Fight Aging!

The state of the gut microbiome is probably as influential as the state of physical fitness when it comes to effects on long-term health. With age the balance of microbial populations shifts for the worse, in fact one of the earlier detrimental aspects of aging. Studies suggest that meaningful changes are in evidence by the time someone reaches their mid-30s. Beneficial species producing metabolites that contribute to tissue function diminish in number, while harmful species that provoke chronic inflammation increase in number.

Fortunately, it is possible to adjust the gut microbiome, to rejuvenate it and restore a more youthful balance of microbial populations, via approaches such as fecal microbiota transplantation from a young donor to an older patient. In short-lived species, this improves health and even extends life span. Fecal microbiota transplantation is used in the clinic in a limited way, but it remains to be seen as to when this and other forms of therapy that may reverse the aging of the gut microbiome become more widely available. As of the moment, it is largely self-experimenters who are performing this sort of treatment upon themselves.

A review of the preclinical and clinical studies on the role of the gut microbiome in aging and neurodegenerative diseases and its modulation

As the world population ages, the burden of age-related health problems grows, creating a greater demand for new novel interventions for healthy aging. Advancing aging is related to a loss of beneficial mutualistic microbes in the gut microbiota caused by extrinsic and intrinsic factors such as diet, sedentary lifestyle, sleep deprivation, circadian rhythms, and oxidative stress, which emerge as essential elements in controlling and prolonging life expectancy of healthy aging. This condition is known as gut dysbiosis, and it affects normal brain function via the brain-gut microbiota axis, which is a bidirectional link between the gastrointestinal tract and the central nervous system (CNS) that leads to the emergence of brain disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia.

A substantial amount of research has been conducted on the role and abundance of the intestinal microbiome as well as the implications for maintaining a healthy state. Gut microbiota is an ecosystem metabolic of a million different microorganisms living in the gastrointestinal tract and forming a symbiotic connection with the host. Because the gut microbiota helps to maintain physiological homeostasis, alterations in microbiome abundance taxa cause intestinal dysbiosis related to numerous pathological conditions, including neurodegenerative diseases. Thus, microbiota-based therapies emerge as a potential therapeutic target, including prebiotic or probiotic administration, nutrition, and physical activity to reshape the gut microbiota.

Here, we review the role of the gut microbiome in aging and neurodegenerative diseases, as well as provide a comprehensive review of recent findings from preclinical and clinical studies to present an up-to-date overview of recent advances in developing strategies to modulate the intestinal microbiome by probiotic administration, dietary intervention, fecal microbiota transplantation (FMT), and physical activity to address the aging process and prevent neurodegenerative diseases. The findings of this review provide researchers in the fields of aging and the gut microbiome design innovative studies that leverage results from preclinical and clinical studies to better understand the nuances of aging, gut microbiome, and neurodegenerative diseases.

As you may know, the aging heart often exhibits ventricular hypertrophy, an enlargement and weakening of the muscle. This appears driven in large part by the increased burden of cellular senescence in later life, given reversal of hypertrophy observed after senolytic treatment in old animals. This hypertrophy can also be thought as a downstream consequence of hypertension, but biology is rarely so simple as to have a single line of cause and effect. As noted in this paper, people lose muscle mass and strength with age, leading to the weakness and frailty of sarcopenia. The heart is a muscle, and a shrinking of that muscle is observed in sarcopenia patients, a condition here termed cardiosarcopenia. So does the heart become larger or smaller with age? That appears to vary from individual to individual, implying interactions between, or common mechanisms affecting, the state of skeletal muscle and heart muscle.

The traditional view of cardiovascular aging is that of age-related adaptations in the heart characterized by increased left ventricular (LV) mass (LVM) and LV hypertrophy (LVH), which are often secondary to increased systolic blood pressure mainly mediated by arterial stiffening. Yet skeletal muscle sarcopenia occurs with aging but may be accelerated in heart failure states. In advanced stages of heart failure, skeletal muscle wasting accompanied by severe exercise intolerance have long been observed in various cohorts.

To date, observations pertaining to the cardiac muscle-skeletal muscle axis among non-heart failure cohorts have provided useful insights. In a population-based cohort of older Asian subjects without clinical cardiovascular disease, skeletal muscle mass was associated with left ventricular mass, independent of age, diabetes mellitus status, and body size. In a selected cohort of frail sarcopenic older European subjects without severe cardiovascular disease (some had mild cardiovascular disease), appendicular lean mass was strongly associated with LVM and cardiac output.

Although advanced age was associated with loss of skeletal muscle mass, the relationship between LVM and skeletal muscle mass appears to be independent of age. Among 228 community adults aged 65-91 years, individuals with low skeletal muscle mass had lower LVM than those without low skeletal mass, without significant interaction between age and LVM. These observations are hypothesis-generating for possible age-related yet age-independent processes that mediate the cardiac and skeletal muscle systems in older persons.

The observations seem to run counter to the dogma of aging-associated LVH, especially in the context of hypertension which dominates aging. Traditionally, cardiac aging has been associated with increased LV wall thickness, with or without myocyte hypertrophy. High LVM, and not low LVM, has been deemed to be clinically unfavorable. The purpose of this perspective is to summarize the background for this syndrome of concern of low LVM, review the body of work generated by various human aging cohorts, and to explore future directions and opportunities for understanding this syndrome.

Link: https://doi.org/10.3389/fmed.2022.1027466

Psychological stress has a dose response curve in which it is beneficial for some functions at low levels, it seems. This is not a complete surprise, given that hormesis seems to be a universal phenomenon. Mild or short-lived stress produces a lasting protective reaction that more than compensates for any harms caused by the stress, improving cell and tissue function. Here researchers show evidence for low levels of stress to improve memory. We might suspect this effect to be mediated by increased blood flow to the brain, given the copious evidence for improved memory function to result from increased cerebral blood flow, such as resulting from exercise. Portions of the brain operate at the very edge of their supply of nutrients and oxygen, even in youth.

The negative impact of stress on neurocognitive functioning is extensively documented by empirical research. However, emerging reports suggest that stress may also confer positive neurocognitive effects. This hypothesis has been advanced by the hormesis model of psychosocial stress, in which low-moderate levels of stress are expected to result in neurocognitive benefits, such as improved working memory (WM), a central executive function. We tested the hormesis hypothesis, purporting an inverted U-shaped relation between stress and neurocognitive performance, in a large sample of young adults from the Human Connectome Project (n = 1000, mean age 28.74).

In particular, we investigated whether neural response during a WM challenge is a potential intermediary through which low-moderate levels of stress confer beneficial effects on WM performance. Further, we tested whether the association between low-moderate prolonged stress and WM-related neural function was stronger in contexts with more psychosocial resources. Findings showed that low-moderate levels of perceived stress were associated with elevated WM-related neural activation, resulting in more optimal WM behavioral performance. The strength of this association tapered off at high-stress levels. Finally, we found that the benefit of low-moderate stress was stronger among individuals with access to higher levels of psychosocial resources.

By drawing attention to the dose-dependent, nonlinear relation between stress and WM, this study highlights emerging evidence of a process by which mild stress induces neurocognitive benefits, and the psychosocial context under which benefits are most likely to manifest.

Link: https://doi.org/10.1016/j.neuropsychologia.2022.108354

Repair of the aging brain is perhaps the most important of goals in regenerative medicine. We are the data that is stored in some way within the small-scale structures of our brain tissue, and so the options for outright replacement of brain cells and tissues are somewhat constrained. As a thought experiment, it is in principle possible, given significant progress in biotechnology, to manufacture a cloned body to receive a transplanted brain. All of the steps needed either already happen in nature, such as the growth of bodies without brains, and would need control and direction, or have been crudely demonstrated in animal studies, such as brain transplants, albeit with major limitations and risk of failure. There may well be little gain in transplanting an aged brain if it cannot be repaired, however.

In any case, my view is that major surgery involving replacement parts will not be a primary focus for the future of medicine. Instead, increasing control over cells and cell signaling will lead to rejuvenation through either restoration and repair of native cells or, where that is impractical, the delivery of youthful cells to replenish stem cell populations. It is an interesting question as how far one might be able to go with this type of approach for the aging brain. Much of the brain, while vital, is uninvolved directly in the storage of the data of the mind. It might be considered simply a less accessible and more difficult target for regeneration in comparison to other organs. It is those areas of the brain in which data is stored that present a challenge for any sort of replacement therapy, however, and it remains to be seen as how this challenge may be effectively addressed.

Pluripotent stem cell strategies for rebuilding the human brain

Age - it's the one mountain you can't overcome, and as the average life expectancy extends into the eighth decade, neurodegenerative diseases are becoming increasingly prevalent. Despite their increasing incidence, preventative or disease-modifying strategies for these emotionally and financially draining disorders are lacking. Due to the fundamental lack of regeneration within the central nervous system (CNS), neurodegenerative diseases relentlessly attacking discrete populations of neurons are excellent candidates for cell replacement therapies. Here, we review the current prospects on the application of pluripotent stem cell-derived cell types for the treatment of neurodegenerative disease.

Pluripotent stem cells provide a uniquely scalable source of functional somatic cells, including cells of the CNS, that can potentially replace damaged or diseased tissues. Although prospects for using stem cell derivatives seemed fanciful at the start of the millennium, approximately two decades later several clinical trials using cellular products of pluripotent stem cells are underway or about to reach the clinic. It's an incredibly exciting time for stem cell-based regenerative medicine with a number of clinical trials started and more just on the horizon for neurodegenerative diseases, including one for Parkinson's disease.

The demand for neurodegenerative disease therapeutics continues to grow as populations around the globe age. Currently, no pharmacological strategies exist that can significantly alter disease course for neurodegenerative diseases, thus cell replacement therapies remain an attractive avenue of exploration. Although the prospect of using stem cell-derived neurons to treat many of the diseases discussed in this review remains abstract, the Parkinson's disease clinical trials, grounded on years of fetal transplant studies and animal models with high fidelity, will provide important guideposts as others venture into these uncharted territories.

A sizable level of funding in academia and industry is devoted to the goal of enabling cell transplants between different individuals, with large and well funded pharma companies such as Astellas, Sana, and others involved. This would allow for the creation of cost-effective cell therapies of all sorts, in which the donor cells used in every patient originate from the same few well-vetted and well-controlled cell lines.

Logistics is everything in the realm of cell therapies, and the reason why autologous cell therapies, such as CAR-T treatments for cancer, are so expensive is that every treatment site must have the ability to extract cells from the patient, engineer them, slowly expand their numbers over weeks in carefully monitored culture conditions, and then perform quality control before use. Compare this with a universal cell line that is manufactured in one central location, with cells frozen down in a standardized way for storage, transport, and then use by any clinic capable of performing an infusion. It is a very different picture of cost and difficulty.

Regenerative medicine has come a long way since the derivation of the first human pluripotent stem cells (hPSC). As a community, we have become better at sourcing stem cells, differentiating them into therapeutic cell types and transplanting them to cure different diseases. To unlock the full potential of stem cell therapies, we need to overcome the immune barrier to transplantation. The human immune system is incredibly discerning in distinguishing between self and non-self, which could be viral or bacterial proteins, malignant cells, and, of course, cells from a genetically non-identical donor. Genetic differences between the donor and the recipient are recognized as alloantigens if they have never been encountered by the host's immune system before (as opposed to autoantigens) and may prompt allograft rejection.

Based on the nature of the genetic polymorphism and how/when they present themselves to the immune system, three types of alloantigens can be distinguished that, together, define the immune barrier. Human leukocyte antigens (HLA) are the immunodominant barrier to cell and tissue transplantation. Minor histocompatibility antigens (miHA) can vary in their expression from cell type to cell type. Neoantigens (NA) can accumulate during prolonged culture and pose a risk of rejection even of cells of autologous origin.

Initial attempts have focused primarily on the major histocompatibility barrier that is formed by the human leukocyte antigens (HLA). More recently, immune checkpoint inhibitors, such as PD-L1, CD47, or HLA-G, are being explored both, in the presence or absence of HLA, to mitigate immune rejection by the various cellular components of the immune system. In this review, we discuss progress in surmounting immune barriers to cell transplantation, with a particular focus on genetic engineering of human pluripotent stem cells and progenitor cells and the therapeutic cell types derived from them.

Link: https://doi.org/10.1007/s40778-022-00221-0

Currently there is some debate over whether the initial markers used to detect senescent cells, such as as senescence-associated β-galactosidase and P16 expression, are general enough across cell types and specific enough to senescent cells for all uses in research and clinical development. Nonetheless, these markers are well known and the efficiency of senolytic treatments that clear senescent cells does appear to be measurable this way. Greater convenience in that measurement is always useful: at present, the state of the art involves biopsies and post-mortem tissue histology. Here researchers take a step forward by producing a mouse lineage in which senescence-associated β-galactosidase expression is associated with fluorescence, allowing for more cost-effective investigation of cellular senescence and its treatment.

The progressive decline of physiological function and the increased risk of age-related diseases challenge healthy aging. Multiple anti-aging manipulations, such as senolytics, have proven beneficial for health; however, the biomarkers that label in vivo senescence at systemic levels are lacking, thus hindering anti-aging applications. In this study, we generate a Glb1+/m-Glb1-2A-mCherry (GAC) reporter allele at the Glb1 gene locus, which encodes lysosomal β-galactosidase - an enzyme elevated in tissues of old mice.

A linear correlation between GAC signal and chronological age is established in a cohort of middle-aged (9 to 13 months) Glb1+/m mice. The high GAC signal is closely associated with cardiac hypertrophy and a shortened lifespan. Moreover, the GAC signal is exponentially increased in pathological senescence induced by bleomycin in the lung. Senolytic dasatinib and quercetin (D + Q) reduce GAC signal in bleomycin treated mice. Thus, the Glb1-2A-mCherry reporter mice monitors systemic aging and function decline, predicts lifespan, and may facilitate the understanding of aging mechanisms and help in the development of anti-aging interventions.

Link: https://doi.org/10.1038/s41467-022-34801-9

Today's open access paper mounts an interesting argument, based on the use of a large data set for phenotypic aging in mice. They looked at transcriptomic and proteomic data for a sizable number of genes in a variety of different tissues, then grouping these into phenotypes by related function, or relation to specific age-related declines. Differences in expression by age in these phenotypic groups of genes were observed directly in mice and in human data sets.

The researchers then looked the effects on phenotypes of a few very well studied interventions widely thought to slow aging in mice: growth hormone signaling inhibition, mTOR inhibition, and intermittent fasting. The authors argue, based on their data, that these interventions are essentially compensatory rather than age-slowing, in that they appear to be changing phenotypes (mostly for the better) in a similar way in youth and old age, but they are not slowing the age-related change in those phenotypes. At least insofar as those phenotypes are assessed by the selected transcriptomic and proteomic data.

This is a very interesting view, given the present consensus that, yes, these interventions genuinely slow aging, setting aside some arguments as to whether mTOR is extending life in animal models only because it reduces cancer risk. It is a good illustration of the state of the present debate over strategies for intervention in aging, shaped by the lack of a strong consensus on how to define aging in a way that is useful for the assessment of therapies in animal models or human trials. One can always look at obvious external signs of dysfunction, such as grip strength, but it will never be completely clear, given only those biomarkers, as to whether a therapy helps because it is compensating, or because it legitimately does in fact address mechanisms of aging.

It is a reasonable supposition that better therapies will be better because they reverse underlying mechanisms of aging, and therefore will produce lasting benefits to patients in many aspects of health. As a strategy, this is the right way forward, but the expectation of better outcomes for aging-targeting therapies is by no means a given for any specific therapy and specific age-related condition. If we can point to interventions such as mTOR inhibition that appear to slow the age-related decline of a great many of those aspects of health, and show that they are in fact only broadly compensatory instead, it muddies the waters considerably when it comes to steering the research and development communities towards better approaches to therapy.

Deep phenotyping and lifetime trajectories reveal limited effects of longevity regulators on the aging process in C57BL/6J mice

A large body of work, carried out over the past decades in a range of model organisms including yeast, worms, flies and mice, has identified hundreds of genetic variants as well as numerous dietary factors, pharmacological treatments, and other environmental variables that can increase the length of life in animals. Current concepts regarding the biology of aging4 are in large part based on results from these lifespan studies. Much fewer data, however, are available to address the question of whether these factors, besides extending lifespan, in fact also slow aging, particularly in the context of mammalian models.

It is important to distinguish lifespan vs. aging because it is well known that lifespan can be restricted by specific sets of pathologies associated with old age, rather than being directly limited by a general decline in physiological systems. In various rodent species, for instance, the natural end of life is frequently due to the development of lethal neoplastic disorders: Cancers have been shown to account for ca. 70-90% of natural age-related deaths in a range of mouse strains. Accordingly, there is a strong need to study aging more directly, rather than to rely on lifespan as the sole proxy measure for aging.

Deep phenotyping represents a powerful approach to capture a wide range of aging-associated phenotypic changes, since it takes into account alterations at molecular, cellular, physiological, and pathological levels of analysis, thereby providing a very fine-grained view of the consequences of aging as they develop across tissues and organs. The approach is therefore ideally suited to assess genetic variants, pathways, dietary or pharmacological factors previously linked to lifespan extension and, potentially, delayed aging. Deep phenotyping examines hundreds of parameters, many of which are expected to differ between young and old animals (hereafter called age-sensitive phenotypes; ASPs); these can be collectively used to address if and how a given intervention interacts with the biological processes underlying the signs and symptoms of aging.

