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- Reversing the Age-Related Loss of Eosinophils in Visceral Fat Reduces Chronic Inflammation and its Consequences
- Repetitive Element Activity is Reduced in Mice Subject to Interventions that Modestly Slow Aging
- In Rats, Navitoclax Removes Senescent Chondrocytes that Contribute to Osteoarthritis
- Reviewing Present Thought on the Evolution of the Calorie Restriction Response
- Gain and Loss of Flight as a Tool to Search for Import Factors in Longevity
- A Popular Science View of Osteocalcin in Aging
- Reviewing the Cellular Senescence of Astrocytes in Alzheimer’s Disease
- Lipocalin 2 as a Link Between Metabolic Syndrome and Neuroinflammation
- Thermoregulation is Impaired by Aging
- On Defining What it Means to Be Old
- Shear Stress in the Aging Heart Makes Immune Cells Inflammatory, Accelerating Cardiovascular Disease
- Targeting Senescent Cells in the Heart
- Mifepristone Slows Aging in Flies
- Efforts Continue to Use COVID-19 as a Learning Moment Regarding the Costs of Aging
- An Overactive Immune System Protects Against Infection at the Cost of More Rapid Aging
Reversing the Age-Related Loss of Eosinophils in Visceral Fat Reduces Chronic Inflammation and its Consequences
It is well known that visceral fat tissue is an important source of the chronic inflammation that drives the onset and progress of all of the common age-related diseases. This is normally discussed in the context of excess visceral fat, given the high prevalence of overweight individuals in our modern society of cheap calories and too little exercise. Visceral fat encourages the creation of senescent cells and their inflammatory secretions, but also rouses the immune system to inflammation via a range of other mechanisms. Overweight individuals have a shorter, less healthy life with higher lifetime medical expenses as a result.
These mechanisms are not only an issue in overweight individuals. As noted in today’s research materials, even without excess visceral fat, there is a growing imbalance between the pro-inflammatory (macrophage) and anti-inflammatory (eosinophil) immune cell populations resident in visceral fat tissue. This contributes to age-related chronic inflammation, and thus disease and mortality. Having more visceral fat certainly makes the situation worse, but thin people do not remain immune to the harms.
Interestingly, researchers here demonstrate that an eosinophil cell therapy can reverse this process, and bring inflammatory fat tissue back under control. It remains to be seen as to how long this benefit lasts. Is it akin to first generation stem cell therapies in which the transplanted cells reduce inflammation via signaling that influences native cell behavior, but do not survive for long, or do the eosinophils survive to produce a lasting benefit? The former seems more plausible.
Age-related impairments reversed in animal model
For many years scientists speculated that chronic low-grade inflammation accelerates aging processes and the development of age-related disorders. Researchers have now demonstrated that a certain kind of immune cells, known as eosinophils, which are predominantly found in the blood circulation, are also present in belly fat of both humans and mice. Although classically known to provide protection from parasite infection and to promote allergic airway disease, eosinophils located in belly fat are responsible to maintain local immune homeostasis. With increasing age the frequency of eosinophils in belly fat declines, while the number of pro-inflammatory macrophages increases. Owing to this immune cell dysbalance, belly fat turns into a source of pro-inflammatory mediators accumulating systemically in old age.
In a next step, the researchers investigated the possibility to reverse age-related impairments by restoring the immune cell balance in visceral adipose tissue. “In different experimental approaches, we were able to show that transfers of eosinophils from young mice into aged recipients resolved not only local but also systemic low-grade inflammation. In these experiments, we observed that transferred eosinophils were selectively homing into adipose tissue.” This approach had a rejuvenating effect on the aged organism. As a consequence, aged animals showed significant improvements in physical fitness as assessed by endurance and grip strength tests. Moreover, the therapy had a rejuvenating effect on the immune system manifesting in improved vaccination responses of aged mice.
Eosinophils regulate adipose tissue inflammation and sustain physical and immunological fitness in old age
Adipose tissue eosinophils (ATEs) are important in the control of obesity-associated inflammation and metabolic disease. However, the way in which ageing impacts the regulatory role of ATEs remains unknown. Here, we show that ATEs undergo major age-related changes in distribution and function associated with impaired adipose tissue homeostasis and systemic low-grade inflammation in both humans and mice. We find that exposure to a young systemic environment partially restores ATE distribution in aged parabionts and reduces adipose tissue inflammation. Approaches to restore ATE distribution using adoptive transfer of eosinophils from young mice into aged recipients proved sufficient to dampen age-related local and systemic low-grade inflammation.
Importantly, restoration of a youthful systemic milieu by means of eosinophil transfers resulted in systemic rejuvenation of the aged host, manifesting in improved physical and immune fitness that was partially mediated by eosinophil-derived IL-4. Together, these findings support a critical function of adipose tissue as a source of pro-ageing factors and uncover a new role of eosinophils in promoting healthy ageing by sustaining adipose tissue homeostasis.
Repetitive Element Activity is Reduced in Mice Subject to Interventions that Modestly Slow Aging
Today’s open access paper is a companion piece to a recent discussion of repetitive element activity as a potential biomarker of biological aging. In today’s paper, the authors note that a number of interventions that modestly slow aging in mice also reduce the activity of repetitive elements in the genome. Many forms of repetitive element are the remnants of ancient viruses, sequences that are capable of copying themselves into new locations in the genome, but are normally suppressed. A fair amount of attention has been given to retrotransposons, one category of repetitive elements, in the context of aging in recent years, but all repetitive elements appear to become more active with age. The systems responsible for repressing their activity begin to run awry, for reasons that are incompletely understood.
