Fight Aging! Newsletter, August 8th 2022

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  • Changes in the Behavior of Lipid Rafts in Aging
  • Aging and the Severity of Inflammatory Infectious Disease Such as SARS-CoV-2
  • Are Pharmacological Approaches to Slow Aging in Fact Promising?
  • Interviews on Aspects of Aging with Judith Campisi and Dena Dubal
  • A Modest Gain in Mouse Lifespan via Pharmacological Means of CISD2 Upregulation
  • Cancers Subvert the Immune System to Create a Protective Population of Regulatory T Cells
  • Investigating Mechanisms of Increased Muscle Strength Following Exercise
  • Oxidized LDL in Cancer Metastasis
  • Complaining About the Remaining Unknowns in Aging, in the Context of the Hallmarks of Aging
  • Does Acarbose Extend Life in Short Lived Species via Gut Microbiome Changes?
  • Glutamine Supplementation in Old Age May Produce Similar Effects to mTOR Inhibition
  • Correlating Epigenetic Age Acceleration with Survival in Older Individuals
  • PTPσ Inhibition Promotes Repair of the Brain Following Injury
  • Continuing the Debate Over Viral Contributions to Alzheimer's Disease
  • Weak Grip Strength Correlates with Increased Mortality Risk in Old Age

Changes in the Behavior of Lipid Rafts in Aging

It is fair to say that everything changes with age, every aspect of cellular biochemistry. That doesn't mean that researchers can point to any specific change and say that it is important, however. It could be far downstream from underlying causes. It could be hard to fix in comparison to those causes. It may be shown to detrimentally affect a range of vital cellular processes, but those mechanisms could turn out to be minor and unimportant in comparison to others. The major challenge in aging research is exactly that everything changes. It is thus very hard to determine the importance of any given change, given that it takes place in this complex environment of interacting dysfunction, chains of cause and consequence, a network falling into failure.

Lipid rafts are assemblies that constantly form and break down in and around the cell membrane, a complex little world in and of itself. The cell membrane influences everything to do with cell signaling, uptake of materials from the environment, export of materials from the cell, and a good many other things besides. Thus any changed aspect of the cell membrane, such as altered behavior of lipid rafts, will also influence these line items. But is it important?

That is a hard and expensive question to answer. Theorizing costs little, however, and thus we see a great deal of theorizing. Today's open access paper is good example of a fairly aggressive joining of dots with little to no support for the importance of the proposed mechanisms as a target for intervention. Which is, sadly, business as usual in the matter of aging: the only practical way to prove that any given approach is a good approach is to try it. Unfortunately, building the means to try it in the context of something as complex as lipid raft behavior gets us right back to hard and expensive again.

Crosstalk between Lipid Rafts and Aging: New Frontiers for Delaying Aging

Lipid rafts (LRs) are microdomains (10-200 nm) with a short life, and their components, such as sphingolipids, cholesterol, and proteins, are assembled to function and disassemble quickly afterward. The components and sizes of LRs are not constant, and they can merge with each other to become larger when necessary. As hubs for signal transduction, LRs contain various signal proteins. Because signal transduction is essential for aging processes, the relationship between LRs and aging has attracted increasing attention. Aging drastically affects the components and functions of LRs. Further, considering the evidence, the influences of LRs on the hallmarks of aging are apparent. Many of these hallmarks contribute to the development of sustained inflammatory stage and aging. Hence, attempts to "cure" aging should involve amelioration of inflammaging (chronic, sterile, low-grade inflammation during aging), which can be achieved by regulating LRs.

Modulation of cholesterol is one way to regulate LRs, as cholesterol is a critical constituent of LRs. Most cellular cholesterol exists in the membrane and is enriched in LRs. Depleting cholesterol can disrupt the form of LRs and reduce the content of LRs, suggesting that cholesterol-lowering drugs such as statins, can alleviate inflammaging to anti-aging by inhibiting the formation of LRs. As expected, clinical results have demonstrated that new statin use is associated with a decreased death rate among American veterans (75 years and older).

However, one of the frequently reported adverse reactions of statins is memory impairment and cognitive decline. Coincidentally, Alzheimer's disease, which is characterized by cognitive and memory deterioration, is associated with reduced levels of cholesterol and LRs in the frontal cortex. Based on these results, we speculate that the adverse effects of statins on memory and cognitive alterations may partly be due to their cholesterol-lowering effects and hindered formation of LRs. Therefore, when using statins to delay aging, it is recommended to adopt some pharmaceutical modifications to increase the polarity of the statins or to choose hydrophilic statins instead of lipophilic statins for making them selective and inaccessible to the central nervous system, thus reducing their side effects.

Overall, aging has been proven modifiable, and some drugs for slow aging have been discovered. For example, rapamycin inhibits mTOR activation to delay aging; senolytics can target and eliminate senescent cells; sirtuin activators, which enhance sirtuin activity; Nicotinamide adenine dinucleotide (NAD) precursors that can supply cellular NAD levels; antidiabetic drugs such as metformin and acarbose; and non-steroidal anti-inflammatory drugs, can also be used. However, none of drugs target LRs to delay aging, making it a future objective. Overall, targeting LRs will be a novel strategy for prolonging life, and statins might be promising candidates for new anti-aging agents.

Aging and the Severity of Inflammatory Infectious Disease Such as SARS-CoV-2

Today I'll point out a couple of papers on the topic of why SARS-CoV-2 is so much more severe in the old. There has been a great deal of discussion about the age-related nature of COVID-19 mortality these past few years, though near entirely within the scientific community. The more severe cases involve runaway inflammation, and old people already suffer a raised level of chronic inflammatory signaling, making them that much more vulnerable to cytokine storm events in which the immune system runs wild to cause severe pathology and death. Sepsis is a similar problem, similarly age-related for reasons relating to increased vulnerability.

