RTB101, had a stronger response to a flu vaccine. Their immune systems looked younger, with fewer exhausted T cells - a depressingly common feature of aging called immunosenescence. "This was the first evidence that if you target a pathway in humans, you may actually impact how we age." The results of a trial of RTB101 were particularly strong for people 85 and older; they had 67 percent fewer infections. That's good news, because - in part due to an age-related weakening of the immune system - respiratory infections are the fourth-leading reason older U.S. adults wind up in the hospital and their eighth-leading cause of death.

Alas, there's more going wrong in older cells than on-the-fritz mTOR. Among these issues: inflammation; out-of-whack metabolism; inactive stem cells that can't repair body tissues; damage from stress, environmental toxins and free radicals; reduced "quality control," which can't eliminate rogue cells. These glitches boost the risk for everything from heart disease and stroke to diabetes, osteoarthritis, Alzheimer's disease, Parkinson's and cancer. If these and other cellular issues are the underlying causes of so many diseases, preventing cells from succumbing to them as they age is a key to preventing disease. That's why resTORbio, other biotech start-ups and university aging labs across the U.S. are launching an unprecedented number of human clinical trials with experimental compounds aimed at these mechanisms.

One big target: senescent cells that refuse to die, instead glomming up in joints and other body tissues. They pump out dozens of inflammatory compounds and other chemicals that contribute to age-related diseases. In a raft of mouse studies, clearing out these senescent cells boosted health - easing arthritis pain, improving kidney and lung function, increasing fitness, extending life and even making fur thicker. In January, the first-ever human study of a treatment to kill senescent cells in the lungs was published. Fourteen people with the fatal lung disease idiopathic pulmonary fibrosis took a mix of the drugs dasatinib and quercetin for three weeks. The verdict: The drug combo was safe, triggered just one serious side effect (pneumonia), and seemed to improve study volunteers' basic ability to stand up and walk. There were also hints it may have reduced senescent-cell activity, but the researchers say bigger, longer studies are needed.

Right now, simply staying healthy into our 80s, 90s and beyond is a lot like hitting the lottery jackpot. In a survey of 55,000 Americans age 65-plus, just 48 percent rated their health as very good or excellent. No wonder drugstores, the internet, and human history are littered with unproven rejuvenation come-ons. Meanwhile, as researchers slowly test these more legitimate drugs, what can we do today if we wish to retain good health longer? That answer has been with us all along. Not smoking, eating healthy, getting exercise, managing stress and sleep.

Link: https://www.aarp.org/health/drugs-supplements/info-2019/pill-drug-aging.html

Researchers here report on the finding that modest impairment of the histones responsible for packaging nuclear DNA into chromatin leads to slowed aging in short-lived laboratory species. This adds to the sizable number of existing forms of stress that can somewhat slow aging via hormetic processes, such as heat, lack of nutrients, and so forth. A little damage induces greater cellular maintenance activities, which on balance leads to more efficient, less damaged cells and tissues over the long term. Unfortunately, effects on life span are very much smaller in long-lived species such as our own, when compared with effects in short-lived species such as flies, worms, and mice.

In the nucleus of cells, DNA wraps itself around histone proteins forming a 'beads-on-a-string' structure called chromatin. Other proteins bind along chromatin and the structure folds further into more complicated configurations. Everything involving DNA would have to deal with this chromatin structure. For example, when a particular gene is expressed, certain enzymes interact with the chromatin structure to negotiate access to the gene and translate it into proteins. When chromatin stress happens, disruption of the chromatin structure can lead to unwanted changes in gene expression, such as expression of genes when they are not supposed to or lack of gene expression when it should occur.

In this study, researchers worked in the lab with the yeast Saccharomyces cerevisiae to investigate how the dosage of histone genes would affect longevity. They expected that yeast genetically engineered to carry fewer copies of certain histone genes than normal or control yeast would have chromatin changes that would result in the yeast living less than controls. "Unexpectedly, we found that yeast with fewer copies of histone genes lived longer than the controls." Yeast with a moderately low dose of histone genes showed a moderate reduction of histone gene expression and significant chromatin stress. Their response to chromatin disruption was changes in the activation of a number of genes that eventually promoted longevity.

"We have identified a previously unrecognized and unexpected form of stress that triggers a response that benefits the organism. The mechanism underlying the chromatin stress response generated by moderate reduction of histone dosage is different from the one triggered by histone overexpression we had previously described, as shown by their different profiles of protein expression responses." The researchers found that chromatin stress also occurs in other organisms such as the laboratory worm C. elegans, the fruit fly, and mouse embryonic stem cells, and in yeast and C. elegans the chromatin stress response promotes longevity. "Our findings suggest that the chromatin stress response may also be present in other organisms. If present in humans, it would offer new possibilities to intervene in the aging process."

Link: https://www.bcm.edu/news/molecular-and-human-genetics/novel-form-of-stress-longevity

Atherosclerosis causes a sizable fraction of all deaths in our species. It is the generation of fatty deposits in blood vessel walls, distorting, narrowing, and weakening the blood vessels. This ultimately leads to the major structural failure of a stroke or heart attack, in which a vital blood vessel ruptures or is blocked. Lipids, such as cholesterols, are carried in the blood stream throughout life, associated with low-density lipoprotein (LDL) particles. The innate immune cells known as macrophages are responsible for removing cholesterol from blood vessel walls via the processes of reverse cholesterol transport: macrophages ingest the cholesterol and pass it on to high-density lipoprotein (HDL) particles, which carry it back to the liver for excretion.

In youth, reverse cholesterol transport keeps blood vessels in good shape. With age, however, an increasing fraction of lipids become oxidized and damaged. This is in part a consequence of mitochondrial dysfunction and increasing chronic inflammation, leading to more oxidizing molecules in the body. Oxidized lipids, even in comparatively small amounts, cause macrophages to become dysfunctional, inflammatory, and sometimes senescent. This degrades the effectiveness of their activities, and leads to macrophage death. The fatty atherosclerotic plaques in blood vessels are in large part the debris of dead macrophages, in addition to lipids and oxidized lipids.

The growth of atherosclerotic plaques is thus a feedback loop, in which macrophages are overwhelmed by oxidized cholesterol, and their struggles attract more macrophages that attempt (and fail) to assist in clearing up the issue. Any signaling or chronic inflammation that induces more macrophages into a pro-inflammatory state rather than a pro-regenerative state will tend to accelerate the progression of atherosclerosis, either by calling in more macrophages, or by making macrophages less effective at reverse cholesterol transport.

That the state of macrophages can influence aging and age-related disease has become a topic of great interest in the research community in recent years, and not just in the context of atherosclerosis. Many age-related conditions have a strong inflammatory component, and it is possible to argue that in all such cases, this inflammation detrimentally affects the activities of macrophages. Researchers divide macrophage populations into the M1, inflammatory and aggressive phenotype and M2, pro-regenerative phenotypes. Both are needed, but with age, the balance shifts too far towards M1, characteristic of the rising chronic inflammation that takes place in later life. A variety of potential therapeutic approaches have been developed in recent years that aim to shift macrophages into the M2 phenotype, to override the signaling that leads them to adopt the M1 phenotype. The example here is one of the more recent ones.

Single systemic transfer of a human gene associated with exceptional longevity halts the progression of atherosclerosis and inflammation in ApoE knockout mice through a CXCR4-mediated mechanism

In recent years, different approaches have been developed to counteract the progression of vascular atherosclerosis, including cholesterol-level lowering and inflammation modulation. Owing to the large numbers of inflammatory molecular and cellular mediators, it is unlikely that blockade of a single cytokine will be therapeutically effective. Long-living individuals (LLIs) delay or escape atherosclerosis-related cardiovascular disease (CVD). We have previously found that LLIs are enriched for a longevity-associated variant (LAV) in BPI fold containing family B, member 4 (BPIFB4).

We report here new exciting results on the pleiotropic activity of LAV-BPIFB4 on different mechanisms of the atherogenic process. These benefits were not associated with changes in the lipid profile. In addition, we provide ex vivo and in vitro evidence that these beneficial actions may extend to human vasculature until to be inversely associated to subclinical index of atherosclerosis in selected patients. Mechanistically, the effects of LAV-BPIFB4 seem to be attributable to a CXCR4-dependent mechanism.

LAV-BPIFB4 gene therapy succeeded in the two primary endpoints, namely improving endothelial dysfunction and reducing adverse vascular effects in ApoE knockout mice fed a high-lipid diet. Interestingly, LAV-BPIFB4 gene therapy did not affect the serum cholesterol profile, but it did contrast the ability of oxidized cholesterol to induce endothelial dysfunction by positively modulating the inflammatory/immune background of atherosclerosis. In line with this, LAV-BPIFB4 redistributed the pool of monocyte subpopulations, redirecting them towards a pro-resolving phenotype.

This was reflected by the increased abundance of CXCR4+Ly6C-high monocytes in bone marrow and spleen, the two major tissue reservoirs of monocytes available to mobilize towards injured tissues. In the margination process, CXCR4 is considered the retention force in the vasculature. Therefore, we speculate that the higher level of CXCR4 in blood Ly6C-high monocytes after LAV-BPIFB4 treatment in mice may finely tune the transit time into the circulation, completing a protective intravascular differentiation process. Consistent with their functionally distinct immunological roles, newly recruited Ly6C-high but not Ly6C-low monocytes uniquely differentiate into pro-resolving M2 macrophages, driving murine atherosclerotic regression at the early stages of the disease. Accordingly, we documented an enrichment of M2 splenic macrophages, which can contribute to dampen T cell activation and proliferation in a CXCR4-dependent manner. This latter result is in keeping with the reported ability of CXCR4 to promote the acquisition of the M2 phenotype in healthy monocyte-derived macrophages.

It is reasonable to hypothesize that the mechanisms of hunger might mediate some fraction of the short-term and long-term benefits to health and life span noted to occur as a result of calorie restriction. Which in turn suggests that strategies for the practice of calorie restriction that suppress hunger might be counterproductive. The hormone ghrelin is involved in the response to hunger, and like most proteins it is involved in a range of processes in metabolism. Evolution tends to result in reuse of protein machinery in many mechanisms. Researchers here report on the connection between ghrelin and memory function, which, like many of the interactions between body and brain, is quite indirect.

Ghrelin is produced in the stomach and secreted in anticipation of eating, and is known for its role to increase hunger. For example, ghrelin levels would be high if you were at a restaurant, looking forward to a delicious dinner that was going to be served shortly. Once it is secreted, ghrelin binds to specialized receptors on the vagus nerve - a nerve that communicates a variety of signals from the gut to the brain. Researchers recently discovered that in addition to influencing the amount of food consumed during a meal, the vagus nerve also influences memory function. The team hypothesized that ghrelin is a key molecule that helps the vagus nerve promote memory.

Using an approach called RNA interference to reduce the amount of ghrelin receptor, the researchers blocked ghrelin signaling in the vagus nerve of laboratory rats. When given a series of memory tasks, animals with reduced vagal ghrelin signaling were impaired in a test of episodic memory, a type of memory that involves remembering what, when, and where something occurred, such as recalling your first day of school. For the rats, this required remembering a specific object in a specific location.

The team also investigated whether vagal ghrelin signaling influences feeding behavior. They found that when the vagus nerve could not receive the ghrelin signal, the animals ate more frequently, yet consumed smaller amounts at each meal. Researchers think that these results may be related to the episodic memory problems. "Deciding to eat or not to eat is influenced by the memory of the previous meal. Ghrelin signaling to the vagus nerve may be a shared molecular link between remembering a past meal and the hunger signals that are generated in anticipation of the next meal."

Link: https://www.eurekalert.org/pub_releases/2019-07/sfts-he070519.php

Stem cells are responsible for maintaining surrounding tissue function via generation of daughter cells to make up losses. Stem cell activity declines with age, and research of the past twenty years suggests that a sizable fraction of this decline is a reaction to rising levels of cell and tissue damage, rather than being due to intrinsic damage to the stem cells themselves. Thus researchers are searching for the signals that influence stem cell activity, with the intent of interfering in order to boost stem cell activity in old tissues. This seems a worse strategy than repairing the underlying damage that causes stem cell decline, but it is nonetheless a popular field of research, and there is plenty of evidence for it to be possible to produce some degree of benefits via this approach.

Researchers have discovered how regenerative capacity of intestinal epithelium declines when we age. Targeting of an enzyme that inhibits stem cell maintaining signaling rejuvenates the regenerative potential of an aged intestine. This finding may open ways to alleviate age-related gastrointestinal problems, reduce side-effects of cancer treatments, and reduce healthcare costs in the ageing society by promoting recovery.

The age-induced reduction in tissue renewal makes dosing of many common drugs challenging. Targeting of an inhibitor called Notum may provide a new way to increase the therapeutic window and to promote recovery in societies with the aging population. Researchers believe that in addition to direct targeting of Notum, lifestyle factors such as diet may also provide means to reduce Notum, and thus improve tissue renewal and repair.

Using organoid culture methods, researchers understood that poor function of tissue repairing stem cells in old intestine was due to aberrant signals from the neighboring cells, known as Paneth cells. "Modern techniques allowed us to examine tissue maintenance at a single cell level, and revealed which cell types contribute to the decline in tissue function. We were surprised to find that even young stem cells lost their capacity to renew tissue when placed next to old neighbors."

Normally intestinal epithelium is renewed by stem cells that rely on activity of Wnt-signaling pathway. Surrounding cells produce molecules that activate this pathway. The study shows that during ageing, Paneth cells begin to express a secreted Wnt-inhibitor called Notum. Notum enzymatically inactivates Wnt-ligands in the stem cell niche, decreasing regenerative potential of intestinal stem cells. However, pharmacologic inhibition of Notum rejuvenated stem cell activity and promoted the recovery of old animals after treatment with a commonly used chemotherapeutic drug with severe side-effects in the gut.