Haphazard copying of repetitive elements is a form of stochastic mutational DNA damage, capable of randomly disrupting the blueprint of specific genes. This can result in the manufacture of broken proteins or the loss of expression of functional proteins. A higher pace of mutational damage raises the risk of cancer through an unlucky combination of mutations, but is thought to also lead to the disruption of tissue function more generally. In most cases mutational damage to the nuclear genome will occur in unused genes, or to genes that have little importance. Where it does disrupt important genes, it usually occurs in somatic cells that do not replicate widely and have a limited life span. In order for this sort of damage to cause significant downstream effects, it must occur in stem cells or progenitor cells that can spread it widely throughout tissue. This is known as somatic mosaicism, and certainly does occur, but it is still unclear as to how large a detrimental effect it produces, in comparison to other issues in aging.
Healthy aging interventions reduce non-coding repetitive element transcripts
Advances in transcriptomics (e.g., RNA-seq) have led to important insight on many genes and pathways linked with ‘the hallmarks of aging’ and broader health outcomes. However, most of these studies have focused on coding sequences – a small fraction of the genome. Non-coding, repetitive elements (RE, more than 60% of the genome) have been particularly neglected as ‘junk DNA’, despite growing evidence that they have many important biological functions. RE include DNA transposons, retrotransposons, tandem repeats, satellites and terminal repeats. A major fraction of RE, mainly DNA transposons and retrotransposons, are transposable elements (TE) with the ability to propagate, multiply, and change genomic position.
Most RE/TE are in genomic regions that are chromatinized and suppressed (inactive), but recent reports show that certain TE become active during aging, perhaps due to reduced chromatin architecture/stability (e.g., histone dysregulation). Activation of these specific TE may contribute to aging by causing genomic and/or cellular damage/stress (e.g., inflammation). However, we recently reported that aging is associated with a progressive, global increase in transcripts from most RE (not only TE) in model organisms and humans. This global dysregulation of RE may have an important, more general role in aging, as RE transcripts have been linked with other key hallmarks of aging including oxidative stress and cellular senescence. In fact, it has been suggested that RE dysregulation itself may be an important hallmark of aging. If so, a logical prediction would be that interventions that increase health/lifespan and reduce hallmarks of aging (e.g., calorie restriction [CR], select pharmacological agents and exercise) should also suppress RE/TE.
Here, we analyze RE in RNA-seq datasets from mice subjected to robust healthspan- and lifespan-increasing interventions including calorie restriction, rapamycin, acarbose, 17-α-estradiol, and Protandim. We also examine RE transcripts in long-lived transgenic mice, and in mice subjected to high-fat diet, and we use RNA-seq to investigate the influence of aerobic exercise on RE transcripts with aging in humans. We find that: 1) healthy aging interventions/behaviors globally reduce RE transcripts, whereas aging and age-accelerating treatments increase RE expression; and 2) reduced RE expression with healthy aging interventions is associated with biological/physiological processes mechanistically linked with aging. Thus, RE transcript dysregulation and suppression are likely novel mechanisms underlying aging and healthy aging interventions, respectively.
In Rats, Navitoclax Removes Senescent Chondrocytes that Contribute to Osteoarthritis
Senescent cells are created constantly throughout life, largely as a result of somatic cells reaching the Hayflick limit on replication, but the pace at which they are cleared by programmed cell death or the immune system slows with age. Senescent cells thus accumulate in old tissues, and this accumulation directly contributes to the progression of age-related disease and dysfunction. Senescence cells secrete a mix of molecules that cause chronic inflammation, disrupt tissue structure, and alter surrounding cell behavior. The more senescent cells there are in an organ, the worse the outcome.
Fortunately, this contributing cause of aging now has potential solutions. Senolytic treatments are those that selectively destroy some fraction of senescent cells, as much as half in some tissues for first generation senolytic drugs. Given that senescent cells work to actively maintain an aged, damaged state of tissue, removing them is a form of rejuvenation. This rejuvenating effect been demonstrated in numerous animal studies, showing that senolytics can reverse many specific age-related diseases, as well as extend healthy life span.
Today’s open access paper reports on a representative example of such animal studies of senolytic drugs. The authors used perhaps the worst of the early senolytics, navitoclax, a drug that certainly kills senescent cells, but also kills or disrupts the function of enough normal cells to have significant side-effects that prevent easy clinical use in humans. Nonetheless, one can use this proven senolytic in animal studies to demonstrate the quite rapid reversal of age-related disease produced by the destruction of senescent cells – as is the case here.
Navitoclax (ABT263) reduces inflammation and promotes chondrogenic phenotype by clearing senescent osteoarthritic chondrocytes in osteoarthritis
Cell senescence is characterized by arrest of cell cycle, changes in metabolism, and loss of proliferative ability. Various markers have been used to identify senescent cells (SnCs), including gene expression of p21, p16, and p53, elevated levels of reactive oxygen species (ROS), and activation of senescence-associated β-galactosidase (SA-β-Gal). In aging articular cartilage, the senescent-related alterations in chondrocytes and mesenchymal stem cells (MSCs) during osteoarthritis, such as hypertrophy and loss of cell proliferative and differentiation capacity, may affect chondrogenic differentiation of MSCs and bring obstruction to cartilage regeneration.
In this regard, the term “chondrosenescence” was proposed to describe the age-dependent destruction of chondrocytes and highlight its hallmarks, and explain how they affect the phenotype of these cells and their specialized functions. Furthermore, SnCs have been shown accumulation in OA cartilage tissues with aging. These SnCs exhibit positive staining of SA-β-Gal, increased level of the senescence-related gene p16INK4a, senescence-associated secretory phenotype (SASP), increased production of pro-inflammatory mediators, and increased secretion of cytokines and chemokines.