We here refer to the mechanisms of aging as the sets of processes that underlie age-dependent phenotypic change. Accordingly, an intervention that targets the mechanisms underlying aging should slow the transformation of a phenotypically young to a phenotypically aged organism. In other words, the intervention should attenuate the age-dependent change in ASPs (the delta in phenotype between young and old). For instance, a specific intervention or genotype could ameliorate the age-dependent loss of neurons by promoting processes concerned with maintaining the integrity of neurons over time.

An intervention could mimic a targeting of age-dependent change by affecting ASPs directly (i.e., independently of age-dependent change in these phenotypes). For instance, a specific genetic variant may increase the number of neurons by promoting neurogenesis during brain development, without affecting the rate of subsequent age-dependent neuron loss. This variant would regulate neurodevelopmental processes but would not affect the mechanisms underlying age-dependent change. Although this would also result in increased neuronal numbers in old age, it cannot be taken as evidence of a slowed progression of aging because the rate of age-dependent change remains unaltered

Here, we employ large-scale phenotyping to analyze hundreds of markers in aging male C57BL/6J mice. For each phenotype, we establish lifetime profiles to determine when age-dependent change is first detectable relative to the young adult baseline. To cover key genetic longevity interventions and study their effects on aging in mice, we here chose genetic models targeting the mTOR pathway as well as growth hormone signaling. In parallel to our studies in mice, we applied multi-dimensional phenotyping combined with stratification based on genetic expression variants in GHRHR and MTOR in a human population across a wide age range, spanning from 30 to 95 years. The analyses in humans complement our work in animal models and allowed us to address, in parallel to the work in mice, whether or not a potential genetic modification of human ASPs occurs in an age-independent fashion or not.

We examine these key lifespan regulators (putative anti-aging interventions; PAAIs) for a possible countering of aging. Importantly, unlike most previous studies, we include in our study design young treated groups of animals, subjected to PAAIs prior to the onset of detectable age-dependent phenotypic change. Many PAAI effects influence phenotypes long before the onset of detectable age-dependent change, but, importantly, do not alter the rate of phenotypic change. Contrary to a general expectation that 'anti-aging' treatments should produce a broad change in aging rate across many phenotypes, our study shows that the PAAIs we examined - that are concerned with some of the very core mechanisms proposed to be involved in aging - often did not seem to work through targeting age-dependent change.

In conclusion, the PAAIs examined (i.e. mTOR loss of function, Ghrhr loss of function, intermittent fasting-based version of dietary restriction) often influenced age-sensitive traits in a direct way and not by slowing age-dependent change. Previous studies often failed to include young animals subjected to PAAI to account for age-independent PAAI effects. However, any study not accounting for such age-independent intervention effects will be prone to overestimate the extent to which an intervention delays the effects of aging on the phenotypes studied. This can result in a considerable bias of our view on how modifiable aging-related changes are.

You might recall a recent small clinical trial in which oral supplementation with large amounts of glutathione precursors produced improvements in health in older adults, the size of the outcome surprisingly large for a treatment based on supplements. Here, researchers enthusiastically advocate for glutathione upregulation, reversing the normal age-related decline in glutathione levels, as a basis for improving the health of older people and slowing the onset of age-related degeneration.

Many local and systemic diseases especially diseases that are leading causes of death globally like chronic obstructive pulmonary disease, atherosclerosis with ischemic heart disease and stroke, cancer, and COVID-19, involve both, (1) oxidative stress with excessive production of reactive oxygen species (ROS) that lower glutathione (GSH) levels, and (2) inflammation. The GSH tripeptide, the most abundant water-soluble non-protein thiol in the cell, is fundamental for life by (a) sustaining the adequate redox cell signaling needed to maintain physiologic levels of oxidative stress fundamental to control life processes, and (b) limiting excessive oxidative stress that causes cell and tissue damage.

GSH activity is facilitated by activation of the Keap1-Nrf2-antioxidant response element (ARE) redox regulator pathway, releasing Nrf2 that regulates expression of genes controlling antioxidant, inflammatory, and immune system responses. GSH exists in the thiol-reduced (98%+ of total GSH) and disulfide-oxidized (GSSG) forms, and the concentrations of GSH and GSSG are indicators of the functionality of the cell. GSH depletion may play a central role in inflammatory diseases and COVID-19 pathophysiology, host immune response, and disease severity and mortality.

Therapies enhancing GSH could become a cornerstone to reduce severity and fatal outcomes of inflammatory diseases and COVID-19 and increasing GSH levels may prevent and subdue these diseases. The life value of GSH makes for a paramount research field in biology and medicine and may be key against systemic inflammation and COVID-19 disease. In this review, we emphasize (1) GSH depletion as a fundamental risk factor for diseases like chronic obstructive pulmonary disease and atherosclerosis (ischemic heart disease and stroke), (2) importance of oxidative stress and antioxidants in COVID-19 disease, (3) significance of GSH to counteract persistent damaging inflammation, inflammaging, and early (premature) inflammaging associated with cell and tissue damage caused by excessive oxidative stress and lack of adequate antioxidant defenses in younger individuals, and (4) new therapies that include antioxidant defenses restoration.

Link: https://doi.org/10.3389/fnut.2022.1007816

Researchers here discuss the ways in which the aging of the immune system influences the aging of the kidney, such as through disruption of the normal participation of immune cells in tissue maintenance and repair. With age the immune system falls into a state of chronic inflammation, and unresolved inflammatory signaling is disruptive to the structure and operation of tissues throughout the body. The kidney is but one example of how this contributes to the declines of aging.

With the steady increase in the number of elderly individuals globally, age-related diseases emerge as a major challenge to health care workers. Apart from functional and structural changes in the kidneys introduced by aging, immune system decline also significantly increases the risk of age-related kidney diseases. Immunosenescence is a loose definition of age-related changes in the innate and adaptive immune responses, which is characterized by shrinkage of naïve immune cell reservoirs, accumulation of late-stage differentiated cells with a senescent phenotype, and immunoglobulin class switching. These changes in the immune system result in two seemingly incompatible aspects: diminished immune response and increased inflammatory response, also known as inflammaging.

Tubular epithelial cells (TECs) senescence and tertiary lymphoid tissue formation occur following acute kidney injury. Senescent kidney cells promote a chronic inflammatory microenvironment, which can subsequently cause local tissue damage, hinder tissue repair, and promote immune system senescence. Intrarenal inflammation underlies the development of renal fibrosis and chronic kidney disease (CKD) later in life. Immunosenescence is exaggerated in patients with CKD and end-stage renal disease (ESRD). Hallmarks of immunosenescence, including decreased naïve T cells, reduced CD28 expression, and increased proinflammatory macrophages, are convincing predictors of mortality in patients with CKD and ESRD. Renal replacement therapy for old patients with ESRD results in a lower acute rejection rate after the kidney transplantation. However, immunosenescence may increase the risk of chronic, but severe, graft failure. In addition, immunosenescence has been reported to speed up during kidney transplantation and immunosuppressive treatment.

Link: https://doi.org/10.1186/s12979-022-00313-9

You may recall a study from a few years back suggesting that increasing level of exercise in later life, after a low level of exercise in earlier life, removes a perhaps surprisingly large fraction of the negative consequences of that low level of exercise. This is at least the case when it comes to age-related mortality. Nonetheless, in that study, maintaining a high level of exercise across life was still shown to be much better for health than only beginning high levels of exercise in later life.

Today's open access paper reports on a similar study, but here the metrics are specifically focused on measurements of frailty, such as grip strength. The interesting portion of the outcome is that the people who moved from low levels of exercise to greater exercise look similar to those that always maintained that higher level of exercise. The conclusion that one could make from this is that frailty as presently observed in the wealthier parts of the world is a large part a consequence of inactivity, and that at least that portion of the problem is reversible given sufficient effort.

Associations of physical activity participation trajectories with subsequent motor function declines and incident frailty: A population-based cohort study

Increasing evidence reports the benefits yielded by regular physical activity (PA) on the motor function in older people by preserving mobility, muscle strength, and balance. However, there is a methodological limitation that PA are evaluated at single time-point (primarily the baseline level) or short time-scales without considering the long-term dynamic nature of PA behavior. Group-based trajectory modeling (GBTM) allows grouping of subjects presenting with similar baseline values and longitudinal patterns of change according to their direction and magnitude. Using this method, some studies have detected different PA trajectories among older adult cohorts. Three studies examined the association of PA trajectories with mortality in older adults. But, there isn't an investigation of the temporal association of long-term PA participation trajectories with subsequent motor function changes and incident frailty.

Therefore, the main objectives of this study were to investigate different trajectories of long-term PA participation over a 6-year span by the GBTM and evaluate their associations with subsequent motor function decline and incident frailty in middle-aged and elderly adults. Our hypotheses are that older adults maintaining PA over time will have a slower motor function decline and a lower risk of incident frailty compared with persistently inactive subjects or those reducing PA levels, and that increasing PA even at older ages promotes healthy aging characterized by reduced motor function decline and incident frailty.

Five distinct trajectories of long-term PA participation were identified in the aging cohort, including persistently low-active trajectory (N = 2,039), increasing active trajectory (N = 1,711), declining active trajectory (N = 216), persistently moderate-active trajectory (N = 2,254), and persistently high-active trajectory (N = 2,007). Compared with the persistently low-active group, the participants in persistently moderate- and high-active groups experienced significantly decelerated grip strength decline, decreased gait speed decline, and faster chair rises after multiple-adjustment. Similarly, participants maintaining moderate- and high-active PA were also associated with a lower risk of incident frailty (multiple-adjusted hazard ratio 0.70 and 0.42 respectively), compared with those with persistently low PA. Notably, the participants with the increasing active trajectory got similar health benefits as those with persistently moderate and high levels of PA.

Thus in conclusion, in addition to persistent PA, increasing PA was linked to a slower decline in motor function and lower risk of incident frailty in the cohort. Our findings suggest that regular PA is never too late.

The immune system declines into a state of incapacity (immunosenescence) and chronic inflammation (inflammaging) with advancing age. Unresolved inflammatory signaling is disruptive of tissue function in many ways, from reduced stem cell activity to pathologically altered somatic cell behavior. It is thought to be important in the declining muscle mass and strength that contributes to age-related frailty. Thus addressing immune aging is a significant and important target in the treatment of aging as a whole.

Frailty is a highly prevalent geriatric syndrome that has attracted significant attention from physicians and researchers due to its associated increase in vulnerability and healthcare costs, especially in the elderly population. Generally, frail patients suffer from multiple chronic diseases, with comorbidities and polypharmacy greatly challenging their health management. Gerontologists suggest that targeting the common pathogenesis of comorbidities rather than a single disease is probably a better solution for older people. Multiple factors contribute to development of frailty with advancing age, thus the therapeutic target is diversed depends on specific condition. Nutrition supplements and physical exercise are proved to be helpful in preventing and treatment of frailty, however, valid pharmaceutical intervention is scarce.

Mesenchymal stem cells (MSCs) can exert regenerative effects and possess anti-inflammatory properties, offering a promising therapeutic strategy to address the pathophysiologic problems of frail syndrome. Currently, MSC therapy is undergoing phase I and II trials in human subjects to endorse the safety and efficacy of MSCs for aging frailty.

Numerous studies have shown that rapamycin and rapalogs, considered novel and promising longevity agents, can extend lifespan. Interestingly, these agents showed an immunosuppressive effect at high doses and an immune stimulatory effect at low doses. However, the reason for these immunity-boosting effects is unclear. The inhibition of mammalian target of rapamycin (mTORC1) is a possible explanation, as mTOR can regulate the STAT signaling pathway. A study showed a significant difference in STAT phosphorylation levels in the T cells of healthy people compared with unhealthy senescent people.

Senolytics are a novel type of agent. The interference of stem cell signaling pathways temporarily disables senescent cell anti-apoptotic pathway (SCAP), thus targeting selectively senescent cells. In addition to its main effect on clearing senescent cells, senolytics can also eliminate pro-inflammatory cytokines. According to the study, inflammation symptoms are relieved after the administration of senolytics. A recent study found reduced SASP and coronavirus-related mortality in old mice after the administration of senolytics.

A low level of nicotinamide adenine dinucleotide (NAD)+ is reportedly associated with the poor function of mitochondria and metabolic reprogramming of immune cells; therefore, NAD+ is also recognized as a therapeutic target for aging immunity. Promising data has demonstrated that administrating nicotinamide mononucleotide, the NAD+ precursor, into mice could maintain NAD+ levels and mitochondrial function, with the mitochondrial function of immunocytes being essential for controlling virus propagation.

A centenarian study revealed that longevity is associated with gut microbial structures, making individuals more potent against age-associated disorders and leading to a longer life. The microbiota-targeting probiotic and dietary interventions affect natural aging by enhancing oxidation resistance, regulating metabolism, suppressing chronic inflammation, and promoting immune homeostasis. Immunosenescence may have a certain influence on human microbial composition, function, and diversity. In addition, fecal microbiota transplantation or prebiotic/probiotic/synbiotic supplementation in the diet is beneficial for restoring active microbiota and extending a healthy lifespan. Thus, there are multiple ongoing developments in this field to ease the process of aging and reduce the risk of potential disabilities that could lead to a significant decrease in the quality of life of elderly individuals.

Link: https://doi.org/10.21037/atm-22-4405

Calorie restriction, and related approaches such as protein restriction, tend to improve the outcomes for cancer patients, making cancers more vulnerable to therapies by reducing the normally rampant replication of cancer cells. Here, researchers explore the role of mTOR signaling in the mechanisms underlying this effect, finding the link between dietary intake of amino acids and mTOR activity in cell growth. Manipulating these mechanisms isn't enough on its own to deal with cancer, but there is a lot to be said for low cost improvements to the odds of success for patients undertaking any form of cancer therapy.

Researchers found in cells and in mice that a low-protein diet blocked the nutrient signaling pathway that fires up a master regulator of cancer growth. The regulator, mTORC1, controls how cells use nutritional signals to grow and multiply. It's highly active in cancers with certain mutations and is known to cause cancer to become resistant to standard treatments. A low-protein diet, and specifically a reduction in two key amino acids, changed the nutritional signals through a complex called GATOR.

GATOR1 and GATOR2 work together to keep mTORC1 in business. When a cell has plenty of nutrients, GATOR2 activates mTORC1. When nutrients are low, GATOR1 deactivates mTORC1. Limiting certain amino acids blocks this nutrient signaling. Previous efforts to block mTORC1 have focused on inhibiting its cancer-causing signals. But these inhibitors cause significant side effects - and when patients stop taking it, the cancer comes back. The study suggests that blocking the nutrient pathway by limiting amino acids through a low-protein diet offers an alternative way to shut down mTORC1.

Researchers confirmed their findings in cells and mice, where they saw that limiting amino acids stopped the cancer from growing and led to increased cell death. They also looked at tissue biopsies from patients with colon cancer, which confirmed high markers of mTORC correlated with more resistance to chemotherapy and worse outcomes.

Link: https://labblog.uofmhealth.org/lab-report/dietary-change-starves-cancer-cells-overcoming-treatment-resistance

First generation stem cell transplants have not as yet produced the reliably improved regeneration that was hoped for, but they do suppress chronic inflammation for some months. This effect is mediated by cell signaling on the part of the transplanted cells in the short time that they survive after transplantation. Much of that signaling is carried by exosomes and other classes of extracellular vesicle, and hence similar outcomes result from therapies based on delivery of exosomes harvested from cultured stem cells.

One of the effects of the unresolved inflammatory signaling characteristic of aging is a suppression of stem cell activity, such as in the cell populations responsible for producing new neurons in the brain. Neurogenesis is essential to brain maintenance, as well as memory and learning. From what is known to date, greater neurogenesis appears to be beneficial at any age. Thus one of the ways in which first generation stem cell and exosome therapies might act to improve cognitive function in older people is via suppression of inflammation leading to improved neurogenesis in the aging brain.

Mesenchymal stem cells and exosomes improve cognitive function in the aging brain by promoting neurogenesis

Brain aging is a significant cause of most neurodegenerative diseases and is often irreversible and lacks an effective treatment, leading to a dramatic decline in quality of life. As with other organ systems, brain function gradually declines during the aging, mainly in learning and memory functions. Some studies point out that age-related cognitive decline is characterized by a considerable reduction or even death of neurons in the brain. In the hippocampus (and perhaps in other brain areas), neuronal death can partially compensated by neuronal generation. However, neuronal production is significantly impaired with age. In the adult mammalian hippocampus, new neurons are derived from the stem cell and progenitor cell divisions, a process known as adult neurogenesis.

In recent years, evidence has accumulated that neurogenesis can restore a more youthful state during aging. In addition, increased adult neurogenesis contributes to a variety of human diseases, including cognitive impairment and neurodegenerative diseases. Neuroinflammation has been shown to alter neurogenesis in adults. Various inflammatory components, such as immune cells, cytokines, or chemokines, regulate neural stem cells' survival, proliferation, and maturation. During normal brain aging, increased inflammatory activity is caused by the activation of glial cells.

It has been shown that mesenchymal stem cells (MSCs) can stimulate neurogenesis and angiogenesis and delay neuronal cell death. At the same time, their secreted exosomes are smaller in size and cause less immune response in the body, which is a hot topic of current research. This manuscript describes how MSCs and their derived exosomes promote brain neurogenesis and thereby delay aging by improving brain inflammation.

The problem with metformin as a drug to slow aging is that the evidece to support that use is very poor. In animal studies, the results are very unreliable, and the Interventions Testing Program found no effect in its highly overengineered studies. Further, the existing human data is not supportive, taken as a whole. Even if we did want to cherry pick the better data and be hopeful, the effect size compares unfavorably with that achieved through regular exercise, and further appears to be only achieved in people with the abnormal metabolism associated with obesity and diabetes. All of the work that was done to convince the FDA to endorse the TAME human clinical trial to test the ability of metformin to slow aging is useful, but the resulting agreement on trial structure should be applied to an intervention more likely to produce an outcome that is worth the effort, such as senolytic therapies.