It isn't just a higher base level of inflammatory signaling with age, however. Nor is it only inflammatory signaling coupled with immunosenescence, the growing inability of the adaptive immune system to engage effectively with pathogens. Infectious diseases that are shrugged off in youth would be serious threats to the old and frail even if immunosenescence was the only consequence of aging. Unfortunately many other aspects of aging also conspire to make an old person more vulnerable to inflammatory infectious disease. This has long been well illustrated by the mortality that attends every winter influenza season, COVID-19 was an unneeded lesson. And yet the broader public is still largely unaware that working towards rejuvenation therapies is perhaps the best, most cost-effective way to prevent these continued losses of life.

Inflammaging at the Time of COVID-19

Most people infected with SARS-CoV-2 have a self-limiting infection and do recover; others experience more severe disease, with 10% of patients requiring intensive care unit (ICU) admission. The case-fatality rate of COVID-19 is approximately 1.5%. Most COVID-19-related deaths have occurred in those 60 years and older, and an even higher mortality was registered among the oldest old (ie, ≥80 years). The presence of a least 1 underlying chronic condition (eg, cancer, diabetes, hypertension, obesity, cardiovascular disease, cerebrovascular disease) is a major risk factor for death. Older adults are more susceptible to SARS-CoV-2 infection, more prone to develop severe COVID-19, and more frequently admitted to ICUs, with consequent increased mortality.

An extraordinary proliferation of studies suggests that SARS-CoV-2 infection unleashes an abnormal inflammatory response, the so-called cytokine storm. Indeed, severe COVID-19 in hospitalized patients is characterized by high circulating levels of C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), and lymphopenia. The abnormal inflammatory response, along with hypercoagulability and defective viral clearance, contributes to the development of severe pneumonia and acute respiratory distress syndrome (ARDS), with subsequent end-organ damage, multiorgan system failure, and eventually death. Although severe COVID-19 disproportionally affects older people, systemic inflammation during SARS-CoV-2 infection is detected in patients of all ages, including children, in whom a severe multisystem inflammatory syndrome has been described. This implies that COVID-19-induced inflammation is not per se sufficient at inducing negative health outcomes. This article provides a pathophysiologic view of COVID-19 in older adults within the frame of inflammaging, with a focus on antiinflammatory treatments for acute and postacute disease.

How can Biology of Aging Explain the Severity of COVID-19 in Older Adults

Aging has been identified as one of the most relevant risk factors for poor outcomes in COVID-19 disease, independently from the presence of preexisting diseases. The COVID-19 mortality risk sharply increases for elderly subjects, as showed by the reports of China, Italy, and the United States. In particular, in Italy, case fatality rate for patient aged 40 to 49 years or younger was reported of about 0.4% or lower, 1% among those aged 50 to 59 years, 3.5% in those aged 60 to 69 years, 12.8% in those aged 70 to 79 years, to 20.2% from 80 years and older.

Age is not only an important predictor for mortality, but it is also associated with higher disease severity, in terms of increased hospitalization rates, length of hospital stay, need for intensive care, and invasive mechanical ventilation. Since now, different mechanisms responsible for worse outcomes in the elderly have been suggested, which include the remodeling of immune system, the higher prevalence of malnutrition and sarcopenia, the increased burden of multimorbidity, and, to a lesser extent, the direct effects of age on the respiratory system and hormonal profile. The interplay between all these causes, rather than the individual pathophysiological mechanism, explains the increased severity of the disease with age.

Are Pharmacological Approaches to Slow Aging in Fact Promising?

Today's open access review paper looks over a selection of what I would consider to be largely unpromising small molecules, each with evidence for their ability to slow aging, but very modestly and unreliably in most cases. Looking at the bigger picture, for much of the public it is still surprising to hear that the pace of aging can be adjusted via any form of therapy, so there is probably a role for simple, low-cost small molecule drugs in the process of education that leads to more serious efforts aimed at producing the means of human rejuvenation. Still, entirely too much effort is devoted towards small molecules that have inconsistent animal data (such as metformin), and also small effect sizes (such as metformin), and further are probably outpaced by the benefits of exercise - metformin again, but near all of the panoply of other calorie restriction mimetics that function via upregulation of cellular stress responses such as autophagy.

There are small molecules that are worth the effort, however. For example, senolytic therapies that selectively destroy senescent cells and produce rapid rejuvenation in animal models. This is far more interesting than the marginal slowing of aging produced by improved cell maintenance, not least because a single senolytic treatment results in lasting improvement as a result of the reduced burden of senescent cells. That said, there is at present a great deal more interest in the research and development community in producing small molecule drugs that alter metabolism to modestly slow aging, which have to be taken continuously over time, and which are unlikely to do better than lifestyle choices. A change in priorities is very much needed if we are to realize the promise of treating aging in our lifetimes.

Pharmacological Approaches to Decelerate Aging: A Promising Path

Aging is the principal risk factor for many illnesses such as cancer, cardiovascular disorders, and neurodegenerative diseases like Alzheimer's disease. Therefore, most elderly are being treated for a variety of chronic diseases and are suffering from side effects of the drugs. Only a 2% hindrance in the progression of aging, comparing with treatment of a disabling illness such as cancer would end up to a 10 million rise in healthier individuals and saving a large amount of budget. Hence, identifying smart therapeutic options that uphold the process of aging on one hand and simultaneously cease or decelerate the progression of age-related illnesses is of great significance.