Selective removal of these SnCs through a senolytic molecule (UBX0101) from osteoarthritic chondrocytes has been shown to reduce the expression of inflammation- and age-related molecules, and simultaneously delay the progression of post-traumatic osteoarthritis in p16-3MR mice. This finding supports a promising therapeutic strategy by targeting SnCs for osteoarthritis treatment. Another senolytic pharmacological agent navitoclax (also named ABT263), a specific inhibitor of the BCL-2 and BCL-xL proteins, has been reported to selectively clear SnCs in the hematopoietic system from premature aging mice after total-body irradiation by inducing cell apoptosis, and thus, rejuvenating aged tissue stem cells in normally aged mice.
In this study, we examined the ability of the senolytic drug ABT263 to clear SnCs and further evaluated the therapeutic effect of ABT263 on post-traumatic osteoarthritis. A destabilization of the medial meniscus (DMM) rat model was established for in vivo experiments. We found that ABT263 reduced the expression of inflammatory cytokines and promoted cartilage matrix aggregation by inducing SnC apoptosis. Moreover, osteoarthritis pathological changes in the cartilage and subchondral bone in post-traumatic osteoarthritis rat were alleviated by ABT263 intra-articular injection. These results demonstrated that ABT263 not only improves inflammatory microenvironment but also promotes cartilage phenotype maintenance]. Furthermore, ABT263 might play a protective role against post-traumatic osteoarthritis development. Therefore, strategies targeting SnC elimination might be promising for the clinical therapy of osteoarthritis.
Reviewing Present Thought on the Evolution of the Calorie Restriction Response
The practice of calorie restriction involves reducing calorie intake by up to 40% while maintaining an optimal intake of micronutrients. It can meaningfully extend life span in short-lived species such as mice, but does not add more than a few years in humans. The effect on lifespan of this and other interventions known to slow aging via upregulation of stress response mechanisms scale down as species life span increases – though, interestingly, the short-term benefits to health look quite similar across mammalian species.
The most important mechanism of action in the calorie restriction response, as well as responses to heat and other stresses, appears to be an increased operation of autophagy. Autophagy is the name given to a collection of cellular maintenance processes that break down unwanted or damaged proteins and cell structures by conveying them to a lysosome, a membrane packed full of enzymes capable of breaking down most of the molecules a cell will encounter. It is noteworthy that disabling autophagy, or important related processes such as the formation of stress granules to protect vital proteins from increased autophagy, blocks the benefits the calorie restriction response. It is similarly noteworthy that the efficiency of autophagy becomes impaired with age, and this is thought to contribute to many manifestations of aging.
The present consensus on why calorie restriction extends life notably in mice but not in humans is that the calorie restriction response evolved to enhance reproductive fitness in the face of seasonal famine, extending life to allow individuals to survive and reproduce once food was again plentiful. A season is a large fraction of a mouse life span, but not a large fraction of a human life span, and therefore only the mouse evolves to experience sizable increases in life span when calorie intake is low. This is far from the only evolutionary explanation for the calorie restriction response, however. Today’s open access paper is a review of the topic, providing an overview of present viewpoints.
Lifespan Extension Via Dietary Restriction: Time to Reconsider the Evolutionary Mechanisms?
Dietary restriction (DR), a moderate reduction in food intake whilst avoiding malnutrition, is the most consistent environmental manipulation to extend lifespan and delay ageing. First described in rats, DR has since been shown to extend lifespan in wide range of taxa: from model lab species such as Drosophila melanogaster and mice, to non-model species such as sticklebacks, crickets, and non-human primates. Owing to this taxonomic diversity, it is presumed that the underlying physiological mechanisms of DR are evolutionarily conserved and thus DR has been widely used to study the causes and consequences of variation in lifespan and ageing. Despite this attention, both the evolutionary and physiological mechanisms underpinning DR responses remain poorly understood.
Since its inception DR has become an all-encompassing description for multiple forms of dietary interventions. The most widely studied form of DR is calorie restriction (CR), a reduction in overall calorie intake whilst avoiding malnutrition. Common forms of CR include providing a restricted food portion, dilution of the diet, or restricting food availability temporally. Positive effects of CR on lifespan are well supported. Initial explorations of the role of specific dietary components, such as protein content, found that the effects were largely driven by caloric intake. Consequently, until recently DR and CR were largely interpreted as synonymous terms. Owing to this focus on CR, the predominant evolutionary explanations of the DR effect were developed to explain responses to CR and not macronutrient availability.
The Resource Reallocation Hypothesis
The most widely accepted evolutionary explanation of DR is a trade-off model based around the disposability theory of ageing. This theory suggests that a trade-off exists between reproduction and somatic maintenance (lifespan). The Resource Reallocation Hypothesis (RRH) proposes that during periods of famine (e.g., CR), natural selection should favor a switch in allocation, in which context organisms reallocate energy almost exclusively to somatic maintenance and not to reproduction. By investing heavily in somatic maintenance, organisms will improve their chances of surviving the period of famine, when it is likely that the cost of reproduction is high and offspring survival low, resulting in lower fitness returns. Once conditions improve, investment in reproduction can resume, and that should result in higher fitness. Critically, the reinvestment strategy described in the RRH will only lead to higher fitness if conditions improve. Owing to the trade-off, the RRH predicts that under DR conditions in the lab, there should be an increase in lifespan accompanied by a corresponding decrease in reproduction.
The Nutrient Recycling Hypothesis
Recently, the RRH has been critiqued, the argument against it being that adopting a pro-longevity investment strategy is unlikely to increase survival in the wild, where the main sources of mortality are extrinsic (i.e., predation, wounding, or infection). An alternative evolutionary explanation was proposed that we will term here the nutrient recycling hypothesis (NRH). As with the RRH, the NRH was proposed to explain an effect of CR, not the more recent suggestion of specific macronutrient effects. The NRH proposes that rather than sacrificing reproduction to increase longevity, organisms under DR attempt to maintain reproduction as much as possible in the face of reduced energy resources.