The study that is most often cited as evidence that metformin slows the aging process in humans was released with a press release misleadingly titled "Type 2 diabetics can live longer than people without the disease." But the underlying study had a design flaw that first unintentionally selected only the healthiest diabetic patients (those on metformin) and compared them to patients with poorer glycemic control (those on other drugs) and a random assortment of the nondiabetic population - and then systematically pushed subjects on metformin "off the books" as soon as their diabetes progressed.

The same problem (or related ones) have plagued most of the observational studies that you may have heard cited as showing that metformin lowers the risk of atherosclerosis, total mortality, and especially cancer. Drawing inferences from such studies about effects on aging in otherwise-healthy people would thus be misguided even if these studies didn't share this design flaw, since none of these other studies include a separate group of people without diabetes. Rather, such studies have compared metformin-taking diabetic people to other people with diabetes taking other diabetic drugs. But actually, even in such diabetics-only studies, the apparent benefits of metformin vanish when the studies are designed to avoid survivorship bias and selection bias.

When put to the test in human trials, metformin has no effect on blood sugar control in obese women with normal glucose tolerance and only modest effects on fasting glucose in normal-weight, nondiabetic men. Similarly, exercise but not metformin tames glycemic variability (dangerously wide swings in blood sugar over the course of the day) in prediabetic people. And importantly, adding metformin to such lifestyle interventions doesn't lower the risk of developing diabetes any more than lifestyle all by itself.

You may be surprised to learn that there has already been a trial with followup that gives fairly long-term human data on mortality in a group of people who were not yet diabetic - and again, metformin came up short. This was report from the long-term follow-up of the Diabetes Prevention Program (DPP). The volunteers in the DPP were on average 50 years old, and all had prediabetes. The DPP itself lasted only 2.8 years, but the researchers followed up with the participants at 10, 15, and as much as 20 years later. And to get to the punchline, people who had been taking metformin lived no longer than people in the control group.

Link: https://www.sens.org/tame-attempt-slow-aging-part-2-human-studies-survival-risk-of-diabetes/

It now costs little to determine the contents of the gut microbiome, producing a list of microbial species and their prevalence. Numerous companies offer this service. This data can be sliced in numerous ways, but as researchers note here, it is the gain and loss of specific populations with advancing age that produces contributions to aging. More general measures of diversity or change, those that give little to no weight to which specific microbial populations alter in abundance, do not produce good correlations with degenerative aging. It is important to consider the actions and mechanisms of specific microbes: are they causing chronic inflammation, are they generating beneficial or harmful metabolites, and so forth.

The gut microbiome is a modifier of disease risk because it interacts with nutrition, metabolism, immunity, and infection. Aging-related health loss has been correlated with transition to different microbiome states. There is broad consensus how the microbiome changes with age, but specific intervention targets are less clear. Moreover, terms like diversity, assumed by many to be desirable, and 'uniqueness', which has been cast as a marker of healthy aging, need greater precision and should not be used agnostic of the loss or gain of specific taxa in aging. Other summary statistics include different measures of uniqueness that capture specific aspects of gut microbiome variability and are calculated using different distance measures.

This study explored whether determining the gain or loss of specific taxa represent a more precise metric of healthy/unhealthy aging than summary microbiome statistics, such as diversity and uniqueness. We analyzed microbiome diversity and four measures of microbiome uniqueness in 21,000 gut microbiomes for their relationship with aging and health. We show that diversity and uniqueness measures are not synonymous; uniqueness is not a uniformly desirable feature of the aging microbiome, nor is it an accurate biomarker of healthy aging. Different measures of uniqueness show different associations with diversity and with markers of health and disease.

The study identifies that the gut microbiome alterations associated with both aging in general and unhealthy aging are characterized by a common theme: loss of the core microbiome structure (specifically a coabundant species-level guild of the core microbiome) and concomitant increase of a specific guild of disease-associated taxa.

Link: https://doi.org/10.1038/s43587-022-00306-9

The goal of cancer research should be to produce a robust, highly effective universal cancer therapy, or as close to universal as possible. One treatment that can be deployed for every type of cancer, with a very good chance of inducing remission. Attempting to tackle cancer subtypes one by one based on their genetic peculiarities is simply not efficient enough to produce meaningful progress in our lifetimes. Further, most cancers are subject to high mutation rates, and in a sizable fraction of patients will prove to be quite capable of evolving immunity to any therapy that targets a non-essential aspect of cancer biochemistry.

Cancer cells as a class are metabolically very different from normal cells; they have to be in order to power the rampant growth characteristic of tumor tissue. This presents a broad area of discovery for the development of prodrugs, molecules in which a toxic drug is amended to become non-toxic in a way that can be reversed by the activity of enzymes present only in the the targeted cell populations. This in principle allows for any usefully toxic chemotherapeutic drug, of which there are many, to be amended into a non-toxic form that will be near entirely processed back into the original toxic drug only by cancer cells. Importantly, at least some prodrug strategies of this nature might be applicable to a broad range of cancers.

Researchers Design 'Prodrug' That Targets Cancer Cells' Big Appetite for Glutamine, Leaving Healthy Cells Unharmed

"Our goal was to modify an old cancer drug that had shown robust efficacy but was too toxic, especially to the gut, to be developed clinically. To do this, we used a prodrug approach." The newly modified prodrug takes advantage of a common property of cancer cells: a voracious appetite for an amino acid called glutamine, which is a critical building block for proteins, lipids, and nucleotides, as well as for energy formation. Rapidly growing cancer cells use a tremendous amount of glutamine, a phenomenon called "glutamine addiction," but other healthy cells with rapid turnover, like those lining the gut, also rely on glutamine.

"DRP-104 is a tumor-targeted prodrug of the glutamine mimic drug called DON (6-Diazo-5-Oxo-L-norleucine), which inhibits multiple glutamine-utilizing enzymes in cancer cells. Many early studies of DON showed it was robustly efficacious in people and mice, but its development was halted due to its toxicity to normal tissues, especially the gut. We added chemical groups, called promoieties, to DON that rendered it inactive in the body until it reached the tumor, where the promoieties were clipped off by enzymes that are abundant in the tumor but not in the gut."

Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug

6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism but concurrently enhances the metabolic fitness of tumor CD8+ T cells. DON showed promising efficacy in clinical trials; however, its development was halted by dose-limiting gastrointestinal (GI) toxicities. Given its clinical potential, we designed DON peptide prodrugs and found DRP-104 [isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate] that was preferentially bioactivated to DON in tumor while bioinactivated to an inert metabolite in GI tissues.

In drug distribution studies, DRP-104 delivered a prodigious 11-fold greater exposure of DON to tumor versus GI tissues. DRP-104 affected multiple metabolic pathways in tumor, including decreased glutamine flux into the TCA cycle. In efficacy studies, both DRP-104 and DON caused complete tumor regression; however, DRP-104 had a markedly improved tolerability profile. DRP-104's effect was CD8+ T cell dependent and resulted in robust immunologic memory. DRP-104 represents a first-in-class prodrug with differential metabolism in target versus toxicity tissue. DRP-104 is now in clinical trials under the FDA Fast Track designation.

There are a score or so of proteins in the human body capable of producing amyloid when they misfold, by encouraging other molecules of the same protein to misfold in the same way, linking together to produce solid deposits in and around cells. Only those amyloids for which there is clear evidence of disease association or toxicity to cells have been well studied, unfortunately. That doesn't mean that the others are harmless! As demonstrated here, it may just be the case that researchers have to look a little harder to find the ways in which these amyloids are causing pathology in older people.

Medin belongs to the group of amyloids. Of these proteins, amyloid-β is best known because it clumps together in the brains of Alzheimer's patients. These aggregates then deposit both as so-called plaques directly in the brain tissue, but also in its blood vessels, thereby damaging the nerve cells and the blood vessels, respectively. But while many studies have focused on amyloid-β, medin has not been a focus of interest.

However, medin is actually found in the blood vessels of almost everybody over 50 years of age, making it the most common amyloid known. Medin even develops in aging mice. The older the mice get, the more medin accumulates in the blood vessels of their brains. What's more, when the brain becomes active and triggers an increase in blood supply, vessels with medin deposits expand more slowly than those without medin. This ability of blood vessels to expand, however, is important to optimally supply the brain with oxygen and nutrients.

Now researchers were able to show in Alzheimer's mouse models that medin accumulates even more strongly in the brain's blood vessels if amyloid-β deposits are also present. Importantly, these findings were confirmed when brain tissue from organ donors with Alzheimer's dementia was analysed. However, when mice were genetically modified to prevent medin formation, significantly fewer amyloid-β deposits developed, and as a result, less damage to blood vessels occurred. "There are only a handful of research groups worldwide working on medin at all. We have now been able to show through many experiments that medin actually promotes vascular pathology in Alzheimer's models, and this indicates that medin is one of the causes of the disease."

Link: https://www.dzne.de/en/news/press-releases/press/new-target-for-alzheimers-therapies-found/

Researchers here describe an interesting approach to slowing aspects of neurodegeneration that contribute to, among other things, female reproductive aging. That is the focus of this paper, but numerous other aspects of the aging brain are also involved. IGF1 is well studied in the context of aging, and manipulation of the signaling pathways linking insulin, IGF1, and growth hormone has been shown to extend life span in a number of species. Where we can make direct comparisons between mice and humans, such as between growth hormone receptor knockout mice and humans with Laron syndrome, the effects are nowhere near as large. Suppression of growth hormone signaling can extend life by 70% or so in mice, but Laron syndrome doesn't appear to make humans live meaningfully longer. Many approaches to slowing aging have much larger effects in short-lived mammals than they do in long-lived mammals.

The inflammatory environment characteristic of the aged brain is caused by activation of glial cells, mainly microglia. Several studies report that neuroinflammation leads to reduced gonadotropin-releasing hormone (GnRH) secretion, which is associated with multiple aging-related physiological changes, including bone loss, skin atrophy, muscle weakness, and memory loss. Indeed, GnRH administration amend aging-impaired neurogenesis and decelerates aging in mice. In addition, the same authors also describe that inhibition of NF-κB-directed immunity, specifically in hypothalamic microglia cells, has an anti-aging effect.

GnRH secretion is regulated by hormonal and environmental signals such as kisspeptin. This peptide plays a critical role in controlling the onset of puberty and reproductive function in adulthood. There are two populations of kisspeptin neurons, one in the anteroventral periventricular nucleus (AVPV) and one in the arcuate nucleus (Arc), that are targets of positive and negative feedback regulation of estrogen, respectively. Aging female rats transition from regular to irregular estrus cycles, constant estrus, and finally to an anestrus stage. Changes within the hypothalamic-pituitary-ovarian axis, manifested by altered secretion of neurotransmitters, altered secretion of pituitary hormones and altered follicular development and steroid content, lead to the final cessation of reproductive cycles. These processes that lead to reproductive senescence are associated with an increase in circulating cytokines and proinflammatory markers produced by microglial cells. Indeed, several studies describe that hypothalamic and systemic inflammation affect kisspeptin neurons, which are responsible for regulating GnRH neurons.

IGF1 is a neurotrophic factor with an outstanding neuroprotective action in the central nervous system. Previous studies of our group showed that intraparenchymal hypothalamic IGF1 gene therapy was capable to prolong the operation of reproductive cycles in rats. Indeed, we have demonstrated that intracerebroventricular IGF1 gene therapy restores motor performance and generates cognitive and morphological changes in the dorsal hippocampus in senile rats. In addition, we have reported that IGF1 gene therapy modifies microglia number and phenotype in senile rats and decreases astrocytic inflammatory response in vitro, supporting the extensive idea that IGF1 plays a potent anti-inflammatory effect.

The aim of the present study is to investigate the effect of IGF1 gene therapy on estrous cycle, kisspeptin, and GnRH neurons, and microglial cells in middle-aged female rats. Our data indicate that IGF1 gene therapy prolongs the operation of reproductive cycles in middle-aged rats by modulating kisspeptin/GnRH secretion in the hypothalamus and altering microglial cell number and reactivity. Based on our findings, we propose IGF1 gene therapy to delay reproductive senescence as a potential strategy to optimize lifespan and combat age-related health problems in women.

Link: https://doi.org/10.18632/aging.204360

A core point regarding wealth, realized by many but only acted on by a few to date, is that being the wealthiest individual in the graveyard begins to look very foolish in an era in which research and development is producing the basis for rejuvenation therapies. Historically, people traded time for wealth. Now, we enter the start of the era in which people can trade wealth for time. Fortunately, this is a collaborative venture: no-one wins on their own. Either sufficient funding is devoted to the right projects in rejuvenation biotechnology, and all humanity benefits as a result, or we as a society collectively fail to achieve that goal.

Another important point made in this article is that it is challenging for outsiders to make sense of a field of endeavor in which half of the participants appear, on the surface at least, to be modernized versions of 1970s snake oil supplement salespeople, along with a good scattering of eccentric or fraudulent larger than life characters, as well as unhelpful ventures that are clearly chasing or talking up the hype of a longevity industry while providing nothing of any great value.

How does a layperson pick out the legitimate, exciting science of rejuvenation, such as senolytic therapies, or epigenetic reprogramming, from the garbage that is discussed and marketed in exactly the same terms? Eventually the good drives out the bad, but for now we're still stuck with a mess of alchemists pretending to be scientists, alongside supplement salespeople making hay while the sun shines, siphoning attention and funding away from actually valuable projects.

Inside the billion-dollar meeting for the mega-rich who want to live forever

The super-rich eventually reach a point where having more money doesn't improve their lives very much. "If you buy a yacht, you can always get a bigger yacht; if you buy a plane, you can always get a bigger plane. But the extent to which your life is changing with more money is actually very minimal." It makes more sense to direct funds to being healthier and living longer. Such deep-pocketed individuals and groups are looking to be the biggest investors in longevity research. Most of the $4.4 billion invested over the last five years into understanding whether or not reprogramming our cells might help us live longer has gone into Altos Labs, a biotech company whose funders are thought to include Jeff Bezos and Yuri Milner.

A sense of hope and optimism was palpable at the Longevity Investors Conference. I got the impression that most people believed that, with enough funding, positive scientific results were just a few years away. And with that, we'd be on the road to reliably extending human healthspan. The presenters were a mix of longtime academics, biotech startups, and people selling the idea of longevity as a high-end luxury good for those who frequent spas and lavish retreats. Some have been studying the biology of aging for decades, and are well-respected among their peers. But I also met a young man who told me that breathing low-oxygen air could benefit multiple aspects of my health - and who then commented that he "didn't believe" in covid vaccines. A 67-year-old man took to the stage to tell us that, since he'd been taking his own supplement, his biological age had reversed, and he was now biologically only 49 years old.

How is an investor - or anyone else, for that matter - meant to make sense of all these claims? Ask an academic, and they'll tell you that the answer is education-the more people know about the biology of aging and how clinical trials work, the better placed they are to work out how much faith to put in any claim. Many agree that it's the wild claims made by some - claims that we could live to be a thousand years old, or avoid death entirely - that have helped bring attention and investment to the field. But they have also tarnished its reputation as a scientific discipline.

Others say that while there's more hype in biotech than academia, they thinks that any hype tends to be short-lived. "If you're selling hot air, you can't get away with doing that for very long." I've been writing about the science of aging for over a decade myself, and I'm not sure I fully agree with him. I've seen shoddy science get plenty of press attention. I've seen smart scientists fall prey to flimsy claims about health-extending supplements. But I've also seen some fascinating and tantalizing research - enough to want to follow it through and find out if these approaches really will be as beneficial for people as they are for lab animals.

A fair number of studies have shown reduced late life mortality to correlate with, or result from, programs of resistance exercise. While a great many studies of aerobic exercise have indicated that at very high levels of exercise there is increased mortality versus more modest programs of exertion, in other words that the dose-response curve is U-shaped, it isn't completely clear that this is also the case for resistance exercise. While a fair number of studies have taken place, there isn't as much evidence to assess. This short paper provides a high level discussion of the present state of knowledge and some references to follow up on for those interested in the details.

Regular physical activity (PA) promotes healthy aging, and activities aiming to increase muscular strength (i.e., resistance exercise, RE) are important PA modalities for achieving health benefits. Previous meta-analyses demonstrated that both RE and muscular strength were associated with mortality benefits, even when RE was performed above the PA targets recommended by current guidelines.

While optimal volumes of endurance-type exercise (aerobic moderate-to-vigorous PA, MVPA) to reduce mortality from all causes have been suggested to amount to or even exceed 700 minutes per week, recent meta-analyses suggest that large amounts of RE may be associated with adverse outcomes. Although these analyses demonstrated an overall inverse association between RE and mortality risk from all causes and/or from cardiovascular diseases (CVD), diabetes, and cancers, this was only true up to a certain threshold of RE volume per week (i.e., there is a U-shaped dose-response relationship between RE and mortality). Should the many individuals engaging in RE volumes exceeding the reported cutoffs for optimal benefits be worried?

Overall, excessive RE may put a small number of individuals at a higher risk for adverse health outcomes, which is similar to the effect of extreme endurance exercise. This risk may vary with age and sex (e.g., while young subjects may be more susceptible than older ones to arterial stiffness following RE, men are much more likely than women to be injured performing RE) and can increase with inappropriate execution of RE, overconfidence, and/or subtle pre-existing comorbidities.

