Fight Aging! Newsletter, July 18th 2022

Previously, we showed that extracellular matrices (ECMs), produced ex vivo by various types of stromal cells, direct bone marrow mesenchymal stem cells (BM-MSCs) in a tissue-specific manner and recapitulate physiologic changes characteristic of the aging microenvironment. In particular, BM-MSCs obtained from elderly donors and cultured on ECM produced by young BM stromal cells showed improved quantity, quality, and osteogenic differentiation. In the present study, we searched for matrix components that are required for a functional BM-MSC niche by comparing ECMs produced by BM stromal cells from "young" (≤25 years old) versus "elderly" (≥60 years old) donors.

With increasing donor age, ECM fibrillar organization and mechanical integrity deteriorated, along with the ability to promote BM-MSC proliferation and responsiveness to growth factors. Proteomic analyses revealed that the matricellular protein, Cyr61/CCN1, was present in young BM-ECM, but undetectable in elderly BM-ECM. To assess the role of Cyr61 in the BM-MSC niche, we used genetic methods to down-regulate the incorporation of Cyr61 during production of young ECM and up-regulate its incorporation in elderly ECM. The results showed that Cyr61-depleted young ECM lost the ability to promote BM-MSC proliferation and growth factor responsiveness. However, up-regulating the incorporation of Cyr61 during synthesis of elderly ECM restored its ability to support BM-MSC responsiveness to osteogenic factors such as BMP-2 and IGF-1.

We next examined aging bone and compared bone mineral density and Cyr61 content of L4-L5 vertebral bodies in "young" (9-11 m/o) and "elderly" (21-33 m/o) mice. Our analyses showed that low bone mineral density was associated with decreased amounts of Cyr61 in osseous tissue of elderly versus young mice. Our results strongly demonstrate a novel role for ECM-bound Cyr61 in the BM-MSC niche, where it is responsible for retention of BM-MSC proliferation and growth factor responsiveness, while depletion of Cyr61 from the BM niche contributes to an aging-related dysregulation of BM-MSCs. Our results also suggest new potential therapeutic targets for treating age-related bone loss by restoring specific ECM components to the stem cell niche.

Cancer survivors are at a significantly higher risk of age-related diseases than non-cancer controls, comparable to incident rates in the elderly population. Cellular senescence is a biologic aging hallmark and plays a causative role in numerous age-related diseases, many of which affect cancer survivors. Furthermore, many cancer therapies induce senescence, suggesting that therapy induced senescence (TIS) may be responsible for cancer survivors' various side effects.

A seminal study showed that treating fibroblasts with the chemotherapeutic doxorubicin induces senescence, as indicated by higher SA-β-gal, p16INK4, p21CIP1, and DNA damage response expression. Notably, doxorubicin induces senescence systemically and not only in tumor cells. In addition, doxorubicin significantly impairs hematopoietic stem cell function by reducing the number of colony-forming units, an effect rescued by ganciclovir-mediated (GCV-mediated) clearance of senescent cells (SCs). Furthermore, cardiomyopathy, a well-known side effect of doxorubicin, was almost entirely prevented by GCV treatment. Treating mouse breast cancer models with doxorubicin arrests tumor growth, with later cancer relapse, but combining doxorubicin with GCV significantly improves the survival of mice, reduces the incidence of metastasis, and reduces the number of metastatic foci in mice that developed metastasis. Lastly, the nocturnal running time of mice was significantly impaired after doxorubicin treatment, and GCV treatment almost entirely rescued this effect.

Eliminating SCs alleviates many acute effects (elevated inflammatory markers and cardiotoxicity) and chronic effects (fatigue, cancer relapse, metastasis) of doxorubicin, suggesting TIS-dependent pathogenesis of cancer therapy-related adverse effects in survivors, at least those treated with doxorubicin.