The mTOR inhibitor rapamycin was first identified as an antifungal metabolite. The role of mTOR signaling pathway in longevity and extend of life span has been studied in numerous species. In general, inhibition of the mTOR pathway, either genetically or pharmacologically, has shown to increase lifespan in different species. The antiaging effects of rapamycin are exerted through various mechanisms, but the main route of action of rapamycin on the aging process is through inhibition of mTOR pathway. SIRT1 and AMPK occurs following inhibition of mTOR, so rapamycin can also be indirectly effective in the aging process by activating SIRT1 and AMPK following inhibition of the mTOR pathway. As known, mortality rate from infectious diseases is higher in older ages, which may be due to reduced immune function in old ages. One of the mechanisms by which the immune system is rejuvenated is the activation of autophagy. Inhibition of mTOR pathway can increase autophagy and therefore may be effective in increasing immune function during the aging process.

Resveratrol belongs to the polyphenol family exerting medical properties. The antiaging effect of resveratrol is exerted through several mechanisms. Resveratrol mimics the effects of caloric restriction (CR) and shows positive effects of CR in the aging process. It can have antiaging effects by inducing inhibitory effects on inflammation, improving mitochondrial function, suppressing oxidative stress, and regulating apoptosis. Another antiaging mechanism of resveratrol is through the activation of SIRT1. Activation of SIRT1 increases the antioxidant capacity of tissues and improves mitochondrial function.

Metformin is a biguanide and antidiabetic for the first-line treatment of type 2 diabetes. Metformin can lower plasma glucose levels and reduce the amount of glucose absorbed by the body and the amount of glucose produced by the liver. Metformin also enhances tissue sensitivity to insulin. Antiaging effects of metformin are governed by several mechanisms. In general, metformin activates AMPK and inhibits mTOR, downregulates IGF-1 signaling, reduces insulin levels, and inhibits electron transport chain (ETC) and mitochondrial complex 1.

Lithium is an alkali metal that is present in trace amounts in the body. The antiaging effect of lithium may be related to autophagy regulation, increasing telomere length, and enhancement of mitochondrial function in the brain. Inositol monophosphatase (IMPase) and glycogen synthase kinase-3 (GSK-3) contribute to the role of lithium in the regulation of autophagy.

Spermidine is a natural polyamine that is essential for cell proliferation and growth. Spermidine, as a polycation, binds to molecules such as DNA, RNA, and lipids, so it can play an important role in cellular functions. Spermidine affects autophagy, inflammation, DNA stability, transcription, and apoptosis. According to previous studies, spermidine can cause autophagy in multiple organs such as the liver, heart, and muscles. Spermidine induces autophagy by regulating the expression of autophagy-related genes such as Atg7, Atg15, and Atg11. Increased expression of elF5A and transcription factor EB (TFEB) by spermidine also induces autophagy.

Pterostilbene is an analogue of resveratrol from blueberries, which is obtained by both natural extraction and biosynthesis. Pterostilbene has anti-inflammatory, antioxidant, and antitumor effects. In a study investing the effect of pterostilbene on sepsis-induced liver injury, it was found that pterostilbene activates SIRT1, so it can also affect FOXO1, p53, and NF-κB. Pterostilbene also decreases the levels of inflammatory cytokines such as TNF-α and IL-6, decreases myeloperoxidase (MPO) activity, and increases Bcl-2 expression. Accordingly, pterostilbene can have anti-inflammatory and antiapoptotic effects.

Melatonin is a hormone in the pineal gland that affects many physiological functions. Melatonin secretion gradually decreases with aging. One of the antiaging mechanisms of melatonin is due to its antioxidant effects and reduction of oxidative stress, which leads to improved mitochondrial function. Melatonin has the ability to scavenge toxic free radicals and decrease reactive oxygen species (ROS) and can indirectly stimulate antioxidant enzymes such as GPx, glutathione reductase (GRd), and SOD. Melatonin also exerts its antiaging effects by increasing SIRT1 expression.

Acetylsalicylic acid or aspirin is obtained from the bark of the willow tree. Aspirin has a variety of medical uses. One of the main uses is to prevent secondary cardiovascular diseases. It also has analgesic and antitumor properties. The antiaging effects of aspirin on C. elegans, mice, and Drosophila melanogaster have been investigated. Lifespan increases when germ cell progenitors become ablated. One of the proposed antiaging mechanisms of aspirin is through its effect on the reduction of germline stem cells. Another proposed mechanism is improving intestinal barrier function by restricting the K63-linked ubiquitination and preventing intestinal immune deficiency.

Fisetin is a natural compound in the category of flavonoids. Fisetin can reduce age-related decline in brain function. This action can also be due to its antioxidant and anti-inflammatory effects. Fisetin can have a direct antioxidant effect and maintain mitochondrial function in the existence of oxidative stress and increase glutathione levels in cells. It has also anti-inflammatory effects against microglial cells by inhibition of 5-lipoxygenase and decreasing the production of lipid peroxides and inflammatory products. Fisetin can prevent neuroinflammation, neurodegeneration, and memory impairment by reducing oxidative stress. These functions are mediated by preventing the accumulation of ROS, inhibiting inflammatory cytokines, and regulating endogenous antioxidant mechanisms. Fisetin has senolytic effects as well by inhibiting the PI3K/AKT pathway. Downstream molecules of the mentioned pathway are involved in different parts of cellular processes by acting on the Akt/mTOR pathway that eventually leads to elimination of senescent cells. A study in mice found that taking fisetin reduces oxidative stress and inflammation and removes senescent cells; thus, tissue homeostasis is restored and lifespan is increased.