Although low-to-moderate intensity RE is usually well tolerated and widely recommended for individuals with and without cardiovascular disease, heart rate and systolic blood pressure values in cardiac patients are higher during low-intensity as compared to high-intensity RE. As low-intensity RE is typically performed at higher volumes than high-intensity RE, vulnerable individuals performing high volumes of low-intensity RE might be at higher mortality risk than previously assumed.

Link: https://doi.org/10.1016/j.jshs.2022.11.004

This scientific commentary describes an interesting join the dots exercise in which scientists link together a number of different topics that have shown up over the years in research into aging. Here, the Hippo pathway (activated by YAP and TAZ), the shape and maintenance of the nuclear envelope, inflammatory cGAS/STING signaling, and cellular senescence are all connected. Declining expression of YAP and TAZ occur with aging, for reasons to be explored, and that decline appears sufficient in and of itself to trigger the rest of the linked cascade of changes and consequent cellular senescence and tissue dysfunction.

A recent study tested the possibility that altered mechanosensing of the extracellular environment, i.e., the extracellular matrix (ECM), is a signal for physiological aging. The transcriptional coactivators and end effectors of the Hippo signaling pathway, YAP and TAZ, are established mediators that link mechanosensation to changes in cell behavior through the regulation of transcriptional programs.

To explore the hypothesis that YAP/TAZ mediate effects of aging, the authors first performed a series of experiments employing single-cell RNA-seq data that indicated the downregulation of a YAP/TAZ activation signature gene set in dermal fibroblasts of old mice. This pattern of depressed YAP/TAZ activity was also observed in other stromal cells (e.g., kidney fibroblasts) as well as contractile cells (cardiomyocytes, vascular smooth muscle cells) but not in epithelial cells, hepatocytes, or lymphocytes, indicating cell-type specificity.

Depletion of YAP/TAZ in young mice reduced dermal fibroblast number and phenocopied aged skin in control mice. Targeted deletion of YAP/TAZ in vascular smooth muscle cells elicited aortic dissection, rupture, and death in several weeks, thereby accelerating aging-associated pathology. To further substantiate YAP/TAZ regulation of cellular senescence, transcriptome profiling in freshly isolated dermal fibroblasts from young mice demonstrated increased senescence-associated secretory phenotype (SASP) genes as well as increased β-gal expression, both hallmarks of senescence, in YAP/TAZ deficient cells. On the other hand, supplementing YAP to fibroblasts cultured from old mice led to suppression of SASP and β-gal positivity.

cGAS-STING signaling modulates innate immune responses and has been previously implicated in the regulation of senescence. Through multiple complementary approaches, researchers showed that YAP/TAZ suppressed cGAS activation in several cell and tissue types, and involved the inappropriate release of genomic DNA into the cytosol. How does YAP/TAZ restrain cGAS-STING? The authors astutely recognized a relationship between decreased YAP/TAZ activity and distorted nuclear architecture in old cells. Moreover, the addition of active YAP rescued abnormal nuclear structure caused by aging. Additional screens revealed that YAP/TAZ directly promote the expression of two key factors that maintain proper nuclear envelope integrity, lamin B1 and ACTR2.

These findings demonstrate that YAP/TAZ is a critical upstream modulator of nuclear integrity and functions in young cells to keep cGAS-STING in check to prevent the aging phenotype of cellular senescence.

Link: https://doi.org/10.20517/jca.2022.33

As Giving Tuesday approaches once again, it is time to consider charitable donations for the end of 2022. If your priority is to reduce human suffering in the world, then by far the most cost-effective approach is to support scientific programs that enable the development of rejuvenation therapies. In comparison to the vast and inflated cost of medicine, the scientific research that produces the means to make new medicines is cheap. Given the right infrastructure of advocacy and networking between the scientific community and industry, new scientific results achieved at low cost can inspire a great deal of investment in further development.

Our community of patient advocates, scientists, fundraisers, and entrepreneurs has spent the past two decades building out that infrastructure: people and organizations that identify the most promising research programs, help to fund them, and then transfer the successful results into venture-funded biotech startups. That ecosystem grows with time, and the original efforts are now spread out over a number of non-profits, collaborating with a network of allied researchers. All of these non-profits merit ongoing philanthropic support, so that they continue to build a pipeline from academia to industry for the most promising approaches to human rejuvenation.

Firstly the SENS Research Foundation, spun out from the Methuselah Foundation, the original starting point for this community. SENS Research Foundation maintains a research group and laboratory that has led to a number of spin-out companies focused on aspects of rejuvenation via damage repair, such as Cyclarity. It further funds research in a number of allied institutions around the world, focused on enabling repair of the cell and tissue damage that causes aging, particularly in parts of the field that appear to be neglected or moving too slowly.

Secondly, Aubrey de Grey's new Longevity Escape Velocity (LEV) Foundation will perform similar work to the SENS Research Foundation, with an initial focus on combining approaches to demonstrate that repairing different forms of cell and tissue damage simultaneously will produce greater, synergistic gains, as expected from a damage-focused view of aging. If you were a supporter of the SENS Research Foundation, you might take a look at the projects that will be undertaken at the LEV Foundation and choose to support both organizations.

Thirdly, the Methuselah Foundation continues to perform a range of important work in the field of rejuvenation research, in combination with an allied venture fund, the Methuselah Fund. The primary focus is tissue engineering and production of replacement organs, but they are also involved in numerous other projects relevant to research into aging and rejuvenation.

The principals at all of these organizations are involved behind the scenes in networking, arranging connections between scientists and entrepreneurs, agitating for specific programs to receive support, and in general trying to move humanity closer to an era in which aging is a medical condition that can be controlled, repaired, reversed. Their actions over the past twenty years have helped bring us to the point at which a longevity biotech industry actually exists, and many formerly languishing research programs have made the leap to preclinical and clinical development.

We live in exciting times! A great deal of work remains to be carried out, however. Many scientific programs necessary to the repair of cell and tissue damage remain poorly funded. If a comprehensive toolkit of rejuvenation therapies is to be produced in our lifetime, something must be done about that. The field moves as fast as we collectively help it to move; science runs on funding as much as it runs on enthusiasm. So pick one of these worthy non-profits and make a donation!

TREM2 has become a gene of interest in Alzheimer's research, particularly now that a greater focus is given to chronic inflammation, and other aspects of immune aging, in the development and progression of this and other neurodegenerative conditions. TREM2 is a receptor that mediates the ability of microglia, innate immune cells of the brain, to take up and clear amyloid-β aggregates from the brain. Targeting TREM2 with antibodies appears to improve the ability of microglia to perform this task. Absent this sort of intervention, however, microglia in aged individuals both lose TREM2 expression and become less capable of amyloid-β clearance.

Age-associated microglial dysfunction contributes to the accumulation of amyloid-β (Aβ) plaques in Alzheimer's disease. Although several studies have shown age-related declines in the phagocytic capacity of myeloid cells, relatively few have examined phagocytosis of normally aged microglia. Furthermore, much of the existing data on aging microglial function have been generated in accelerated genetic models of Alzheimer's disease. Here we found that naturally aged microglia phagocytosed less Aβ over time. To gain a better understanding of such dysfunction, we assessed differences in gene expression between young and old microglia that either did or did not phagocytose Aβ.

Young microglia had both phagocytic and neuronal maintenance signatures indicative of normal microglial responses, whereas, old microglia, regardless of phagocytic status, exhibit signs of broad dysfunction reflective of underlying neurologic disease states. We also found downregulation of many phagocytic receptors on old microglia, including TREM2, an Aβ phagocytic receptor. TREM2 protein expression was diminished in old microglia and loss of TREM2+ microglia was correlated with impaired Aβ uptake, suggesting a mechanism for phagocytic dysfunction in old microglia. Combined, our work reveals that normally aged microglia have broad changes in gene expression, including defects in Aβ phagocytosis that likely underlies the progression to neurologic disease.

Link: https://doi.org/10.1038/s41598-022-21920-y

Of the various simple measures that correlate with mortality and risk of age-related disease, grip strength remains a relatively good option, even in this modern era of epigenetic clocks. Illustrative of this point, researchers here show a correlation between grip strength and epigenetic age data in a sizable study population. The degree to which an individual suffers from the chronic inflammation of aging may be an important determinant of this relationship. Inflammation disrupts tissue function throughout the body, and maintenance of muscle mass and strength is one of the aspects of health negatively affected by unresolved inflammatory signaling.

Researchers modeled the relationship between biological age and grip strength of 1,274 middle aged and older adults using three "age acceleration clocks" based on DNA methylation, a process that provides a molecular biomarker and estimator of the pace of aging. The clocks were originally modeled from various studies examining diabetes, cardiovascular disease, cancer, physical disability, Alzheimer's disease, inflammation, and early mortality. Results reveal that both older men and women showed an association between lower grip strength and biological age acceleration across the DNA methylation clocks. The real strength of this study was in the eight to 10 years of observation, in which lower grip strength predicted faster biological aging measured up to a decade later.

Past studies have shown that low grip strength is an extremely strong predictor of adverse health events. One study even found that it is a better predictor of cardiovascular events, such as myocardial infarction, than systolic blood pressure - the clinical hallmark for detecting heart disorders. Researchers have previously shown a robust association between weakness and chronic disease and mortality across populations. This evidence coupled with the recent findings shows potential for clinicians to adopt the use of grip strength as a way to screen individuals for future risk of functional decline, chronic disease and even early mortality.

Future research is needed to understand the connection between grip strength and age acceleration, including how inflammatory conditions contribute to age-related weakness and mortality. Previous studies have shown that chronic inflammation in aging - known as "inflammaging" - is a significant risk factor for mortality among older adults. This inflammation is also associated with lower grip strength and may be a significant predictor on the pathway between lower grip strength and both disability and chronic disease multimorbidity.

Link: https://labblog.uofmhealth.org/body-work/muscle-weakness-new-smoking

Epigenetic reprogramming is a process of exposing cells to the Yamanaka factors for a long enough period of time to shift their epigenome towards that found in youthful tissues, but not for so long as to cause any meaningful number of them to change state into pluripotent stem cells. It is an attempt to reproduce aspects of the cellular rejuvenation that occurs in the initial stages of embryogenesis, without harming the functional specialization of the cells so altered. It works surprisingly well in animal studies, considering all of the very reasonable a priori objections as to why we should believe that such an embryonic process would be harmful and cancerous (at the very least) in the very different, structured environment of adult, aging somatic tissue.

There is a school of thought-slash-marketing-to-investors regarding mechanisms of aging that suggests epigenetic reprogramming of cells in vivo will be sufficient to produce comprehensive rejuvenation, addressing near all issues. That reprogramming the epigenetic landscape to a youthful configuration will provoke tissues into repair and clearance of enough of the damage of aging that further therapies would be superfluous. This really doesn't appear to be the case, however.

Based on the animal studies to date, reprogramming will produce significant benefits, just like, say, clearance of senescent cells, but it won't be the whole of the picture. There are forms of damage that a young body cannot repair. Many forms of persistent molecular waste, such as components of lipofuscin or some advanced glycation endproducts, cannot be broken down effectively by our cells. Nuclear DNA damage won't be repaired once present. Localized excesses of cholesterol, such as that found in atherosclerotic lesions, would overwhelm the macrophages responsible for clearing this damage even in a young person. And so on and so forth.

SENSible Question: Wouldn't Cellular Reprogramming Be Enough?

Cellular reprogramming turns an old person's cells young again. So can't we fix aging by just reprogramming a person's old cells with reprogramming factors? This is a tantalizing idea that's on a lot of our supporters' minds these days. On the one hand, it's certainly true that we lose cells with aging and that other cells become dysfunctional. And on the other hand, the cellular reprogramming experiments have in some senses rejuvenated cells in a way that can and should spark excitement - first and foremost, because the technology will greatly enable cell therapy of various kinds, which will be critical to the medical defeat of aging. But the quite rational enthusiasm for a specific technology can sometimes spark a kind of irrational biomedical exuberance so great that even some very prominent geroscientists seem to have begun to fall into a kind of fallacy of composition: the body is made up of cells; therefore, if we rejuvenate all our cells, we will rejuvenate our entire bodies.

People making this intuitive leap are in for an inelegant crash. We simply are not composed entirely of cells, and replacing lost cells and restoring the original differentiation of cells with epigenetic changes won't do anything to remove or repair aging damage to the many other functional units that are lost or damaged as we age and that contribute to diseases and disabilities of aging.

For one thing, there's aging damage to the extracellular matrix (ECM). The ECM is the lattice of proteins that provide both physical structure and signaling cues for our cells and tissues, and that also have important roles of their own in the body's movement and plumbing. In addition to damage to the ECM, another critical kind of aging damage that would impair the youthful function even of pristine reprogrammed cells is the various extracellular aggregates ("amyloids") that accumulate outside cells. These are damaged proteins that either physically impede cells' ability to carry out their function, or cause cellular dysfunction in other ways.

We've been thinking about using reprogramming technology either to create replacement cells for those that have been lost to aging processes, or to reprogram cells already in the tissues in order to (as advocates would have it) rejuvenate their function. These applications could in principle deal with cells that are either missing entirely, or that are still present but behaving badly due to reversible changes in their epigenetics - but they can't do anything about cells that survive, but have suffered certain other kinds of aging damage.

For instance, cells overtaken by mitochondria with large deletion mutations (which are the most problematic kind of mitochondrial damage in aging) almost certainly can't be restored to normal functioning through reprogramming. In all probability, the presence of mitochondrial mutations and other aging damage (such as intracellular aggregates, the abnormal splice protein lamin A, and some mutations and epimutations) is one of the main reasons why only a tiny fraction of cells exposed to reprogramming factors ever actually get reprogrammed. And in addition to not repairing all aging damage, reprogramming itself causes other kinds of damage to some cells that make them useless for rejuvenation biotechnology, such as the newly-created mitochondrial DNA mutations, or abnormal numbers of chromosomes, or the paradoxical mixed bag of reprogramming-induced senescence (RIS).

And there are even narrowly cellular forms of aging damage that you can't or wouldn't want to "repair" using reprogramming. Yes, you can reverse cellular senescence by reprogramming, and with a few additional tricks you can even reverse reprogramming-induced senescence, but is that a good idea? Remember, the cellular senescence machinery is a kind of emergency brake, which the cell pulls when it is in danger of careening out of control, such as by progressing to become a cancer or by laying down excessive collagen after an injury, leading to fibrosis.

Clearance of metabolic waste from the brain falters with age, leading to an increased presence of toxic protein aggregates, such as the amyloid-β associated with Alzheimer's disease, but also others. Evidence has emerged for mechanical issues in the flow of cerebrospinal fluid out of the brain to be important in this contributing cause of neurodegenerative disease. If the cerebrospinal fluid isn't carrying away enough of the metabolic waste, then a garbage catastrophe of one sort or another is the inevitable result. Here, compelling new evidence for one of the many possible deeper causes of those mechanical issues is discussed.

With age, the brain's ability to clear aggregating proteins such as amyloid-β (Aβ) wanes. Researchers have found that the macrophages that cozy up to arteries in the brain help thin out extracellular matrix around these vessels. Macrophages inhabit spaces that border the brain parenchyma, namely along blood vessels and in the meninges. In both locations, they make direct contact with cerebrospinal fluid (CSF). Although these cells have been implicated in conditions such as hypertension, stroke, and Alzheimer's disease (AD), no one knew exactly what they did in healthy brain.

To explore this, researchers killed off border macrophages in wild-type mice by injecting liposomes containing a toxin into the CSF, where they were selectively taken up by macrophages. One week later, researchers injected a fluorescent tracer into CSF at the base of the brain, and tracked its diffusion along vessels. In control mice, arterial pulsing pushed the tracer into parenchyma. In liposome-treated mice, however, it penetrated only half as far as it did in control mice, indicating weaker CSF flow. To see why this was, the authors directly examined arterial movement through a cranial window while they stimulated brain activity by tickling the mice's whiskers. In mice lacking perivascular macrophages, blood vessels dilated less than they did in controls.

Why might this be? Perivascular macrophages are known to pump out matrix metalloproteases (MMPs), which chew up extracellular matrix (ECM) proteins. The authors found that MMP activity around brain blood vessels was suppressed after macrophage depletion, and the ECM was thicker. This overgrowth hindered dilation of blood vessels, in effect making them stiffer. In addition, nearby fibroblasts released more ECM proteins in the absence of macrophages. The authors concluded that macrophages keep vessels supple both by breaking down ECM and via crosstalk with fibroblasts that regulates their output.

Not all perivascular macrophages contribute to CSF flow. An analysis of gene expression revealed two subsets. One expressed the immune marker MHCII, and clustered around veins. Based on their expression profile, the authors believe these cells may recruit circulating leukocytes to brain. The other group expressed LYVE1, a membrane glycoprotein. These cells resided mainly around arteries and arterioles, and were scavengers, engulfing nearby debris. LYVE1 cells seem to be the ones controlling CSF flow, as genetically ablating only this subset thickened ECM and stiffened vessels.

Link: https://www.alzforum.org/news/research-news/perivascular-macrophages-new-target-aging-and-alzheimers-disease

The data in this study is more interesting for the size of the effect than for the reduction in metastatic cancer risk in and of itself, as one expects exercise to reduce manifestations of aging across the board, via many direct and indirect mechanisms. Whether the important mechanism in this case, as the researchers suggest, that high intensity exercise consumes metabolic resources that would otherwise be available to tumor tissue, is an open question. It could well be effects on immune surveillance, for example, or any number of other differences in metabolism, such as reduced levels of chronic inflammation, that act to make a less hospitable environment for metastasis.