Focusing on cellular senescence over other mechanisms assumes that senescence drives accelerated aging processes in cancer survivors while conferring a relatively limited role to other biologic aging hallmarks. This, however, has not been proven; but since transformative preclinical advancements in alleviating age-related health conditions have been achieved by elimination of SCs, we feel it appropriate to focus on cellular senescence and advocate that considering cellular senescence as the driver of early aging in survivors could have great benefits in advancing the implementation of potential cutting-edge interventions to mitigate premature aging.

Undoubtedly, there is a concerted effort from the scientific community to address the phenotypes, mechanisms, biomarkers, and interventions of early aging in cancer survivors. Knowledge about cellular senescence has exponentially increased in recent years on the basis of preclinical studies, but only the outcomes of well-designed, robust clinical studies can prove whether senotherapies will be beneficial in decreasing morbidity, increasing longevity, and improving quality of life in survivors. Thus, the scientific community must go through the rigorous process of translating bench work into clinical trials with a well-defined outcome. Only after completion of randomized trials, if senolytics and other anti-aging drugs show excellent short- and long-term safety and efficacy, should these drugs be used in the clinic.

Aging clocks can be devised from any biological system that changes during age. Measuring the amount of variation in those biological systems may allow scientists to peer into how far an organism has drifted from youthful function or how close they are to mortality. Aging clocks specifically aim to inform subjects of their biological age, but many of these clocks deliver no information on how long a subject may have left. However, in cases where the data can deliver information on impending death (unless some type of intervention is taken), then those clocks are also mortality timers that can better serve a subject's decision making or the advice from a healthcare practitioner. Three categories exist, aging clocks that deliver biological age, aging clocks and mortality timers that deliver biological age and information to predict death, and mortality timers that only offer information that can be used to predict the onset of disease or death.

Even though aging clocks have become popular, the term mortality timer should also be used (where applicable) across the industry to deliver sobering information that may assist in changing poor decision making related to a subject's lifestyle. Many aging clocks and mortality timers exist, such as blood biomarkers (proteomics), epigenetic mechanisms, extracellular vesicles, immune system factors, telomere length, glycomic levels, grip strength, blood vessel health, and many more biological systems could be used to determine a subject's age. However, the accuracy to predict age, overall health, or impending demise may be lacking. From analyzing various aging clocks to mortality timers, it becomes evident that even though some aging clocks may deliver vast amounts of biological data, no single clock can deliver all biological data across all tissues from the generic samples collected with commercial kits.

All clocks appear to have limitations on the data they can deliver, albeit the data are extremely extensive from some aging clocks such as epigenetic, blood tests, and glycomic clocks. The findings of this article are (in no order of effectiveness) that epigenetic, glycomic, and blood/serum biomarkers are the three most powerful clocks that can be used, as not only can a biological age prediction be made, along with disease potential to disease penetrance, but they can also function as rough mortality timers. An impending mortality diagnosis is a sobering prediction to any subject, so clocks that can also deliver rough time of death also function as extreme motivation for subjects to change their lifestyle habits as a matter of urgency. Aging clocks will continue to evolve as new biomarkers are found; however, any biological machinery that wanes with age can be used to elucidate data regarding biological age.

Infections of different etiologies, neurotropic or not, have been associated with acute and long-term neurological consequences. These consequences involve cognitive decline and behavioral disorders such as depression and anxiety. The main cause of these sequelae is an inflammatory condition in the central nervous system (CNS) characterized by an increase in pro-inflammatory mediators secreted by glial cells, such as microglia and astrocytes.

Microglia, which has long been described as a resident immune cell in the CNS, is currently considered an essential and versatile cell, having well-defined roles in maintaining neuronal networks, supporting synaptic plasticity, repairing injuries, and participating in the inflammatory process. Microglial cells express pattern recognition receptors (PRRs) that recognize molecules known as pathogen-associated molecular pattern (PAMP) molecules and damage-associated molecular patterns (DAMPs). During infection, irrespective of whether the pathogen can invade the CNS, the microglia will respond quickly by altering its state. Once confronted with stimuli, microglia induce and modulate a broad spectrum of molecular and cellular responses in an attempt to eradicate the pathogen.