Link: https://www.helsinki.fi/en/news/life-science-news/repair-of-aged-tissue-can-be-enhanced-by-inhibiting-signals-from-neighbouring-cells

Mitochondria are the power plants of the cell, hundreds of bacteria-like organelles that divide like bacteria and are selectively destroyed when damaged by cellular quality control mechanisms. They carry out the energetic chemical reactions needed to package the chemical energy store molecule ATP that is used to power cellular processes. Some of the protein machinery vital to this function is encoded in mitochondrial DNA, a circular genome that resides in mitochondria themselves rather than in the cell nucleus with the majority of a cell's DNA. It is this DNA that is the Achilles' heel of mitochondria, as it is less well protected and repaired than is the case for nuclear DNA. It becomes damaged over time, and this damage leads to dysfunction in mitochondria and the cells that host them, particularly as cellular quality control mechanisms decline in efficiency with advancing age.

This mitochondrial dysfunction that manifests with age is an important component of age-related disease and disruption of normal tissue function. It is better studied in energy hungry tissues such as muscles and the brain, but it is a global phenomenon throughout the body. Evidence strongly implicates loss of mitochondrial function in sarcopenia, the loss of muscle mass and strength that occurs with age, and in all of the common age-related neurodegenerative conditions.

What can be done about this? The SENS approach is to create backups of mitochondrial genes in the cell nucleus, a process known as allotopic expression, with the challenge being that the resultant proteins have to be altered in ways that allow them to be delivered to mitochondria where they are needed. In principle this can eliminate the consequences of damage to mitochondrial DNA. This has been carried out as proof of principle at least for several mitochondrial genes. Other researchers have proposed the use of tools that can selectively destroy mutated mitochondrial DNA. Still others have suggested delivering new mitochondria into cells by exploiting one of a number of mechanisms by which this can happen naturally.

Of these approaches, only allotopic expression has made much progress towards realization, and even that line of work is arguably only at an advanced stage for one mitochondrial gene, via the work at Gensight Biologics. The open access paper here is illustrative of the present state of work on convincing cells to take up new mitochondria: the specific process used only works in cell cultures, and is thus only of potential near term use in rescuing the deteriorated function of cells from an aged patient prior to use in cell therapy. Even that might not be as useful a technique as induced pluripotency, which appears to clear out damaged mitochondria fairly effectively.

There is also the question of whether delivering new mitochondria without clearing out the old, damaged mitochondria will actually help in the long term. Damaged mitochondria can take over cells because their damage grants them either resistance to quality control mechanisms or the ability to replicate more readily than their undamaged peers. In that circumstance, new mitochondria will be quickly outcompeted by the existing damaged population, and whatever benefit is obtained will be short-lived.

Primary allogeneic mitochondrial mix (PAMM) transfer/transplant by MitoCeption to address damage in PBMCs caused by ultraviolet radiation

A substantial number of in vitro and in vivo assays have demonstrated the natural ability of cells to transfer mitochondria amongst each other. This phenomenon is most commonly observed in mitochondrial transfer from healthy mesenchymal stem/stromal cells (MSCs) to damaged cells. The transfer replaces or repairs damaged mitochondria and thereby reduces the percentage of dead cells and restores normal functions. In 1982, researchers introduced a type of artificial mitochondrial transfer or transplant (AMT/T) model using a co-incubation step between the recipient cell and exogenous mitochondria. Their pioneering study demonstrated for the first time that the mitochondrial DNA (mtDNA) of donor cells could be integrated into recipient cells and subsequently transmit hereditary traits and induce functional changes. AMT/T mimics the natural process of mitochondrial transfer, reprograms cellular metabolism, and induces proliferation. The introduction of this model elucidated the possible use of mitochondria as an active therapeutic agent.

Our study tests a modification of the original MitoCeption protocol which reduces the time and complexity of the protocol. We sought to determine if primary allogenic mitochondrial mix (PAMM) MitoCeption could be used to repair peripheral blood mononuclear cells (PBMCs) damaged by ultraviolet radiation (UVR). PAMM is composed of the PBMCs of at least three donors. Our results showed that when PBMCs are exposed to UVR, there is a decrease in metabolic activity, mitochondrial mass, and mtDNA sequence stability as well as an increase in p53 expression and the percentage of dead cells. When PAMM MitoCeption was used on UVR-damaged cells, it successfully transferred mitochondria from different donors to distinct PBMCs populations and repaired the observed UVR damage.

To our knowledge, this study is the first to demonstrate in-vitro that MitoCeption can be used to re-establish mitochondrial function loss caused by UVR exposure. Additionally, we successfully transferred a mix of different PBMC donors to one PAMM that was used to repair damaged cells. Other research groups have successfully transferred mitochondria from one cell donor type to others; however, none of them have mixed mitochondria isolated from different donors for the transfer/transplant. This study elucidates the potential to use mitochondria from different donors (PAMM) to treat UVR stress and possibly other types of damage or metabolic malfunctions in cells, resulting in not only in-vitro but also ex-vivo applications.

Cancer cells depend on lengthening their telomeres, usually via telomerase activity. Telomeres are the caps of repeated DNA sequences at the ends of chromosomes. A little length is lost with each cell division, and when short a cell either self-destructs or becomes senescent and ceases replication. Cancer cells can only replicate continually if telomeres are extended continually. Thus some research groups are looking into sabotage of telomerase or the alternative lengthening of telomeres (ALT) processes as the basis for a truly universal cancer therapy. Others, as here, are investigating ways to interfere in mechanisms that protect telomeres from degradation, hopefully obtaining much the same result in the end.

In the context of tumorigenesis, telomere shortening is associated with apparent antagonistic outcomes: on one side, it favors cancer initiation through mechanisms involving genome instability, while on the other side, it prevents cancer progression, due to the activation of the DNA damage response (DDR) checkpoint behaving as a cell-intrinsic proliferation barrier. Consequently, telomerase, which can compensate for replicative erosion by adding telomeric DNA repeats at the chromosomal DNA extremities, is crucial for cancer progression and is upregulated in nearly 90% of human cancers.

In human cells, telomeric chromatin is organized into a terminal loop (t-loop), nucleosomes, the non-coding RNA TERRA, the protein complex shelterin, and a network of nuclear factors. The shelterin complex is essential for telomere protection and comprises six subunits: Three subunits bind telomeric DNA (TRF1, TRF2, and POT1), while the three others establish protein-protein contacts: RAP1 with TRF2, TIN2 with TRF1, TRF2, and TPP1 with TIN2 and POT1. Each shelterin subunit has a specific role in telomere protection, i.e., TRF1 prevents replication stress, TRF2 blocks ataxia telangiectasia-mutated (ATM) signaling and non-homologous end joining (NHEJ), while POT1 blocks ataxia telangiectasia and Rad3-related (ATR) signaling.

A wealth of recent findings points toward shelterin as a valuable alternative to telomerase to fight cancer. Researchers have identified small molecule compounds targeting TRF1 using an FDA-approved library to screen for TRF1 expression and localization. Several of the drugs downregulating TRF1 expression interfere with common cancer signaling pathways. Treatment of lung cancer and glioblastoma cells with these compounds triggered DDR activation at telomeres and telomere replication defects. In patient-derived glioblastoma stem cells (GSC), these TRF1 inhibitors reduced stemness in vitro.

Link: https://doi.org/10.15252/emmm.201910845

Exercise is known to improve cognitive function, and researchers here delve into one of the mechanisms that may be responsible for this effect. Specifically, this work relates to synaptic plasticity in the brain, the ability of neurons to restructure their connections. This is important for learning and memory function. The work here is not the only project to have picked out specific genes and proteins relating to the regulation of brain function. It remains to be seen whether this can lead to some form of enhancement therapy at the end of the day, as may be the case for klotho and its effects on cognitive function.

The beneficial cognitive effects of physical exercise cross the lifespan as well as disease boundaries. Exercise alters neural activity in local hippocampal circuits, presumably by enhancing learning and memory through short and long-term changes in synaptic plasticity. The dentate gyrus is uniquely important in learning and memory, acting as an input stage for encoding contextual and spatial information from multiple brain regions. This circuit is well suited to its biological function because of its sparse coding design, with only a few dentate granule cells active at any one time. These properties also provide an ideal network to investigate how exercise-induced changes in activity-dependent gene expression affect hippocampal structural and synaptic plasticity in vivo.

While exercise is a potent enhancer of learning and memory, we know little of the underlying mechanisms that likely include alterations in synaptic efficacy in the hippocampus. To address this issue, we exposed mice to a single episode of voluntary exercise, and permanently marked activated mature hippocampal dentate granule cells using conditional Fos-TRAP mice. Exercise-activated neurons (Fos-TRAPed) showed an input-selective increase in dendritic spines and excitatory postsynaptic currents at 3 days post-exercise, indicative of exercise-induced structural plasticity.

Laser-capture microdissection and RNASeq of activated neurons revealed that the most highly induced transcript was Mtss1L, a little-studied I-BAR domain-containing gene, which we hypothesized could be involved in membrane curvature and dendritic spine formation. shRNA-mediated Mtss1L knockdown in vivo prevented the exercise-induced increases in spines and excitatory postsynaptic currents. Our results link short-term effects of exercise to activity-dependent expression of Mtss1L, which we propose as a novel effector of activity-dependent rearrangement of synapses.

Link: https://doi.org/10.7554/eLife.45920

There has been much discussion in the aging research community these past few years on the topic of whether or not there is a limit to human life span, and how one might even go about defining such a thing. While life spans are in a slow upward trend due to general improvements in medical technology, can this trend continue without end, or will it run into a roadblock? In essence this is a debate over what can be extracted from poor data, and which data is in fact poor. Since there are few extremely old people, and since verifying age becomes ever harder the further back one has to go to search for records, the data for human mortality at advanced ages is very open to interpretation and reinterpretation, highly dependent on statistical methodologies used, and opinions on reliability of various sources of data.

In a more practical sense, this is all a storm in a teacup. Obviously there are mechanisms at work that ensure that even the statistical outliers don't make it much past 120. Autopsies carried out on supercentenarians revealed transthyretin amyloidosis, and consequent heart failure, as the dominant cause of death. It is reasonable to hypothesize that this form of age-related damage ensures the effective upper limit on human life span - in the sense that there is no hard limit, but if critical organ dysfunction ensures that mortality rates are 50% yearly or higher, then the odds catch up pretty quickly.

Equally obviously, all of this is absolutely dependent on the present state of medical technology. If transthyretin amyloid can be broken down, such as via the theraputic approach developed by Covalent Bioscience, then the result will be that everyone who periodically undergoes the treatment will live longer. The same goes for clearance of senescent cells, and all the rest of the SENS program of ways to repair the causes of aging. If medical technology addresses the damage of aging, then the length of life changes.

A related topic is the question of whether or not mortality rates stop increasing in very late life. Studies show that extremely old flies stop aging, in the sense that aging is defined as an increase in mortality rate per unit time. The flies have very high mortality rates, as is fitting for being in very poor shape, burdened by the damage of aging, but those very high rates appear to plateau. Over the past fifteen years, various analyses have suggested and then refuted that such a plateau exists in humans. Again we come back to the point that the data for very advanced ages isn't all that great, and so there tends to be a great deal of debate. At present, the balance of evidence and argument suggests that, for our species at least, mortality rates do keep increasing past the age of 110.

Are We Approaching a Biological Limit to Human Longevity?

Until recently human longevity records continued to grow in history, with no indication of approaching a hypothetical longevity limit. Also, earlier studies found that age-specific death rates cease to increase at advanced ages (mortality plateau) suggesting the absence of fixed limit to longevity too. In this study we re-examine both claims with more recent and reliable data on supercentenarians (persons aged 110 years and over).

We found that despite a dramatic historical increase in the number of supercentenarians, further growth of human longevity records in subsequent birth cohorts slowed down significantly and almost stopped for those born after 1879. We also found an exponential acceleration of age-specific death rates for persons older than 113 years in more recent data. Slowing down the historical progress in maximum reported age at death and accelerated growth of age-specific death rates after age 113 years in recent birth cohorts may indicate the need for more conservative estimates for future longevity records unless a scientific breakthrough in delaying aging would happen.

Many gerontologists are now more conservative regarding the future growth of longevity, citing results confirm that further growth of maximum lifespan for humans becomes an increasingly difficult task. Still there are reasons for cautious optimism here. Systematic analysis of human mortality throughout the 20th century revealed that, once a particular cause of death is accounted for, there is a proportional increase in both median age of death and maximum life span. So the authors of this study believe that application of aging-focused interventions could result in a continued increase not only in the median, but in maximal life span in humans as well.

Further research is needed to overcome obvious limitations of our study by addressing remaining concerns about data quality and representativeness, as well as increasing sample sizes. Still the data used in our study are the best available data so far, and their analysis suggests that there may be a provisional limit to human life in our current state of biomedical knowledge.

The blood-brain barrier is a lining of specialized cells wrapping blood vessels, in place to keep the central nervous system isolated from the rest of the body. Unfortunately, and like all aspects of our biology, the blood-brain barrier becomes dysfunctional with age, and this allows cells from other parts of the body to infiltrate the brain. As the research results here demonstrate, this is particularly problematic in the case of immune cells that should not normally be present in the brain. By generating inflammatory signals, these invading cells can disrupt vital activities of neurons or the stem cells responsible for generating new neurons.

Many a spot in a young mammal's brain is bursting with brand new neurons. But for the most part, those neurons have to last a lifetime. Older mammals' brains retain only a couple of neurogenic niches, consisting of several cell types whose mix is critical for supporting neural stem cells that can both differentiate into neurons and generate more of themselves. New neurons spawned in these niches are considered essential to forming new memories and to learning, as well as to odor discrimination.

In order to learn more about the composition of the neurogenic niche, researchers catalogued, one cell at a time, the activation levels of the genes in each of nearly 15,000 cells extracted from the subventricular zone (a neurogenic niche found in mice and human brains) of healthy 3-month-old mice and healthy 28- or 29-month-old mice. When the researchers compared their observations in the brains of young mice (equivalent in human years to young adults) with what they saw in the brains of old mice (equivalent to people in their 80s), they identified a couple of cell types in the older mice not typically expected to be there - and barely present in the young mice. In particular, they found immune cells known as killer T cells lurking in the older mice's subventricular zone.

The healthy brain is by no means devoid of immune cells. In fact, it boasts its own unique version of them, called microglia. But a much greater variety of immune cells abounding in the blood, spleen, gut and elsewhere in the body are ordinarily denied entry to the brain, as the blood vessels pervading the brain have tightly sealed walls. The resulting so-called blood-brain barrier renders a healthy brain safe from the intrusion of potentially harmful immune cells on an inflammatory tear as the result of a systemic illness or injury.