Studies have demonstrated that physical exercise reduces the risk for some types of cancer by up to 35%. This positive effect is similar to the impact of exercise on other conditions, such as heart disease and diabetes. In this study researchers added new insight, showing that high-intensity aerobic exercise, which derives its energy from sugar, can reduce the risk of metastatic cancer by as much as 72%. If so far the general message to the public has been 'be active, be healthy', now researchers can explain how aerobic activity can maximize the prevention of the most aggressive and metastatic types of cancer.

The study combined an animal model in which mice were trained under a strict exercise regimen, with data from healthy human volunteers examined before and after running. The human data, obtained from an epidemiological study that monitored 3,000 individuals for about 20 years, indicated 72% less metastatic cancer in participants who reported regular aerobic activity at high intensity, compared to those who did not engage in physical exercise.

The animal model exhibited a similar outcome, also enabling the researchers to identify its underlying mechanism. Sampling the internal organs of the physically fit animals, before and after physical exercise, and also following the injection of cancer, they found that aerobic activity significantly reduced the development of metastatic tumors in the lymph nodes, lungs, and liver. The researchers hypothesized that in both humans and model animals, this favorable outcome is related to the enhanced rate of glucose consumption induced by exercise.

Link: https://www.eurekalert.org/news-releases/971237

Why has the tone of writing by ethicists on the topic of treating aging as a medical condition, with consequent extension of health human life span, shifted from from hostility to endorsement over the last twenty years? One possibility is that while a technological capability is thought to be a far future possibility, or unattainable, only those with an ax to grind will talk about it. The years since the turn of the century have seen tremendous progress towards implementing therapies capable of addressing mechanisms of aging, and in lockstep with that the scientific community, and a small but sizable fraction of the public at large, have come to understand that rejuvenation and slowing of aging are viable near future goals. Some of those people are ethicists lacking an ax to grind, and some of those ethicists write on the topic.

Another possibility is that we now know a great deal more about what the first age-slowing and rejuvenating therapies will look like, and many of them are cheap small molecule drugs. Many of those are repurposed from the existing spectrum of approved therapies, not new molecules, and so out of patent and cheap. Not all of the options on the table will eventually manufactured for cents per dose, given a world in which near everyone uses that treatment. Enough of the first generation interventions are in that category, however, to make it challenging for ethicists to view the treatment of aging as something that will be deployed only for the elites, or to employ the usual arguments made against progress: that it will cost too much; be too challenging to implement broadly; that only the wealthy will have access to these options.

Aging, Equality and the Human Healthspan

John Davis (New Methuselahs: The Ethics of Life Extension) advances a novel ethical analysis of longevity science that employs a three-fold methodology of examining the impact of life extension technologies on three distinct groups: the "Haves", the "Have-nots" and the "Will-nots". In this essay, I critically examine the egalitarian analysis Davis deploys with respect to its ability to help us theorize about the moral significance of an applied gerontological intervention.

Rather than characterizing, as Davis does, an aging intervention as a form of "life extension", in this article, I argue that an ethical analysis of an aging intervention should focus on what the primary health impact of such an intervention would likely have on population health - namely, increasing the human healthspan so that the risks of disease, frailty, and disability would be reduced in late life. A by-product of such an intervention is that it may increase the number of years people also live.

Rather than deploying an egalitarian analysis into the far future of a potential new longevity-caste society, I believe it is more prudent and practical to deploy such an ethical analysis to the intrinsic health inequalities that exist between persons at different stages of the human lifespan, e.g., between young adults (age 20-30) and older persons (age 85+), as well as the health inequalities that already exist with respect to variations in the rate of biological aging.

In this essay, I will deploy a comprehensive "present-day" (vs. futuristic) egalitarian analysis that highlights the health consequences of the "status quo" of biological aging, including the health inequalities that exist between persons with "accelerated" aging (e.g., progeria), "normal" aging, and "retarded" aging (e.g., centenarians and supercentenarians). Doing so can help re-frame the ethical arguments concerning intervening in aging, so that an applied gerontological intervention is recognized as a significant form of preventative medicine, rather than a technology that raises serious concerns about radical life extension, boredom, or the creation of a new caste system between the "longevity-haves" and "have-nots".

Like Davis, I believe "that developing life extension is, on balance, a good thing and that we should fund life extension research aggressively". But unlike Davis, I do not believe the best way to promote societal discussion about, or the policy regulation of, an applied gerontological intervention should begin by contemplating the potential future inequalities radical life extension might potentially create. Instead, I believe an ethical analysis should begin from (1) the existing health vulnerabilities of today's aging populations, (2) the existing inequalities of the "aging status quo", and (3) address the most likely aging technology to be developed in the immediate future and reasonable empirical assumptions concerning its fair diffusion.

Aspiring to increase the healthspan, vs. merely delaying death, could constitute an innovative approach to human health and help us realize the noble aspiration of "adding life to years" vs. "adding years to life". Given where the science is today, the goal of a century of disease-free life is a realistic and compelling aspiration. The priority should be on making an applied gerontological intervention a top public health priority for the world's aging populations. If we do this, then the 2 billion persons over age 60 by the year 2050 could enjoy more health and a compression of disease, frailty, and disability.

The use of chemotherapy to destroy as much of the peripheral immune system as possible, followed by some form of stem cell transplant to rebuild it, has been used for some years as a way to treat multiple sclerosis. In this autoimmune condition, the problem resides in the immune memory, and getting rid of that memory is the solution. The only approach currently demonstrated to work is this somewhat drastic treatment, and the balance of risk and cost means that it is only used for severe diseases such as multiple sclerosis. But in principle, clearance and restoration of the immune system could solve a great many of the issues present in an aged immune system, were there a way to go about it that didn't have the same level of risk and trauma.

Multiple sclerosis (MS) is an autoimmune disease in which the body's own immune system attacks the myelin sheath of the nerve cells in the brain and spinal cord. The disease leads to paralysis, pain, and permanent fatigue, among other symptoms. Fortunately, there have been great advances in therapies in recent decades. 80 percent of patients remain disease-free long-term or even forever following an autologous hematopoietic stem cell transplant. During the treatment, several chemotherapies completely destroy the patients' immune system - including the subset of T cells which mistakenly attack their own nervous system. The patients then receive a transplant of their own blood stem cells, which were harvested before the chemotherapy. The body uses these cells to build a completely new immune system without any autoreactive cells.

Previous studies have shown the basic workings of the method, but many important details and questions remained open. Some unclear aspects were what exactly happens after the immune cells are eliminated, whether any of them survive the chemotherapy, and whether the autoreactive cells really do not return. In a recently published study, researchers systematically investigated these questions for the first time by analyzing the immune cells of 27 MS patients who received stem cell therapy. The analysis was done before, during and up to two years after treatment. This allowed the researchers to track how quickly the different types of immune cells regenerated.

Surprisingly, the cells known as memory T cells, which are responsible for ensuring the body remembers pathogens and can react quickly in case of a new infection, reappeared immediately after the transplant. Further analysis showed that these cells had not re-formed, but had survived the chemotherapy. These remnants of the original immune system nevertheless posed no risk for a return of MS, as they were pre-damaged due to the chemotherapy and therefore no longer able to trigger an autoimmune reaction.

In the months and years following the transplant, the body gradually recreates the different types of immune cells. The thymus gland plays an important role in this process. This is where the T cells learn to distinguish foreign structures, such as viruses, from the body's own. Adults have very little functioning tissue left in the thymus. But after a transplant, the organ appears to resume its function and ensures the creation of a completely new repertoire of T cells which evidently does not trigger MS or cause it to return.

Link: https://www.news.uzh.ch/en/articles/media/2022/MS-Stem-Cell-Transplantation.html

Researchers here show that blocking increased PGE2 signaling in the aging lung helps to restore resistance to influenza infection. There is an interaction between PGE2, cellular senescence in cells of the alveoli in the lung, and the behavior of local macrophages of the innate immune system. It remains to be seen whether PGE2 signaling is regulating much the same issues connected to cellular senescence elsewhere in the body.

Previous research by another group showed that when macrophages from an old mouse were put into a young mouse, and cells looked young again. Signs pointed to a lipid immune modulator known as prostaglandin E2 (PGE2) with wide ranging effects. The study team discovered there is more PGE2 in the lungs with age. This increase in PGE2 acts on the macrophages in the lung, limiting their overall health and ability to generate. The team suspects that the buildup of PGE2 is yet another marker of a biological process called senescence, which is often seen with age.

The study showed that with age, the cells lining the air sacs in the lungs become senescent, and these cells lead to increased production of PGE2 and suppression of the immune response. To test the link between PGE2 and increased susceptibility to influenza, they treated older mice with a drug that blocks a PGE2 receptor. "The old mice that got that drug actually ended up having more alveolar macrophages and had better survival from influenza infection than older mice that did not get the drug." The team plans to next investigate the various ways PGE2 affects lung macrophages as well as its potential role in inflammation throughout the body.

Link: https://labblog.uofmhealth.org/body-work/study-hints-at-why-older-people-are-more-susceptible-to-flu

The challenge in understanding degenerative aging is at this point less a matter of identifying mechanisms, and more a matter of establishing which of the many mechanisms involved in every specific aspect of aging are actually important. Cellular biochemistry is a complex interconnected web, and it is very hard to make changes to just one mechanism in isolation, so as to establish exactly its contribution. Now that biotechnology has advanced to the point at which near every biological mechanism is a viable target for intervention, it matters whether or not the research and development communities focus on the right targets, those that can produce meaningful benefits to patients.

Correlations are observed between the state of the gut microbiome and late life health, and the gut microbiome changes with age in ways thought to provoke inflammation and reduce the generation of beneficial metabolites. In today's open access paper, researchers propose that generation of excessive oxidative molecules via activities of the gut microbiome is an important factor in the onset and progression of age-related frailty.

It is almost certainly the case that the mechanisms described in the paper exist, but it is very hard to say how important they are in humans versus other layered and interacting issues in aging, such as chronic inflammation, or loss of stem cell function in muscle tissue, or immunosenescence. One way forward would be to perform fecal microbiota transplants in old people, using young donors, an approach shown to rejuvenate the gut microbiome in animal studies, but even this would mix in effects on inflammation and tissue function. It is challenging to make isolated changes in the body.

Oxidative stress bridges the gut microbiota and the occurrence of frailty syndrome

Frailty is one of the most complicated clinical syndromes and is defined as a decrease in the reserve and restoring capacity of the body. For frail people, a slight irritant can result in strong responses, which require a longer period to recover. Thus, frailty can also be regarded as a decline in the ability to maintain homeostasis. Multiple organs and systems, such as the skeletal muscle, immune, endocrine, hematopoiesis, and cardiovascular systems, are involved in the process of frailty. Patients with frailty have a high risk of developing age-related diseases, including neurodegenerative diseases (such as dementia), type II diabetes, atherosclerosis, and chronic heart failure.

Although there are a few hypotheses at present, the mechanisms involved in frailty remain unknown. Researchers have different opinions about the origin of frailty. It is generally accepted that frailty is related to aging. With the increasing focus on frailty, emerging evidence has increased our understanding of this syndrome. Findings from centenarians suggest that specific gut microbiota (GM) constituents may contribute to healthy aging. The diversity and abundance of the GM vary between elderly adults and centenarians.

However, the bridge between the GM and the occurrence of frailty remains unclear. In this review, we proposed the possible mechanisms involved in frailty from the perspective of the GM and oxidative stress (OS). Specific GMs and their metabolites stimulate the production of ROS and affect OS in the body, leading to damage to multiple biological macromolecules. The occurrence of OS may be the intermediate process of the GM that leads to frailty, producing a direct action on the body. This may be one of the precipitating factors of frailty syndrome.

The idea of using GM biomarkers to predict frailty is proposed prospectively. Notably, frailty is not an irreversible status. Timely interventions have the potential to revert the prefrailty or frailty state to a nonfrailty state. By understanding the role of the GM and OS in frailty, several interventions have been proposed to improve this syndrome and to achieve the goal of healthy aging. According to existing research, dietary interventions are the most commonly used treatment for frailty.

Mitochondrial DNA becomes damaged more readily than nuclear DNA, as the systems of DNA repair in mitochondria are less effective, and the DNA structures are less well protected. Some forms of mitochondrial DNA damage can cause mitochondria to become dysfunction while also replicating more efficiently than their peers, leading to pathological cells overtaken by pathological mitochondria that cause damage to their surroundings. As an opposing force, there appear to be ways in which mitochondria can selectively eliminate damaged DNA under some circumstances. Can these mechanisms be meaningfully enhanced to reduce mitochondrial DNA damage and its consequences in aging?

Understanding the mechanisms governing selective turnover of mutation-bearing mitochondrial DNA (mtDNA) is fundamental to design therapeutic strategies against mtDNA diseases. Here, we show that specific mtDNA damage leads to an exacerbated mtDNA turnover, independent of canonical macroautophagy, but relying on lysosomal function and ATG5. Using proximity labeling and Twinkle as a nucleoid marker, we demonstrate that mtDNA damage induces membrane remodeling and endosomal recruitment in close proximity to mitochondrial nucleoid sub-compartments.

Targeting of mitochondrial nucleoids is controlled by the ATAD3-SAMM50 axis, which is disrupted upon mtDNA damage. SAMM50 acts as a gatekeeper, influencing BAK clustering, controlling nucleoid release and facilitating transfer to endosomes. Here, VPS35 mediates maturation of early endosomes to late autophagy vesicles where degradation occurs.

In addition, using a mouse model where mtDNA alterations cause impairment of muscle regeneration, we show that stimulation of lysosomal activity by rapamycin, selectively removes mtDNA deletions without affecting mtDNA copy number, ameliorating mitochondrial dysfunction. Taken together, our data demonstrates that upon mtDNA damage, mitochondrial nucleoids are eliminated outside the mitochondrial network through an endosomal-mitophagy pathway. With these results, we unveil the molecular players of a complex mechanism with multiple potential benefits to understand mtDNA related diseases, inherited, acquired or due to normal ageing.

Link: https://doi.org/10.1038/s41467-022-34205-9

Mitophagy is the process of selecting and breaking down worn mitochondria. There are hundreds of mitochondria in every cell, and regular removal of damaged mitochondrial followed by replacement through replication of viable mitochondria is needed in order to prevent harm to cell functions. Unfortunately, mitophagy appears to become less effective with age, for a variety of reasons, including changes in mitochondrial dynamics, and failures in broader autophagic processes responsible for moving mitochondria to a lysosome for enzymatic deconstruction. Numerous research groups aim to produce small molecule drugs or supplements capable of improving mitochondrial function in later life by improving the operation of mitophagy, and a range of approaches exist that appear to produce incremental benefits, such as mitoQ and urolithin A. As of yet, producing a greater positive impact than that resulting from exercise has proven to be a challenge, however.

The principal process by which overall mitochondrial quality is maintained is through selective culling of dysfunctional and damaged organelles by mitochondrial autophagy, or mitophagy. It is posited that age-related deterioration in mitophagy, and the consequent interruption of mitochondrial quality control, can contribute to adverse aging phenotypes partly because of increased elaboration of mitochondria-derived ROS from improperly retained damaged organelles. A corollary to this hypothesis is that improving the overall fitness of the cellular mitochondrial collective by forced mitophagy activation might delay age-related cell degeneration and ameliorate age-associated diseases. Experimental systems using overexpression of mitophagy and related factors support this proposition.

Mitochondrial quality control is the canonical role for mitophagy, and likely the mechanism by which its enhancement prevents premature senescence. However, culling defective mitochondria is not the sole purpose of mitophagy, nor is the PINK-Parkin pathway the only pathway to mitophagy. Accumulating evidence in mammalian systems suggests that Parkin-mediated mitophagy may be more important as a stress-induced or developmentally regulated mechanism, and that other paths comprise the major mechanism for homeostatic quality control through "maintenance mitophagy". Moreover, Parkin-mediated mitophagy can play an essential role during cell-wide mitochondrial replacement, generally accelerating mitochondrial turnover for either quantity control (i.e., removing excess mitochondria) or provoking a metabolic adaptation in response to an altered environmental context (as in converting the mitochondrial collective from lipid- to carbohydrate-based metabolism and vice versa).

Mitochondrial abnormalities such as fragmentation, loss of inner membrane polarization and increased ROS production have been widely reported in both chronically progressive neurodegenerative diseases and genetic neurological syndromes manifesting an age-dependent phenotype. There is growing interest in developing approaches to correct secondary mitochondrial abnormalities as one component of an ensemble therapy approach to these incurable and largely untreatable diseases. One promising approach attacks the problem of mitochondrial fragmentation, either by inhibiting mitochondrial fission or stimulating mitochondrial fusion. It is intriguing to speculate that these tactics might act synergistically with pharmaceutical activation of mitophagy to correct mitochondrial abnormalities in neurodegenerative diseases.

Link: https://doi.org/10.20517/jca.2022.36

Klotho is one of the few robustly determined longevity genes capable of altering life span in both directions in mice. A reduced expression of klotho shortens life span, while increased klotho levels lengthen life. Klotho has been shown to improve cognitive function, but investigation to date has suggested that it primarily functions in the kidney, and that kidney function mediates effects elsewhere in the body.

Today's open access paper is focused instead on the relationship between klotho and vascular calcification. Prior research on this topic has focused on the relationship between klotho and FGF23, but here the authors are interested in how klotho affects the cellular maintenance processes of autophagy. Efficiency and amount of autophagy may determine FGF23 expression; as is always the case, biochemistry is a web of connections.