Interviews on Aspects of Aging with Judith Campisi and Dena Dubal

Today I'll point out a pair of interviews with researchers Judith Campisi and Dena Dubal, in which they discuss quite different aspects of aging. Campisi's research has a heavy focus on cellular senescence in aging. Cells become senescent constantly in the body, most because they hit the Hayflick limit on replication imposed upon the somatic cells that are the overwhelming majority of cells in our tissues. Cells can also become senescent because of damage, or encouraged into senescence by the signaling of other, nearby senescent cells. Once senescent, cells are normally quickly removed by the immune system or programmed cell death mechanisms, but the balance between creation and destruction is disrupted with age, allowing the number of senescent cells to grow. These cells secrete a potent mix of signals that produce chronic inflammation and disruption of tissue structure and function, an important contribution to degenerative aging.

Dubal, on the other hand talks about the well known gender difference in longevity. There are many, many theories as to why women life longer than men. It is a feature of species with mating patterns like our own, so it is unlikely to result from anything particularly human, such as median male versus median female lifestyle choices peculiar to our species, such as smoking. Evolution interacts with mating strategies to favor women in this way. Under the hood, identifying the mechanisms involved in the comparative longevity of women suffers from the same issue as many other areas in aging - everything changes with age! While the principle differences between male and female tissues are well known and easily enumerated, it is very challenging to link those fundamental differences to specific changes in the pace of aging or late life mortality. This remains an actively debated topic.

Why Do We Get Old, and Can Aging Be Reversed?

Campisi: Many of the processes that happen during aging really happen as a consequence of the declining force of natural selection. That is, there was no natural selection for these diseases. The process we study, cellular senescence, it's now clear - and certainly in mouse models - that this process, the cellular process, drives a large number of age-related diseases, everything from macular degeneration, to Parkinson's disease, cardiovascular disease, and even late-life cancer, but it evolved to protect young organisms from cancer. So we certainly don't want to stop it when we're young.

Senescence is a state that the cell enters, in which it adopts three new traits. One of them is it gives up almost forever, almost forever, the ability to divide. It will tend to resist dying. And most important, it tends to secrete a lot of molecules that can have effects on neighboring cells, and also in the circulation. Not that many cells have been studied when they become senescent. And almost everything else we know about senescence is slowly changing as we learn more and more about different cell types and different ways that cells enter senescence.

There are still very few of them even in very old and very diseased tissue. A few percent at the most. So why do people think this has anything to do with aging? That has to do with the third thing that happens when cells become senescent is they begin to secrete a large number of molecules that have biological activity outside the cell. And that means that those senescent cells can call immune cells to the site where they are, it can cause neighboring cells to fail to function. And it basically causes a situation that is classically termed chronic inflammation.

If you eliminate senescent cells, it is possible to do one of three things to an age-related pathology: You either make it less severe, or you postpone its onset, or - and this is, of course, the one we all love - in a few cases, you can even reverse that pathology.

Dubal: in every society that records mortality across the world, women live longer than men. From Sierra Leone, where lifespan is lower, to Japan and Sweden, where lifespan is much longer. But here's a really interesting piece of information: When we look historically across multiple countries and societies, at times of extreme mortality, like famine and like epidemics, the girls will live longer than the boys and the women will live longer than the men. And this, this really suggests to us that there is a biologic underpinning for female longevity, because even when there is very high and equal stress in the environment with very high mortality, the girls are outliving the boys and the women are outliving the men. There's some very, very sad and really remarkable times that, that demonstrate this including the Irish famine and many, many other examples in our world history.

If we think about this, biologically, why there could be sex differences and human longevity. One has to do with chromosomes, our genetics, our genetic code, and every single one of our cells in our bodies. And that is that female mammals and certainly female human mammals have two X chromosomes in every cell. One of them is inactivated during development, but there are two X chromosomes, and that is the sex chromosome complement of women and girls. In contrast, boys and men have one X and one Y chromosome. And so here already at the outset, there is a very clear and striking difference in our genetics. And so with this difference, and XX in females compared to XY in males, there, there arises for biologic reasons, for sex differences in longevity. One is that in males, there's a presence of a Y. And it is thought, although not experimentally shown, that maybe there are toxic effects or deleterious effects of the presence of a Y chromosome.

Further, all the mitochondria in all of your cells are inherited from our mothers. So in the process of cellular division and the creation of a zygote, mothers pass on their mitochondria, not fathers. And so this becomes really important because mitochondria can only undergo evolution in a female body. Males will never pass their mitochondria on. And so at the end of the day, what that predicts is that mitochondrial function is more evolved to female physiology, when compared to male physiology. And this may make a difference with aging when things begin to go awry. The female cells may be more fit because their mitochondria are more evolved to the female cells compared to male cells.

A Modest Gain in Mouse Lifespan via Pharmacological Means of CISD2 Upregulation

The usual progression of ways to tinker with metabolism in order to affect the pace of aging is much as follows: (a) identify an interesting mechanism associated with a single gene; (b) create mouse lineages in which the expression of this gene is manipulated in a controlled way via genetic engineering, to observe the outcomes; (c) use some form of gene therapy to overexpress or knock down that gene in mice, and note differences in life span and manifestations of aging; (d) search the drug databases for small molecules that might affect expression of the gene of interest without causing too many undesirable side-effects; (e) produce animal studies to show that the small molecule approach produces the same outcome as the genetic studies, but to a smaller degree.

If further development is then undertaken, it typically picks up from the small molecule demonstration, which is almost always unimpressive in comparison to the gene therapy. The economics of development still heavily favor working with small molecules, however, to the point at which producing a marginal therapy that is less likely to help patients is an acceptable cost of doing business. This is particularly the case since early investors typically make their returns, and are on to the next project, well before the issues associated with marginal effect sizes arise in phase II or phase III clinical trials. It is a broken system, and the obvious fix, that most small molecule development should in fact be gene therapy development, is slow in arriving. Gene therapies must fall in cost by a sizable amount to be competitive in this way.