To achieve this, organisms upregulate the activity of cell recycling mechanisms such as autophagy and apoptosis. This allows better use, and even recycling, of the available energy, which can then be used to maintain reproductive function. The argument here is not that the level of reproduction achieved under DR is greater or even matched to that of a fully fed individual, rather that the loss of reproduction is minimized. An interesting suggestion of the NRH is that the pro-longevity effect of DR is an artefact of benign lab environments. The main sources of mortality in the laboratory are old age pathologies such as cancer, which are ameliorated by upregulation of autophagy and apoptosis. However, in the wild, cancer and other old-age pathologies are a relatively minor source of mortality, so the protective effect of the DR response may not be observed.
The Toxic Protein Hypothesis
A more recent hypothesis to be put forward is the toxic protein hypothesis (TPH), which is a constraint-based model rather than an evolutionary theory. Unlike the theories already discussed, the TPH was put forward in light of renewed focus on the role of macronutrients in DR responses. The TPH argues that protein is essential for reproductive function, where increasing protein intake leads to higher reproductive rates. However, it is proposed that high consumption of protein has direct negative effects on late-life health and lifespan, through increased production of both toxic nitrogenous compounds from protein metabolism and mitochondrial radical oxygen species.
Therefore, organisms face a constraint in the amount of protein they can consume, balancing high protein intake to maximize early life reproductive output whilst avoiding overconsumption, which may reduce lifespan and ultimately result in lower fitness. As with the other hypotheses, under the TPH there would be an optimal protein intake that maximizes lifetime reproductive success or fitness. However, the TPH argues that the DR response of increased lifespan is the result of protein restriction reducing the direct physiological costs of protein ingestion.
Gain and Loss of Flight as a Tool to Search for Import Factors in Longevity
The capacity for flight is frequently associated with greater species longevity, such as in bats, for example. The present consensus suggests that the cellular adaptations needed to support the greater metabolic capacity required for flight also resist some forms of molecular damage important in aging. This is particularly the case for adaptations in mitochondria, the power plants of cells, where damage and loss of function is known to be important in aging. The membrane pacemaker hypothesis is one way of looking at this; species that evolve cell membranes that are more resilient to oxidative damage will live longer as a result.
Today’s open access paper reports on the interesting approach of using gain and loss of flight in evolutionary history as a way to look for genes and functions that might be important in aging. It is a good idea, but unfortunately didn’t pan out in this particular study – commonalities between species were lacking. That a modest selection of species failed to produce shared genetic adaptations that appear relevant to aging and longevity may indicate the existence of broad a diversity of mechanisms relevant to metabolism and flight, rather than just a few important mechanisms, or perhaps a very complex, multifaceted relationship between metabolism and longevity. Other lines of work, such as the so far largely unsuccessful search for longevity-related genes with meaningful effect sizes in humans, support the latter conjecture.
Genetic factors for short life span associated with evolution of the loss of flight ability
Maximum life span (MLS) is a fundamental life-history trait related to the rate of aging and senescence in animals. It has been proposed that species with lower extrinsic mortalities have longer life spans because they can invest in long-term survival. Extrinsic mortality is generally determined by ecological factors, such as climate and predation risk, and may drive shortened or extended life spans through natural selection. However, MLS is influenced by complex molecular and metabolic processes such as mitochondrial homeostasis.
Mitochondria of aerobic animals produce reactive oxygen species (ROS), which can damage lipids, proteins, and nucleic acids. A low rate of mitochondrial ROS generation reportedly leads to long life spans in both long-lived and calorie-restricted animals because of low levels of both oxidative stress and accumulation of mutations in somatic mitochondrial DNA. Because animals with higher metabolic rates produce more ROS, a causal relationship between metabolic rate and life span can be expected. Additionally, a positive relationship between body mass and life span is pervasive in vertebrates. Because metabolic rates per mass are lower with increasing body mass, animals with smaller body masses could suffer more from ROS, and their life spans would be correspondingly shorter.
However, flight ability significantly affects MLS and aging rates in both mammals and birds regardless of body mass. Flight typically requires higher rates of energy consumption and generates more ROS than other types of locomotion, such as walking or swimming. However, a prolonged life span often evolved with the acquisition of flight ability, suggesting that there is no simple relationship between metabolism and life span.
Here, we examine the parallel evolution of flight in mammals and birds and investigate positively selected genes at branches where either the acquisition (in little brown bats and large flying foxes) or loss (in Adélie penguins, emperor penguins, common ostriches, emus, great spotted kiwis, little spotted kiwis, okarito brown kiwis, greater rheas, lesser rheas, and cassowaries) of flight abilities occurred. Although we found no shared genes under selection among all the branches of interest, 7 genes were found to be positively selected in 2 of the branches. Among the 7 genes, only IGF2BP2 is known to affect both life span and energy expenditure. The positively selected mutations detected in IGF2BP2 likely affected the functionality of the encoded protein. IGF2BP2, which has been reported to simultaneously prolong life span and increase energy expenditure, could be responsible for the evolution of shortened MLS associated with the loss of flying ability.
A Popular Science View of Osteocalcin in Aging
In recent years, researchers have shown that osteocalcin levels decline with age. Restoring osteocalcin in mice has been shown to reverse age-related loss of memory via increased BDNF. In fact, BDNF shows up as a common mechanism of action for many interventions shown to improve cognitive function, such as restoring a more youthful gut microbiome. Among other things, increased BDNF means increased neurogenesis, the process by which new neurons are generated and integrated into neural circuits. This is certainly essential to memory function, but also to maintenance and function of the brain more generally.
As we age, all of us inevitably lose bone. Research shows that humans reach peak bone mass in their 20s; from then onwards, it is a slow decline that can eventually lead to frailty and diseases such as osteoporosis in old age. Over the past decade, new findings have suggested that this reduction in bone mass may also be linked to the weakening of muscles – referred to in medical terms as sarcopenia – as well as the memory and cognitive problems that many of us experience as we grow older. This appears to be connected to the levels of osteocalcin in the blood, through its role as a master regulator, influencing many other hormonal processes in the body.
