Fight Aging! Newsletter, September 25th 2017

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

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

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

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

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

The genetic pathways and biochemical processes that modulate aging and longevity are well conserved from budding yeast to the nematode worm Caenorhabditis elegans and mammals. The forkhead transcription factor FOXO as the key downstream regulator that integrates different signals from these pathways plays a crucial role in aging and longevity. The roundworm C. elegans has been considered to be an excellent system for studying molecular mechanisms in regulating animal aging and longevity. Here we discuss the evidence for the role of DAF-16/FOXO in aging and longevity, especially the data in C. elegans, which could give clues to the further studies for human aging and longevity.

FOXOs belong to the class O of the Forkhead transcription factors, which is featured by a conserved DNA-binding domain that participates a wide range of important cellular processes such as cell cycle arrest, apoptosis, and metabolism besides its function in stress resistance and longevity. There are four FOXO genes in mammals: FOXO1 (FKHR), FOXO3 (FKHRL1), FOXO4 (AFX), and FOXO6 sharing high similarity in their structure and function as well as regulation with each other, while invertebrates have only one FOXO gene, named daf-16 in C. elegans.

"Deregulated nutrient sensing" as one of the aging hallmarks to be firstly described to influence longevity, is mainly regulated by the insulin and IGF-1 signaling (IIS) pathway. And this pathway is so highly conserved to modulate aging and longevity across a great evolutionary distance from invertebrates to mammals that the components in every step found in C. elegans could be corresponded to the homologs in mice or human. Any conditions that cause inner stress to block the IIS pathway, like in the presence of food restriction or signals failing to be transduced to DAF-16/FOXO, would increase the transcriptional activity of DAF-16/FOXO by inducing the translocation of DAF-16/FOXO to the cell nucleus, which could subsequently promote or repress the expression of downstream targets to trigger the resistance to different kinds of stress and prolong the lifespan of the organisms.

Another pathway correlated with nutrition affecting longevity is the TOR (target of rapamycin) pathway, which was firstly described in C. elegans and was proved evolutionarily conserved later in other organisms. Various dietary interventions such as caloric restriction may inactivate TOR pathway to promote lifespan extension. The TOR kinase exists in two distinct complexes, TORC1 and TORC2. TORC1-mediated longevity is dependent on DAF-16/FOXO.

AMPK pathway as an energy-sensing signaling pathway responses to stimuli of decreased energy as well as reduced glucose or leptin levels, and it is the theoretical basis of dietary restriction regimen that is considered to extend both the mean and maximal lifespan in a wide range of species. DAF-16 is necessary for AMPK function in oxidative stress resistance and longevity, as the increased longevity caused by overexpression of AMPK was reverted when DAF-16 was inhibited.

The JNK (Jun N-terminal kinase) family, a subgroup of MAPK (mitogen-activated protein kinase) superfamily, as a part of a signal transduction cascade that is activated by cytokines such as TNF and IL-1, serves as a molecular sensor for various stresses including UV irradiation, ROS (reactive oxygen species), DNA damage, heat, and inflammatory cytokines. In C. elegans, overexpression of JNK showed extension lifespan and resistance to heavy metal toxicity, which may function through phosphorylation of DAF-16.

A reproductive system that may integrate nutrient signaling and communicate with other tissues through germline to affect aging has been observed in C. elegans, flies, and mice, indicating a conserved regulation mechanism across different organisms. And it has been reported that lifespan could be extended by 40-60% if the germline precursor cells were removed or the germline stem cell division were prevented in C. elegans. A steroid hormone pathway that includes the key components DAF-36/NVD, DAF-9/CYP27 as well as DAF-12/NHR is required for lifespan extension in response to germline loss, and DAF-12/NHR and DAF-9/CYP27 probably form a complex with DAF-16/FOXO to function, although the detailed mechanisms remain to be further determined.