Autophagy has a complex relationship with calcification, and calcification itself is a complex phenomenon. In essence cells in the vasculature change to adopt characteristics of osteoblasts, responsible for generating bone tissue. This is the result of changes in the signaling environment, with many contributing causes, including chronic inflammation. Greater autophagy can in principle slow calcification by amending cell behavior to reduce bone-formation activities, and correlations between greater autophagy and lesser calcification are observed. Yet there are mechanisms by which autophagy and its outcomes might accelerate processes of calcification.

Klotho Ameliorates Vascular Calcification via Promoting Autophagy

Vascular calcification (VC) is associated with increased risk of major adverse cardiovascular events in several clinical conditions, such as chronic kidney disease and atherosclerosis and aging. The formation of VC is associated with complex pathological mechanisms, including osteogenic differentiation and apoptosis of vascular smooth muscle cells (VSMCs) and release of matrix vesicles loaded calcium (Ca) and phosphate (Pi). By inhibiting these processes, VC can be effectively treated.

Klotho, a protein highly expressed in the kidney, is thought to be involved in various aging-associated pathologies. Studies have reported that Klotho-deficient mice developed obvious aortic VC, which can be reversed by Klotho overexpression. To date, the mechanisms whereby Klotho protects against VC have focused on not only its role as an obligate co-factor for FGF23 signaling in regulating Pi and vitamin D systems in kidney, but also its direct effects on the vasculature as a circulating anti-calcific factor. However, the mechanisms of this direct effects have not yet been fully explored.

Growing evidence indicates that autophagy, defined as the dynamic, refined, and controlled process of cellular self-digestion, protects VSMCs against calcification. Although autophagic activity reportedly increases in the aorta of Klotho-deficient mice, its role in the Klotho's regulation of VC remains unclear. The present study investigated whether Klotho deficiency could induce protectively-increased autophagy and whether Klotho administration ameliorated calcification through said autophagy increase.

Results indicated that, based on Agatston score, serum Klotho level was negatively associated with aortic calcification. Then, Klotho-deficient mice exhibited aortic VC, which could be alleviated with the supplementation of Klotho protein. Moreover, autophagy increased in the aorta of Klotho-deficient mice and protected against VC. Finally, we found that Klotho ameliorated calcification by promoting autophagy both in the aorta of Klotho-deficient mice and in mouse vascular smooth muscle cells under calcifying conditions. These findings indicate that Klotho deficiency induces increased autophagy to protect against VC and that Klotho expression further enhances autophagy to ameliorate calcification.

Numerous epidemiological studies have shown that the risk of suffering dementia in later life is in decline, even as demographic aging of the population drives an increase in the overall incidence of age-related disease. Why is the individual risk of dementia declining? It is potentially a consequence of the broad use of statins to reduce the consequences of atherosclerosis, as well as ever greater attention given to control of blood pressure in later life. The state of the vasculature is an important contribution to the state of the aging brain, with a variety of different mechanisms involved. The brain is an energy-hungry organ, and blood flow and supply of nutrients declines with age. The blood-brain barrier becomes leaky with age, allowing inflammatory molecules and cells into the brain. Raised blood pressure results in increased pressure damage, such as rupture of small blood vessels in the brain. And so forth; cardiovascular health is important for many reasons.

In 2021, about 6.2 million U.S. adults aged 65 or older lived with dementia. Because age is the strongest risk factor for dementia, it has been predicted that increasing life expectancies will substantially increase the prevalence of Alzheimer's disease and related dementias from about 50 million to 150 million worldwide by 2050. However, there is growing evidence that age-adjusted dementia prevalence has been declining in developed countries, possibly because of rising levels of education, a reduction in smoking, and better treatment of key cardiovascular risk factors such as high blood pressure.

A new study employs a novel model to assess cognitive status based on a broad set of cognitive measures elicited from more than 21,000 people who participate in the national Health and Retirement Study, a large population-representative survey that has been fielded for more than two decades. The model increases the precision of dementia classification by using the longitudinal dimension of the data. Importantly for the study, the model is constructed to ensure the dementia classification is calibrated within population subgroups and, therefore, it is equipped to produce accurate estimates of dementia prevalence by age, sex, education, race, and ethnicity, and by a measure of lifetime earnings.

The prevalence of dementia in the United States dropped 3.7 percentage points from 2000 to 2016. The age-adjusted prevalence of dementia declined from 12.2 percent of people over age 65 in 2000 to 8.5 percent of people over age 65 in 2016 - a nearly one-third drop from the 2000 level. The prevalence of dementia decreased over the entire period, but the rate of decline was more rapid between 2000 and 2004. The study further found that education was an important factor that contributed, in a statistical sense, to the reduction in dementia, explaining about 40 percent of the reduction in dementia prevalence among men and 20 percent of the reduction among women.

Link: https://www.rand.org/news/press/2022/11/07.html

Epigenetic change occurs with age, altering cellular behavior for the worse. Epigenetic reprogramming, via approaches derived from the use of Yamanaka factors to produce induced pluripotent stem cells, offers the potential to reset cell behavior in order to restore a more youthful tissue function. In mice, this is producing promising results. It remains an open question as to how age-related epigenetic change relates to fundamental causes of aging. It appears to be a far downstream consequence of underlying damage and dysfunction, but more recent work suggests that it may be an immediate consequence of stochastic DNA damage, and thus closer to root causes of aging than suspected. How distant epigenetic aging is from the causes of aging should set expectations regarding how effective and long-lasting epigenetic reprogramming will prove to be as a class of therapy.

Aging is accompanied by the decline of organismal functions and a series of prominent hallmarks, including genetic and epigenetic alterations. These aging-associated epigenetic changes include DNA methylation, histone modification, chromatin remodeling, non-coding RNA (ncRNA) regulation, and RNA modification, all of which participate in the regulation of the aging process, and hence contribute to aging-related diseases. Therefore, understanding the epigenetic mechanisms in aging will provide new avenues to develop strategies to delay aging. Indeed, aging interventions based on manipulating epigenetic mechanisms have led to the alleviation of aging or the extension of the lifespan in animal models.

Small molecule-based therapies and reprogramming strategies that enable epigenetic rejuvenation have been developed for ameliorating or reversing aging-related conditions. In addition, adopting health-promoting activities, such as caloric restriction, exercise, and calibrating circadian rhythm, has been demonstrated to delay aging. Furthermore, various clinical trials for aging intervention are ongoing, providing more evidence of the safety and efficacy of these therapies.

Here, we review recent work on the epigenetic regulation of aging and outline the advances in intervention strategies for aging and age-associated diseases. A better understanding of the critical roles of epigenetics in the aging process will lead to more clinical advances in the prevention of human aging and therapy of aging-related diseases.

Link: https://doi.org/10.1038/s41392-022-01211-8

The gly-low combination of common supplements is sold as GLYLO by Juvify Health, another of the supplement-focused spinout companies from the Buck Institute, an organization that should consider starting spinning out companies that are doing something more ambitious to treat aging as a medical condition. The scientifically interesting part of the underlying research is that inhibiting glycation to reduce methylglyoxal based advanced glycation endproducts (AGEs) appears, for reasons yet to be determined, to reduce appetite in mice. This leads to modest calorie restriction, and calorie restriction is well known to produce a broad range of benefits in short-lived species such as mice, including slowed aging and extended life span.

Are all of the benefits in mice reported to result from gly-low supplementation occurring due to calorie restriction? The researchers believe that other mechanisms are involved, but at present it is hard to argue definitively one way or another. A human trial is planned, though given that it will involve only obese individuals the outcome will be of little use as a comparison with effects in wild-type mice. Calorie restriction produces much larger effects on life span in mice than it does in humans, based on evidence to date. It is always interesting to have another point of comparison, provided it involves metabolically normal, relatively healthy older mice and humans.

Combination therapy of glycation lowering compounds reduces caloric intake, improves insulin sensitivity, and extends lifespan

Food overconsumption and obesity are also contributing factors to chronic hyperglycemia and enhanced glycolysis, which enhance the production of reactive a-dicarbonyls (a-DC's), such as methylglyoxal (MGO). MGO reacts nonenzymatically with biomolecules such as proteins, lipids, and DNA to form advanced glycation end-products (AGEs). These covalent adducts contribute to pathogenesis across several diseases by compromising protein function, forming extracellular crosslinks that disrupt tissue architecture, and modifying lipids and nucleic acids. Cellular protection against AGEs occurs by endogenous glyoxalase enzymes, which detoxify MGO and prevent AGEs formation. Given that increased sugar consumption, which drives obesity, is accompanied by enhanced glycolysis and concomitant production of toxic glycolytic byproducts, we hypothesized that detoxification of AGEs may be a viable therapeutic against obesity and its associated pathologies.

To develop a therapeutic for AGEs burden we utilized compounds previously reported to reduce MGO. In vitro treatment of N27 cells with alpha lipoic acid, nicotinamide, piperine, pyridoxamine, and thiamine was effective in rescuing neurite length retraction following exposure to MGO. The combination of these compounds, termed Gly-Low, displayed synergistic effects in protecting against MGO toxicity, and showed improvement compared to treatment with a single compound. In vivo treatment of C57BL/J6 control mice with Gly-Low resulted in significant lowering of body weights and food consumption compared to those on a control diet. Intraperitoneal injection of Gly-Low, as well as standard starving procedures, also reduced food consumption ruling out taste aversion as a potential caveat in reduction of food intake.

Administration of Gly-Low reduced food consumption and body weight, improving insulin sensitivity and survival in both leptin receptor deficient (Lepr db) and wildtype control mouse models. Unlike calorie restriction, Gly-Low inhibited ghrelin-mediated hunger responses and upregulated Tor pathway signaling in the hypothalamus. Gly-Low also extended lifespan when administered as a late life intervention, suggesting its potential benefits in ameliorating age-associated decline by inducing voluntary calorie restriction and reducing glycation.

Is it possible to predict outcomes of exercise well enough to be able to prescribe a specific dose of exercise for an individual to achieve a certain outcome in improvement of long-term health? This is an interesting question, and the answer is probably "no" at the present time, given all of the variables involved, such as the state of the gut microbiome, for example. It does seem a plausible goal for the near future, though, given the trend towards the cost-effective collection of ever more biological data from individuals. In the meanwhile, there are likely useful stepping stones towards greater rigor in determining likely outcomes for exercise, such as that noted here.

Research explains that when exercise is personally prescribed based on what is called "critical power," the results show greater improvement in endurance and greater long-term benefits for the individual. The authors define critical power as the highest level of our comfort zone. "It's the level at which we can perform for a long period of time before things start to get uncomfortable."

It works something like this: Suppose two friends have the same Max Heart Rate. Previous understanding of exercise would suggest that if they run together at the same speed, they should have very similar experiences. However, it so happens that when these two friends run at 6 mph, the exercise is easy for one, but difficult for the other. These distinctive experiences at the same speed and same percent of Max Heart Rate are because 6 mph is below the one friend's critical power, but above the other's critical power.

When exercise is below a person's critical power, their body can compensate for the energy challenge and reach a comfortable and controlled homeostasis. However, when exercise is above one's critical power, their body cannot completely compensate for the energy demand, resulting in exhaustion. Traditionally, individualized exercise has been recommended based on a fixed percentage of one's maximum rate of oxygen consumption (VO2 Max) or their Max Heart Rate.

Researchers discovered that prescribing exercises based on VO2 Max as a reference point results in alarming variability in results. There were participants who benefited significantly from the training period and others who did not, even though the training was personalized to them. They compared this to each individual's critical power and found that it accounted for 60% of the variability in their findings. If exercises had been prescribed using critical power as a reference point versus their heart rate, the results would have varied less, meaning the training sessions would have been more effective and beneficial for each participant. Using "critical power" is a better way of prescribing exercise because it not only accurately serves athletes and those in great shape, but it also serves those who are older or have a more sedentary lifestyle.

Link: https://news.byu.edu/intellect/byu-exercise-science-researchers-pinpoint-new-method-to-optimize-personal-aerobic-workouts

Up to a point, greater calorie restriction in mice produces greater benefits to health and longevity. Most animal studies do not examine moderate calorie restriction, however, so it is interesting to see one that does. The results reported in this study are much as expected; it is by now well established that calorie restriction is beneficial, shifting metabolism into a state more conducive to lasting good health.

Chronic calorie restriction (CR) results in lengthened lifespan and reduced disease risk. Many previous studies have implemented 30-40% calorie restriction to investigate these benefits. The goal of our study was to investigate the effects of calorie restriction, beginning at 4 months of age, on metabolic and physical changes induced by aging. Male calorie restricted and ad libitum fed control mice were obtained from the National Institute on Aging (NIA) and studied at 10, 18, 26, and 28 months of age to better understand the metabolic changes that occur in response to CR in middle age and advanced age.

Food intake was measured in ad libitum fed controls to assess the true degree of CR (15%) in these mice. We found that 15% CR decreased body mass and liver triglyceride content, improved oral glucose clearance, and increased all limb grip strength in 10- and 18-month-old mice. Glucose clearance in ad libitum fed 26- and 28-month-old mice is enhanced relative to younger mice but was not further improved by CR. CR decreased basal insulin concentrations in all age groups and improved insulin sensitivity and rotarod time to fall in 28-month-old mice.

The results of our study demonstrate that even a modest reduction (15%) in caloric intake may improve metabolic and physical health. Thus, moderate calorie restriction may be a dietary intervention to promote healthy aging with improved likelihood for adherence in human populations.

Link: https://doi.org/10.1007/s10522-022-09996-5

As is true of excess weight, the raised blood pressure appears to have a lower threshold for causing long-term harm to health than is commonly thought. Negative effects increase as blood pressure increases, but the point at which harms start is surprisingly close to normal blood pressure ranges. More aggressive control of blood pressure via antihypertensive drugs and lifestyle changes produces benefits even when pushing it back down into what the normal range. The boundary at which raised systolic blood pressure is considered to be a problem, veering into the territory of hypertension, was recently lowered by ten points.

There are any number of mechanisms by which raised blood pressure causes harm. It accelerates the onset and progression of atherosclerosis. It increases the pace at which small blood vessels rupture in the brain, where neural tissue is not effectively repaired once so damaged. It helps to disrupt the blood-brain barrier and other aspects of endothelial function. Thus it isn't to surprising to note the correlations between blood pressure and later life cognitive function, and between lifestyle choices that affect blood pressure and later life cognitive function, as in today's open access paper.

Mean arterial pressure, fitness, and executive function in middle age and older adults

Physical activity and associated gains in fitness have been shown to be neuroprotective for older adults, with evidence suggesting preserved brain structure, function, and better cognitive functioning. Many recent meta-analyses suggest that exercise interventions and subsequent gains in fitness may have a selective effect on cognition in older adulthood, with the greatest impact on executive functioning. Some evidence suggests that changes in executive function may be occurring earlier in middle age and may be predictive of future cognitive decline. Therefore, there is a need to examine how fitness may be related to executive function across a younger adult sample.

Cardiorespiratory fitness (CRF) is a measure of the ability of the circulatory and respiratory systems to deliver oxygen, and the peak rate at which oxygen can be consumed, during sustained physical activity at a maximal effort. Higher CRF has been shown to be related to greater brain volume, particularly in gray matter regions like the prefrontal cortex. Higher CRF has also been associated with preserved white matter integrity, and functional connectivity, as well as better cognitive functioning in older adults. However, the mechanisms underlying these positive effects are not fully understood.

The purpose of the current study was to examine whether mean arterial pressure (MAP) mediated the association between CRF and executive function in middle age and older adults. Participants were adults (age 40+) without any self-reported psychiatric and neurological disorders or cognitive impairment from the Nathan Kline Institute Rockland Sample (N = 224, M age = 56). CRF was defined by V̇O2max estimated via a bike test, neuropsychological testing was used to examine executive functioning, and MAP was calculated from systolic and diastolic blood pressure recordings. Mediation models were analyzed controlling for age, sex, and education.

Results indicated that higher CRF was associated with better inhibition and there was a significant indirect effect of greater CRF on better inhibition through lower MAP. There were additional significant indirect effects of greater CRF and better fluency and planning through lower MAP. This suggests that MAP may be an underlying physiological mechanism by which CRF influences executive function in mid- and older adulthood.

Vascular issues arguable precede the protein aggregates and other noted signs of neurodegenerative conditions. The brain is an energy-hungry organ, and the nutrients and oxygen to fuel it arrive via blood flow through the vasculature. Parts of the brain already operate at the edge of capacity, as illustrated by the ability of exercise to rapidly improve neural function such as memory for a short period of time, due to increased blood flow. The decline of the vasculature with age impairs the brain in a range of different ways, not just a reduced supply of nutrients, but also leakage of the blood brain barrier to provoke inflammation, as well as other issues.

Vascular contributions to cognitive impairment and dementia (VCID) is a complex syndrome that encompass a diverse array of pathologies resulting in disruptions of blood flow in the brain. It is becoming increasingly recognized that VCID is one of the leading causes of dementia along with Alzheimer's disease (AD) and is frequently found co-morbid with AD pathologies. Experts project a significant increase in the number of patients presenting with both cerebrovascular and neurodegenerative co-morbidities as the number of persons living into their 80s and 90s increases. Recent studies have even demonstrated pathologic vascular changes precede the appearance of amyloid (Aβ) plaques and neurofibrillary tangles, characteristic proteinopathies associated with AD, further implicating cerebrovasculature pathologies as an important topic of study in the fields of dementia and neurodegeneration.