“Osteocalcin acts in muscle to increase the ability to produce ATP, the fuel that allows us to exercise. In the brain, it regulates the secretion of most neurotransmitters that are needed to have memory. The circulating levels of osteocalcin declines in humans around mid-life, which is roughly the time when these physiological functions, such as memory and the ability to exercise, begin to decline.”
Researchers have conducted a series of experiments in which he has shown that by increasing the levels of osteocalcin in older mice through injections, you can actually reverse many of these age-related ailments. “Osteocalcin seems to be able to reverse manifestations of ageing in the brain and in muscle. What is remarkable is that if you give osteocalcin to old mice, you restore memory and you restore the ability to exercise to the levels seen in a young mouse. That makes it potentially extremely attractive from a medical point of view.” Scientists have also found that for humans, one way of naturally maintaining the levels of this hormone in the blood, even as we age, is through exercise, something that makes intuitive sense, as physical activity has long been known to have anti-ageing properties.
Reviewing the Cellular Senescence of Astrocytes in Alzheimer’s Disease
It is becoming apparent that cellular senescence in supporting cells of the brain is a significant contributing factor in the development and progression of neurodegenerative conditions such as Alzheimer’s disease. Researchers have demonstrated that partial clearance of senescent microglia and astrocytes via the senolytic dasatinib, a small molecule that can pass the blood-brain barrier, reverses neuroinflammation and disease pathology in animal models. Here, researchers review what is known of the senescence of astrocytes, one of the largest group of supporting cells in the brain, in the context of Alzheimer’s disease. Given the way that the evidence is shaping up, there is a decent chance that the best of the first generation of usefully effective Alzheimer’s treatments will turn out to be senolytics that clear senescent cells in the brain.
Alzheimer’s disease (AD) is a chronic degenerative disorder of the brain related to progressive decline of memory and cognition. The disease is characterized by brain atrophy, extracellular accumulation of beta-amyloid peptide (Aβ), neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein, and loss of synapses and dysfunctions of neurotransmission, as well as neuroinflammation.
Many of the cellular pathologies of AD present on neurons, such as neuronal extracellular deposits of Aβ, intracellular deposition of NFTs, and Lewy bodies. These classical pathologies are still central to diagnosing AD. However, although neurons have significant correlations with AD, other cell types and factors in the brain may also contribute to cognitive decline during AD. Additionally, astrocytes are the major glial cells and are vital for the normal physiological functions of the central nervous system (CNS). They perform critical roles in regulation of homeostasis and metabolism of the neurons, mediating uptake and recycling of neurotransmitters. Astrocytes also play a key role in maintenance of the blood-brain barrier (BBB). They also act as modulators of synaptic plasticity and transmission, supporting the view that astrocytes play an integral role in the initiation and progression of cognitive decline and AD.
Aging is considered the most significant risk factor for the occurrence and development of AD. The incidence of AD has been shown to increase with advancing age and cellular senescence. Studies regarding to the link and role of senescence in age-related diseases have become increasingly common, and are gradually becoming a new research area. Transcriptome analysis of AD and the aged human brain showed neurons and other non-neuronal CNS cell types including astrocytes, microglia, and oligodendrocytes displayed senescence-associated phenotypes.
Senescent astrocytes showed decreased normal physiological function and increased secretion of senescence-associated secretory phenotype (SASP) factors, which contribute to Aβ accumulation, tau hyperphosphorylation, and the deposition of NFTs in AD. Astrocyte senescence also leads to a number of detrimental effects, including induced glutamate excitotoxicity, impaired synaptic plasticity, neural stem cell loss, and blood-brain barrier (BBB) dysfunction.
Thus, therapies to alleviate astrocyte senescence could prevent the onset of AD or delay its progress. In many age-related disorders such as osteoarthritis, atherosclerosis, and diabetes mellitus type 2, the removal of senescent cells of transgenic mice models has shown an impaired associated pathology and extended the healthy lifespan. Success has also been observed in a mouse model of tau-associated pathogenesis. This study was the first to demonstrate a causal relationship between glial senescence and neurodegeneration. In this study, accumulations of senescent astrocytes and microglia were found in tau-associated neurodegenerative disease model mice. Elimination of these senescent cells via a genetic approach can reduce tau deposition and prevent the degeneration of cortical and hippocampal neurons.
Most recently, it was shown that clearance of senescent oligodendrocyte progenitor cells in AD model mice with senolytic agents could lessen the Aβ plaque load, reduce neuroinflammation, and ameliorate cognitive deficits. This seno-therapeutic approach is currently being tested in neurodegenerative diseases and despite expected challenges and difficulties, more detailed investigation is warranted.
Lipocalin 2 as a Link Between Metabolic Syndrome and Neuroinflammation
Obesity and its immediate consequences, such as non-alcoholic fatty liver disease and type 2 diabetes, are associated with greater neuroinflammation and risk of dementia. Excess visceral fat tissue does its part to produce chronic inflammation throughout the body, but here researchers focus on a specific metabolic dysregulation in the liver that produces inflammation in the brain. That inflammation in turn drives a faster progression towards neurodegenerative conditions. The lesson here, as in so much of this research: don’t get fat, don’t stay fat. You won’t like the consequences.
Researchers have revealed the cause behind the previously established link between non-alcoholic fatty liver disease (i.e., NAFLD, recently reclassified as metabolic associated fatty liver disease or MAFLD) and neurological problems. The link they discovered, the unique role of an adipokine (Lipocalin-2) in causing neuroinflammation, may explain the prevalence of neurological Alzheimer’s disease-like and Parkinson’s disease-like phenotypes among individuals with MAFLD.