Thus multiple signaling pathways such as the insulin/IGF-1 signaling pathway, TOR signaling, AMPK pathway, JNK pathway, and germline signaling have been found to be involved in aging and longevity. DAF-16/FOXO, as a key transcription factor, could integrate different signals from these pathways to modulate aging, and longevity via shuttling from cytoplasm to nucleus. Hence, understanding how DAF-16/FOXO functions will be pivotal to illustrate the processes of aging and longevity.

The answer to regenerative medicine's most compelling question - why some organisms can regenerate major body parts such as hearts and limbs while others, such as humans, cannot - may lie with the body's innate immune system, according to a new study of heart regeneration in the axolotl, or Mexican salamander. Researchers found that the formation of new heart muscle tissue in the adult axolotl after an artificially induced heart attack is dependent on the presence of macrophages, a type of white blood cell. When macrophages were depleted, the salamanders formed permanent scar tissue that blocked regeneration.

The goal is to activate regeneration in humans through the use of drug therapies derived from macrophages that would promote scar-free healing directly, or those that would trigger the genetic programs controlling the formation of macrophages, which in turn could promote scar-free healing. The team is already looking at molecular targets for drug therapies to influence these genetic programs. "If humans could get over the fibrosis hurdle in the same way that salamanders do, the system that blocks regeneration in humans could potentially be broken. We don't know yet if it's only scarring that prevents regeneration or if other factors are involved. But if we're really lucky, we might find that the suppression of scarring is sufficient in and of itself to unlock our endogenous ability to regenerate."

The prevailing view in regenerative biology has been that the major obstacle to heart regeneration in mammals is insufficient proliferation of cardiomyocytes, or heart muscle cells. But researchers found that cardiomyocyte proliferation is not the only driver of effective heart regeneration. The findings suggest that research efforts should pay more attention to the genetic signals controlling scarring. When a human experiences a heart attack, scar tissue forms at the site of the injury. While the scar limits further tissue damage in the short term, over time its stiffness interferes with the heart's ability to pump, leading to disability and ultimately to terminal heart failure. The next step is to study the function of macrophages in salamanders and compare them with their human and mouse counterparts. Ultimately, researchers would like to understand why macrophages produced by adult mice and humans don't suppress scarring in the same way as in axolotls and then identify molecules and pathways that could be exploited for human therapies.

In dramatic contrast to the poor repair outcomes for humans and rodent models such as mice, salamanders, and some fish species are able to completely regenerate heart tissue following tissue injury, at any life stage. This capacity for complete cardiac repair provides a template for understanding the process of regeneration and for developing strategies to improve human cardiac repair outcomes. Using a cardiac cryo-injury model we show that heart regeneration is dependent on the innate immune system, as macrophage depletion during early time points post-injury results in regeneration failure.

In contrast to the transient extracellular matrix that normally accompanies regeneration, this intervention resulted in a permanent, highly cross-linked extracellular matrix scar derived from alternative fibroblast activation and lysyl-oxidase enzyme synthesis. The activation of cardiomyocyte proliferation was not affected by macrophage depletion, indicating that cardiomyocyte replacement is an independent feature of the regenerative process, and is not sufficient to prevent fibrotic progression. These findings highlight the interplay between macrophages and fibroblasts as an important component of cardiac regeneration, and the prevention of fibrosis as a key therapeutic target in the promotion of cardiac repair in mammals.

Chronic tissue inflammation resulting from obesity is an underlying cause of insulin resistance and type 2 diabetes. But the mechanism by which this occurs has remained cloaked. Researchers have now identified exosomes - extremely small vesicles or sacs secreted from most cell types - as the missing link. "The actions induced by exosomes as they move between tissues are likely to be an underlying cause of intercellular communication causing metabolic derangements of diabetes. By fluorescently labeling cells, we could see exosomes and the microRNA they carry moving from adipose tissue through the blood and infiltrating muscle and liver tissues."