Further experiments demonstrated several aspects of the killer T cells' not-so-mellow interaction with neural stem cells. For one thing, tests in cell cultures and in living animals indicated that killer T cells isolated from old mice's subventricular zone were far more disposed than those from the blood of the same mice to pump out an inflammation-promoting substance that stopped neural stem cells from generating new nerve cells. Second, killer T cells were seen nestled next to neural stem cells in the subventricular zones of old mice and in tissue taken from the corresponding neurogenic niche in autopsied brains of old humans; where this was the case, the neural stem cells were less geared up to proliferate.

Link: http://med.stanford.edu/news/all-news/2019/07/immune-cells-invade-aging-brains-disrupt-nerve-cell-formation.html

Cells are state machines whose behavior is regulated by the pace of production of specific proteins from their genetic blueprints, a process called gene expression. Feedback loops exist between cell activities, the surrounding environment, signals coming and going, and gene expression. Researchers here examine the first part of the gene expression process, in which RNA transcript molecules are generated, and find that there is an association between the size of these molecules and changes in abundance with age. This suggests that some fundamental part of the machinery of transcription is degraded with age, likely producing dysfunction in a range of cellular behavior. The researchers point the finger at SFPQ, though it might be a little early in the investigation of this effect to say anything with confidence about why it happens and what the root causes might be.

The transcriptome responds rapidly, selectively, strongly, and reproducibly to a wide variety of molecular and physiological insults experienced by an organism. While the transcripts of thousands of genes have been reported to change with age, the magnitude by which most transcripts change is small in comparison with classical examples of gene regulation and there is little consensus among different studies. We hence hypothesize that aging is associated with a hitherto uncharacterized process that affects the transcriptome in a systemic manner. We predict that such a process could integrate heterogenous, and molecularly distinctive, environmental insults to promote phenotypic manifestations of aging.

We use an unsupervised machine learning approach to identify the sources of age-dependent changes in the transcriptome. To this end, we measure and survey the transcriptome of 17 mouse organs from 6 biological replicates at 5 different ages from 4 to 24 months raised under standardized conditions. To identify whether there are universal architectural or regulatory features informative on age-dependent changes, we systematically analyze feature importance across models. The most informative feature to those models is the median length of mature transcript molecules, which is closely followed by the number of transcription factors, the length of the gene, and the median length of the coding sequence. We conclude that during aging, transcript length is the most informative feature.

We report a hitherto unknown phenomenon, a systemic age-dependent length-driven transcriptome imbalance that for older organisms disrupts the homeostatic balance between short and long transcript molecules for mice, rats, killifish, and humans. We also demonstrate that in a mouse model of healthy aging, length-driven transcriptome imbalance correlates with changes in expression of splicing factor proline and glutamine rich (Sfpq), which regulates transcriptional elongation according to gene length. Furthermore, we demonstrate that length-driven transcriptome imbalance can be triggered by environmental hazards and pathogens. Our findings reinforce the picture of aging as a systemic homeostasis breakdown and suggest a promising explanation for why diverse insults affect multiple age-dependent phenotypes in a similar manner.

Link: https://doi.org/10.1101/691154

Telomeres are caps of repeated DNA sequences at the ends of chromosomes. They shorten with each cell division, a part of the mechanism that ensures somatic cells can only replicate a limited number of times. Telomerase acts to lengthen telomeres, and in humans telomerase is only active in stem cells. Thus our cells exist in a two-tier system, in which only tiny populations of privileged stem cells are permitted unrestricted replication, while the vast majority of somatic cells are limited. Matters are similar across all higher animals, and this state of affairs likely evolved because it keeps cancer to a low enough level, and pushed off far enough into late life, for allow for evolutionary success.

A lot of ink has been spilled on the topic of telomere length because, statistically across large populations, average telomere length and proportion of short telomeres tends to decrease with advancing age. Given that stem cell activity declines with age, this is most likely a reflection of a lower pace of creation of new somatic cells with long telomeres. The human data is complicated by the fact that telomere length is most commonly measured in immune cells from a blood sample, and is thus a very dynamic measure influenced by the day to day reactions of the immune system. In individuals, there isn't much anyone can do with measures of telomere length, given that it is so variable over time and between people of similar health and age: it is a terrible biomarker for any practical purpose.

Further, can we actually use anything that we learn about telomere dynamics in other species? It is well known that mouse telomere dynamics and telomerase expression are quite different from that of humans. This might make us suspect that positive results from telomerase gene therapies in mice, where life span is extended and health improved, without raising the risk of cancer, may not hold up in humans. There is no particular reason why increased cancer risk through putting damaged cells back to work will be balanced in the same way by improved tissue function and improved immune function, from species to species. The research and development community will find out in the years ahead by trying telomerase gene therapies in primates and then humans.

I feel that the open access paper here adds to doubts about the value that the research community can extract from a study of telomeres and telomerase in other mammalian species, though the researchers don't present it in that way. If various short and long lived mammals can have such a range of telomere dynamics, what are we supposed to make of the data resulting from animal studies of any therapeutic approach to targeting telomeres?

Telomeres and Longevity: A Cause or an Effect?

Since telomere dynamics were found to be better predictors of survival and mortality than chronological age in wild populations, many cross-sectional and longitudinal studies have been conducted on different organisms with variations in maximum life span investigating the relationship between chronologic age and telomere shortening. Yet, some studies have reported a lack of telomere shortening with age or even an increase in telomere length in organisms with exceptional longevity. Therefore, studying telomere dynamics in long-lived organisms is of particular importance since they may have developed mechanisms that actively postpone senescence and promote effective defenses against the deteriorating effects of aging processes.

The naked mole-rat (Hetercephallus glabers/NMR) and the blind mole-rat (Spalax ehrenbergi) are both considered excellent models for studying aging. They both exhibit extraordinary longevity with a maximum lifespan of approximately 30 years in NMRs (10 times longer than any other rodent of the same size) and 20 years in captivity for Spalax. They exhibit lifelong maintenance of superior anti-aging mechanisms leading to unchanged physiological functions and negligible senescence. Moreover, both of these mole-rats live in a presumably relatively stressful environment due to their subterranean lifestyle where they experience darkness, low oxygen and high carbon dioxide concentrations. Despite all these common features, NMRs and Spalax belong to different families; they are different in size and have different social lifestyles.

Whether telomere length is a "biological thermometer" that reflects the biological state at a certain point in life or a biomarker that can influence biological conditions, delay senescence, and promote longevity is still an ongoing debate. In the current study, we aimed to investigate the relationship between telomere length and age in NMRs and Spalax. We tested blood telomeres in NMRs and three different tissues in Spalax and compared each one with a short-lived animal of their size.

While blood telomere length of the naked mole-rat (NMR) did not shorten with age but rather showed a mild elongation, telomere length in three tissues tested in the Spalax declined with age, just like in short-lived rodents. These findings in the NMR suggest an age buffering mechanism, while in Spalax tissues the shortening of the telomeres are in spite of its extreme longevity traits. Therefore, using long-lived species as models for understanding the role of telomeres in longevity is of great importance since they may encompass mechanisms that postpone aging.

Stem cells spend much of their time in the quiescent stage of the cell cycle, resting without replication in a state of lower metabolic activity. The open access review paper here is an interesting look at why quiescence is both helpful and problematic in the context of the contribution of stem cell dysfunction to aging and age-related disease. The purpose of stem cells is to support the surrounding tissue by providing a supply of daughter somatic cells to replace losses and repair damage. Stem cell populations decline in this activity with aging, due to a mix of cellular damage, a fall in numbers, and increasing quiescence. To the degree that the latter of these issues is dominant, it should be possible to find ways to push stem cells back into greater activity. Indeed, many present approaches to regenerative medicine aim at this goal.

The quiescence stage of stem cells has beneficial and adverse effects on stem cell aging. Stem cell quiescence delays stem cell aging by reducing DNA replication, metabolic activity, gene transcription, and mRNA translation, since all of these activities are accompanied by induction of molecular damage. Stem cell quiescence comes at the cost of impaired expression of repair factors in quiescence and increased vulnerability in response to stem cell activation requiring the concerted and faithful activation of multiple molecular circuits controlling biosynthetic processes, repair, and metabolic activity.

Aging-associated increases in stem cell-intrinsic accumulation of molecular damage as well as stem cell-extrinsic alterations (e.g., chronic inflammation, niche cell defects) contribute to the deregulation of quiescence maintenance and increasing vulnerability during exit from quiescence. Epigenetic alterations occur during aging in quiescent and activated stem cells and lead to aberrant expression of developmental genes resulting in alterations of quiescence maintenance, self-renewal, and differentiation.

In conclusion, quiescence protects stem cells against molecular damage but comes at the cost of aging-associated failure in the correct regulation of quiescence maintenance and exit. Activation of quiescent stem cells - an essential process for organ homeostasis/regeneration - requires concerted and faithful regulation of multiple molecular circuits controlling biosynthetic processes, repair mechanisms, and metabolic activity. Thus, while protecting stem cell maintenance, quiescence comes at the cost of vulnerability during the process of stem cell activation.

Link: https://doi.org/10.1016/j.tcb.2019.05.002

A sizable body of evidence points to the ability of resistance training undertaken in later life to reduce the risk of suffering age-related disease, and to improve the prognosis for existing diseases. In a glass half empty sort of a viewpoint, we might take this to mean that next to nobody puts in the effort necessary to maintain the body in an optimal state of health. A surprisingly sizable fraction of the declines in strength and fitness observed in the wealthier parts of the world are actually self-inflicted, not an inevitable consequence of aging. This is particularly apparent in comparisons with hunter-gatherer populations, where exercise and fitness persist into late middle age, and the declines that are inevitable are lessened.

The progressive decline of skeletal muscle mass and strength with aging is collectively referred to as sarcopenia, and is prognostic for mobility disability and chronic disease risk. Regular physical activity (defined here as any bodily movement produced by the contraction of skeletal muscle that increases energy expenditure) and exercise (physical activity that is planned, structured, and repetitive) are cornerstones in the primary prevention of chronic diseases and also for mitigating risk of mobility disability in older persons.

Resistance exercise (RE) and aerobic exercise (AE) are modalities of exercise that are traditionally conceptualized as existing on opposite ends of an exercise continuum in terms of the phenotypes they lead to. A common misconception is that RE training (RET) and AE training (AET) also result in separate health benefits, but we propose this is an artifact of the greater volume of data that currently exists for AET as opposed to RET. Currently, most physical activity guidelines advise, as their primary message, that older adults should perform at least 150 min of moderate-to-vigorous or 75 min of vigorous AET weekly for the reduction of chronic disease risk and maintenance of functional abilities. However, there is an emerging body of evidence to suggest that RET can be as effective as AET in reducing chronic disease risk and is particularly potent for maintaining mobility in older adults.

It may be that RET is more effective than AET in some regards; the converse is likely also true. We posit that the perceived divergent exercise mode-dependent health benefits of AET and RET are likely small in most cases. In this short review, our aim is to examine evidence of associations between the performance of RET and chronic health disease risk (mobility disability, type 2 diabetes, cardiovascular disease, cancer). We also postulate on how RET may be influencing chronic disease risk and how it is a critical component for healthy aging. Accumulating evidence points to RET as a potent and robust preventive strategy against a number of chronic diseases traditionally associated with the performance of AET, but evidence favors RET as a potent countermeasure against declines in mobility. On the basis of this review we propose that the promotion of RET should assume a more prominent position in exercise guidelines particularly for older persons.

Link: https://doi.org/10.3389/fphys.2019.00645

The accumulation of senescent cells with age is one of the root causes of aging. Senescent cells never amount to more than a few percent of all cells, even in late life, but they secrete a mix of extracellular vesicles and various proteins that is inflammatory and disruptive to tissue function. This is known as the senescence-associated secretory phenotype, or SASP. Since senescent cells inflect harm through signaling, it doesn't take many such cells to act as a contributing cause of age-related disease and organ dysfunction.

The research community is nowadays fully invested in the concept that senescent cells are a meaningful cause of aging. This is a comparatively recent development, despite the fact that the evidence was sizable and evident for several decades. It took a great deal of hard work, advocacy, and philanthropy in order to bring about this change; the medical research and development communities had essentially relinquished their responsibilities in the matter of aging. Now, however, there is a great deal of funding for research groups interested in the biochemistry of senescent cells.

While most clinical development is focused on selective destruction of senescent cells as a way to reverse their contribution to the aging process, and this seems the best path forward, there is nonetheless a sizable faction in the research community whose members are more interested in modulating the bad behavior of senescent cells. This largely means interfering the generation or consequences of the SASP in some way. One of the consequences of SASP signaling is that nearby cells are encouraged to become senescent themselves. In today's open access paper, the authors report on their investigation of the mechanisms involved in this behavior.

Small Extracellular Vesicles Are Key Regulators of Non-cell Autonomous Intercellular Communication in Senescence via the Interferon Protein IFITM3

The establishment of cellular senescence is categorized by a stable cell-cycle arrest and the capacity to modify the microenvironment through a particular secretome called SASP (senescence-associated secretory phenotype). The activation of senescence is a response to different cellular stresses to prevent the propagation of damaged cells and has been shown to occur in vitro and in vivo. In fact, an enrichment in the number of senescent cells has been observed in vivo during both biological and pathological processes such as development, cancer, fibrosis, and wound healing.

The SASP controls its surroundings by reinforcing senescence in an autocrine (cell autonomous) and paracrine (non-cell autonomous) manner, by recruiting immune cells to eliminate senescent cells and by inducing a stem cell-like phenotype in damaged cells. The SASP provides the necessary balance to restore tissue homeostasis when it has been compromised. Paradoxically, the SASP can also contribute to the enhancement of tissue damage and the induction of inflammation and cancer proliferation. Overall, the mechanisms behind the pleiotropic activities of the SASP in different contexts are not well understood.

Most studies in vitro and in vivo have attributed the diverse functions of the SASP to individual protein components such as interleukin-6 (IL-6) or IL-8 to reinforce autocrine senescence or transforming growth factor β (TGF-β) as the main mediator of paracrine senescence or to a dynamic SASP with a switch between TGF-β and IL-6 as predominant individual components. However, it is still unclear how these diverse SASP components regulate senescence. In fact, inhibition of the SASP by blocking the mammalian target of rapamycin (mTOR) only partially prevents paracrine senescence, suggesting that alternative mechanisms may exist.