“Lipocalin 2 is one of the important mediators exclusively produced in the liver and circulated throughout the body among those who have nonalcoholic steatohepatitis – or NASH – which is a more advanced form of MAFLD. The research is immensely significant because MAFLD patients have been shown to develop Alzheimer’s and Parkinson’s-like symptoms as older adults. Scientists can use these results to advance our knowledge in neuroinflammatory complications in MAFLD and develop appropriate treatments.”
Ninety percent of the obese population and 40-70 percent of those with type 2 diabetes appear to have MAFLD, according to the Centers for Disease Control and Prevention. In addition to overweight/obese status and diabetes, other risk factors include high cholesterol and/or triglycerides, high blood pressure and metabolic syndrome. These individuals have a higher risk for having diseased livers, which are associated with increased lipocalin 2 – as found in the present study. The lipocalin 2 circulates throughout the body at higher levels, possibly inducing inflammation in the brain.
Thermoregulation is Impaired by Aging
The old are more vulnerable to all stresses, and heat is no exception. Older people make up a majority of the fatalities in heatwaves. This topic isn’t frequently discussed in comparison to other aspects of aging, however. Impairment of the physiological response to heat is a dysfunction of high level processes in numerous organs, not just the skin, and results from a long chain of cause and consequence under the hood. That chain linking low-level molecular damage to high level outcomes is poorly explored, to say the least. This is one of the reasons why targeting the repair of that low-level damage of aging is a more effective strategy for the treatment of aging as a medical condition.
Tens of thousands of deaths have been caused by heat waves across Europe since 2000. There are an estimated 1,500 heat-related deaths every year in the United States. A health center in Paris recorded 2,814 deaths during the 2003 heat wave, 81% of these were in people older than 75 years. Exposure to hotter than usual temperatures poses a thermoregulatory challenge to the human body, particularly when this occurs suddenly, precluding opportunities for acclimatization. Nevertheless, heat illness can be managed through simple behavior changes such as drinking more water and seeking shelter in air-conditioned buildings. Such behavioral strategies rely on effective efferent-afferent physiological responses, but these have been shown to decrease with aging.
Aging impacts thermoregulation in several ways. Older adults (≥ 50 years) store 1.3 to 1.8 times more body heat when exposed to the same heat load than younger adults (19-30 years) during both exercising and passive heat exposure in both humid and dry conditions. The higher heat storage in the older individuals is due to a reduction in heat loss caused by an attenuated sweat response and increased dry heat gain.
Sweating is a critical mechanism for heat loss in humans, particularly when ambient temperature is above skin temperature as dry heat exchange results in heat gain in these situations. Sweating function declines with age at differing rates. Sudomotor function declines first in the legs, followed by progressive decrements in the upper body. Loss of sweating capacity comes from reduced function of each sweat gland rather than a reduction in the number of sweat glands, and is thought to be caused by local rather than central factors. Older adults have a higher core temperature threshold for the onset of sweating. The delayed onset of sweating coupled with the inability to increase and maintain a high sweat rate will delay the effect of cooling from sweat reducing its effectiveness, resulting in a higher core temperature and greater heat strain in the elderly.
With aging, the cardiovascular system experiences functional and structural changes. Total blood volume decreases, reactive oxygen species increase, and nitric oxide availability reduces, yielding a decrease in endothelial-dependent dilation and a reduced blood flow. Older adults increase their skin blood flow (SkBF) ~2-3 times less than their younger counterparts during passive and active heat exposure. Attenuated SkBF will reduce dry heat loss, and therefore increase heat strain on the body. The elderly will struggle to dissipate heat effectively compared with their younger counterparts, resulting in increased thermal and physiological strain.
On Defining What it Means to Be Old
An increasing interest in intervening in the aging process, in treating aging as a medical condition, inevitably produces a greater interest in measuring aging. When is an individual old? Even in the absence of new biotechnologies of rejuvenation, people clearly age at different rates, the result of lifestyle choices such as exercise and weight, exposure to persistent pathogens, and related factors. One sixty year old can be more aged or less aged than another. It might seem a little academic to be debating today how to determine whether or not someone is old, but given the ability to actually produce rejuvenation – such as via senolytic drugs that clear senescent cells from old tissues – this becomes a much more practical concern.
One widely used measure of population aging is the potential support ratio, the inverse of the old age dependency ratio. The potential support ratio divides the population 20 years of age and older into two disjoint age groups. Conceptually, the ratio is meant to reflect the stages of the human life cycle, distinguishing between adults who are elderly and those who are not. To compute the ratio two sorts of information are needed, the number of people at each age starting from 20 and a threshold age that divides the adult population into a group who are elderly and a group who are not.
On its website Profiles of Ageing 2019 the UN now publishes a conventional potential support ratio (PSR) and a prospective potential support ratio (PPSR). The difference between the two variants is based solely on different threshold ages at which people first become categorized as”old” . In the PSR that threshold age is age 65 and is fixed independent of time or place. In the PPSR the threshold age is the age where remaining life expectancy is 15 years. We call the first, the conventional old age threshold (COAT) and the second the prospective old age threshold (POAT). The COAT is the most commonly used old age threshold, but it has the disadvantage that it does not change over time and is the same for all countries regardless of their trajectories of aging.
The choice of whether to use the COAT or the POAT in assessing the extent of population aging is not arbitrary. It is not like choosing between Celsius and Fahrenheit in the measurement of temperature. Having measures of population aging based on the COAT and the POAT is like having two kinds of thermometers, where sometimes both indicate that the temperature is increasing and sometimes one indicates it is getting warmer while the other indicates it is getting cooler. Indeed, sometimes measures of population aging based on the two old age thresholds change in the same direction and sometimes they do not.