During chronic inflammation, the primary tissue to become inflamed is adipose. Forty percent of adipose tissue in obesity is comprised of macrophages - specialized immune cells that promote tissue inflammation. Macrophages in turn create and secrete exosomes. When exosomes get into other tissues, they use the microRNA (miRNA) they carry to induce actions in the recipient cells. The macrophage-secreted miRNAs are on the hunt for messenger RNAs. When the miRNA finds a target in RNA, it binds to it, rendering the messenger RNA inactive. The protein that would have been encoded by the messenger RNA is no longer made. Thus, the miRNAs are a way to inhibit the production of key proteins.

Researchers took macrophages found in adipose tissue of obese mice and harvested their exosomes. Lean, healthy mouse models were treated with these "obese" exosomes and once-normal mice began exhibiting obesity-induced insulin resistance despite not being overweight. When reversing the process, the team found that they could restore insulin sensitivity to obese mice by treating them with exosomes from lean mice. The obese mice remained overweight, but were metabolically healthy. Similarly, during an in vitro study, when human liver and fat cells were treated with "obese" exosomes, these cells became insulin resistant. Conversely, when they were treated with "lean" macrophage exosomes, they became highly sensitive to insulin. "This is a key mechanism of how diabetes works. This is important because it pins the pathophysiology of the disease in inflamed adipose tissue macrophages which are making these exosomes. If we can find out which of the microRNAs in those exosomes cause the phenotype of diabetes, we can find drug targets."

MiRNAs are regulatory molecules that can be packaged into exosomes and secreted from cells. Here, we show that adipose tissue macrophages (ATMs) in obese mice secrete miRNA-containing exosomes (Exos), which cause glucose intolerance and insulin resistance when administered to lean mice. Conversely, ATM Exos obtained from lean mice improve glucose tolerance and insulin sensitivity when administered to obese recipients.

miR-155 is one of the miRNAs overexpressed in obese ATM Exos, and earlier studies have shown that PPARγ is a miR-155 target. Our results show that miR-155 knock out animals are insulin sensitive and glucose tolerant compared to controls. Furthermore, transplantation of wild type bone marrow into miR-15 knock out mice mitigated this phenotype. Taken together, these studies show that ATMs secrete exosomes containing miRNA cargo. These miRNAs can be transferred to insulin target cell types through mechanisms of paracrine or endocrine regulation with robust effects on cellular insulin action, in vivo insulin sensitivity, and overall glucose homeostasis.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

SENS Research Foundation (SRF) has launched a new research program focused on developing monoclonal antibodies against glucosepane. David A. Spiegel will be running the project in his laboratory, which focuses on developing new methods and molecules that will facilitate our understanding and treatment of human disease.

Glucosepane is the most prevalent crosslink found in collagen in people over 65 years of age, and its presence has been correlated to age-related tissue damage through various mechanisms. Understanding of glucosepane has been hampered by the molecule's complex and sensitive chemical structure; it can only be isolated from human samples in minute quantities and in an impure form. To enable these advances in both basic and therapeutic science, the Spiegel laboratory has recently accomplished the first total synthesis of glucosepane.

The lab is now utilizing its novel synthetic glucosepane derivatives to generate the first monoclonal anti-glucosepane antibodies. Access to these antibodies would profoundly accelerate the goal of developing the first discrete, specific reagents for labeling, studying, and perhaps also cleaving glucosepane in vivo. Such tools have tremendous potential to help illuminate, and reverse, age-related damage as it occurs in human tissues.

This research has been made possible through the generous support of Michael Antonov and the Forever Healthy Foundation and its founder Michael Greve. The Forever Healthy Foundation is a private nonprofit initiative whose mission is to enable people to vastly extend their healthy lifespans and be part of the first generation to cure aging. In order to accelerate the development of therapies to bring aging under full medical control, the Forever Healthy Foundation directly supports cutting-edge research aimed at the molecular and cellular repair of damage caused by the aging process.