Exosomes are small extracellular vesicles (sEVs) (30-120 nm) of endocytic origin, whereas microvesicles are formed by the shedding of the plasma membrane. Exosomes and microvesicles are secreted by all cell types and found in most bodily fluids. Although some studies have found an increase in the number of EVs released during senescence, very little is known regarding the role that EVs play as SASP mediators in the senescent microenvironment.

Here, we show that both the soluble and sEV fractions of the SASP transmit paracrine senescence. The analysis of individual cells internalizing sEVs using a reporter system shows a positive correlation between the uptake of sEVs and paracrine senescence. sEV protein characterization by mass spectrometry (MS) followed by a functional small interfering RNA (siRNA) screen identify the interferon (IFN)-induced transmembrane protein 3 (IFITM3) within sEVs as partially responsible for transmitting senescence to normal cells. It is interesting that elderly human donors release more sEVs and that the sEVs found in plasma show higher protein levels of IFITM3 in 60% of the elderly donors. Although it may be tempting to speculate that IFITM3 within sEVs could be involved in aging, a larger cohort of young and elderly patients would be needed.

In conclusion, we show here that sEVs are responsible for mediating paracrine senescence and speculate that they could be involved in inducing bystander senescence during therapy-induced senescence or aging. In fact, when compared to soluble factors, sEVs have different biophysical and biochemical properties as they have a longer lifespan than do soluble factors and they are more resistant to protease degradation. The idea that blocking sEV secretion could be a potential therapeutic approach to alleviate senescence "spreading" during chemotherapy-induced senescence or in aging tissues presents itself as a very attractive tool for the future.

Most classes of therapy benefit from some form of targeting or selectivity, helping to direct them to the tissue of interest, and away from other places where they might cause side-effects. Cells are difficult to work with, but they are also much more capable of selective targeting, since they can migrate. Many types of cell reliably find their way from one part of the body to another in the course of their functions, but where no suitable mechanism exists in human biochemistry, it is sometimes possible to look elsewhere. Here, researchers adapt a bacterial targeting system and apply it to the stem cells that might be used in regenerative therapies for damaged heart tissue.

To date, trials using stem cells, which are taken and grown from the patient or donor and injected into the patient's heart to regenerate damaged tissue, have produced promising results. However, while these next generation cell therapies are on the horizon, significant challenges associated with the distribution of the stem cells have remained. High blood flow in the heart combined with various 'tissue sinks', that circulating cells come into contact with, means the majority of the stem cells end up in the lungs and spleen.

"We know that some bacterial cells contain properties that enable them to detect and 'home' to diseased tissue. For example, the oral bacterial found in our mouths can occasionally cause strep throat. If it enters the blood stream it can 'home' to damaged tissue in the heart causing infective endocarditis. Our aim was to replicate the homing ability of bacteria cells and apply it to stem cells." The team developed the technology by looking at how bacterial cells use a protein called an adhesin to 'home' to heart tissue. Using this theory, the researchers were able to produce an artificial cell membrane binding version of the adhesin that could be 'painted' on the outside of the stem cells. In an animal model, the team were able to demonstrate that this new cell modification technique worked by directing stem cells to the heart in a mouse.

"Our findings demonstrate that the cardiac homing properties of infectious bacteria can be transferred to human stem cells. Significantly, we show in a mouse model that the designer adhesin protein spontaneously inserts into the plasma membrane of the stem cells with no cytotoxity, and then directs the modified cells to the heart after transplant. To our knowledge, this is the first time that the targeting properties of infectious bacteria have been transferred to mammalian cells."

Link: https://www.bristol.ac.uk/news/2019/july/stemcells.html

Oisin Biotechnologies uses a form of programmable suicide gene therapy to target senescent cells for destruction. The therapy can be triggered by expression of specific genes inside a cell, and so beyond senescent cells there is a long, long list of possibly harmful cell populations in aging and disease that it would be beneficial to remove. The obvious first choice is cancerous cells with a mutation in one of the common cancer suppressor genes, such that the gene is expressed but not helping. Thus Oisin Biotechnologies spun out OncoSenX last year. The company is moving forward towards trials, and recently raised a seed round to fund the work of the next few years.

OncoSenX, Inc., a late preclinical-stage company developing therapeutics to kill cancer cells based on their genetics, today announced it has raised $3 million in pre-seed funding to advance its pipeline. "These funds will allow us to accelerate the preclinical research necessary for us to begin phase 1 clinical development. We believe our non-viral gene therapy for solid tumors represents the first in a new class of cancer therapeutics. The OncoSenX team is diligently working to bring this new approach into the clinic for the benefit of a global oncology community clearly in need of new options."

OncoSenX is developing a highly selective tumor-killing platform with two main components: a proprietary lipid nanoparticle (LNP) for cellular delivery and a highly selective DNA payload. The LNP is designed to deliver its non-integrating DNA payload to solid tumors, while an engineered promoter drives expression of a potent, inducible death protein only in the target cell population. The goal is to precisely target cell populations based on their genetic activity without harming nearby cells. The platform can be effectively programmed to implement logic gates (IF/OR/AND) to provide selectivity to any target cell based on its genetics.

"Our preclinical studies suggest the OncoSenX approach has the potential to precisely kill cancer cells based on the mutations they harbor. If substantiated in the clinic, the platform could deliver reduced toxicity and improved tolerability over conventional chemotherapy, with the potential for superior targeting over biologics or even CAR-T therapy."

Link: https://www.businesswire.com/news/home/20190708005420/en/OncoSenX-Raises-3-Million-Advance-New-Class

Type 2 diabetes is, for the vast majority of patients, a condition caused by being significantly overweight. Age does has an influence on the risk of being overweight leading to metabolic syndrome and then type 2 diabetes; it is reasonable to say that type 2 diabetes is an age-related condition. In essence, the younger you are, the more fat tissue it requires to push your metabolism over the red line. A few years back, researchers demonstrated that it is specifically fat in the pancreas that causes type 2 diabetes. Of course the only way to put that fat into the pancreas in the normal course of affairs is to become very overweight, creating fat tissue around all of the organs important to metabolism, and negatively influencing their function.

Now, a few years down the line, and as a result of the rapid growth of interest in senescent cells as a cause of aging and age-related disease, we know that (a) excess visceral fat tissue produces chronic inflammation through, among other mechanisms, a more rapid generation of senescent cells, and (b) much of the detrimental effects of type 2 diabetes appear to be mediated by the presence of senescent cells in the pancreas. Treating animals with senolytic drugs reverses many of the effects of the condition. So this all ties together quite nicely as a view of how and why type 2 diabetes occurs. Given that cellular senescence becomes more prevalent in older individuals, that also fits.

While I'm sure that there will be, soon enough, tremendous interest in senolytic therapies from the sizable overweight and diabetic population of the wealthier portions of the world, it remains the case that the most reliable approach to reversing type 2 diabetes, even at the later stages, is to lose the excess weight. Excess visceral fat tissue is required to maintain that harmful fat in the pancreas, and losing weight removes it. Fasting and very low calorie diets also seem quite effective at removing fat from the pancreas, perhaps more rapidly than would occur just by losing the visceral fat tissue via the usual, slow calorie deficit method, based on human trials of this approach.

Promising approach: Prevent diabetes with intermittent fasting

Fatty liver has been thoroughly investigated as a known and frequently occurring disease. However, little is known about excess weight-induced fat accumulation in the pancreas and its effects on the onset of type 2 diabetes. Researchers have now found that overweight mice prone to diabetes have a high accumulation of fat cells in the pancreas. Mice resistant to diabetes due to their genetic make-up despite excess weight had hardly any fat in the pancreas, but instead had fat deposits in the liver.

The team of scientists divided the overweight animals, which were prone to diabetes, into two groups: The first group was allowed to eat ad libitum - as much as they wanted whenever they wanted. The second group underwent an intermittent fasting regimen: one day the rodents received unlimited chow and the next day they were not fed at all. After five weeks, the researchers observed differences in the pancreas of the mice: Fat cells accumulated in group one. The animals in group two, on the other hand, had hardly any fat deposits in the pancreas.

In order to find out how fat cells might impair the function of the pancreas, researchers isolated adipocyte precursor cells from the pancreas of mice for the first time and allowed them to differentiate into mature fat cells. If the mature fat cells were subsequently cultivated together with the Langerhans islets of the pancreas, the beta cells of the islets increasingly secreted insulin. "We suspect that the increased secretion of insulin causes the Langerhans islets of diabetes-prone animals to deplete more quickly and, after some time, to cease functioning completely. In this way, fat accumulation in the pancreas could contribute to the development of type 2 diabetes."

Pancreatic adipocytes mediate hypersecretion of insulin in diabetes-susceptible mice

Ectopic fat accumulation in the pancreas in response to obesity and its implication on the onset of type 2 diabetes remain poorly understood. Intermittent fasting (IF) is known to improve glucose homeostasis and insulin resistance. However, the effects of IF on fat in the pancreas and β-cell function remain largely unknown. Our aim was to evaluate the impact of IF on pancreatic fat accumulation and its effects on islet function.

New Zealand Obese (NZO) mice were fed a high-fat diet ad libitum (NZO-AL) or fasted every other day (intermittent fasting, NZO-IF) and pancreatic fat accumulation, glucose homoeostasis, insulin sensitivity, and islet function were determined and compared to ad libitum-fed B6.V-Lepob/ob (ob/ob) mice. To investigate the crosstalk of pancreatic adipocytes and islets, co-culture experiments were performed.

NZO-IF mice displayed better glucose homeostasis and lower fat accumulation in both the pancreas (-32%) and the liver (-35%) than NZO-AL mice. Ob/ob animals were insulin-resistant and had low fat in the pancreas but high fat in the liver. NZO-AL mice showed increased fat accumulation in both organs and exhibited an impaired islet function. Co-culture experiments demonstrated that pancreatic adipocytes induced a hypersecretion of insulin and released higher levels of free fatty acids than adipocytes of inguinal white adipose tissue.

Kidney degeneration goes hand in hand with cardiovascular disease and neurodegeneration in aging; kidney function is one of the better examples of the way in which deterioration in one organ system causes issues in many others. Nothing in our biology exists in isolation. Researchers here discuss the present state of knowledge regarding vascular calcification in the context of age-related chronic kidney disease. There is a particular focus on the role of chronic inflammation, given the way in which it disrupts all sorts of essential tissue maintenance processes. The accumulation of senescent cells is one of the more important contributions to chronic inflammation, and there is evidence for these cells to be influential in the calcification of blood vessels, and corresponding loss of flexibility.

Low kidney function is linked to poor health outcomes, with clinical manifestations in a wide variety of other organ systems, and is associated to a much higher risk of cardiovascular disease. The risk of cardiovascular disease exponentially increases as kidney function declines, being the major contributor to the high incidence of cardiovascular complications and death in this population. This is partially due to vascular calcification (VC) and accelerated atherosclerosis, as a result of the mineral and bone disorder that often accompanies low kidney function and complicates chronic kidney disease (CKD).

In addition to the complexity of mechanisms involved in VC initiation and progression, it is currently accepted that it cannot be regarded as an isolated pathological process, with several studies providing compelling evidence that VC is highly interconnected with inflammation. In fact, it has been suggested that pathological calcification and chronic inflammation are involved in a positive feedback loop driving disease progression.

Early stages of CKD are already associated with up-regulation of proinflammatory and pro-osteogenic molecules in the vascular wall and calcification of the aortic media. In fact, several lines of evidence indicate that inflammation triggers and precedes osteogenic conversion of vascular smooth muscle cells (VSMCs) and the release of calcifying extracellular vesicles (EVs), promoting the calcification process. It is likely that the effect of inflammation on VC occurs at multiple and interconnected levels. It has been proposed that inflammation might regulate VC, at least in part, through activation of an endoplasmic reticulum stress pathway, which in turn may increase inorganic phosphate uptake, leading to increased VSMCs osteogenic differentiation and increased mineral deposition.

Remarkably, this inflammation/vascular calcification crosstalk described in CKD pathology shares many similarities with the aging process in the general population, including the inflammaging and VSMCs senescence. Inflammaging is a recently adopted term do define a state of low grade chronic inflammatory condition, associated with a significant risk factor for morbidity and mortality in the elderly. Cellular senescence, in general, has been proposed as a potential mechanism of aging and age-related diseases, which can be triggered by a number of mechanisms and leading to an altered secretome, termed the senescence-associated secretory phenotype (SASP). In the particular case of VSMCs, senescence has been shown to enhance vascular calcification and inflammation, with pro-calcific and pro-inflammatory SASPs.

VSMCs senescence and associated SASP have been suggested to contribute to chronic vascular inflammation and calcification, loss of arterial function, and the development of age-related diseases. Thus, it has been suggested that altered vascular health under CKD settings might represent an example of premature aging. In this context, it could be conceivable that new knowledge about molecular mechanisms, such as the crosstalk between VC and inflammation, in CKD, might shed new light on the aging process, and vice versa.

Link: https://doi.org/10.18632/aging.102046

Most neurodegenerative conditions are associated with the build up of damaging protein aggregates that degrade cell function or kill cells in the brain. The amyloid-β and tau of Alzheimer's disease and α-synuclein of Parkinson's disease are well known, but TDP-43 is not as well recognized beyond the that part of the research community focused on it. Here, scientists outline a potential approach to small molecule drugs that might reduce the tendency of TDP-43 to form aggregates. That is a first step on the road to therapies capable of slowing the progression of conditions such as amyotrophic lateral sclerosis (ALS) that are associated with TDP-43 pathology, but it is still a way removed from a full solution to the problem.

Researchers discovered that prolonged cellular stress, such as exposure to toxins, triggers TDP-43 clumping in the cytoplasm of human motor neurons grown in a laboratory dish. Even after the stress is relieved, TDP-43 clumping persists in ALS motor neurons, but not in healthy neurons. The team then screened and identified chemical compounds (potential precursors to therapeutic drugs) that prevent this stress-induced, persistent TDP-43 accumulation. These compounds also increased the survival time of neurons with TDP-43 proteins containing an ALS-associated mutation.