We propose that the old age threshold should be determined using an equivalency criterion – in other words, people at the old age threshold should be roughly similar to one another in terms of relevant characteristics regardless of when and where they lived. Using historical data on five-year death rates at the old age threshold as an indicator of one aspect of health, we assessed the extent to which the two approaches used by the UN are consistent with the equivalency criterion. The results indicate that the old age threshold based on a fixed remaining life expectancy is consistent with the equivalency criterion, while the old age threshold based on a fixed chronological age is not.
Shear Stress in the Aging Heart Makes Immune Cells Inflammatory, Accelerating Cardiovascular Disease
Researchers here note a process by which the hardening of heart valves, known as aortic valve stenosis, accelerates in its later stages. The condition causes greater shear stress in blood flow, which in turn causes immune cells in the bloodstream to become more inflammatory. The resulting greater chronic inflammation in heart tissue accelerates the mechanisms that cause stenosis. This hardening of tissue is due to calcification; a growing fraction of cells in the valves adopt behaviors more appropriate to bone tissue, creating calcium structures. Inflammatory signaling, such as that produced by the presence of senescent cells in aged tissues, is known to contribute to this inappropriate cellular activity.
Aortic valve stenosis is the most common type of heart valve disease in the elderly and affects more than one in eight people aged over 75. The condition is typically caused by degeneration and thickening of the aortic valve, which narrows the valve opening and reduces blood flow. Blood cells that have to squeeze through the narrow valve come under intense frictional force, known as shear stress. A team of researchers and clinicians set out to investigate the effect of this shear stress on white blood cells – key players in our immune system’s first line of defense. They found the constant stress of squeezing through the narrow aortic valve activates these cells, leading to harmful inflammation that accelerates the progression of aortic stenosis.
The team have identified a potential drug target by pinpointing the receptor that controls this white blood cell overactivity. The research combined clinical work, such as blood samples and valve measurements, with lab experiments using organ-on-a-chip technology that replicated the pathological conditions inside the aortic valve. “In someone with severe aortic valve stenosis, circulating blood cells come under heavy shear stress about 1500 times a day. We now know this constant frictional force makes the white blood cells hyperactive. If we can stop that inflammatory response, we can hope to slow down the disease. The same organ-on-a-chip technology that helped us make these discoveries will also enable us to easily test potential drugs to treat this harmful immune response.”
Targeting Senescent Cells in the Heart
Senescent cells accumulate with age, and their inflammatory secretions disrupt tissue structure and function. In the heart, the presence of senescent cells contributes to fibrosis, hypertrophy, and other aspects of the progression towards heart failure. Since senescent cells actively maintain a disrupted state of cells and tissue, targeted removal can quickly and significant reverse aspects of aging and age-related disease. This has been demonstrated in numerous organs, including the heart, in animal studies. For example, even the structural changes of ventricular hypertrophy can be reversed via treatments that selectively destroy senescent cells.
Adult stem cells and progenitor cells are a small population of cells that reside in tissue-specific niches and possess the potential to differentiate in all cell types of the organ in which they operate. Adult stem cells are implicated with the homeostasis, regeneration, and aging of all tissues. Tissue-specific adult stem cell senescence has emerged as an attractive theory for the decline in mammalian tissue and organ function during aging. Cardiac aging, in particular, manifests as functional tissue degeneration that leads to heart failure. Adult cardiac stem/progenitor cell (CSC) senescence has been accordingly associated with physiological and pathological processes encompassing both non-age and age-related decline in cardiac tissue repair and organ dysfunction and disease.
Senescence is a highly active and dynamic cell process with a first classical hallmark represented by its replicative limit, which is the establishment of a stable growth arrest over time that is mainly secondary to DNA damage and reactive oxygen species (ROS) accumulation elicited by different intrinsic stimuli (like metabolism), as well as external stimuli and age. Replicative senescence is mainly executed by telomere shortening, the activation of the p53/p16INK4/Rb molecular pathways, and chromatin remodeling. In addition, senescent cells produce and secrete a complex mixture of molecules, commonly known as the senescence-associated secretory phenotype (SASP), that regulate most of their non-cell-autonomous effects.
Here we discuss the molecular and cellular mechanisms that regulate different characteristics of the senescence phenotype and their consequences for adult CSCs in particular. Because senescent cells contribute to the outcome of a variety of cardiac diseases, including age-related and unrelated cardiac diseases like diabetic cardiomyopathy and anthracycline cardiotoxicity, therapies that target senescent cell clearance are actively being explored. Moreover, the further understanding of the reversibility of the senescence phenotype will help to develop novel rational therapeutic strategies.
Mifepristone Slows Aging in Flies
Researchers here note that mifepristone, an abortifacient drug, slows aging in flies. This is interesting, but the mechanisms of action so far have the look of being quite specific to circumstance and gender – it blocks a detrimental effect of mating in female flies that increases inflammation. So I’d wager that this will turn out to be of academic interest only at the end of the day. If reductions in inflammation are the primary downstream benefit, this class of drug probably compares poorly to senolytics in any case.
Studying one of the most common laboratory models used in genetic research – the fruit fly Drosophila – researchers found that the drug mifepristone extends the lives of female flies that have mated. Mifepristone, also known as RU-486, is used by clinicians to end early pregnancies as well as to treat cancer and Cushing disease. During mating, female fruit flies receive a molecule called sex peptide from the male. Previous research has shown that sex peptide causes inflammation and reduces the health and lifespan of female flies. Researchers found that feeding mifepristone to the fruit flies that have mated blocks the effects of sex peptide, reducing inflammation and keeping the female flies healthier, leading to longer lifespans than their counterparts who did not receive the drug.