As a promising approach to tissue repair, multiple types of stem cells have entered the stage of clinical testing. However, their efficacy is limited by low retention and engraftment of transplanted cells, together with the potential risk of inflammation and immunoreaction when allogeneic or xenogeneic cells are used. Heart diseases including myocardial infarction (MI) and heart failure remain the leading cause of death worldwide. Even with the most advanced pharmacological and medical device treatment methods, mortality and morbidity of heart disease stay high. Cardiac tissue engineering and stem cell transplantation approaches aim at de novo cardiac regeneration after injury. Clinical outcomes of cardiac stem cell (CSC) therapy are hampered by low cell retention rate and side effects associated with immune rejection if allogeneic cells are used.

Injectable hydrogels have been used to treat MI, and the studies have been demonstrated to improve cardiac function via increased heart wall thickness and reduced wall stress. Various natural polymers such as fibrin, collagen, Matrigel, chitosan, keratin, and hyaluronic acid have been investigated as injectable hydrogels to treat MI. They have excellent biocompatibility and can promote cell migration, proliferation, and/or differentiation, leading to ultimate heart regeneration/repair. However, the drawbacks of natural polymers hampering their clinical applications are their batch-to-batch variation and expensive cost.

Synthetic polymers hold the potential to replace natural polymers as injectable hydrogels to treat MI. One appealing regenerative medicine strategy for MI is encapsulating stem cells such as CSCs inside the hydrogels and deliver the cell-laden hydrogels into the damage tissues. Here, we propose the use of P(NIPAM-AA) nanogel, a synthetic injectable carrier to encapsulate human CSCs in mouse and pig models of MI. The nanogel serves as a scaffolding material to enhance cell retention and as a barrier to prevent T cells from entering and attacking the encapsulated CSCs. The treatment ultimately resulted in augmented cardiac function and stimulation of endogenous regeneration.

The mechanisms underlying the therapeutic benefits of nanogel-encapsulated CSC therapy are likely to be complicated. Our findings indicated that the P(NIPAM-AA) nanogel-encapsulated hCSCs promoted post-MI cardiac repair by the inhibition of apoptosis and promotion of angiomyogenesis. Collectively, these favorable actions lead to reduced fibrosis and improved cardiac function. Fast degrading natural polymers do not support long-term support to the heart. In contrast, synthetic polymers cannot be quickly removed by enzyme activities. In real scenarios, we expect the nanogel will provide a shield for allogeneic stem cells or induced pluripotent cells, which are likely to trigger immune reaction in the host tissue. In addition, the polymer carrier can drastically improve cell retention rate.

Microglia normally gobble up and break down amyloid-β (Aβ). However, in Alzheimer's disease (AD), an altered inflammatory state causes them to stop clearing the aggregated peptide. How does this happen, and can it be stopped? Researchers blame the microglial enzyme RIPK1, and believes that blocking it may help return microglia to their normal state. The kinase appears to set off transcriptional changes that cripple the microglial lysosome system. The cells start producing new gene products, some characteristic of the recently identified disease-associated microglia (DAM) surrounding plaques in AD model mice. Genetically deleting or pharmacologically inhibiting RIPK1 both sped up Aβ clearance and improved memory in an AD mouse model. The findings lay the groundwork for a new treatment for AD, and, since RIPK1 has been implicated in amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), for those diseases as well.

"It's the first paper that shows blocking RIPK1 alleviates the inflammatory response, reduces plaque, and improves behavior in AD mice. It points out directly the beneficial effects of inhibiting RIPK1 for the treatment of multiple diseases characterized by inflammation and cell death. Microglial lysosome biology is poised to become the next hot topic in Alzheimer's research. A lot of recent data are pointing to failure of the lysosome in microglia and other innate immune cells as the problem in AD, and rebalancing that as the way forward."

RIPK1, short for Receptor-interacting protein 1 kinase, gets induced in response to the inflammatory signals tumor necrosis factor (TNFa) and ligands of the toll-like receptor (TLR) family. It causes an inflammatory response, controls inflammation-induced cell death (necroptosis), and leads to some forms of apoptosis. The researchers first peered into postmortem human brains and found more phosphorylated RIPK1 in slices from AD patients than controls. This implied that the kinase was activated in the disease. That RIPK1 co-localized with microglial markers suggested that it was expressed primarily in these cells.