In recent years, several studies have shown the involvement of the microglial inflammatory response caused by infections in the development of neurodegenerative diseases. This has been associated with a transitory microglial state subsequent to an inflammatory response, known as microglial priming, in which these cells are more responsive to stimuli. Thus, systemic inflammation and infections induce a transitory state in microglia that may lead to changes in their state and function, making priming them for subsequent immune challenges.

Thus, repeated infectious processes can act as a second hit and trigger a response in the primed microglia. However, it is important to emphasize that the aging process itself can be considered a second hit. It was shown that early postnatal infection of rats with LPS combined with the aging process resulted in less successful cognitive aging in these animals. Aging is a risk factor for the development of many neurodegenerative diseases because the natural aging process includes functional and structural changes within the brain. Among these changes is immune system dysfunction, which generates a low-grade chronic pro-inflammatory condition called inflammaging. Considering that microglia are long-lived cells and are repeatedly exposed to infections during a lifetime, microglial priming may not be beneficial, as it may contribute indirectly to neurodegenerative disorders.

Cerebrospinal fluid (CSF) imparts neurorestorative functions, serving unique roles in development, immunity, and brain maintenance. It exchanges with brain interstitial fluid (ISF) by traversing a brain-wide network of perivascular spaces (PVS). Notably, CSF-ISF exchange has been demonstrated to facilitate the clearance of metabolic brain waste, such as β-amyloid. PVS are often regarded as Virchow-Robin spaces (VRS), yet the anatomy and boundaries of these spaces have never been clearly depicted. Indeed, original descriptions disputed VRS structure, although subsequent literature has generally summarized them as homogeneous perivascular reflections comprised of simple pial membranes. Some have suggested that CSF crosses pial membranes to enter PVS by percolating through pial pores that localize to adventitia of leptomeningeal vessels. However, others argue against the existence of PVS and the localization of associated pial pores.

Whereas these theories form the bases for current PVS models, anatomic evidence remains limited and little work has been published since the time of early PVS descriptions. Surprisingly few investigations have comprehensively and systematically evaluated the morphology of pia mater or the fluid pathways next to cerebral vessels, and discrepant reporting has resulted in an abundance of nomenclatures and partial anatomic descriptions. Given inconsistent interpretations, this study was undertaken with the aim of elucidating pial and PVS structure and tracer movement patterns at cerebral cortical surfaces in mice.

We show that pia is perforated and permissive to PVS fluid flow. Furthermore, we demonstrate that pia is comprised of vascular and cerebral layers that coalesce in variable patterns along leptomeningeal arteries, often merging around penetrating arterioles. Heterogeneous pial architectures form variable sieve-like structures that differentially influence cerebrospinal fluid (CSF) transport along PVS. Additionally, pial layers atrophy with age. Old mice also exhibit areas of pial denudation that are not observed in young animals, but pia is unexpectedly hypertrophied in a mouse model of Alzheimer's disease. Moreover, pial thickness correlates with improved CSF flow and reduced β-amyloid deposits in PVS of old mice.

In conclusion, we show that PVS morphology in mice is variable and that the structure and function of pia suggests a previously unrecognized role in regulating CSF transport and amyloid clearance in aging and disease.

The female ovary contains a finite number of oocytes, and their release at ovulation becomes sporadic and disordered with aging and with obesity, leading to loss of fertility. Understanding the molecular defects underpinning this pathology is essential as age of childbearing and obesity rates increase globally. We identify that fibrosis within the ovarian stromal compartment is an underlying mechanism responsible for impaired oocyte release, which is initiated by mitochondrial dysfunction leading to diminished bioenergetics, oxidative damage, inflammation, and collagen deposition.

Furthermore, antifibrosis drugs (pirfenidone and BGP-15) eliminate fibrotic collagen and restore ovulation in reproductively old and obese mice, in association with dampened M2 macrophage polarization and up-regulated MMP13 protease. This is the first evidence that ovarian fibrosis is reversible and indicates that drugs targeting mitochondrial metabolism may be a viable therapeutic strategy for women with metabolic disorders or advancing age to maintain ovarian function and extend fertility.