The drug’s effects in Drosophila appear similar to those seen in women who take it. “In the fly, mifepristone decreases reproduction, alters innate immune response and increases life span. In the human, we know that mifepristone decreases reproduction and alters innate immune response, so might it also increase life span?” Seeking a better understanding of how mifepristone works to increase lifespan, researchers looked at the genes, molecules, and metabolic processes that changed when flies consumed the drug. They found that a molecule called juvenile hormone plays a central role.
Juvenile hormone regulates the development of fruit flies throughout their life, from egg to larvae to adult. Sex peptide appears to escalate the effects of juvenile hormone, shifting the mated flies’ metabolism from healthier processes to metabolic pathways that require more energy to maintain. Further, the metabolic shift promotes harmful inflammation, and it appears to make the flies more sensitive to toxic molecules produced by bacteria in their microbiome. Mifepristone changes all of that. When the mated flies ate the drug, their metabolism stuck with the healthier pathways, and they lived longer than their mated sisters who did not get mifepristone. Notably, these metabolic pathways are conserved in humans, and are associated with health and longevity.
Efforts Continue to Use COVID-19 as a Learning Moment Regarding the Costs of Aging
Near everyone who dies from the SARS-Cov-2 virus responsible for the COVID-19 pandemic is old. The old are vulnerable firstly because their immune systems are much diminished in effectiveness, and secondly because the state of chronic inflammation characteristic of old age makes the cytokine storm that causes much of the SARS-Cov-2 mortality more likely and more severe.
Members of the medical research community focused on intervention in the aging process – a way to treat all age-related conditions by addressing their underlying causes – are attempting to use the attention given to COVID-19 to educate the public and policy makers. Any number of influenza seasons, in which the vast majority of the dead are elderly, seems to have failed to get the point across: that the age-related decline of the immune system causes great harm, and that harm might be significantly reduced in the future given a focus on research and development for immune rejuvenation. But perhaps this pandemic will cause people to listen. Hope springs eternal.
Understanding how drugs can delay aging and related diseases is part of a larger scientific endeavor supported by the National Institute on Aging and others called geroscience. This approach aims to understand and ultimately modify the basic biology of aging and in so doing, develop new paradigms to treat multiple age-related chronic diseases at the same time. Geroscientists have long hypothesized that by targeting the biology of aging, all diseases of aging can be delayed. Hallmarks of aging have been established and shown that they are all interconnected, thus targeting any single hallmark results in improvements in others. In animal preclinical studies, health span and life span have been dramatically increased by targeting those hallmarks, using genetic tools and drugs, demonstrating that aging is a modifiable condition.
Older people are at such risk in part because the vigor of our immune response flags as we age. Of particular importance are the hallmarks of immune dysfunction underlying the vulnerability of older adults to infections and the inflammation which accounts for the response to those infections. In addition to age, many of us are also weakened by coexisting age-related conditions that diminish our resilience further.
Interventions with existing drugs with established safety profiles that target the biology of aging, immune mechanisms and resiliency (i.e. “geroprotectors” or “gerotherapeutics”), should be explored. While many geroprotectors have been successfully tested in pre-clinical settings, to date none of them has been approved as geroprotectors for use in humans. Consequently, self-medication with any of these compounds is highly discouraged.
One such drug is metformin which has been shown to target multiple hallmarks of aging and increase health span and life span in animals. Metformin has already indicated protective capacity against COVID-19. In a retrospective analysis of 283 type 2 diabetes patients from Wuhan, China, with confirmed COVID-19, investigators found no difference in the length of stay in hospital, but persons taking metformin had significantly lower in-hospital mortality (3 of 104, 2.9%) than those not taking metformin (22 of 179, 12.3%).
A second line of drugs are mTOR inhibitors, which have been shown to increase healthspan and lifespan in almost all animals tested, from yeast to rodents. The mTOR inhibitor rapamycin reverses age-related declines in influenza vaccine response in mice and two Phase 2 clinical trials completed by resTORbio showed that the rapamycin derivative everolimus could enhance influenza vaccine response in healthy elderly people. A phase 3 clinical trial failed.
Given the current public health crisis that is disproportionately affecting our aging population, it is imperative that we start discussing pragmatic approaches to rapidly implement the testing of such drugs in the face of the COVID-19 pandemic and an aging global population. At this stage, broad clinical trials of potential geroprotective therapies are needed, to enable extensive data collection and analysis of their potential benefits and indications.
An Overactive Immune System Protects Against Infection at the Cost of More Rapid Aging
Greater immune activity implies greater inflammation, which has a negative impact on tissue function if maintained over time. In aging, a great deal of damage is done by the chronic inflammation of an overactive immune system. Researchers here provide evidence to indicate that the evolved state of immunity is a balancing act between a faster pace of aging on the one hand, resulting from an immune system that is more active, and vulnerability to infection on the other, resulting from an immune system that is less active.
As we age, the immune system gradually becomes impaired. One aspect of this impairment is chronic inflammation in the elderly, which means that the immune system is constantly active and sends out inflammatory substances. Such chronic inflammation is associated with multiple age-related diseases including arthritis and Alzheimer’s disease, and impaired immune responses to infection. One of the questions in ageing research is whether chronic inflammation is a cause of ageing, or a consequence of the ageing process itself?
From their work in the tiny roundworm, Caenorhabditis elegans, the scientists discovered a change in an evolutionarily conserved gene called PUF60, which made the worms long lived but at the same time dampened the immune response. Worms with this change lived about 20% longer than normal worms, but when they were infected with certain bacteria, they succumbed more quickly to the infection. This means that an overactive immune system also has a price: it shortens life span. Conversely, a less active immune system pays off as longer life span – as long as the animal does not die from an infection.
PUF60 works as a splicing factor, and is involved in the removal (or “splicing out”) of segments in the ribonucleic acid, RNA. This process is essential to generate functional proteins. The scientists found that the genetically changed PUF60 perturbs this process and alters the regulation of other genes that are involved in immune functions.