Today's open access paper is an example of step (e) noted above in ongoing research into the role of CISD2 in aging. Researchers have in in the past demonstrated that CISD2 decreases in expression with age, and that producing mice that overexpress CISD2 extends their life span. This effect may arise because CISD2 influences autophagy and mitochondrial function, but like most longevity-associated genes, it participates in many cellular processes, and picking apart the relevant from the irrelevant is a challenging task. Here, researchers are trying to manipulate CISD2 with non-genetic means, and in doing so produce the predictably modest extension of life span in mice. If autophagy and other stress response mechanisms are the primary way in which CISD2 upregulation produces life extension, then it is unlikely to have any meaningful effect on life span in humans. Even given that the intervention in this study was started in late life, it is well known that this sort of calorie restriction mimetic approach works very much better in short-lived species than in long-lived species such as our own.

Hesperetin promotes longevity and delays aging via activation of Cisd2 in naturally aged mice

The human CISD2 gene is located within a longevity region mapped on chromosome 4q. In mice, Cisd2 levels decrease during natural aging and genetic studies have shown that a high level of Cisd2 prolongs mouse lifespan and healthspan. Here, we evaluate the feasibility of using a Cisd2 activator as an effective way of delaying aging. Hesperetin was identified as a promising Cisd2 activator by herb compound library screening. Hesperetin has no detectable toxicity based on in vitro and in vivo models. Naturally aged mice fed dietary hesperetin were used to investigate the effect of this Cisd2 activator on lifespan prolongation and the amelioration of age-related structural defects and functional decline. Tissue-specific Cisd2 knockout mice were used to study the Cisd2-dependent anti-aging effects of hesperetin. RNA sequencing was used to explore the biological effects of hesperetin on aging.

Three discoveries are pinpointed. Firstly, hesperetin, a promising Cisd2 activator, when orally administered late in life, enhances Cisd2 expression and prolongs healthspan in old mice. Secondly, hesperetin functions mainly in a Cisd2-dependent manner to ameliorate age-related metabolic decline, body composition changes, glucose dysregulation, and organ senescence. Finally, a youthful transcriptome pattern is regained after hesperetin treatment during old age.

Hesperetin is the first compound we have tested as a proof-of-concept for the hypothesis that a Cisd2 activator will have an anti-aging effect. Our findings provide an experimental basis for using Cisd2 as a molecular target for the screening and development of novel compounds that are able to activate Cisd2 pharmaceutically with the goal of translating these drugs into clinical interventions that can be used in geriatric medicine. Most importantly, hesperetin can be rapidly delivered systematically to multiple organs and tissues in vivo. Additionally, it has no detectable in vivo toxicity after long-term oral administration for 6-7 months in mice, specifically when supplemented in food at a dose of 100 mg/kg/day, which has a human equivalent dose of 491 mg/60 kg/day. Accordingly, it will be of great interest to develop hesperetin as a medicinally or nutritionally functional food for preventive purposes related to extending healthy lifespan and/or therapeutic purpose related to treating age-related diseases.

Cancers Subvert the Immune System to Create a Protective Population of Regulatory T Cells

Researchers here identify distinctive markers for a population of regulatory T cells that act to protect at least some types of tumor tissue from the rest of the immune system. Cancers subvert the immune system in a range of ways, making it blind to cancer cells, and even making immune cells assist in the growth of the cancer. In principle destroying these protective, subverted immune cells could produce a renewed attack on a tumor, or at the very least make it more vulnerable to present therapies, particularly those that encourage immune cells to attack cancer cells.

Some types of T cells work to calm their over-active brethren. Known as regulatory T cells, or T-regs, they typically tamp down inflammation, quieting that mob and thereby protecting nearby healthy tissues. In tumor tissue, researchers found a different flavor of T-regs. These immune-suppressing cells, swarming in tumor-environment specimens, were different from T-regs found elsewhere in the body. Their cell surfaces are marked by two distinct protein receptors. These specially marked T-regs were particularly good at tamping down inflammation, expanding in number and protecting the tumor cells from attack by other types of T cells.

To a casual observer, the T-regs from the tumor samples would look no different from those found elsewhere in the body. But the team used new techniques that allow scientists to identify characteristics of tens of thousands of individual cells in a sample, and advanced computing methods to sift through data. It allowed them to spot two types of receptor proteins on the surfaces of T-regs collected from the tumor. The telltale proteins have names only a scientist could love: IL-1R1 and ICOS. "What makes these cells unique is that they express both those proteins. You just don't see that co-expression on other T-reg cells."

One reason this pair of proteins may have been overlooked by researchers previously is that they occur in human T-regs, not in those of mice. Much of laboratory work in immunology relies on mouse models of the immune response, but this study focused on human tissues, taken from patients who either had cancer or non-cancerous lesions. Researchers hypothesize that these tumor-resident T-regs have been tricked by cancer into working for the wrong team. Surrounded by T cells searching for cancer cells to destroy, the tumors acquired an ability to either attract or generate a blanket of these ICOS/IL-1R1-bearing T-regs. Exactly how they did so is not clear, but their impact is to build up an immunosuppressive environment, protecting the tumor from ordinary T cells doing their jobs.

Investigating Mechanisms of Increased Muscle Strength Following Exercise

Mapping the regulation of improved muscle strength resulting from exercise may lead to interventions that increase or mimic these beneficial effects of exercise. Here, researchers report on a part of their investigation of proteins involved in regulating the response to exercise. They do not show that the new regulatory protein discovered in their work can be manipulated to enhance the effects of exercise on muscle strength, but they do show that it is important by removing it in mice to produce the outcome of greatly reduced muscle function.