The overlap between VCID and AD continues when considering significant risk factors associated with their disease progressions. Hypertension, diabetes, hyperhomocysteinemia (HHCy) and hyperlipidemia are risk factors for both AD and VCID all leading to a state of both chronic neuroinflammation and chronic cerebral hypoperfusion or hypoxia. Neuroinflammation is both an important instigator and consequence of cerebrovascular pathology making this an important potential therapeutic target for impeding disease progression. While there is currently no cure for VCID, several studies have been focused on mitigating the aforementioned risk factors leading to chronic hypoxia and inhibiting the subsequent neuroinflammatory sequalae.

In the following review a brief overview of the current knowledge surrounding VCID will be provided with a focus on the basic mechanisms linking well-established risk factors with the distinct signaling cascades of neuroinflammation and chronic hypoperfusion. Then the coalescence of these two pathologic signaling cascades and their synergistic impact on the downstream activation of further neurodegenerative sequalae will be discussed. Finally, several potential therapeutic interventions to target specific aspects of the degenerative cascade leading to VCID progression will be highlighted.

Link: https://doi.org/10.1016/j.cccb.2021.100030

The primary thrust of Alzheimer's research and clinical development of therapies remains the targeting of amyloid-β and tau aggregates. The failure to produce meaningful benefits in patients, even given reductions in amyloid-β and tau, is not shifting the focus of most research groups to other entirely different approaches, but rather to question whether the complexity of amyloid-β and tau biochemistry means that the wrong locations or types of these molecules were targeted by the immunotherapies used to date in human trials.

For optimal design of anti-amyloid-β (Aβ) and anti-tau clinical trials, we need to better understand the pathophysiological cascade of Aβ- and tau-related processes. Therefore, we set out to investigate how Aβ and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with positron emission tomography (PET) and subsequent cognitive decline across the Alzheimer's disease (AD) continuum.

Using human cross-sectional and longitudinal neuroimaging and cognitive assessment data, we show that in early stages of AD, increased concentration of soluble cerebrospinal fluid (CSF) p-tau is strongly associated with accumulation of insoluble tau aggregates across the brain, and CSF p-tau levels mediate the effect of Aβ on tau aggregation. Further, higher soluble p-tau concentrations are mainly related to faster accumulation of tau aggregates in the regions with strong functional connectivity to individual tau epicenters. In this early stage, higher soluble p-tau concentrations is associated with cognitive decline, which is mediated by faster increase of tau aggregates. In contrast, in AD dementia, when Aβ fibrils and soluble p-tau levels have plateaued, cognitive decline is related to the accumulation rate of insoluble tau aggregates.

Our data suggests that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD, before widespread insoluble tau aggregates.

Link: https://doi.org/10.1038/s41467-022-34129-4

Immune checkpoint inhibition, such as via targeting PD1, is used to fire up the immune system to attack cancer, temporarily disabling some of the natural mechanisms intended to prevent immune cells from running amok. In the case of cancer, this is intended to overcome the abuse of immune checkpoints by cancerous tissue, one of the many strategies by which an established tumor suppresses or co-opts the immune system. But does inhibition of immune checkpoints improve other aspects of immune function? Apparently so, as in today's open access paper, researchers present evidence for a reduced burden of senescent cells following checkpoint inhibition.

Interestingly, it is unclear as to whether the improvement of measures of health in mice is as much a matter of reducing the harmful pro-inflammatory senescence-associated secretory phenotype (SASP) as it is resulting from clearance of senescent cells. Checkpoint inhibitors, at least PD-L1, appear to be involved in generation of the SASP, as cells lacking that gene produce a more muted SASP.

While this is interesting research, checkpoint inhibition seems unlikely to be a viable addition to the range of senolytic therapies presently under development, however. If one looks at the clinical trial data for established checkpoint inhibitors used to treat cancer, there appears to be something like a 7% chance of lasting complications resulting from treatment. That list of problems includes the possibility of developing forms of autoimmunity - immune checkpoints exist for a reason. The cost-benefit equation for a cancer that will go on to kill you, and for which the alternative treatments are worse, is somewhat different to that for an increased burden of senescent cells that will kill you very much more slowly, and for which the range of alternative treatments come with next to no risk of lasting side-effects.

Blocking PD-L1-PD-1 improves senescence surveillance and ageing phenotypes

The accumulation of senescent cells is a major cause of age-related inflammation and predisposes to a variety of age-related diseases. However, little is known about the molecular basis underlying this accumulation and its potential as a target to ameliorate the ageing process. Here we show that senescent cells heterogeneously express the immune checkpoint protein programmed death-ligand 1 (PD-L1) and that PD-L1+ senescent cells accumulate with age in vivo. PD-L1- cells are sensitive to T cell surveillance, whereas PD-L1+ cells are resistant, even in the presence of senescence-associated secretory phenotypes (SASP).

Single-cell analysis of p16+ cells in vivo revealed that PD-L1 expression correlated with higher levels of SASP. Consistent with this, administration of programmed cell death protein 1 (PD-1) antibody to naturally ageing mice or a mouse model with normal livers or induced nonalcoholic steatohepatitis reduces the total number of p16+ cells in vivo as well as the PD-L1+ population in an activated CD8+ T cell-dependent manner, ameliorating various ageing-related phenotypes.

These results suggest that the heterogeneous expression of PD-L1 has an important role in the accumulation of senescent cells and inflammation associated with ageing, and the elimination of PD-L1+ senescent cells by immune checkpoint blockade may be a promising strategy for anti-ageing therapy.

Neurodegenerative conditions, such as Parkinson's disease, are strongly connected to chronic inflammation of brain tissue. Unresolved inflammation is disruptive to tissue function in many ways, and the immune cells of the brain are tightly integrated into the normal functioning of neurons and their synaptic connections. It is thus an important goal for the research community to find ways to suppress excessive, unresolved inflammation without also disrupting necessary inflammatory signaling required for health and the normal operation of the immune system. Early immunomodulatory treatments are blunt tools, usually targeting a single signal molecule involved in inflammation, and can cause long term harm via suppression of the normal immune response. It is hoped that the inflammasome and its role in the regulation of inflammation will prove to be a better target.

Parkinson's disease (PD) is the second-most common neurodegenerative disease, predominantly affecting the elderly. The pathogenesis of PD contributed by both environmental and genetic factors is rather complex and not fully understood. The limited treatment options also add to its socioeconomic impact. Importantly, to date, no therapies are able to prevent or delay the disease progression. Thus, there is an enormous need to have a deeper understanding of PD pathogenesis and develop novel therapeutic approaches to improve the lives of PD patients.

Among the various novel approaches to manage PD, immunomodulation has gained much popularity recently. This approach is conceived based on the heavy involvement of the immune system in the pathogenesis and progression of PD. Neuroinflammation is one of the immune processes of paramount importance in PD. Reactive microglia increased significantly in the substantia nigra region of PD patients upon post-mortem examinations. Moreover, enhanced microglial activation was also observed in various PD animal models. Besides central nervous system (CNS) inflammation, peripheral inflammation is also believed to play a pivotal role in PD. Peripheral pro-inflammatory stimuli can be transported to the brain, activate the primed microglia, prompt neuroinflammation, and exacerbate disease progression.

An important mechanism of neuroinflammation is the NLRP3 inflammasome activation that has been implicated in PD pathogenesis. In this perspective, we will discuss the relationship of some key PD-associated proteins including α-synuclein and Parkin and their contribution to inflammasome activation. We will also review promising inhibitors of NLRP3 inflammasome pathway that have potential as novel PD therapeutics. Finally, we will provide a summary of current and potential in vitro and in vivo models that are available for therapeutic discovery and development.

Link: https://doi.org/10.3389/fnagi.2022.957705

Amyotrophic lateral sclerosis (ALS) is not an age-related condition per se, but most cases do occur in later life. Is this because one or more mechanisms of aging are relevant to the onset of ALS? Researchers here argue for cellular senescence to be involved. It is already the case that cellular senescence has been implicated in a broad range of conditions, not all of which are age-related, such as type 1 diabetes. The advent of effective senolytic therapies to clear senescent cells from tissues will benefit more than just aged people.

Our unbiased proteomic analysis of plasma and peripheral blood mononuclear cells (PBMCs) in blood samples from patients with ALS has shown the activation of molecular pathways involved in immunoregulation and cell senescence in faster progressing ALS and at a later stage of disease. We and others have also reported an increased blood and cerebrospinal fluid concentration of proinflammatory cytokines in individuals with ALS. These inflammatory mediators are enumerated within the senescence-associated secretory phenotype (SASP) and have been described in age-related immune dysregulation.

The SASP inflammatory microenvironment spreads the tissue-disrupting effect of senescence regionally and systemically, impairing the function of other immune cells. Critically, other alterations observed in aging and senescence are aligned with brain-specific changes seen in ALS, including a disturbed autophagy/lysosomal protein degradation, altered RNA splicing, and errors in nuclear-cytoplasmic transport. We can therefore hypothesize a potential role for cell senescence in the immunologic dysregulation identified in ALS.

In this study, we used a two-stage approach to first investigate the immunophenotype of PBMCs from individuals living with ALS and then focused on lymphocytes expressing known features of immunosenescence. We showed that lymphocytes from patients with ALS are skewed toward a senescent and late memory state when compared with those from age-matched healthy controls.

Link: https://doi.org/10.1212/NXI.0000000000200042

Regular moderate exercise delays the onset of neurodegeneration in late life. Since exercise produces sweeping changes throughout the body and the operation of cellular metabolism. It is easy enough to look at what is known of the connections to brain aging, such as a reduction in the chronic inflammation associated with aging, or upregulation of beneficial metabolites leading to an increase in BDNF expression and consequent neurogenesis, and say that these are the most important factors. But one suspects that any number of other relevant mechanisms may remain to be discovered and characterized, and since researchers don't have a good grasp on the relative importance of the known mechanisms, those unknown mechanisms could well account for a sizable fraction of the outcome.

Regardless, the difference in late life health between highly active hunter-gatherer populations and largely inactive populations in wealthier regions of the world is sizable. This is particularly true for cardiovascular disease, but also applies to much of the panoply of common conditions that afflict older people. Degree of life-long exercise is likely a primary contributing factor in that difference. Given that we know that exercise is one of the safest forms of intervention, not to mention one of the cheapest, it seems self-sabotaging not to undertake more of it.

New insights into how exercise protects against neurodegenerative diseases

Accumulating evidence finds that exercise can improve brain function and delay or prevent the onset of neurodegenerative diseases such as Alzheimer's and Parkinson's disease. While the underlying mechanisms remain unclear, recent research suggests that exercise-induced activation of peripheral systems such as muscle, gut, liver, and adipose tissue may affect neural plasticity. Cathepsin B (CTSB), a myokine, and brain-derived neurotrophic factor (BNDF) have been found to possess robust neuroprotective effects.

In a new study, investigators looked at whether increasing aerobic exercise intensity would increase the amount of CTSB and BDNF circulating in the blood. Sixteen young healthy subjects completed treadmill-based aerobic exercise at maximum capacity and then at 40%, 60%, and 80% of capacity. Circulating CTSB and BDNF were measured in blood samples taken after each bout of exercise, and CTSB protein, BDNF protein, and mRNA expression were measured in skeletal muscle tissue. Researchers found that high intensity exercise elevates circulating CTSB in young adults immediately after exercise, and that skeletal muscle tissue expresses both message and protein of CTSB and BDNF.

Further, new review articles cover interorgan crosstalk between muscle, liver, adipose tissue, the gut microbiome, and the brain. While it is well known that exercise protects the central nervous system, it has only recently been found to depend on the endocrine capacity of skeletal muscle. Researchers highlight the impact of myokines, metabolites, and other unconventional factors that mediate effects of muscle-brain and muscle-retina communication on neurogenesis, neurotransmitter synthesis, proteostasis, mood, sleep, cognitive function and feeding behavior following exercise.

They also raise the possibility that detrimental myokines resulting from inactivity and muscle disease states could become a novel focus for therapeutic intervention. "We propose that tailoring muscle-to-central nervous system signaling by modulating myokines and metabolites may combat age-related neurodegeneration and brain diseases that are influenced by system signals."

Researchers here note the discovery that vaccinating mice with senescent cancer cells ensures that the immune system will more aggressively attack a later introduction of cancerous cells. Since we know that most cancer therapies induce senescence in cancerous cells to a fair degree, one has to think that the effectiveness of this approach will diminish as a cancer progresses to form a solid tumor and co-opts the immune system in various ways. Still, it sounds as though it could be a potentially useful after, for example, surgical resection of a tumor, to help reduce the odds that the cancer will reoccur.

Scientists have studied how inducing senescence in cancer cells improves the effectiveness of the immune response to a greater degree than the dead cancer cells. After vaccinating healthy mice with senescent cancer cells and then stimulating the formation of tumours, the researchers observed that the animals did not develop cancer or that the number that do is significantly reduced. They also analysed the efficacy of vaccination in animals that had already developed tumours. In this setting, although the results were more moderate due to the protective barrier of the tumour, improvements were also observed.

The researchers tested the technique in animal models of melanoma, a type of cancer characterised by high activation of the immune system, and also in pancreatic cancer models, which present strong barriers against immune cells. Prophylactic vaccination therapy with senescent cancer cells was effective against both types of tumors. They also complemented the study with tumour samples from cancer patients and confirmed that human cancer cells also have a greater capacity to activate the immune system when they are previously rendered senescent. The group is now studying the combined efficacy of vaccination with senescent cells and immunotherapy treatments.

Link: https://www.irbbarcelona.org/en/news/scientific/senescent-cells-vaccines-against-cancer

Here find an interesting view of aging as the evolution of a complex dynamic system, at the point of criticality between stability and instability, towards a lesser ability to recover from perturbations. Eventually the usual small day to day changes that occur throughout life, to the environment, to exposure to stresses, to the normal operation of biological systems, will push an old organism into catastrophic failure, where a young organism would easily recover.

Aging is a very slow process that occurs at characteristic time scales far exceeding times associated with molecular processes or operations of an organism's functional subsystems. Typically, such a hierarchy of scales arises from criticality, which is a special case of a dynamic system operating close to a tipping point separating the stable and unstable region. We proposed that aging results from inherent dynamic instability of the underlying regulatory networks and manifests itself as small deviations of the organism state variables (physiological indices) get exponentially amplified and lead to the exponential acceleration of mortality. The first principal component score is then an approximation to the order parameter characterizing the unstable phase and having the meaning of the total number of regulatory errors accumulated in the course of life of the animal. Hence, we believe that aging at criticality conjecture provides a good explanation for the success of Principal Components Analysis (PCA) as a semi-quantitative tool in aging research.

However, the abilities of linear rank reduction techniques, such as PCA, to unravel an accurate dynamic description of aging are limited for the following reasons. First, there are no reasons to believe that the effects of non-linear interactions between different dynamic subsystems are small. That is why a biomarker produced from such a linear analysis cannot be expected to perform well in different biological contexts. To compensate for the drawbacks of PCA, we combined analytical and machine learning tools to describe the aging process in large sets of longitudinal measurements. Assuming that aging results from a dynamic instability of the organism state, we designed a deep artificial neural network, including auto-encoder and auto-regression (AR) components. The AR model tied the dynamics of physiological state with the stochastic evolution of a single variable, the "dynamic frailty indicator" (dFI). In a subset of blood tests from the Mouse Phenome Database, dFI increased exponentially and predicted the remaining lifespan.

Link: https://doi.org/10.1038/s41467-022-34051-9

Mitophagy is the selective version of autophagy focused on recycling mitochondria. Every cell contains hundreds of mitochondria, their primary responsibility the generation of chemical energy store molecules to power cellular processes. Mitochondria are the descendants of ancient symbiotic bacteria. They lead dynamic lives, replicating like bacteria, passing component parts around, and fusing together. Mitophagy is a quality control mechanism, removing damaged mitochondria in order to prevent cellular dysfunction. A good deal of evidence suggests that age-related declines in mitochondrial function are in large part caused by a progressive failure of the operation of mitophagy.

Like the general processes of autophagy, mitophagy is thought to decline in efficiency with age. This can result from reasons peculiar to the involvement of mitochondria, such as changes in their dynamics that lead to greater resistance to mitophagy, or to defects in the common mechanisms of autophagy, such as formation or transport of autophagosomes, or defects in the function of the lysosomes responsible for breaking down cellular waste. It isn't always completely clear that specific metrics of autophagy are relevant in every tissue, or that autophagy is declines with age in all tissues, however. Too much autophagy can cause as much harm as too little autophagy, but a raised level of a specific autophagy-associated protein might in fact indicate a breakage in later portions of the autophagic process, rather than greater autophagy per se. Other ambiguities attend the various means of assessing autophagy. It is an area of research that still requires considerable work aimed at improving fundamental understanding.

Mitophagy in the aging nervous system

Living longer is changing our global population, with major ramifications for brain health and cognition. Why some humans experience accelerated neural aging compared to others remains to be fully understood. Autophagy and mitophagy are pathways of outstanding clinical interest with major relevance for neural integrity because human neural function depends upon quality control over a timespan of decades. Although mitophagy levels decline in short-lived model organisms, it remains unclear if decreased levels of mitophagy are a hallmark of all cell types during natural aging in the mammalian nervous system. Furthermore, it remains unclear if certain cerebral regions and cellular subtypes exhibit greater susceptibility to age-related changes than others. For example, cortical thickness is a widely used metric in human aging studies but the first large-scale heterochronic datasets (brain charts) are only beginning to emerge. Delineating the regional and cell subset-specific regulation of mitophagy will be critical to develop neuroprotective interventions that might improve healthspan or even reverse human age-related degeneration.