In this work, we refer to the measurement made by an aging clock as biological age (BA) given that the disparity between BA and chronological age (CA) significantly correlates with age-related health outcomes such as mortality and disease burden. Whether or not the metric provided by an aging clock truly represents BA is, however, debatable. Ultimately, these clocks make a calculation based on a set of inputs, which are typically molecular in nature and predictably vary with age in a population. In the case of epigenetic models, the methylation status (i.e., methylated or demethylated) of CpGs is utilized. If an intervention decreases the number outputted by an epigenetic clock, this means that the status of specific DNA methylation sites resembles that of a younger individual. While such a change may indicate that an individual has become biologically younger, it is feasible that a more youthful epigenetic signature can be induced irrespective of BA. One way to explore these two possibilities would be to determine if inputs used by aging clocks represent downstream biomarkers or instead causally contribute to age-related dysfunction.

Future trials using aging clocks should also take care to make traditional clinical measurements. Tests that assess functional performance in older adults - such as grip strength, gait speed, the 6-min walk test, and the timed up-and-go test - are especially valuable. In addition to estimating BA, it would be helpful to measure classical clinical biomarkers that are known to associate with lifespan and healthspan. Ultimately, the utility of BA being reduced without a concomitant functional improvement and/or a decreased risk of mortality is questionable. Conversely, a reduction in BA that is tethered to a clear enhancement in health and/or longer life is of interest. Long-term, longitudinal trials in older populations would be exceptionally valuable and offer insight into how a change in BA alters mortality-risk on an individual level. As more trials are published, we will gain a more thorough understanding of how clinically significant altering an aging clock is.

We would like to speculate that the dysfunctional nature of senescent cell mitochondria could be an advantage for interventions that aim to induce senescent cell apoptosis. Anti-senescence interventions, including both senolytic approaches (which aim to specifically ablate senescent cells) and senostatic/senomorphic approaches (designed to block the senescence-associated secretory phenotype (SASP) and thus the proliferation of senescence via bystander signaling), have been extraordinarily successful in relieving a very wide range of broadly age-associated degenerative conditions in experimental mice, and clinical trials for many of these are ongoing.

The low mitochondrial membrane potential (MMP) of senescent cells might be advantageous. Like many cancer cells, senescent cells have less capacity to maintain MMP compared with normal cells and are thus exposed to prolonged mitochondrial permeability transition pore (mPTP) opening, suggesting MMP as a selective functional target for senescent cells. We expect that low doses of mitochondrial uncouplers, such as FCCP or CCCP, will lead to a persistent depolarization of the mitochondrial membrane in senescent cells, resulting in constant mPTP opening and cell death. However, the same doses of uncoupler should be well tolerated by non-senescent cells with their more robust OXPHOS machinery and thus better ability to maintain MMP.

Accordingly, combination of a senolytic drug with an uncoupler should enhance senolytic sensitivity and specificity, enabling therapeutic efficacy to be reached at substantially lower doses of senolytic drugs, thus broadening the therapeutic window and reducing the risk of side effects for senolytic interventions.

A new study has shown how a protein called tau, a critical factor in the development of Alzheimer's disease, turns from normal to a disease state - and demonstrates how this discovery could deliver a therapeutic target. The findings provide hope for preventing the tau transformation process from happening, thereby keeping tau in a healthy state and avoiding toxic effects on brain cells. In the course of Alzheimer's disease development, tau accumulates in deposits inside brain cells. During this process, tau gets heavily modified, with various deposits made up of tau carrying multiple small changes at many different positions within the tau molecule. While such changes to tau have been known to neuropathologists for decades, it remained unclear how tau arrives at this multi-modified stage. The new study has solved part of this mystery and provides a new mechanism to explain how tau gets progressively modified.