Exercise induces signaling networks to improve muscle function and confer health benefits. To identify divergent and common signaling networks during and after different exercise modalities, we performed a phosphoproteomic analysis of human skeletal muscle from a cross-over intervention of endurance, sprint, and resistance exercise. This identified 5,486 phosphosites regulated during or after at least one type of exercise modality and only 420 core phosphosites common to all exercise.

One of these core phosphosites was S67 on the uncharacterized protein C18ORF25, which we validated as an AMPK substrate. Mice lacking C18ORF25 have reduced skeletal muscle fiber size, exercise capacity, and muscle contractile function, and this was associated with reduced phosphorylation of contractile and Ca2+ handling proteins. Expression of C18ORF25 S66/67D phospho-mimetic reversed the decreased muscle force production. This work defines the divergent and canonical exercise phosphoproteome across different modalities and identifies C18ORF25 as a regulator of exercise signaling and muscle function.

Oxidized LDL in Cancer Metastasis

LDL particles carry cholesterol from the liver throughout the body via the circulatory system. As the prevalence of oxidative molecules rises with age, a consequence of inflammation and mitochondrial dysfunction, ever more of these LDL particles become oxidized. This allows them to interact with cells in novel ways that contribute to atherosclerosis, the formation of fatty deposits in blood vessel walls, either by overwhelming them with additional cholesterol uptake, aggravating the lysosomal recycling system, or interacting with specialized receptors such as LOX-1 in ways that spur inflammatory behavior. Here, researchers report that one of the receptors known to be involved in these processes is also important to cancer metastasis - and so the same oxidative stress of aging that contributes to atherosclerosis is also contributing to a greater risk of severe cancer via this mechanism.

Cancer is the uncontrolled growth of body cells leading to the formation of tumors, triggered by the accumulation of mutations in a cell's genome. In order to become malignant, metastasizing cancer, tumor cells go through a series of transformations involving interactions between the body's immune system and the tumor. However, many mechanistic details in this process are still unclear, making the prevention and treatment of cancer notoriously difficult. However, there is growing evidence that in tumor progression to metastasis, inflammation of blood vessel-lining endothelial cells is a key process.

Researchers showed that metastasizing tumors, in contrast to non-metastasizing ones, accumulate proteoglycan molecules; these, in turn, attach to and accumulate LDL to the walls of blood vessels. The bound LDL becomes oxidized. There are also high levels of its receptor, called LOX-1, in the endothelial cells of metastasizing tumors. This, they found, causes these cells to produce inflammation signals that attract neutrophils. They then proved that in mice, the suppression of LOX-1 can significantly reduce tumor malignancy, and also that LOX-1 overexpression caused an increase in signaling molecules attracting neutrophils.

The study also points to a promising approach for treating and preventing malignant cancer - and cardiovascular disease - by targeting neutrophil recruitment to endothelial cells. "The number of patients with cancer who die not of cancer, but of cardiovascular events, is increasing. Targeting the LOX-1/oxidized LDL axis might be a promising strategy for the treatment of the two diseases concomitantly."

Complaining About the Remaining Unknowns in Aging, in the Context of the Hallmarks of Aging

This paper is, more or less, a complaint that the research community still knows far too little of the relative importance of different mechanisms of aging. That is fair enough, certainly true. The authors put that complaint in the context of the current prevalent attitude of using the hallmarks of aging as a checklist for development of therapies to intervene in aging, which in some cases (such as the dysregulation of nutrient sensing) is also fair enough. Not all of the hallmarks are evidently good places to intervene, as they are most likely far downstream of the causes of degenerative aging. That said, I do feel that the authors are deliberately ignoring the copious in vivo evidence for the efficacy of clearing senescent cells in the service of making their point, however. Given the many studies showing rapid reversal of diverse forms of age-related pathology in mice following treatment with senolytic drugs, it is a little ridiculous to suggest that we really don't know much about whether nor not removing of senescent cells is meaningfully beneficial.

The critical outstanding question is: Can aging processes be slowed down? Evidence in nature suggests a positive answer to this fundamental question. For instance, similar pathobiological changes associated with aging develop over very different time scales in different mammalian species. While it may take 70 years for a senile cataract to develop in a human, similar age-related changes develop in horses within 20 years, in dogs within 10 years, and in mice in even only 2 years. Analogous considerations also apply to many other age-related alterations (hair greying, muscle loss, etc.). Although the biology underlying these differences in aging rate are not well understood, these examples demonstrate that similar aging phenomena in comparable tissues can develop over very different absolute time scales. Therefore, there seems to be some plasticity that could be harnessed, in theory, for slowing down the aging process.

Much of what is currently thought to be known about the biological underpinnings of the aging process has been presented in concepts like the "hallmarks of aging" which summarize processes claimed to be involved in driving organismal aging phenomena. Here, we carefully examine the evidence presented in favor of such links between these processes and aging. As we will explain in detail below, we identify limitations that are often grounded in the choice of models and/or the way aging is measured. We conclude by outlining experimental designs that are suited to overcome these current limitations and that can be used to address if and to what extent putative aging regulators are in fact involved in regulating organismal aging rate.

Aging research essentially deals with a many-to-many mapping problem. There are changes in many age-sensitive phenotypes (collectively representing the aging process, i.e., the transition of a young adult organism to an aged one) that could, in theory, each be influenced by a large set of regulators. Advances in aging research will critically depend on a better definition of this problem. In conclusion, aging research will benefit from a better definition of how specific regulators map onto age-dependent change, considered on a phenotype-by-phenotype basis. Resolving some of these key questions will shed more light on how tractable (or intractable) the biology of aging is.