What did the kinase do? The authors tested this in APP/PS1 mice by adding to their drinking water a RIPK1 inhibitor the group had previously developed called necrostatin-1 (Nec-1s). After a month, the treated mice had fewer plaques and less soluble and insoluble Aβ in the brain. What's more, whereas five-month-old APP/PS1 mice scurried around an open field in a hyperactive state, a month of Nec-1s treatment calmed them down. The researchers also examined spatial memory with a T-shaped water maze, where mice are trained to find a hidden platform at the end of one arm, then retrained to find it in another. At five months, APP/PS1 mice had trouble learning a new platform location, but a month of Nec-1s restored their performances to match those of wild-type mice.

How does a microglial kinase do this? The researchers added Aβ1-42 to microglia isolated from wild-type mice and mice lacking the kinase. Wild-type cells bumped up production of the inflammatory cytokines TNFa and IL6, mutant cells less so. Wild-type microglia pretreated with Nec-1s also produced less TNFα and IL6. Intriguingly, microglia lacking RIPK1 action better digested synthetic Aβ1-42 oligomers. What whetted their appetites? Analyzing the microglial transcriptomes, reserchers found that one of the proteins upregulated by RIPK1 was cystatin F. Encoded by the Cst7 gene, cystatin F inhibits the endosomal/lysosomal system responsible for breaking down unwanted proteins and other metabolic waste.

As we age, we may be less able to perform daily activities because we may feel frail, or weaker than we have in the past. Frailer older adults may walk more slowly and have less energy. Frailty also raises a person's risks for falling, breaking a bone, becoming hospitalized, developing delirium, and dying. No one knows exactly how many older adults are frail - estimates range from 4 percent to 59 percent of the older adult population. Researchers say that frailty seems to increase with age, and is more common among women than men and in people with lower education and income. Being in poorer health and having several chronic illnesses also have links to being frail.

Frailty also tends to worsen over time, but in at least two studies, a small number (9 percent to 14 percent) of frail older adults became stronger and less frail as they aged. The researchers examined information gathered from more than 5,000 men aged 65 or older (average age was about 73) who had volunteered for a study about bone fractures caused by osteoporosis. At the start of the study, between 2000 and 2002, the men all lived independently and could walk; none had had hip replacements. Most of the men participated in a second examination about four years after the study began.

At the start of the study, the researchers determined the participants' frailty status by measuring levels of weakness, exhaustion, lean muscle mass, walking speed, and physical activity. The men were categorized as frail, pre-frail (had one or more signs of frailty, such as low grip strength, low energy, slow walking speed, low activity level or unintentional weight loss), or robust (showing no signs of frailty). At the start of the study, nearly 8 percent of the men were frail and 46 percent were pre-frail. The most common problems for the frail men were weakness, slowness, and low activity.

Over four and a half years, the number of frail men increased while the proportion of robust men decreased. Among the men who were frail at both visits: 56 percent had no change in frailty status, 35 percent had become frailer or had died, 15 percent of pre-frail or frail men improved. Having greater leg power, being married, and reporting good or excellent health were linked to improvements in frailty status.

White blood cells called neutrophils are like soldiers in your body that form in the bone marrow and at the first sign of microbial attack, head for the site of injury just as fast as they can to neutralize invading bacteria or fungi using an armament of chemical weapons. But when that injury is an intracerebral hemorrhage, which releases blood into the brain, neutrophils arrive at the point of battle only to discover that there's no infection to attack. Unless immediately removed from the brain by other immune cells, they actually cause damage and deploy an array of toxic chemicals into the brain that worsen injury.

Now researchers have discovered a way to temporarily suppress these soldiers' pro-killing effect and turn them into beneficial weapons that scavenge for toxins, potentially opening a door for a therapeutic approach to hemorrhagic stroke treatment. A hemorrhagic stroke occurs when an artery inside the brain leaks or ruptures. It is the second-most common form of stroke after ischemic stroke, has a 30 to 67 percent mortality rate and is the main cause of disabilities among adults. Because half of hemorrhagic stroke victims die within the first two days, researchers believe that deadly secondary damage, including through toxicity of iron from the breakdown of red blood cells, leads to an excess in free radicals and inflammation.