The study set out to answer whether one change at one specific spot in tau would make it easier for another spot to be modified. The team focussed on the relationship between tau and protein kinases, which are enzymes that introduce changes in tau. Usually, protein kinases target specific spots, called phosphorylation sites, in tau and other proteins, and introduce changes only at these specific spots. Researchers suspected that some of these enzymes are able to target several spots in tau and would do so even more efficiently if tau were already modified at one spot to begin with. While the study did discover that one change in tau does makes it easier for another change to be introduced, it was also able to identify "master sites" in tau, being specific spots that govern subsequent modifications at most of the other sites.

The next step for the team was to see whether master sites could be targeted to reduce the toxic properties of tau in Alzheimer's, in a bid to improve memory function. The current study employed mice that have both amyloid and tau and developed Alzheimer's-like symptoms, including memory deficits. The researchers found that mice did not develop memory deficits when they had a version of tau that lacked one of the identified master sites, compared with mice that had the usual version of tau. The team will now investigate how its findings can be translated into a treatment.

Alzheimer's disease (AD) is characterized by senile plaques comprising β-amyloid (Aβ) proteins and neurofibrillary tangles formed by hyperphosphorylated tau aggregates. Massive efforts and resources have been poured into interventions aimed at removing or decreasing the production of Aβ. Until recently, amyloid and tau have been the focus of most drugs in development for AD. Beyond the accumulation of plaques and tangles, numerous processes go awry with aging that contribute to, or exacerbate, the pathology and progression of AD, including inflammation, impaired proteostasis, vascular dysfunction, mitochondrial/metabolic dysfunction, epigenetic dysregulation, and synaptic dysfunction. Thus, a combination of drugs to address many of these defects may be necessary to effectively treat AD. In recent years, an increasing number of drugs targeting these biological processes have emerged in the drug development pipeline for AD.

Currently, there are 143 agents in clinical trials for AD, of which 119 agents are disease-modifying agents. Of the disease-modifying agents, there are now more agents in AD clinical trials that are targeting inflammation (23; 19.3%) than amyloid (20; 16.8%) or tau (13; 10.9%). Inflammation is a major hallmark of aging, and chronic systemic inflammation is associated with brain volume shrinkage and impaired cognitive functions. While broad-spectrum anti-inflammatory drugs have failed to improve cognitive outcomes in AD patients, recent efforts have targeted specific aspects of inflammation that are harmful to the brain while sparing normal immune function. For example, senescent cells are thought to fuel age-related pathologies by evading cell death while continuing to release proinflammatory cytokines and chemokines to damage the surrounding tissue. Senolytic drugs can selectively induce apoptosis of these senescent cells, and there are currently 3 phase II clinical trials underway to test a senolytic combination of dasatinib (tyrosine kinase inhibitor) and quercetin (flavonoid) in mild cognitive impairment or early-stage AD.

Between the breadth of new drug targets under investigation that address the biology of aging, the rapid development and validation of new biomarkers, and the improved design and rigor of clinical trials, we are in a new era of Alzheimer's research and drug development. Given the multifaceted nature of AD pathogenesis and progression, and the many biological processes that become impaired with aging, it is unlikely that drugs addressing a single target will have enough efficacy in treating AD in a clinically meaningful manner. However, if incremental benefits are observed with some agents, combination trials should be considered. Combination therapies are the standard of care for many diseases of aging, including cancer and cardiovascular diseases, and will likely be necessary to successfully treat AD.

Inflammation in the brain has drawn widespread attention due to its implication in several diseases at multiple stages of life. For instance, some studies have suggested a relationship between neuroinflammation and several types of dementia. Several insults can cause neuroinflammation, such as viral infection in the central nervous system, peripheral inflammation such as chronic joint pain and gut inflammation, and autoimmune issues. In patients with specific types of cancer, such as small cell lung cancer, the immune system cross-reacts with distinct antigens to cause damage to neural tissue and trigger neuroinflammation.