Does Acarbose Extend Life in Short Lived Species via Gut Microbiome Changes?

Acarbose is one of a few diabetes medications shown to modestly slow aging in short-lived species. Researchers here take a look at the evidence for this effect on life span to be mediated by changes in the gut microbiome. The gut microbiome changes with age: the relative numbers of harmful microbes increasing, contributing to the chronic inflammation of aging, while relative numbers of beneficial microbes decreases, causing a reduction in metabolites known to help tissue function. Directly changing the gut microbiome to a more youthful configuration via fecal microbiota transplantation has been shown to improve health and extend life in laboratory species, so it is not unreasonable to hypothesize that some of the pharmaceutical approaches that slow aging act at least in part by adjusting the gut microbiome.

The existing literature provides evidence that acarbose can affect the life span. This review links inflammation, mitochondria, and telomeres with the gut microbiota, illustrating individual mechanisms involved in acarbose-associated life span extension. Acarbose improves the immune system, inflammatory response, and mitochondrial function by affecting the gut microbiota. Acarbose supplementation is a cost-effective method for delaying aging given its potential health-restorative effects and limited side effects. This offers hope for analyzing the use of acarbose to improve health and reduce the risk of age-related diseases.

Additional experiments should be undertaken to verify our speculations; for instance, which bacteria affect the length of telomeres and mitochondrial function after acarbose intervention needs to be studied. The role of acarbose in affecting telomere length by regulating the gut microbiota should be investigated with a more rigorous scientific approach.

The present review describes several mechanisms by which acarbose affects the life span through the gut microbiota by considering different viewpoints and provides a new theoretical basis for the mechanism of acarbose-extended life spans. Hitherto, to the best of our knowledge, no other reviews have explained the mechanisms underlying life span extension by acarbose based on the perspective of gut microbiota. In general, many factors that affect the life span and mechanisms of acarbose that can help extend the life span of humans remain to be studied.

Glutamine Supplementation in Old Age May Produce Similar Effects to mTOR Inhibition

Researchers here link lower levels of glutamine with rising activation of mTOR signaling in aging, showing that it increases the burden of cellular senescence and impairs the cellular maintenance processes of autophagy. Either glutamine supplementation or mTOR inhibition addresses these specific defects. This is an interesting addition to what is known of the role of mTOR in aging, an area of active interest, with numerous mTOR inhibitor small molecule drugs presently under development. If the less costly and more readily available approach of glutamine supplementation can produce much the same benefits, that is a promising development.

Glutamine is a conditionally essential amino acid involved in energy production and redox homeostasis. Aging is commonly characterized by energy generation reduction and redox homeostasis dysfunction. Various aging-related diseases have been reported to be accompanied by glutamine exhaustion. Glutamine supplementation has been used as a nutritional therapy for patients and the elderly, although the mechanism by which glutamine availability affects aging remains elusive.

Here, we show that chronic glutamine deprivation induces senescence in fibroblasts and aging in Drosophila melanogaster, while glutamine supplementation protects against oxidative stress-induced cellular senescence and rescues the D-galactose-prompted progeria phenotype in mice. Intriguingly, we found that long-term glutamine deprivation activates the Akt-mTOR pathway, together with the suppression of function. However, the inhibition of the Akt-mTOR pathway effectively rescued the autophagy impairment and cellular senescence caused by glutamine deprivation.

Collectively, our study demonstrates a novel interplay between glutamine availability and the aging process. Mechanistically, long-term glutamine deprivation could evoke mammalian target of rapamycin (mTOR) pathway activation and autophagy impairment. These findings provide new insights into the connection between glutamine availability and the aging process.

Correlating Epigenetic Age Acceleration with Survival in Older Individuals

An epigenetic clock produces an epigenetic age from a patient blood or tissue sample. These clocks are trained on data from many individuals at varying ages. When the measured epigenetic age is greater than chronological age, in other words that their biochemistry looks more like that of older people from the training data, this is referred to as epigenetic age acceleration, and is thought to represent a more rapid progression of degenerative aging. Numerous studies have correlated epigenetic age acceleration with risk of specific age-related conditions. Here, researchers correlate it with odds of survival to late life. The worse the epigenetic age acceleration, the worse the odds of survival.

To our knowledge, this cohort study is the first study examining the association between epigenetic age acceleration (EAA) and healthy longevity among older women. In this racially and ethnically diverse cohort of older women, increased EAA as measured by Horvath, Hannum, PhenoAge, and GrimAge clocks was associated with lower odds of survival to age 90 years with intact mobility. Results were similar when including intact cognitive functioning.

Among 1813 women, there were 464 women (mean age at baseline, 71.6 years) who survived to age 90 years with intact mobility and cognitive functioning, 420 women (mean age at baseline, 71.3 years) who survived to age 90 years without intact mobility and cognitive functioning, and 929 women (mean age at baseline, 70.2 years) who did not survive to age 90 years. Women who survived to age 90 years with intact mobility and cognitive function were healthier at baseline compared with women who survived without those outcomes or who did not survive to age 90 years. The odds of surviving to age 90 years with intact mobility were lower for every 1 standard deviation increase in EAA compared with those who did not survive to age 90 years as measured by Horvath (odds ratio 0.82), Hannum (odds ratio 0.67), PhenoAge (odds ratio 0.60), and GrimAge (odds ratio 0.68) clocks.

This cohort study's findings suggest that EAA may be a valid biomarker associated with healthy longevity among older women. Our results suggest that EAA may be used for risk stratification and risk estimation for future survival with intact mobility and cognitive functioning within populations. Future studies could usefully focus on the potential for public health interventions to reduce EAA and associated disease burden while increasing longevity.