The researchers generated motor neurons from induced pluripotent stem cells (iPSCs) that had been converted from human skin cells. To mimic cellular aspects of ALS, they exposed these laboratory motor neurons to toxins such as puromycin, which stressed the cells and led to TDP-43 clumps. Normally, TDP-43 proteins help process molecules called messenger RNA, which serve as the genetic blueprints for making proteins. But when they clump outside the nucleus, TDP-43 proteins can't perform their normal duty, and that can have a profound effect on many cellular functions.

The researchers tested thousands of chemical compounds for their effects on RNA-protein aggregation. They were surprised to find compounds that not only reduced the overall amount of clumping by up to 75 percent, but also varied clump size and number per cell. Some of the compounds tested were molecules with extended planar aromatic moieties - arms that allow them to insert themselves in nucleic acids, such as DNA and RNA. TDP-43 must bind RNA in order to join ALS-associated clumps. Thus it makes sense that a compound that interacts with RNA would prevent TDP-43 from clumping.

Link: https://ucsdnews.ucsd.edu/pressrelease/protein_clumps_in_als_neurons_provide_potential_target_for_new_therapies

Researchers here report on data showing a correlation between species life span and pace of telomere shortening. Telomeres are the repeated DNA sequences at the ends of chromosomes. A little is lost with each cell division, during replication of DNA, and cells with very short telomeres become senescent or self-destruct. This is how the vast majority of cells in the body are limited in their replicative capacity, in order to lower the risk of damaged cells becoming cancerous to an evolutionarily acceptable level. Not a personally acceptable level, of course.

With age, average telomere length tends to shorten in most species, and this is most likely a reflection of loss of stem cell function. Stem cells maintain long telomeres via use of telomerase, and thus the daughter somatic cells they provide to support surrounding tissue also have long telomeres. Given fewer such daughter cells, average telomere length diminishes, along with tissue function - but that loss of telomere length isn't the cause of loss of tissue function.

Nonetheless, telomerase gene therapy extends life in mice, most likely by inducing damaged cells to greater activity in tissue maintenance. Since the immune system is most likely improved as well, this treatment doesn't lead to a greater incidence of cancer, which would be the usual outcome of making damage cells do more work. This hypothesis on what takes place in telomerase gene therapy is still not a suggestion that telomere shortening is a cause of aging. In this view telomerase gene therapy is conceptually similar to stem cell therapies or signaling therapies that increase native cell activity without repairing the underlying damage that caused the decline. As noted in the publicity materials, this particular research group is generally in favor of the opposite viewpoint, that telomere shortening is an important causative mechanism of aging, rather than a largely downstream reflection of other issues.

Researchers discover that the rate of telomere shortening predicts species lifespan

After analyzing nine species of mammals and birds, researchers found a very clear relationship between the lifespan of these species and the shortening rate of their telomeres, the structures that protect the chromosomes and the genes they contain. The fit is better when using the average lifespan of the species - 79 years in the case of humans - rather than the maximum lifespan -the 122 documented years lived by the Frenchwoman Jeanne Calment.

Until now, however, no relationship had been found between telomere length and lifespan of each species. There are species with very long telomeres that are short-lived and vice versa. The researchers decided not to compare the absolute length of the telomeres, but rather their rate of shortening. It is the first large-scale study that compares this highly variable parameter between species: human telomeres lose on average about 70 base pairs - the building blocks of the genetic material - per year, whereas those of mice lose about 7,000 base pairs per year.

"This study confirms that telomeres play an important role in aging. There are people who are not convinced, and they say that for example mice live two years and have very long telomeres, while humans live much longer and have short telomeres; but we have shown that the important thing is not the initial length but the rate of shortening and this parameter predicts the longevity of a species with a high degree of precision."

Telomere shortening rate predicts species life span

Telomere shortening to a critical length can trigger aging and shorter life spans in mice and humans by a mechanism that involves induction of a persistent DNA damage response at chromosome ends and loss of cellular viability. However, whether telomere length is a universal determinant of species longevity is not known. To determine whether telomere shortening can be a single parameter to predict species longevities, here we measured in parallel the telomere length of a wide variety of species (birds and mammals) with very different life spans and body sizes, including mouse (Mus musculus), goat (Capra hircus), Audouin's gull (Larus audouinii), reindeer (Rangifer tarandus), griffon vulture (Gyps fulvus), bottlenose dolphin (Tursiops truncatus), American flamingo (Phoenicopterus ruber), and Sumatran elephant (Elephas maximus sumatranus).

We found that the telomere shortening rate, but not the initial telomere length alone, is a powerful predictor of species life span. These results support the notion that critical telomere shortening and the consequent onset of telomeric DNA damage and cellular senescence are a general determinant of species life span.

It is well recognized that physical activity and strength training correlate with improved life expectancy in later life. In animal studies, it can be shown that exercise causes increased healthy life spans. The study here reinforces that mountain of data. It is also interesting for adding to the evidence to show that the greatest benefits for increased activity occur in people who were sedentary. The dose response curve for exercise provides the greatest benefits when moving between no exercise and a sensible level of regular moderate exercise. Above that, there are still further benefits to be obtained, but gains in life expectancy taper off. To turn that around, being sedentary is very harmful to health over the long term. Try not to be sedentary.

Physical activity is associated with lower risks of all cause mortality, cardiovascular disease, and certain cancers. However, much of the epidemiology arises from observational studies assessing physical activity at a single point in time, and associations with subsequent mortality and chronic disease outcomes. As physical activity behaviours are complex and vary over the life course, assessing within-person trajectories of physical activity over time would better characterise the association between physical activity and mortality.

Participants in this study were 14,599 men and women (aged 40 to 79) from the European Prospective Investigation into Cancer and Nutrition. Physical activity energy expenditure (PAEE) was derived from questionnaires, and calibrated against combined movement and heart rate monitoring. Long term increases in PAEE were inversely associated with mortality, independent of baseline PAEE. For each 1 kJ/kg/day per year increase in PAEE (equivalent to a trajectory of being inactive at baseline and gradually, over five years, meeting the World Health Organization minimum physical activity guidelines of 150 minutes/week of moderate-intensity physical activity), hazard ratios were: 0.76 for all cause mortality, 0.71 for cardiovascular disease mortality, and 0.89 for cancer mortality, adjusted for baseline PAEE, and established risk factors.

In conclusion, we showed that middle aged and older adults, including those with cardiovascular disease and cancer, stand to gain substantial longevity benefits by becoming more physically active, irrespective of past physical activity levels and established risk factors - including overall diet quality, body mass index, blood pressure, triglycerides, and cholesterol. Maintaining or increasing physical activity levels from a baseline equivalent to meeting the minimum public health recommendations has the greatest population health impact, with these trajectories being responsible for preventing nearly one in two deaths associated with physical inactivity. In addition to shifting the population towards meeting the minimum physical activity recommendations, public health efforts should also focus on the maintenance of physical activity levels, specifically preventing declines over mid to late life.

Link: https://doi.org/10.1136/bmj.l2323

The heat shock response is one of a number of cellular maintenance processes that works to keep cells functional under circumstances of stress. As the name implies, heat is one of those stresses in this case, but the heat shock response is also triggered by other stresses as well. Further, the heat shock response has a role in resolving inflammation. Researchers here note that the heat shock response is suppressed in atherosclerosis, possibly as a result of the chronic inflammation induced by the presence of senescent cells, possibly due to other mechanisms, and that this might be an important factor in the progression of the condition. The study shows that upregulating the heat shock response via heat treatment produces benefits in atherosclerotic mice, and the authors suggest this might function via reductions in cholesterol levels and reductions in inflammation.

While acute inflammatory responses evolved to protect organisms against pathogens and to provide tissue repair under sterile injuries, they are rapidly resolved by several physiological feedback systems aimed at avoiding the perpetuation of inflammation. In this sense, the heat shock (HS) response, i.e., the anti-inflammatory program mainly centered in heat shock factor-1 (HSF1)-dependent expression of heat shock proteins (HSPs) and other anti-aggregative protein chaperones, powerfully resolves acute inflammation by shutting off nuclear factor κB (NF-κB) and other downstream pro-inflammatory signals.

Nevertheless, if injuring stimuli become chronic, HSF1 expression is severely blunted and cells stop producing cardioprotective HSPs (e.g., HSP27, HSP72), which are anti-inflammatory. This is the case of many (if not all) chronic degenerative diseases of inflammatory nature. In contrast, inducers of the HS response clearly reverse vascular lesions in atherosclerotic models. However, the development of atherosclerotic lesions is also associated with the blockade of the expression and activity of sirtuin-1 (SIRT1), which, in turn, underlies both HSF1 expression and transcribing activity. Therefore, in an atherosclerotic milieu, the physiological resolution of inflammation is critically jeopardized thus contributing to foam cell formation and vascular senescence observed in atherosclerosis.

These observations led us to hypothesize that disruption of the anti-inflammatory and anti-senescent HS response pathways could underlie the perpetuation of vascular inflammation in atherosclerosis, as observed in other chronic inflammatory diseases, and that in vivo heat treatment, the most powerful trigger of the HS response, should be effective in re-establishing SIRT1-HSF1-HSP axis in atherosclerotic mice.

Aortic expressions of SIRT1, HSF1, HSP27, HSP72 and HSP73 were progressively depressed in atherosclerotic animals, as compared to normal healthy counterparts, which was paralleled by increased expression of NF-κB-dependent VCAM1 adhesion molecule. Conversely, heat treatment completely reversed suppression of the above HS response proteins, while markedly inhibiting both VCAM1 expression and NF-κB DNA-binding activity. Also, HT dramatically reduced plasma levels of triacylglycerols, total cholesterol, LDL-cholesterol, oxidative stress, fasting glucose, and insulin resistance while rising HDL-cholesterol levels. Heat treatment also decreased body weight gain, visceral fat, cellular infiltration, and aortic fatty streaks, and heart ventricular congestive hypertrophy, thereby improving aortic blood flow and myocardial performance indices. Remarkably, heat-treated mice stopped dying after the third heat treatment session, suggesting a curative effect.

Link: https://doi.org/10.1016/j.biochi.2018.09.011

The consensus view on the progression of Alzheimer's disease is that it begins with rising levels of amyloid-β aggregates, misfolded proteins forming solid deposits to disrupt cellular behavior. This increase in amyloid-β might be due to persistent infection, as amyloid-β is an antimicrobial peptide, a part of the innate immune system. It might be due to failing drainage of cerebrospinal fluid, causing all molecular wastes to build up in the brain. There are other possibilities as well, such as progressive failure of the ability of immune cells to clear out amyloid-β.

In and of itself this rising level of amyloid-β seems to, at worst, cause mild cognitive impairment via dysfunction of neurons. Unfortunately it also causes microglia and other support cells to become dysfunctional and inflammatory. That in turn sets the stage for tau protein to become altered and form its own solid deposits. Tau aggregates are far worse than amyloid-β aggregates, and lead to widespread and severe cell dysfunction and death in the brain.

Even given the decades of failure in clearance of amyloid-β from the brain, primarily via immunotherapies, it still seems plausible that early enough intervention to reduce amyloid-β levels should prevent the development of Alzheimer's disease. Late intervention is simply too late - the disease mechanisms are chronic inflammation and tau aggregation by that time. A potentially promising new area of intervention is to prevent the impact of amyloid-β on microglia and other support cells from producing this chronic inflammation and tau aggregation. Promising results have been achieved in animal models via clearance of senescence microglia and astrocytes, reducing the level of inflammation and aggregated tau in the brain by removing these dysfunctional support cells from the picture.

Today's open access research takes a different approach to the same point of intervention. The authors have identified one of the critical proteins involved in the ability of microglia to ingest and break down amyloid-β. This offers the possibility of enhancing their ability to do so, and in turn reduce the fraction of microglia that become inflammatory and dysfunctional due to the presence of too much amyloid-β. Time will tell how well this works, but the evidence from other approaches to removing or replacing microglia in the aging brain suggests that this is worth the attempt.

Pathway discovered that prevents buildup of Alzheimer's protein

Researchers called the pathway LC3-associated endocytosis or LANDO. They found the pathway in microglial cells, the primary immune cells of the brain and central nervous system. However, preliminary evidence suggests LANDO is a fundamental process that functions in cells throughout the body. Investigators showed that LANDO protected against deposits of neurotoxic β-amyloid protein in mice. Activation of the pathway also guarded against toxic neuroinflammation and neurodegeneration, including memory problems.

β-amyloid protein accumulation in neurons is a hallmark of Alzheimer's. Scientists knew microglial cells take up β-amyloid proteins. Discovery of the LANDO pathway answers questions about what comes next. The researchers compared LANDO to the operator of an automatic carwash. In this case, the cars are the receptors on the microglial cells that bind to neurotoxic β-amyloid proteins and bring the protein into the car wash. And, just as cars return to the streets after the dirt is gone, when the β-amyloid is disposed of, the receptor returns to the microglial surface where it can pick up additional β-amyloid.

Several proteins are required for LANDO functioning. The proteins - Rubicon, Beclin 1, ATG5, and ATG7 - are better known for their roles in a related cell pathway used to recycle unneeded and unwanted cell components. These proteins decline with age as their expression decreases.

LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer's Disease

The expression of some proteins in the autophagy pathway declines with age, which may impact neurodegeneration in diseases, including Alzheimer's disease (AD). We have identified a novel non-canonical function of several autophagy proteins in the conjugation of LC3 to Rab5 +, clathrin + endosomes containing β-amyloid in a process of LC3-associated endocytosis (LANDO).

We found that LANDO in microglia is a critical regulator of immune-mediated aggregate removal and microglial activation in a murine model of AD. Mice lacking LANDO but not canonical autophagy in the myeloid compartment or specifically in microglia have a robust increase in pro-inflammatory cytokine production in the hippocampus and increased levels of neurotoxic β-amyloid. This inflammation and β-amyloid deposition were associated with reactive microgliosis and tau hyperphosphorylation. LANDO-deficient AD mice displayed accelerated neurodegeneration, impaired neuronal signaling, and memory deficits. Our data support a protective role for LANDO in microglia in neurodegenerative pathologies resulting from β-amyloid deposition.