Taken together, persistent systemic inflammation increases the likelihood of neuroinflammation. Meanwhile, factors such as lifestyle also contribute to neuroinflammation. Unhealthy eating habits have been shown to influence the balance of intestinal microbiota, change the blood-brain barrier (BBB) permeability, and cause neuroinflammation. Moreover, mental stress has been shown to increase the levels of several cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1) to trigger neuroinflammation. Among the known causes of neuroinflammation, the influence of systemic inflammation on neuroinflammation has scarcely been explored. Recent evidence suggests that chronic peripheral inflammation causes systemic inflammation which may enhance the synthesis of pro-inflammatory cytokines and other inflammation-promoting mediators, activating neuroinflammation in the diseased brain.

Some studies have pointed out the relationship between systemic inflammation and microglial activation via multiple neurotoxic factors, including TNF-α, IL-1, and ROS. Microglia activation is the principal driver of inflammation in the brain. It has been suggested that chronic inflammation breaks down the BBB, degrading the separation of central and peripheral circulation system, leaving the central nervous system (CNS) vulnerable. The close bidirectional relationship of the gut-brain axis, which includes neural, hormonal, and immune communication also plays a vital role in neuroinflammation caused by systemic inflammation. Thus, the persistence of peripheral inflammation causes systemic inflammation and the enhancement of pro-inflammatory factors and disruption of the brain tissue protection, all lead to neuroinflammation.

Fasting modifies energy utilisation by consuming glucose and glycogen, inducing gluconeogenesis, and subsequently activating ketogenesis. In the switch to ketosis during fasting, circulating levels of fatty acids, including linoleic acid, increase. Intriguingly, linoleic acid tightly binds to the spike protein of SARS-CoV-2, the cause of COVID-19. The attachment of linoleic acid to the spike reduces the affinity of SARS-CoV-2 for ACE2. An acute rise in linoleic acid while a person is fasting, thus, provides a direct mechanism for fasting to acutely reduce the severity of COVID-19.

In terms of chronic protection from severe outcomes of infection, the multifaceted protein galectin-3 was increased, independent of weight change, by low-frequency intermittent fasting in the 6-month Weekly One-Day Water-only Fasting Interventional (WONDERFUL) Trial. Galectin-3 modulates inflammation with proinflammatory actions during acute infection and anti-inflammatory functions when infection resolves. It minimises risk from chronic metabolic disorders (eg, diabetes), and is elevated in patients with diabetes and heart failure (HF), perhaps as a protective mechanism to reduce risk. Importantly, galectin-3 directly binds to a wide variety of pathogens, activates the innate immune system, impacts respiratory infections, increases expression of human genes encoding proteins with antiviral capacities and inhibits viral replication. Given the wide array of pathogens affected by galectin-3, it may also limit SARS-CoV-2 infection. The chronic increase of galectin-3 by intermittent fasting may, thus, provide a mechanistic link in which long-term participation in fasting could reduce COVID-19 severity.

Previously, routine periodic fasting was associated with lower risk of coronary artery disease (CAD), lower risk of type 2 diabetes, and - in patients with a more than 42-year history of fasting - improved longitudinal outcomes including greater survival and lower risk of incident HF. These associations may result from various mechanisms not related to weight loss. Such risk reductions by fasting of diagnoses that exacerbate the severity of COVID-19 (eg, diabetes, CAD and HF) may indirectly reduce COVID-19 severity, providing a possible third biological mechanism for fasting-induced protection from severe COVID-19 outcomes.

Negligible or negative senescence occurs when mortality risk is stable or decreases with age, and has been observed in some wild animals. Age-independent mortality in animals may lead to an abnormally long maximum individual lifespans and be incompatible with evolutionary theories of senescence. The reason why there is no evidence of senescence in these animals has not been fully understood. Recovery rates are usually very low for wild animals with high dispersal ability and/or small body size (e.g., bats, rodents, and most birds). The only information concerning senescence for most of these species is the reported lifespan when individuals are last seen or caught.