PTPσ Inhibition Promotes Repair of the Brain Following Injury

The brain is in principle capable of far more repair than it actually undertakes in practice. This is generally true of most tissues, since the processes and pathways of developmental growth still exist. New neurons can be produced by neural stem cells, and the synaptic connections between neurons can be rearranged to bypass damage, where possible. It is all a matter of finding the right points of control for cellular activities. With that in mind, researchers here demonstrate a way to upregulate neuroplasticity and show that, this approach produces improved function in mice, even comparatively late in the treatment of stroke damage.

In addition to neuroprotective strategies, neuroregenerative processes could provide targets for stroke recovery. However, the upregulation of inhibitory chondroitin sulfate proteoglycans (CSPGs) impedes innate regenerative efforts. Here, we examine the regulatory role of PTPσ (a major proteoglycan receptor) in dampening post-stroke recovery. Use of a receptor modulatory peptide (a mimetic of the PTPσ regulatory wedge region with a TAT domain to facilitate membrane penetration) or PTPσ gene deletion leads to increased neurite outgrowth and enhanced neural stem cell migration in vitro.

Post-stroke ISP treatment results in increased axonal sprouting as well as neuroblast migration deeply into the lesion scar with a transcriptional signature reflective of repair. Lastly, peptide treatment post-stroke (initiated acutely or more chronically at 7 days) results in improved behavioral recovery in both motor and cognitive functions. Therefore, we propose that CSPGs induced by stroke play a predominant role in the regulation of neural repair and that blocking CSPG signaling pathways will lead to enhanced neurorepair and functional recovery in stroke.

Continuing the Debate Over Viral Contributions to Alzheimer's Disease

Persistent viral infection may be an important contributing cause of Alzheimer's disease, either because the amyloid-β associated with Alzheimer's disease is a part of the innate immune response, and infection thereby increases production, or because persistent infection drives the chronic inflammation that disrupts the biochemistry of brain tissue. If viral infection does drive Alzheimer's disease, it may go some way towards explaining why the disease doesn't correlate with lifestyle factors such as weight, activity, and so forth, anywhere near as well as is the case for other common age-related conditions. It all sounds plausible, and the various mechanisms that may be involved certainly exist, but the supporting evidence from patient data is so far mixed, despite a few quite compelling studies. The hypothesis is by no means concretely demonstrated, but researchers here suggest that pathology may require multiple viruses, a possible explanation for confounding data in studies that only focus on one type of viral infection.

Using a three-dimensional human tissue culture model mimicking the brain, researchers have shown that varicella zoster virus (VZV), which commonly causes chickenpox and shingles, may activate herpes simplex (HSV), another common virus, to set in motion the early stages of Alzheimer's disease. Normally HSV-1 - one of the main variants of the virus - lies dormant within the neurons of the brain, but when it is activated it leads to accumulation of tau and amyloid beta proteins, and loss of neuronal function, signature features found in patients with Alzheimer's.

Researchers re-created brain-like environments in small 6 millimeter-wide donut-shaped sponges made of silk protein and collagen. They populated the sponges with neural stem cells that grow and become functional neurons capable of passing signals to each other in a network, just as they do in the brain. Some of the stem cells also form glial cells, which are typically found in the brain and help keep the neurons alive and functioning.

The researchers found that neurons grown in the brain tissue can be infected with VZV, but that alone did not lead to the formation of the signature Alzheimer's proteins tau and beta-amyloid - the components of the tangled mess of fibers and plaques that form in Alzheimer's patients' brains - and that the neurons continued to function normally. However, if the neurons already harbored quiescent HSV-1, the exposure to VZV led to a reactivation of HSV, and a dramatic increase in tau and beta-amyloid proteins, and the neuronal signals begin to slow down. "It's a one-two punch of two viruses that are very common and usually harmless, but the lab studies suggest that if a new exposure to VZV wakes up dormant HSV-1, they could cause trouble."

Weak Grip Strength Correlates with Increased Mortality Risk in Old Age

The characteristic loss of muscle mass and strength that occurs with age, sarcopenia, is accompanied by increased mortality risk where it is more pronounced. This may be because the causes of sarcopenia, such as loss of stem cell function, chronic inflammation, and so forth, have many other detrimental consequences, contributing to numerous fatal age-related conditions. This study illustrates the point, providing evidence for a weak hand grip strength to correlate with a shorter remaining life expectancy.

Muscle strength is a powerful predictor of mortality that can quickly and inexpensively be assessed by measuring handgrip strength (HGS). What is missing for clinical practice, however, are empirically meaningful cut-off points that apply to the general population and that consider the correlation of HGS with gender and body height as well as the decline in HGS during processes of normal ageing. This study provides standardised thresholds that directly link HGS to remaining life expectancy (RLE), thus enabling practitioners to detect patients with an increased mortality risk early on.

Relying on representative observational data from the Health and Retirement Study, the HGS of 8,156 survey participants aged 50-80 years was z-standardised by gender, age and body height. We defined six HGS groups based on cut-off points in standard deviation (SD) from the mean; we use these as predictors in survival analyses with a 9-year follow-up and provide RLE by gender based on a Gompertz model for each HGS group.

Even slight negative deviations in HGS from the reference group with have substantial effects on survival. RLE among individuals aged 60 years with standardised HGS of up to -0.5 SD from the mean is 3.0/1.4 years lower for men/women than for the reference group, increasing to a difference of 4.1/2.6 years in the group with HGS of -0.5 SD to -1.0 SD from the mean. By contrast, we find no benefit of strong HGS related to survival. Survival appears to decrease at much higher levels of muscle strength than is assumed in previous literature, suggesting that medical practitioners should start to become concerned when HGS is slightly below that of the reference group.

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