Zebrafish are a highly regenerative species, capable of completely regrowing lost heart tissue. This is not the case in mammals, where the heart regenerates very poorly, with injury leading to scar tissue and loss of function. Thus researchers are exploring the mechanisms of regeneration in zebrafish and other highly regenerative species, such as salamanders, in search of important differences that might become the basis for regenerative therapies. The research here is an example of this sort of work. In any case where trigger mechanisms for regeneration are better mapped, there is the possibility that regeneration might be enhanced via intervention at one of the triggers.

Heart muscle cells called cardiomyocytes hold on to the capacity to reprogram themselves and alter their fate in response to heart damage. Although several signalling cues are known to be involved in this regeneration activity, it is not well understood how heart injury switches on these pathways to initiate heart cell reprogramming. "Recent studies suggest that biomechanical forces generated by blood flow can contribute to heart development through modulating cell signalling. We wanted to explore this further by seeing whether mechanical forces caused by altered blood flow during heart injury also activate these signalling pathways to control heart cell reprogramming and regeneration."

The team first looked at how heart injury affects signalling of an important heart development molecule called Notch in zebrafish. They found that injury-induced Notch activity peaks at 24 hours after injury but diminishes as the heart regenerates, so that by 96 hours it has returned to normal. If Notch is blocked, however, this prevents heart cell growth and stops heart precursor cells from reprogramming and maturing into cells that can replace the damaged cells.

They next explored whether heart injury could alter blood flow forces and, in turn, control injury-induced Notch signaling. Klf2a is a molecule that responds to changes in blood flow and switches on certain genes in response. In regions of the injured heart where blood flow was most disrupted, they found that levels of Klf2a were increased. In addition, they found that levels of Klf2a overlapped with the levels of Notch.

Further experiments revealed that, when mutated, Trpv4 - a molecule that is known to 'sense' changes in blood flow and can switch on the gene for Klf2a - led to a reduced amount of genes that drive heart cell growth and fewer cells maturing to replace the damaged tissue. Additionally, the team found that changes in blood flow controls heart cell reprogramming and growth via another two molecules, BMP and Erbb2. As these molecules are important for heart regeneration in mammals, the changes observed in the zebrafish may also hold true for other organisms, including humans.

Link: https://elifesciences.org/for-the-press/7a7fd7c7/changes-in-blood-flow-tell-heart-cells-to-regenerate

This open access paper is a good example of the sort of work that follows identification of a longevity-enhancing mutation in a laboratory species, flies in this case. Finding such a mutation is just the first step on a long road towards a better understanding of metabolism. Unfortunately, most such work will have little relevance to the practical matter of extending human life span. Short-lived species have a great plasticity of longevity in response to metabolic changes, while we humans do not. The operation of cellular metabolism and tissue function is enormously complex, and it is rarely the case that any of the connections between proteins and mechanisms and function are either simple or easy to establish. This is why much of the field of aging research moves slowly indeed, being focused on (a) interventions that cannot possibly do much for human life span, and (b) trying to understand all of the details of the way in which aging progresses.

The E(z) histone methyltransferase heterozygous mutation in Drosophila is known to increase lifespan and stress resistance. However, the longevity mechanisms of E(z) mutants have not been revealed. In the present research we studied the effects of E(z) histone methyltransferase heterozygous mutation on lifespan, stress-resistance, fecundity, and genome-wide transcriptional profile dynamics in Drosophila imagoes. We observed 22-23% lifespan extension in both sexes, and E(z) mutants were significantly more resistant to hyperthermia, oxidative stress, and endoplasmic reticulum stress, and demonstrated enhanced fecundity.

The genome-wide transcriptome analysis identified 239 genes, which expression level was altered more than 2 times by E(z) mutation. Several of the most differentially expressed genes had never been described before as pro-longevity genes. Most likely, these genes may be associated with E(z) mutation, but not related to aging and longevity. The exception is a differential expression of antimicrobial peptides and the Turandot family of genes. These humoral innate immunity factors have been previously discussed in the context of aging and stress-resistance.

A mutation in the E(z) gene surprisingly neither activated nor repressed canonical pro-longevity or anti-longevity genes like mTor or insulin/IGF-signaling elements and either determinants of DNA repair, Sod, Sirtuins, etc. We also did not find strong changes in the expression of the Hox family of genes, for which gene repression by polycomb group proteins such as E(z) was previously shown.

We observed that the E(z) mutation leads to modulation of many genes related to the immune response, ribosome biogenesis, and cell cycle. Although age-dependent changes in the expression of these genes are similar to changes in control flies, it is most likely that mutations in E(z) lead to positive perturbations in the pathways for which age-associated gene expression changes are shown. In addition, the gene expression is sex-specific, despite the fact that the increase in median lifespan for both sexes was broadly similar, which emphasizes the importance of separate preparation and analysis of females and males.

Link: https://doi.org/10.1038/s41598-019-45714-x

When considered in the grand scheme of things, there is presently little that can be done to alter the personal trajectory of longevity. A recent study on survival to 90 years of age well illustrations the bounds of the possible: given today's medical technology, personal choice on lifestyle and fitness can shift the odds in the range between 1% and 30%. Which is to say that even given an optimal life, two thirds of enthusiasts will not make it to their 90th birthday. We can shift the quality of late life, and we can add or subtract just a handful of years of life expectancy.

Even the advent of the first rejuvenation therapies does not greatly change this picture, as they each tackle only one facet of the cell and tissue damage that causes aging. I think it plausible that we'll find out - much later - that first generation senolytic therapies are capable of adding, say, five years to life expectancy. That sounds reasonable for something that can significantly reduce the chronic inflammation of aging. This is a big deal in a world in which the only other available strategies, such as exercise, or staying thin, also seem to be able to move life expectancy by a single digit number of years. Perhaps three, perhaps seven, certainly not more than ten. But these are small numbers against the bigger picture of the passage of centuries.

Medical control of aging to the degree that will enable a life span of centuries is possible to achieve, given suitable advances in biotechnology. The SENS research program tells us how to go about achieving that goal - it is just a matter of time, funding, and will. The will might be lacking in the broader population. Studies suggest that most people want a little additional longevity, something that falls within the bounds of conformity. They want to live a little longer than their peers, to be that little higher in the hierarchy, but not so much longer that it becomes gauche. Yet all of these individuals will make use of rejuvenation therapies when those treatments are available and widely accepted by the medical community, regardless of how many years are added. Therein lies one of the challenges in assessing attitudes towards longevity.

Motivation for Longevity Across the Life Span: An Emerging Issue

In an attempt to integrate some of the different lines of reasoning and research findings, we submit that there exist three widespread classes of attitudes, expectations, and preferences with regard to a possible extension of human lifetime in modern societies that may reflect different schools of thought, such as essentialism, medicalism, and stoicism. The different primary motives that are associated with the three perspectives on longevity and life-time extension are infinite life (striving to overcome biological degeneration and health declines), healthy life (motivation is conditional on physical and mental health), and dignified life (a wish for dignity and meaning even when there is loss and vulnerability). We submit that these three primary motives can be used to characterize different scientific approaches on longevity, as well as individual attitudes and preferences toward longevity in everyday thinking. We refer to such perspectives as mindsets that involve sets of representations, attitudes, and ways of thinking about the meaning and value of a prolonged life.

An essentialist mindset views aging as a degenerative process that is inevitably associated with physical loss. It reflects the idea that aging is a determined and undesirable process, and that the human mind is held captive in a deficient biological organism. Accordingly, pathological aging cannot be differentiated from normal or healthy aging. One implication is that aging per se is viewed as pathological and ought to be pushed back, for example, with antiaging medicine. Consequently, radical extensions of the life span are expected when antiaging research is successful. Recent studies suggest that the prevalence of essentialist mindsets can be estimated in the range of 3-10% of respondents who wish to live forever or wish to "overcome" the natural aging process.

A medicalist mindset involves that human aging is viewed as burdened only when pathology occurs, and that pathological aging is different from normal aging. In this perspective, aging is associated with age-related health risks, and defined as a medical challenge. One implication is that successful aging may be defined as an absence of disease and disability. On an individual level, medicalism is reflected in an appreciation for an extended lifetime if health functioning can be maintained, and degenerative diseases such as dementia can be avoided. Another implication might be that when endorsing a medicalist mindset, individuals may prefer to avoid the vulnerability of old age and wish to die rather than to become chronically ill or demented.

The stoicist mindset for living long reflects the idea that withstanding the challenges and risks of a long or prolonged life is part of the conditio humana, which involves striving for meaning in life, and for acceptance of one's actual life condition. The challenges, needs, risks, or tasks within the aging process may thus appear manageable or at least bearable as long as there is meaning in life and a sense of grace. Preserving dignity and meaning in a prolonged life is pivotal to a stoicist mindset. Thus, having a worthy and dignified life may be emphasized over the absence of chronical diseases in late life. Regarding the desired extension of lifetime, we submit that holding a stoicist mindset may involve that individuals express a valuation of life per se and "as it comes." This may also involve a discomfort or unwillingness to reflect about lifetime extension rather than about dignity and meaning in life.

Most of the interventions demonstrated to slow aging and extend life span to some degree in mice involve upregulation of cellular stress responses. This means increased activity in the repair and maintenance mechanisms, such as autophagy, that keep cells and tissues functional. These approaches are the not the path to radically increased human longevity. As the practice of calorie restriction demonstrates, short-lived mammals have a much greater plasticity of longevity than we long-lived humans when it comes to the effects of stress response mechanisms. Calorie restriction adds 40% to mouse life span, but no more than a few years to human life span. It does, however, improve measures of health in our species, and that should probably set our expectations regarding the benefits that will arise from present efforts to produce calorie restriction mimetics, autophagy enhancers, and similar categories of therapy.

In the research here, scientists report on an effort to calibrate variability in the effects of these stress response upregulation therapies. The ideal life extending treatment is one that (a) extends healthy life, not the period of decline, and (b) does so by a large amount, and (c) is very reliable in achieving that large gain. Stress response upregulation is a failure as a strategy when it comes to the size of the effect, and while we tend to think of calorie restriction as a very reliable intervention, when considering variation in size of effect between individuals, that may not be as much the case as we'd like it to be.

In studies of aging, changes in the length of life are usually analyzed by comparing average (mean) or median longevity. Frequently, some estimate of maximal longevity is also considered. While values of the standard deviations or standard errors of the mean are routinely reported, the distribution of individual age at death is rarely analyzed or discussed. In a recent publication based on analysis of demographic data, it was reported that socio-economic status influences not only the mean longevity but also the variability of human life-span. Using an example of Finnish women, these investigators showed that reduced mean longevity of less educated and less affluent people is associated with greater variability of life-span.

Because of the potential significance of this relationship for the analysis of mortality data and physiological biomarkers in studies of aging as well as for various public health considerations, we thought that it would be of interest to determine whether interventions known to extend the average (or the average and the maximal) longevity of experimental animals have any effect on the variability of life-span. We hypothesized that extension of longevity by genetic, dietary or pharmacological means leads to reduction of life-span variability.

However, inspection of data from the National Institute of Aging Interventions Testing Program (ITP) and from our studies of the interactions of murine longevity genes with calorie restriction (CR) indicated that reciprocal changes of longevity and its variability are not consistently observed. This suggested that our hypothesis would most likely need to be rejected and brought up a new question, namely, what factors influence variability of the lifespan. Here we report results of a study aimed at analyzing the effects of sex, strain, life-extending interventions and their interactions on life-span variation.

The relationship of changes in longevity and in longevity variance was found to depend on sex and treatment and apparently also on strain. Increased longevity of male mice treated with effective anti-aging drugs was accompanied by reduced variance of age at death and apparent reduction of early life mortality. Life extension induced by growth-hormone related mutations and calorie restriction tended to increase longevity variance in females only. We conclude that impact of anti-aging interventions on the variance of age at death and distribution of individual lifespans in laboratory mice is treatment-dependent and sexually dimorphic.

Link: https://doi.org/10.18632/aging.102037

Average telomere length, as presently assessed in immune cells taken from a blood sample, is a truly terrible basis for measuring the pace of aging. Only in large studies is a statistical decline with aging seen, and even then not in all studies. For any given individual this measure is very dynamic, reflecting short term immune system changes that have little to do with aging - and thus a specific measure or set of measures isn't all that actionable.

The study here, in which no correlation was found between telomere length and an epigenetic clock, should be taken as a reinforcement of this point. Despite the challenges remaining in the development of epigenetic clocks, such as the question of what exactly it is that they do measure about aging, they do reliably correlate with risk of age-related disease in individuals and small study groups, which is more than can be said for telomere length. The epigenetic clock is a far, far better foundation for a useful biomarker of aging, one that can be used to quickly assess the results of alleged rejuvenation therapies, than is the case for telomere length.

Aging is accompanied by a range of DNA modifications. Telomere length, which shortens as a consequence of DNA replication, has been widely accepted as a biomarker of aging. While being inversely correlated with chronological age, telomere length is also associated with a range of age-associated phenotypes and clinical diseases. Recently, a novel candidate epigenetic biomarker of aging has been shown to predict an individual's chronological age with high accuracy: the epigenetic clock is based on the weighted DNA methylation fraction of a number of DNA methylation (DNAm) age correlates with cell passage number in vitro and can be predicted across different tissues, including non-proliferating ones in vivo, suggesting that DNA methylation is not exclusively reflecting mitotic age.

This is in line with the finding that DNAm age and relative leukocyte telomere length (rLTL) were independently associated with chronological age and mortality. The few existing studies found no supporting evidence of a significant association between rLTL and DNAm age or reported a weak association. Moreover, rLTL was reported to have a lower predictive power in estimating chronological age in comparison to the epigenetic clock.

While the number of studies reporting a positive correlation between DNAm and chronological age in a range of different study populations rises, there is accumulating evidence suggesting that DNAm age somewhat reflects biological age. Under the assumption that DNA methylation age reflects biological age, calculating the deviation of the epigenetic age estimate and the chronological age gives rise to a second potentially clinically relevant measure: DNAm age acceleration. Here we aim to explore the association of rLTL and the epigenetic clock variables, DNAm age and DNAm age acceleration, in the context of cardiovascular disease in the LipidCardio cohort.