Along with carrying chemicals that could aggravate injury, neutrophils produce and release potentially beneficial molecules including lactoferrin, an iron-binding protein. At the same time the neutrophils are getting ready to attack inside the brain, the brain and spleen are releasing interleukin-27 molecules, which can signal to the neutrophils to produce more lactoferrin and thus benefit the brain as it recovers from the stroke injury. "This is one of the first discoveries showing that you can train neutrophils to act as friendly cells. We've adapted how the body already responds naturally, but it can take 12 to 18 hours for the signal to turn them from damaging neutrophils to the beneficial cells that release lactoferrin and by then, it can be too late. Treatment with lactoferrin in our models is effective in reducing brain damage after hemorrhage and we are working on a modified form of lactoferrin that could penetrate the brain better and quicker."

Physical activity of any kind can prevent heart disease and death, says a large international study involving more than 130,000 people from 17 countries. The Prospective Urban Rural Epidemiology (PURE) study shows any activity is good for people to meet the current guideline of 30 minutes of activity a day, or 150 minutes a week to raise the heart rate. Although previous research, from high income countries, shows leisure time activity helps prevent heart disease and death, the PURE study also includes people from low and middle-income countries where people don't generally don't participant in leisure-time physical activity. "By including low and middle-income countries in this study, we were able to determine the benefit of activities such as active commuting, having an active job or even doing housework." One in four people worldwide do not meet the current activity guideline and that number is nearly three of four in Canada.

The PURE study showed that by meeting the activity guidelines, the risk for death from any cause was reduced by 28%, while heart disease was reduced by 20%, and it didn't matter what type of physical activity the person did. The benefits also continued at very high levels with no indication of a ceiling effect; people getting more than 750 minutes of brisk walking per week had a 36% reduction in risk of death. However, less than 3% of participants achieved this level from leisure time activity while 38% of participants achieved this level from activities such as commuting, being active at work or doing household chores.

"Going to the gym is great, but we only have so much time we can spend there. If we can walk to work, or at lunch time, that will help too. For low and middle income countries where having heart disease can cause a severe financial burden, physical activity represents a low-cost approach that can be done throughout the world with potential large impact. If everyone was active for at least 150 minutes per week, over seven years a total of 8% of deaths could be prevented,"

Cancer, which is one of the leading causes of death worldwide, arises from the disruption of essential mechanisms of the normal cell life cycle, such as replication control, DNA repair and cell death. Thanks to the advances in genome sequencing techniques, biomedical researchers have been able to identify many of the genetic alterations that occur in patients and are common among and between tumor types. But until recently, only mutations in DNA were thought to cause cancer. In a new study, researchers show that alterations in a process known as alternative splicing may also trigger the disease.

Although DNA is the instruction manual for a cell growth, maturation, division, and even death, it's proteins that actually carry out the work. The production of proteins is a highly regulated and complex mechanism: cellular machinery reads the DNA fragment that makes up a gene, transcribes it into RNA and, from the RNA, makes proteins. However, each gene can lead to several RNA molecules through alternative splicing, an essential mechanism for multiple biological processes that can be altered in disease conditions.

Using data for more than 4,000 cancer patients from the Cancer Genome Atlas, a team has analyzed the changes in alternative splicing that occur in each tumor patient and studied how these changes could impact the function of genes. The results of the study show that alternative splicing changes lead to a general loss of functional protein domains, and particularly those domains related to functions that are also affected by genetic mutations in cancer patients. "Thanks to our previous research, we know that tumor type and stage can be predicted by observing alterations in alternative splicing. With this new study, we have discovered that changes in alternative splicing that occur in cancer impact protein functions in a way that is similar to that previously described for genetic mutations." All of these alterations in protein functions would cause changes in cells morphology and function, giving them the characteristics of tumor cells, such as a high proliferative potential or the ability to avoid programmed cell death.