We deduced the probability density function of the reported lifespan based on the assumption that the real lifespan corresponding to Weibull or Gompertz distribution. We show that the magnitude of the increase in mortality risk is largely underestimated based on the reported lifespans with low recovery probability. The risk of mortality can aberrantly appear to have a negative correlation with age when it actually increases with increasing lifespan. We demonstrated that the underestimated aging rate for wild animals with low recovery probability can be generalizable to any aging models.

Our work provides an explanation for the appearance of negligible senescence in many wild animals. Humans attempt to obtain insights from other creatures to better understand our own biology and its gain insight into how to enhance and extended human health. Our advice is to take a second glance before admiring the negligible senescence in other animals. This ability to escape from senescence is possibly only as beautiful illusion in animals.

Aging is a major risk factor for cerebral infarction. Since cellular senescence is intrinsic to aging, we postulated that stroke-induced cellular senescence might contribute to neural dysfunction. Adult male Wistar rats underwent 60-minute middle cerebral artery occlusion and were grouped according to 3 reperfusion times: 24 hours, 3, and 7 days. The major biomarkers of senescence: 1) accumulation of the lysosomal pigment, lipofuscin; 2) expression of the cell cycle arrest markers p21, p53, and p16INK4a; and 3) expression of the senescence-associated secretory phenotype cytokines interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and interleukin-1β (IL-1β) were investigated in brain samples.

Lipofuscin accumulation was scarce at the initial stage of brain damage (24 hours), but progressively increased until it reached massive distribution at 7 days post-ischemia. Lipofuscin granules (aggresomes) were mainly confined to the infarcted areas, that is parietal cortex and adjacent caudate-putamen, which were equally affected. The expression of p21, p53, and p16INK4a, and that of IL-6, TNF-α, and IL-1β, was significantly higher in the ischemic hemisphere than in the non-ischemic hemisphere. These data indicate that brain cell senescence develops during acute ischemic infarction and suggest that the acute treatment of ischemic stroke might be enhanced using senolytic drugs.

According to long-standing canon in evolutionary biology, natural selection is cruelly selfish, favoring traits that help promote reproductive success. However, by the age fertility ceases, the story goes that selection becomes blind to what happens to our bodies. After the age of menopause, our cells are more vulnerable to mutations. In the vast majority of animals, this usually means that death follows shortly after fertility ends. Which puts humans (and some species of whale) in a unique club: animals that continue to live long after their reproductive lives end. How is it that we can live decades in selection's shadow? In most animals, including chimpanzees - our closest primate brethren - this link between fertility and longevity is very pronounced, where survival drops in sync with the ability to reproduce. Meanwhile in humans, women can live for decades after their ability to have children ends.

One of the leading ideas for human longevity is called the Grandmother Hypothesis - the idea that, through their efforts, maternal grandmothers can increase their fitness by helping improve the survival of their grandchildren, thereby enabling their daughters to have more children. Such fitness effects help ensure that the grandmother's DNA is passed down. In a new paper, researchers take the kernel of that idea - intergenerational transfers, or resource sharing between old and young - and show that it has played a fundamental role in the force of selection at different ages. Food sharing in non-industrial societies is perhaps the most obvious example.

"In our model, the large surplus that adults produce helps improve the survival and fertility of close kin, and of other group members who reliably share their food, too. Viewed through the lens of food production and its effects, it turns out that the indirect fitness value of adults is also highest among reproductive-aged adults. But using demographic and economic data from multiple hunter-gatherers and horticulturalists, we find that the surplus provided by older adults also generates positive selection for their survival. Once you take into account that elders are also actively involved in helping others forage, then it adds even more fitness value to their activity and to them being alive."

In contrast, chimpanzees - who represent our best guess as to what humans' last common ancestor may have been like - are able to forage for themselves by age 5. However, their foraging activities require less skill, and they produce minimal surplus. Even so, the authors show that if a chimpanzee-like ancestor would share their food more widely, they could still generate enough indirect fitness contributions to increase the force of selection in later adulthood. "What this suggests is that human longevity is really a story about cooperation. Chimpanzee grandmothers are rarely observed doing anything for their grandkids."