Both rLTL (0.79 ± 0.14) and DNAm age (69.67 ± 7.27 years) were available for 773 subjects (31.6% female; mean chronological age 69.68 ± 11.01 years). While we detected a significant correlation between chronological age and DNAm age, we found neither evidence of an association between rLTL and the DNAm age nor rLTL and the DNAm age acceleration in the studied cohort, suggesting that DNAm age and rLTL measure different aspects of biological age.

Link: https://doi.org/10.3390/ijms20123032

Simple human dignity and self-ownership demands the right to end one's own life on one's own terms, and to be able to help others achieve this goal where they are not capable of doing so themselves. Yet these acts remain forbidden to most people in most parts of the world. Painless, effective euthanasia requires medical assistance, and providing that service remains largely illegal. This state of affairs is slowly starting to change in the US, however, and so late last year the first cryopreservation following voluntary euthanasia took place.

Cryopreservation is the only presently available end of life option that offers a chance at life again in the future. It is an unknown, high risk chance, but it is the only option on the table for those who will age to death prior to the advent of rejuvenation therapies. Given a sufficiently high quality preservation of the brain, using vitrification techniques, then the fine structure that stores the data of the mind can be preserved indefinitely at low temperatures. At some future date, technologies of restoration based on advanced molecular nanotechnology will become plausible, then possible, then used. The preserved individuals have all the time in the world to wait for that to come to pass.

There are challenges, however. The important challenges in cryopreservation are twofold, and ultimately stem from the presently small size and non-profit status of cryonics organizations, which ensures that progress towards technical improvement occurs only slowly. Firstly, cryopreservation as a service is expensive and uncertain because of the inability to assist in euthanasia in most parts of the world. Patients must be watched by standby teams, and any meaningful delay following death allows for greater damage to brain tissue. Further, many forms of age-related death in fact destroy areas of the brain: stroke, neurodegenerative disease, and so forth. Secondly, the quality of vitrification of the brain remains far from perfect. The case here illustrates the point; even with perfect timing due to the assisted death process, there remains some ice formation in the brain. These are challenges that are best solved through growth in the size of the cryonics community, and success in branching out into commercial ventures, such as reversible vitrification of tissues for transplantation.

California Man Becomes the First 'Death With Dignity' Patient to Undergo Cryonic Preservation

On October 30, 2018, Alcor performed its 164th cryopreservation. It was an otherwise unremarkable moment for the nonprofit organization, save for the way Norman Hardy of Mountain View, California met his demise. Hardy was diagnosed with terminal metastatic prostate cancer, and it had spread to his bones and lungs. As noted in Alcor's case summary, his "pain had been poorly managed," so he opted for assisted death, which was legalized in California in 2016 through the End of Life Option Act (EOLOA).

For Alcor, the case was the first time EULOA was used to "reduce the potential ischemic damage that can result from a prolonged dying process," as the foundation noted in its official case report. Indeed, the quicker a patient can be put into cryonic suspension following death the better, as the sudden shortage of oxygen starts to destroy tissues. For Alcor, time is trauma. In this case, Hardy's choice of when to die allowed his neural tissues to be rapidly preserved following his death, or at least, preserved as well as modern cryonic technologies allow.

The procedure to prepare Hardy's head for long-term suspension in a vat of liquid nitrogen was "relatively successful," noted Alcor in its case report. CT scans following preservation showed some ice formation in the cerebellum and frontal lobes, which isn't ideal. That said, the quick turnaround from the declaration of death to placement in one of Alcor's stainless steel dewars meant that decompositional damage to Hardy's brain was minimized. In a best case scenario, Alcor's response team begins the cryopreservation process within seconds after death is declared. But that doesn't always happen.

Case report published on Norman Hardy, A-1990

Alcor has published a case report on Norman Hardy, A-1990. This case was the first time the newly enacted California End of Life Option Act (EOLOA) was used to reduce the potential ischemic damage that can result from a prolonged dying process. The cryoprotective perfusion was relatively successful. Perfusion flow rates were high throughout the procedure. However, the post-cryopreservation CT scan showed poor cryoprotection and extensive CT-visible ice formation in the cerebellum, and incomplete cryoprotection with a small amount of CT-visible ice formation in the frontal lobes.

The endoplasmic reticulum is the site of protein synthesis and lipid synthesis in cells. Damage or other disturbances to cellular processes can lead to an accumulation of unfinished molecules in the endoplasmic reticulum, a condition known as endoplasmic reticulum stress. The cell will respond in various ways when this happens, trying to clear out the unfinished proteins and lipids in order to restore normal function. This all falls under the general heading of cellular housekeeping, and we know that cellular housekeeping mechanisms such as autophagy both decline with age and are influential on the pace of aging. Not influential enough to greatly extend human life spans, probably, but they appear to be a sizable part of the reason why strategies such as calorie restriction can improve long-term health and modestly slow aging in our species.

Under normal circumstances, proteins destined for the secretion are translated directly into the endoplasmic reticulum (ER) via ribosomes embedded in the ER membrane, bound by chaperone proteins, folded, and then packaged into vesicles for secretion. In some cases, however, this pathway can go awry; proteins may become misfolded or unfolded in the ER, and unable to be recovered by the protein quality control machinery. In this instance, the improperly folded protein is targeted for degradation, exported into the cytosol, and degraded by a proteasome. Again, however, this process is imperfect. Some environmental, cellular, or molecular factors can cause disruptions in this pathway, preventing the proper turnover of misfolded or unfolded proteins, potentially leading to their accumulation and aggregation. This generates a cellular condition known as ER stress.

Endoplasmic reticulum stress and the failure to correctly fold proteins are associated with loss of protein function and cell death. To avoid this, the cell resolves misfolded protein stress via two major stress response pathways: the heat shock response (HSR), which handles misfolded proteins in the cytoplasm, and the unfolded protein response (UPR), which takes place in the ER. These protein quality control mechanisms are essential for maintaining the function and integrity of cellular processes. When perturbed, they can lead to whole-cell dysfunction and toxicity. Under normal conditions, both lead to resolution of the cellular stress caused by the presence of misfolded proteins.

The UPR is a complicated signaling pathway which works to resolve ER stress and allow protein synthesis and folding to continue and has been shown to interact with multiple cellular pathways and processes to do so, including (but not limited to) those occurring in the ER. It has also been shown to be impacted by several seemingly unrelated external influences, including aging and lipid metabolism, and dysfunction in this pathway has been linked with shortened cellular lifespan and cell death. Because of this, the study of the molecular mechanisms behind ER stress and the UPR is essential to the understanding of how protein homeostasis impacts the entire cell and its processes, including response to stressors, aging, and cell death.

Aging cells have been shown to have decreased total levels of a number of ER proteins, including protein chaperones which normally supervise and ensure proper protein folding, and assist in targeting misfolded proteins for degradation. This usually prevents the accumulation and aggregation of misfolded proteins and prevents them from having toxic effects on the cell. In addition, the limited chaperones that are still present in the aging ER appear to be impaired. This is possibly due to an increased rate of oxidation of these chaperones in aged cells, leading to structural changes and consequently decreased function.

Link: https://doi.org/10.3389/fcell.2019.00084

Excess visceral fat tissue distorts the operation of metabolism, reduces life expectancy, raises risk of age-related disease, and increases lifetime medical costs. Some fraction of these detrimental effects are mediated by cellular senescence: more senescent cells are created than would otherwise be the case, given extra visceral fat. Given that the accumulation of senescent cells is one of the root causes of aging, we might argue that being overweight literally accelerates the aging process. In the open access paper here, researchers explore some of the underlying mechanisms by which senescent cells are generated more readily in obese individuals. It is worth noting, however, that the epidemiological data on weight shows that any increase above a healthy level is harmful. More is worse, but any gain is bad to some degree.

Subcutaneous adipose tissue (SAT) is the largest and best storage site of excess fat in the body provided that new cells can be recruited as needed (hyperplastic obesity). Inappropriate expansion of the adipose cells (hypertrophic obesity) promotes insulin resistance and other obesity-associated metabolic complications and is a consequence of inability to recruit new adipose cells. This has been shown both in vitro and in direct studies of human adipose cell turnover in vivo.

Our previous extensive studies have shown large inter-individual differences in ability of human SAT stromal vascular fraction (SVF) cells to undergo adipogenesis. Furthermore, markers of reduced SAT adipogenesis are associated with genetic predisposition for type 2 diabetes (T2D) and first-degree relatives (FDR), like individuals with manifest T2D, are characterized by hypertrophic obesity. Human SAT contains a pool of adipose progenitor cells but the detailed signals for recruiting new adipose cells and the reasons for the large individual differences are unclear. Bone morphogenetic protein 4 (BMP4) is important for the commitment of mesenchymal progenitor cells into the adipogenic lineage and BMP-signalling is regulated by different secreted inhibitors. We found Gremlin-1 (GREM1) to be an important BMP4 antagonist and increased in hypertrophic obesity. Thus, impaired commitment of progenitor cells could be one reason for the reduced adipogenesis.

Cell senescence is, in part, a consequence of repeated progenitor cell mitogenic expansion and there is a 10% annual cell turnover in human SAT. Cell senescence leads to permanent cell cycle arrest, secretion of different senescence-associated proteins and inhibited cell differentiation. We here characterize mechanisms for the impaired SAT adipogenesis in adult human subjects with hypertrophic obesity including FDR/T2D. A key mechanism for the impaired adipogenesis in hypertrophic obesity / T2D is increased progenitor cell senescence, dysregulated p53 and P16ink4 and secretion of senescence-associated secretory phenotype (SASP) factors antagonizing normal cell adipogenic differentiation.

Link: https://doi.org/10.1038/s41467-019-10688-x

In recent years, ever more evidence has accumulated for the gut microbiome to be influential on health throughout life, and on the pace of aging. The size of the effect is an open question at this time, but it isn't unreasonable to think that it might be in the same ballpark as that of regular moderate exercise. The gut microbiome changes with age in characteristic ways, and this may produce chronic inflammation and other deleterious effects. Healthier older people tend to have lesser changes in their gut microbiome, a more youthful distribution of bacterial species. In animal studies, transplantation of gut microbe populations from young individuals to old individuals improves the health and life span of old individuals.

For all this, it is far from clear as to which mechanisms are important in the changes that take place in the gut microbiome. Is the age-related decline of the immune system allowing harmful bacteria to prosper? Is it related to dietary changes that tend to take place in later life? Are there other important cell populations in the gut that deteriorate, and this changes the maintenance of gut bacteria? While many questions remain to be answered, researchers are making useful inroads into discovering what exactly it is that beneficial gut bacteria are doing. For example, manufacture of propionate from dietary fiber is known to be helpful to health. Researchers have shown it to improve cardiovascular health, and some of the benefits of dietary fiber intake are most likely mediated by this activity on the part of gut bacteria.

In today's research results, scientists report on the discovery of a bacterial species prevalent in athletes that metabolizes lactate into propionate, and by doing so increases exercise capacity. This is a novel and most interesting finding, though of course we should always look carefully at the size of the effect before becoming too enthusiastic on the topic - glancing at the data in the paper, it looks like about a 10% increase in treadmill time for mice. The important mechanism is the presence of propionate, not the bacteria themselves. This adds evidence to past research that suggests that this compound should be developed as a dietary supplement.

Performance-Enhancing Bacteria Found in the Microbiomes of Elite Athletes

Researchers collected samples during a time span of one week before the Boston Marathon to one week after the Marathon. They also collected samples from sedentary individuals. They then analyzed them to determine the species of bacteria in both cohorts. "One of the things that immediately caught our attention was this single organism, Veillonella, that was clearly enriched in abundance immediately after the marathon in the runners. Veillonella is also at higher abundance in the marathon runners in general than it is in sedentary individuals."

They confirmed the link to improved exercise capacity in mouse models, where they saw a marked increase in running ability after supplementation with Veillonella. Next, they wanted to figure out how it worked. As they dug into the details of Veillonella, they found was that it is relatively unique in the human microbiome in that it uses lactate or lactic acid as its sole carbon source. Lactic acid is produced by the muscles during strenuous exercise. The Veillonella bacteria are able to use this exercise by-product as their main food source. "Our immediate hypothesis was that it worked as a metabolic sink to remove lactate from the system, the idea being that lactate build-up in the muscles creates fatigue. But talking to people in the exercise physiology field, apparently this idea that lactate build-up causes fatigue is not accepted to be true. So, it caused us to rethink the mechanism of how this is happening."

Researchers ran a metagenomic analysis, meaning they tracked the genetics of all the organisms in the microbiome community, to determine what events were triggered by Veillonella's metabolism of lactic acid. They noted that the enzymes associated with conversion of lactic acid into the short chain fatty acid propionate were at much higher abundance after exercise. "Then the question was maybe it's not removal of lactic acid, but the generation of propionate. We did some experiments to introduce propionate into mice via enema and test whether that was sufficient for this increased running ability phenotype. And it was."

Meta-omics analysis of elite athletes identifies a performance-enhancing microbe that functions via lactate metabolism

The human gut microbiome is linked to many states of human health and disease. The metabolic repertoire of the gut microbiome is vast, but the health implications of these bacterial pathways are poorly understood. In this study, we identify a link between members of the genus Veillonella and exercise performance. We observed an increase in Veillonella relative abundance in marathon runners postmarathon and isolated a strain of Veillonella atypica from stool samples. Inoculation of this strain into mice significantly increased exhaustive treadmill run time.

Veillonella utilize lactate as their sole carbon source, which prompted us to perform a shotgun metagenomic analysis in a cohort of elite athletes, finding that every gene in a major pathway metabolizing lactate to propionate is at higher relative abundance postexercise. Using labeled lactate in mice, we demonstrate that serum lactate crosses the epithelial barrier into the lumen of the gut. We also show that intrarectal instillation of propionate is sufficient to reproduce the increased treadmill run time performance observed with V. atypica gavage. Taken together, these studies reveal that V. atypica improves run time via its metabolic conversion of exercise-induced lactate into propionate, thereby identifying a natural, microbiome-encoded enzymatic process that enhances athletic performance.

The mainstream view of Alzheimer's disease is that it begins with a slow increase in aggregation of amyloid-β, though the reasons why only some people exhibit high levels of amyloid-β are much debated. The amyloid-β then rouses the immune cells of the brain into inflammatory behavior and cellular senescence. The resulting chronic inflammation causes sufficient dysfunction to allow tau protein to alter and aggregate, and it is this aggregation that causes the widespread cell death and dysfunction in the later stages of the condition. Thus there is considerable interest in better understanding how amyloid-β causes this inflammatory behavior in immune cells, with an eye to potentially interfering in this mechanism. The brute force approach of destroying senescent cells in the brain has shown promise in animal studies, for example. The results here are more illustrative of the sort of investigative work presently taking place in the scientific community, however.

The classical hallmarks of Alzheimer's disease (AD) include the formation of amyloid-beta (Aβ) plaque deposits and neurofibrillary tangles (NFT) containing abnormal hyperphosphorylation of tau. The mechanisms triggering the deposition of the Aβ or the formation of NFTs are currently under investigation. However, several mechanisms and factors have been suggested to be involved in the initiation and the progression of the disease, including activation of the innate immune system, environmental factors and lifestyle. The innate immune system has been widely studied and has been implicated in several neurodegenerative diseases. Over the last few years, several studies have suggested that inflammation plays a major role in the initiation and progression of AD.

The inflammatory process in the central nervous system (CNS) is generally referred to as neuroinflammation. Glial cells have a leading role in propagating neuroinflammation. Among glial cells, microglia are considered the main source of proinflammatory molecules within the brain. It is believed that sustained release of proinflammatory molecules such as cytokines, chemokines, nitrogen reactive species (NRS) or reactive oxygen species (ROS) can create a neurotoxic environment that drives the progression of AD.

One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer's disease) mice and found specifically expressed in microglia associated with Aβ plaques. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD.

Link: https://doi.org/10.1007/s00401-019-02013-z

It is thought that the burden of infection is an important determinant of pace of the age-related decline of the immune system. This is particularly the case for persistent viral infections such as that caused by herpesviruses. There is plenty of evidence for cytomegalovirus infection to be a cause of immune dysfunction in later life, for example. In this open access paper, the author argues that the interaction between viruses and immune system in the context of aging is very complex and presently poorly understood. It certainly seems clear that some viruses are far worse than others when it comes to the damage done to the immune system.

Our body is in continuous contact with viruses and various defense mechanisms are used to prevent the entry or to eliminate the invader within the body. There is ample evidence demonstrating that the aging-associated decline of the immune system, i.e. immunosenescence, significantly weakens these mechanisms. This is often observed in the case of common viral pathogens, e.g. influenzavirus. On the other hand, it is known that at least some viruses may induce or modify immunosenescence and in this respect cytomegalovirus (CMV) is the classical and extensively investigated example.

However, there is now emerging evidence showing that the number of viruses or virus-like entities is much larger than expected. i) Next generation (NGS) RNA/DNA sequencing based approaches have shown that within our body there are large amounts of various viruses even without known clinical or biological significance, forming the virome, i.e. the classical concept about the "sterility" of the inner body should be rejected; ii) Our genome contains mobile genetic elements, retrotransposons, endogeneous retroviruses (HERV), some of which may still be active and might modify the immune system.

Analysis of the virome (including bacteriophages) is technically more challenging than that of the bacteriome, but the first virome analyses have now been published. It seems that the different compartments of the body harbor distinct viral communities. However, the total number of viruses is highly variable, 10^9 particles per gram in the intestinal content, 10^7/ml in the urine and 10^5/ml in the blood. Studies on gut virome have shown, that the most common viruses are not those infecting eukaryotic cells, but those infecting prokaryotic cells, bacteriophages, form a clear majority.

Thus far the relationship between virome composition and immunosenescence is not known. However, there are several reports demonstrating changes in the gut virome compostion in diseases of immunological nature, e.g. type I diabetes. Based on these, it could be expected that immunosenescence would have an influence on virome composition. However, its possible role in the aging-associated pathologies can presently only be speculated. Does the weaker immunity allow the presence of potentially pathogenic viruses in the blood of elderly individuals? It is also possible that this viral "normal flora" would have a protective effect, in analogy with the bacterial normal flora in several compartments of the human body.

The data shown here indicate that the relationship between viruses, virosphere, and immunosenescence is more complex than previously thought.

Link: https://doi.org/10.1186/s12979-019-0152-0

The Life Extension Advocacy Foundation staff regularly publish interviews with scientists and other figures in the aging research community. In this interview they talk with one of the researchers presently working on the development of biomarkers of aging, specific those based on epigenetic markers such as DNA methylation. These epigenetic decorations to the genome determine the pace at which proteins are produced from their blueprint genes. They shift constantly in response to circumstances, one among myriad feedback loops determining cell behaviors. Eight years ago, researchers started to find that weighted algorithms combining the DNA methylation status of certain sites on the genome produced a score that correlated quite closely with chronological age. The first such algorithm was termed the epigenetic clock, and the name has stuck.

Later it was found that people with a higher score than their chronological age tended to exhibit a greater risk of age-related disease and mortality, and vice versa. Thus epigenetic clocks appear to measure physiological age rather than chronological age, and are an assessment of the burden of cell and tissue damage. Or rather they are measuring certain characteristic changes in cell behavior that take place in response to that underlying damage and its consequences. At this point it remains uncertain as to which of the changes of aging it is that various different epigenetic clocks measure; which mechanisms contribute to the clock, and to what degree. For example, epigenetic clocks seem insensitive to physical fitness, which is odd, given that exercise certainly affects risk of age-related disease.

The research community is very interested in the production of viable biomarkers of aging, as success will greatly speed up the development of rejuvenation therapies. Presently the only way to find out whether a treatment actually slows or reverses aging, or extends healthy life span, is to run a life span study. Those are expensive and time consuming in mice, and impractical in humans. If a potential therapy can be quickly assessed with a biomarker test that runs before and after treatment, then that is a whole different picture, however. It would open the door to the cost-effective exploration and assessment of many more therapies than are presently being tested. It would hopefully also shut the door on many present projects that are most likely a waste of time, but continue to obtain sizable amounts of funding regardless.

Interview with Prof. Morgan Levine

Why do epigenetic changes matter for longevity?

We are finding that age-related epigenetic changes are associated with mortality risk and, perhaps more importantly, with disease incidence. For instance, we have different algorithms that represent levels of DNA methylation that we expect to see for someone of a given age. Individuals who have methylation profiles indicative of someone older than they are have increased risk of morbidity and mortality. For instance, if you compare two 40-year olds and one has the methylation profile of someone who is 45, while the other has the methylation profile of someone who is 35, the former will, on average, live for fewer years and develop disease earlier.

What is the theory/mechanism behind the various epigenetic clocks now available?

This is ongoing work that we are actively pursuing. There are about a dozen epigenetic clocks in the literature - perhaps the most famous being the Horvath clock (although it wasn't the first). However, even though these clocks are all intended to capture the same latent concept (biological aging), they differ in their predictions of age and age-adjusted death and disease risk. Using transcriptomic and proteomic data from both blood and brain, we have found that accelerated aging measured using the most widely known epigenetic clocks seem to relate to mitochondrial dysfunction, PI3K/Akt signaling, and immunosenesence.

There is also some evidence coming out that they may reflect cellular senescence to some degree. That being said, our theory is that the clocks - because they are composites of hundreds of CpGs, cytosine separated from a guanine by one phosphate - represent a grab bag of mechanisms. We are currently working on decomposing the various clocks and are finding that they differ in their proportions of various "types" of methylation changes, each of which may have their own distinct mechanisms. Our hypothesis that breaking the clocks down into constituent parts may facilitate our understanding of the underlying biology that is either driving these age-related changes, and/or the functional implications of such changes.

How far are we from understanding epigenetic changes well enough to be able to turn back the clock by changing the epigenetics in individual organisms?

I think we are quite a long way from that. The epigenome is a complex system, and we are not at the point where we can model these changes very well - there is a lot of room for improvement when it comes to the clocks. That being said, we are even further away from understanding what these changes represent or if they are even causal. I hypothesize that many of these changes are actually reactions to something going wrong in some system. Thus, altering DNA methylation directly will not be beneficial and could, in fact, be harmful if this isn't accompanied by changes to the system/extracellular environment. If some of these changes are effects (read-outs) of aging, then they are not the correct points of intervention. Further, many of the changes may be compensatory, and thus making an old cell epigenetically young but leaving it in an aged organismal environment could be detrimental and possibly contribute to neoplastic transformations.

The early stages of Alzheimer's disease are preceded by rising levels of amyloid-β in the brain. This may be due to impaired drainage of cerebrospinal fluid, chronic infection by persistent pathogens, or other mechanisms. Since amyloid-β can be exported from the brain into the bloodstream, and since there is a dynamic equilibrium between levels in the two locations, it is in principle possible for a blood test to identify those most at risk of developing Alzheimer's disease. Unfortunately developing the necessarily accuracy has proven challenging. Researchers here report on meaningful progress towards this goal, however, which is welcome news.

Currently, a major support in the diagnostics of Alzheimer's disease is the identification of abnormal accumulation of the substance beta-amyloid, which can be detected either in a spinal fluid sample or through brain imaging using a PET scanner. "These are expensive methods that are only available in specialist healthcare. In research, we have therefore long been searching for simpler diagnostic tools." In this study, the researchers investigated whether a simple blood test could identify people in whom beta-amyloid has started to accumulate in the brain, i.e. people with underlying Alzheimer's disease. Using a simple and precise method that the researchers think is suitable for clinical diagnostics and screening in primary healthcare, the researchers were able to identify beta-amyloid in the blood with a high degree of accuracy.

"Previous studies on methods using blood tests did not show particularly good results; it was only possible to see small differences between Alzheimer's patients and healthy elderly people. Only a year or so ago, researchers found methods using blood sample analysis that showed greater accuracy in detecting the presence of Alzheimer's disease. The difficulty so far is that they currently require advanced technology and are not available for use in today's clinical procedures."

The new results are based on studies of blood analyses collected from 842 people in Sweden (the Swedish BioFINDER study) and 237 people in Germany. The participants in the study are Alzheimer's patients with dementia, healthy elderly people and people with mild cognitive impairment. The method studied by the researchers is a fully automated technique which measures beta-amyloid in the blood, with high accuracy in identifying the protein accumulation. "The next step to confirm this simple method to reveal beta-amyloid through blood sample analysis is to test it in a larger population where the presence of underlying Alzheimer's is lower. We also need to test the technique in clinical settings, which we will do fairly soon in a major primary care study in Sweden. We hope that this will validate our results."

Link: https://www.eurekalert.org/pub_releases/2019-06/lu-nbt062519.php

While the primary focus for the development of rejuvenation therapies to address the contribution of senescent cells to the aging process is to destroy these harmful, errant cells, many research groups are more interested in modulating or suppressing the senescence-associated secretory phenotype (SASP). The SASP is a potent mix of inflammatory and other signals that disrupts tissue function and produces a sizable fraction of the chronic inflammation associated with aging, driving the progression of all of the common age-related conditions. In principle, eliminating the SASP should eliminate the contribution of senescent cells to the aging process; the challenge would be doing so without also eliminating the necessary short-term SASP involved in cancer suppression, wound healing, and other positive functions carried out by senescent cells on a temporary basis. Periodic destruction of lingering senescent cells doesn't have this hurdle to clear, as it won't interfere with the short-term presence of senescent cells that come and go as needed.

Cellular senescence is an important protective process with roles in development, tissue homeostasis, and wound healing. However, senescence is also implicated in multiple diseases including cancer, arthritis, atherosclerosis, and a diminished healthspan during aging. The senescence-associated secretory phenotype (SASP) is an important hallmark of senescence that contributes to normal physiology and disease. The SASP is characterised by the release of inflammatory cytokines, chemokines, growth factors, and proteases. This reinforces senescence through autocrine and paracrine signalling, and recruits and instructs immune cells to clear senescent cells. However, senescent cells can also generate an inflammatory environment. Thus, the SASP is often considered a double-edge sword. Whilst promoting immune-mediated clearance of pre-malignant senescent cells is a powerful barrier against transformation, the SASP from uncleared senescent cells, or those arising during natural aging, can create an inflammatory milieu permissive to disease.

The SASP is regulated by interleukin-1 alpha (IL-1α), but the mechanism of IL-1α activation during senescence is unknown. Previous studies have suggested that NLRP3 inflammasomes modulate the SASP, even though caspase-1 cannot activate IL-1α. However, our recent research has demonstrated that caspase-5, which lies upstream of NLRP3 in the non-canonical inflammasome pathway, induces IL-1α activity and regulates the SASP during oncogene-induced senescence (OIS) in vitro and in vivo. Recent research also implicates the non-canonical inflammasome in sterile inflammation, of which the SASP is an important yet rarely cited example.

Our recent investigation demonstrated that caspase-5 or caspase-11, but not caspase-4 or caspase-1, specifically cleaves human or mouse pro-IL-1α at a highly conserved site. We demonstrated that caspase-5/11 is required for IL-1α release from cells. siRNA-mediated caspase-5 knockdown reduced levels of cell-surface and secreted IL-1α, and impaired release of the common SASP factors IL-6, IL-8, and MCP-1 from senescent fibroblasts. Our work identifying caspase-5 as a novel regulator of IL-1α activity and the SASP raises several important questions for future research. Firstly, it will be important to understand how caspase-5 is activated in senescent cells. We demonstrated that knockdown of CGAS results in reduced caspase-5 expression and an impaired SASP, and hypothesised that cGAS/STING activated by cytosolic chromatin in senescent cells may drive caspase-5 expression via type I interferons.

The discovery of caspase-5 as a novel regulator of IL-1α in sterile and non-sterile inflammation has several important clinical implications. Targeting caspase-5 may be a therapeutic strategy that leaves canonical immune responses via caspase-1 and -4 intact. For instance, radiotherapy and chemotherapy induce DNA damage that can trigger tumour cell senescence. However, these non-selective therapies also induce senescence in the underlying stroma, with IL-6 from senescent fibroblasts shown to be a reprogramming factor that drives pluripotency and proliferation of cancer stem cells surviving treatment. Therefore, caspase-5 inhibition during treatment could lessen the chance of tumour recurrence.

Link: https://doi.org/10.18632/aging.102031