It will also be exciting to discover the possible interplay between emerging mitophagy pathways, and age-dependent pathology in the mammalian nervous system. Crosstalk between basal mitophagy and other mitochondrial responses e.g., outer membrane remodeling in response to infection and signalling or degradative mitochondria-derived vesicle (MDV) formation also represent intriguing avenues for future investigation. Whether elevated levels of mitophagy are beneficial for neural integrity also remains a mystery. What is the "minimum effective threshold" of basal mitophagy or macroautophagy required to safeguard neural integrity? How can we control or fine tune mitophagy to prevent a deleterious outcome? What is the relationship between physiological mitophagy and contemporary concepts in geroscience, such as epigenetic aging? The continued development and characterisation of novel tools presents a unique opportunity to resolve these longstanding questions.

What is the role of selective autophagy in the neuroprotective effects afforded by behavioral interventions? There are clear pro-longevity effects of exercise for cognitive, cerebrovascular, and systemic health. Indeed, autophagy and mitophagy are impacted by exercise in different model systems. Developing robust protocols and pharmacological strategies to augment selective autophagy pathways in humans represents a major challenge, because we do not have rapid, non-invasive assays that can reliably monitor distinct forms of autophagy in the clinic (at point of care). Equally, such clinical assays would need to distinguish between the degradative and signalling functions of autophagy (not a trivial task, even under laboratory conditions). Moreover, it remains unknown if changes in serum levels of autophagy markers reflect alterations in cell or tissue-specific autophagy pathways. These are challenging questions, but also exciting opportunities that will lead to a better understanding of physiological mitophagy in tissue development, disease and repair.

There is something of a trend towards picking over the landscape of type 2 diabetes medication in search of therapies that can modestly slow aging, at least in animal models. If metformin is anything to go by, we shouldn't be at all optimistic that this will result in useful outcomes in humans. "Useful" in this context means reliable gains in late life health and life expectancy in metabolically normal people, where those gains are larger than those that can be achieved with exercise, and with minimal side-effects. Otherwise, this seems like time and effort that could be directed to more productive areas of research and development.

Caloric restriction promotes longevity in multiple animal models. Compounds modulating nutrient-sensing pathways have been suggested to reproduce part of the beneficial effect of caloric restriction on aging. However, none of the commonly studied caloric restriction mimetics actually produce a decrease in calories. Sodium-glucose cotransporter 2 inhibitors (SGLT2-i) are a class of drugs which lower glucose by promoting its elimination through urine, thus inducing a net loss of calories. This effect promotes a metabolic shift at the systemic level, fostering ketones and fatty acids utilization as glucose-alternative substrates, and is accompanied by a modulation of major nutrient-sensing pathways held to drive aging, e.g., mTOR and the inflammasome, overall resembling major features of caloric restriction. In addition, preliminary experimental data suggest that SGLT-2i might also have intrinsic activities independent of their systemic effects, such as the inhibition of cellular senescence.

Consistently, evidence from both preclinical and clinical studies have also suggested a marked ability of SGLT-2i to ameliorate low-grade inflammation in humans, a relevant driver of aging commonly referred to as inflammaging. Considering also the amount of data from clinical trials, observational studies, and meta-analyses suggesting a tangible effect on age-related outcomes, such as cardiovascular diseases, heart failure, kidney disease, and all-cause mortality also in patients without diabetes, here we propose a framework where at least part of the benefit provided by SGLT-2i is mediated by their ability to blunt the drivers of aging. To support this postulate, we synthesize available data relative to the effect of this class on: 1) animal models of healthspan and lifespan; 2) selected molecular pillars of aging in preclinical models; 3) biomarkers of aging and especially inflammaging in humans; and 4- COVID-19-related outcomes. The burden of evidence might prompt the design of studies testing the potential employment of this class as anti-aging drugs.

Link: https://doi.org/10.3390/ijms232012325

It is satisfying to see long-standing areas of metabolism-focused aging research find connections to forms of cell and tissue damage thought to drive aging. A great deal of effort has gone towards characterizing growth hormone and IGF1 signaling in aging, as manipulating this part of cellular metabolism has been shown to slow aging in mice. The human population with loss of function in growth hormone receptor, producing Laron syndrome, is the subject of analogous studies. Here, researchers report on evidence for IGF1 stimulation to produce a greater burden of cellular senescence, a possibly important mechanism to explain why reduced IGF1 signaling can slow aging in laboratory animals. Senescent cells, when they linger in increasing numbers with age, produce inflammatory signaling that actively harms tissue structure and function.

The growth hormone (GH)-insulin-like growth factor-1 (IGF1) signaling pathway plays a major role in orchestrating cellular interactions, metabolism, growth, and aging. Studies from worms to mice showed that downregulated activity of the GH/IGF1 pathway could be beneficial for the extension of lifespan. Laron syndrome (LS) is an inherited disorder caused by molecular defects of the GH receptor (GHR) gene, leading to congenital IGF1 deficiency. Life-long exposure to very low endogenous IGF1 levels in LS is associated with small stature as well as endocrine and metabolic deficits. Epidemiological surveys reported that patients with LS have a reduced risk of developing cancer.

Studies conducted on LS-derived cells led to the identification of a novel link between IGF1 and thioredoxin-interacting protein (TXNIP), a multifunctional mitochondrial protein. TXNIP is highly expressed in LS patients and plays a critical role in cellular redox regulation by thioredoxin. Given that IGF1 affects the levels of TXNIP under various stress conditions, including high glucose and oxidative stress, we hypothesized that the IGF1-TXNIP axis plays an essential role in helping maintain a physiological balance in cellular homeostasis.

In this study, we show that TXNIP is vital for the cell fate choice when cells are challenged by various stress signals. Furthermore, prolonged IGF1 treatment leads to the establishment of a premature senescence phenotype characterized by a unique senescence network signature. Combined IGF1/TXNIP-induced premature senescence can be associated with a typical secretory inflammatory phenotype that is mediated by STAT3/IL-1A signaling. Finally, these mechanistic insights might help with the understanding of basic aspects of IGF1-related pathologies in the clinical setting.

Link: https://doi.org/10.3390/cells11203260

Rejuvenation will be achieved in humans by combinations of therapies, provided periodically over time. Each individual therapy will in some way address one of the forms of cell and tissue damage that accumulate to cause the pathologies of aging. There are numerous independent sources of such damage, however. It is the case that the various types of accumulating damage, and the far greater variety of dysfunctions caused by that damage, will interact with one another to make outcomes worse than they would have been alone. Nonetheless, very different forms of rejuvenation therapy will be required to repair each of the very different forms of damage. Each individual repair therapy will produce only incremental outcomes, it will not solve all of aging.

Given this, there is, even at this comparatively early juncture in the development of rejuvenation therapies, far too little work taking place on how to best combine treatments, and on assessing the outcomes of combined treatments. Fortunately that is slowly changing, and a number of groups are at present putting earnest effort into running combinatorial studies in short-lived model organisms. Still, it is far from enough, and largely focused on metabolic adjustments that can only modestly slow aging, not repair the underlying damage.

With that in mind, today's open access paper is an interesting first step towards showing that partial reprogramming, with the effect of improving stem cell function, synergizes well with clearance of senescent cells. Both of these approaches have been shown to improve health and function in old animals, with the caveat that senolytic treatments capable of selectively destroying senescent cells are a less recent innovation, and thus come with far more data - and more robust data - demonstrating rejuvenation. The work here uses inducible expression in genetically engineered flies rather than the delivery of therapeutics into wild-type animals in order to achieve the observed results, but that is a first step towards better studies in mice.

Combining stem cell rejuvenation and senescence targeting to synergistically extend lifespan

While the number of stem cells decreases in aging animals, senescent cells accumulate with age. Manipulating cell fates by cellular reprogramming (to rejuvenate somatic cells) and by senolytic interventions (to remove senescent cells) are two promising approaches to restore homeostasis in aged individuals and to prevent age-dependent diseases. Cellular reprogramming allows differentiated cells to regain plasticity and to take on more stem cell-like qualities. A major step towards this goal was the demonstration of cellular reprogramming of terminally differentiated cells into pluripotent embryonic-like stem cell states. Such reprogramming reverses epigenetic aging marks, demonstrating that even mature, terminally differentiated cells can be returned to a younger state. While continuous expression of the Yamanaka factors (Oct4, Klf4, Sox2, c-Myc; OKSM) in mice led to the formation of teratomas and decreased lifespan, repeated short term expression in adult mice succeeded in ameliorating cellular and physiological signs of aging. Subsequently, several studies have suggested that this approach can be applied to human aging and age-related disease, and cycling expression can rejuvenate stem cells in vitro.

Ablation of senescent cells has been shown to reverse tissue dysfunction and extend healthspan in mice. A recent study using a senolytic construct (FOXO4-DRI peptide) that induced apoptosis in senescent cells, by interfering with the binding of p53 to FOXO4 thereby freeing p53 to activate apoptosis, showed that the clearing of senescent cells both counteracted senescent cell induced chemotoxicity and restored age-dependent declines in physical performance, fur density, and renal function in aging mice. Several studies have further explored applications of different senolytic strategies to ameliorate age-related decline and disease.

Accumulation of senescent cells and loss of stem cells are not independent processes. Through the senescence-associated secretory phenotype (SASP), senescent cells release pro-inflammatory cytokines which contribute to chronic inflammation and mTOR activation, ultimately leading to stem cell exhaustion. This interaction suggests that senolytic therapies might interact with cellular reprogramming strategies in delaying age-dependent decline and disease. We have previously explored drug-drug interactions as synergistic aging interventions, and here we ask whether a combinatorial treatment of OKSM and senolytic (Sen) expression could mitigate or reverse the effects of aging more efficiently than either intervention alone.

To test this hypothesis, we induced expression of OKSM, Sen, and an OKSM-Sen combination in adult flies and compared their effects on health and lifespan. We find that each treatment alone had limited benefits, with OKSM alone benefiting maximum lifespan while Sen expression alone increased mean lifespan but had no effect on maximum lifespan. In contrast, animals subjected to the combined intervention experienced substantially longer mean and maximum lifespan. Our data is consistent with a synergistic interaction between the two interventions, simultaneously rejuvenating stem cells and removing senescent cells.

An important goal in cryopreservation research is to find an efficient way to reversibly cryopreserve whole organs and then larger masses without ice crystal formation and other structural damage, leading up to whole body preservation. Being able to take donated organs and provide them with an indefinite shelf life would revolutionize the logistics of the transplant industry. Later, it would enable an efficient industry for manufacture of new organs, as tissue engineering capabilities increase. The eventual goal for this technological capability is to greatly improve the ability to preserve individuals at clinical death, maintaining them in cold storage indefinitely, with minimal additional damage, until technological progress allows for repair and revival.

The start of the modern field of cryobiology is thought to have happened in 1948, with the discovery of the cryoprotective effects of glycerol, a cryoprotective agent (CPA) that prevents ice crystal formation through the creation of bonds with free water molecules. Since then, a huge aspect of cryobiology and cryopreservation technologies was that we can modulate a given system's chemistry by involving CPAs, which could, in theory, allow us to preserve a live biologic sample for a long time. Many more CPAs, like dimethyl sulfoxide (DMSO), appeared on the scene afterwards, revolutionizing the subfield of human sperm cryopreservation. In 1972, scientists published evidence of the first-ever successful cryopreservation of mammalian embryos using slow-freezing. Eleven years later, the first-ever human embryo was cryopreserved.

A turning point in cryobiology happened in the 1980s, the so-called golden era of cryopreservation. Researchers introduced the process of vitrification to medical cryopreservation. Vitrification is a process of rapid cooling of liquid medium until it becomes a glass-like non-crystalline amorphous solid. It requires the protective effect of CPAs, which lower the freezing point of water, as a major part of biological systems. In its vitrified state, water is locked in place, preventing the formation of ice crystals, and the entire sample becomes a glass-like solid. Vitrification is used widely today in the cryopreservation of very small biological samples (specifically in in vitro fertilization and other reproductive applications), and many cryobiologists believe it could eventually be applied to freeze any biological materials, even organs and whole organisms.

One of the major focus in cryobiology research is, in fact, centered around the process of vitrification and how much and which CPAs to add during this stage, or how to remove these often toxic compounds in the rewarming stages. But, so far, CPA-aided vitrification only enabled the routine preservation of cells and cell suspensions and failed to produce any clinically translatable technique on how to reversibly preserve any complex biological systems like organs outside of the human body.

Methods in cryopreservation haven't changed much in the last few years but there is a different approach currently available called isochoric cryopreservation. The term stands for cryopreservation of biological tissues at a constant volume, versus the more "traditional" way of cryopreservation that's done at constant pressure, called isobaric cryopreservation. During isochoric preservation, the cooling process happens in a confined, constant-volume chamber, representing one of the biggest differences between isochoric and isobaric conditions. Another difference is minimized role of CPAs, which are very much needed in the classical isobaric cryopreservation, but not in several modes of isochoric cryopreservation.

The advantage of isochoric freezing is that it completely avoids the question of the toxicity associated with CPA usage as well as the amount of CPAs needed to be present in the biological sample you might want to freeze. Even if there is a need to use CPAs, their concentrations would be dramatically decreased. Under isochoric conditions, a biological sample is confined within a container with high rigidity and strength, usually made out of titanium. The container is completely absent of the bulk gas phase, and is denied any access to the atmosphere, which changes both the thermodynamic equilibrium and the ice nucleation kinetics within the system inside.

Link: https://www.forbes.com/sites/alexzhavoronkov/2022/10/12/think-outside-the-titanium-box-isochoric-cryopreservation-could-save-lives/

Researchers here note one aspect of many in the changing landscape of lipids in the aging brain. Like all such discoveries, it is initially hard to say where it stands in the complex web of cause and consequence that is degenerative aging. Aging is made up of many layers of cause and effect, leading from fundamental causes of aging, good targets for therapies that might alleviate a broad range of age-related conditions, to far downstream consequences of consequences of consequences that would have only a narrow, limited positive impact on health if targeted for restoration.

3-sulfogalactosyl diacylglycerols (SGDGs) are a class of lipids, also called fats. Lipids contribute to the structure, development, and function of healthy brains, while badly regulated lipids are linked to aging and diseased brains. However, lipids, unlike genes and proteins, are not well understood and have often been overlooked in aging research. Researchers recently made three discoveries involving SGDGs: In the brain, lipid levels are very different in older mice than in younger mice; all SGDG family members and related lipids change significantly with age; and SGDGs may be regulated by processes that are known to regulate aging.

"SGDGs were first identified in the 1970s, but there were few follow-up studies. These lipids were essentially forgotten and missing from the lipid databases. Nobody knew SGDGs would be changing or regulated in aging, let alone that they have bioactivity and, possibly, be therapeutically targetable." The analysis showed that SGDGs possess anti-inflammatory properties, which could have implications for neurodegenerative disorders and other neurological conditions that involve increased inflammation in the brain. The team also discovered that SGDGs exist in human and primate brains, suggesting that SGDGs may play an important role in animals other than mice. Further research will be required to show if SGDGs contribute to human neuroinflammation.

Link: https://www.salk.edu/news-release/salk-scientists-discover-new-molecules-that-decline-in-the-aging-brain/

An enormous amount of biological data can now be obtained from any given study population, and at reasonable cost. The resulting databases have grown to become very large. The epigenome, transcriptome, proteome, metabolome, microbiome, and much more, are at the fingertips of every epidemiological researcher, at multiple time points, before and after interventions, and at different ages. It is easy enough to find differences in the data between more healthy subjects and patients suffering from one or more age-related conditions. It is a harder task to build upon that data in order to find useful therapies. Aging causes sweeping changes in all measures of cellular biochemistry, but few of those changes are connected to good points of intervention. Most are consequences, not causes.

In today's open access paper, the authors discuss this environment of near unlimited biological data in the context of age-related neurodegeneration. Examining the differences characteristic of disease and then laboriously working backwards in search of causes and points of intervention is the polar opposite strategy to that of the SENS vision for rejuvenation, which is to tackle the known root causes of aging and then see what happens as a result. The former involves a great deal more work than the latter before the production of therapies becomes viable.

What we have learned to date from the omics approach to non-Alzheimer's dementias

More than 50 million people live with dementia in worldwide, and due to the rapidly aging population, dementia cases are expected to increase at least five times in 2050. Dementia refers to a clinical syndrome characterized by the deterioration of this memory ability and, progressive cognitive decline that hinders an individual's ability to function. Dementia symptoms are persistent and progressive. Although 60%-70% of dementia cases that develop related are to Alzheimer's disease (AD), the remaining 30%-40% are diagnosed as non-Alzheimer's (non-AD) dementia.

The non-AD pathogenesis is still unknown. Despite advances in modern medicine, the developmental process of dementia is still not fully understood. Although some mechanisms have been defined, they still cannot fully explain the process that develops in all patients. In recent years, new molecular techniques that enable high throughput data to be obtained in laboratories, have created hope for many neurological diseases, such as AD. Thanks to the "omics" concept that has become part of neurological research, these techniques have enabled us to examine the unknown areas of biology, such as the genome, transcriptome, proteome, microbiome, and metabolome, thus providing a new perspective of the interactions between host and microorganisms.

From this point of view, preclinical and clinical data has demonstrated a bidirectional interaction between the host and the microorganism and led to the formation of the term "gut-brain axis" between the gastrointestinal system and the brain. This interaction is very important for the regulation of the neural, hormonal, and immunological balance of human beings. Our gut is therefore named our second brain. Indeed, based on this concept, new relationships between the gut microbiome and dementia have been identified. Alterations in the composition of the gut microbiome have also been shown to independently cause an increase in risk of dementia, along with other traditional risk factors.

The presence of microbiome-associated metabolites and bacterial products in the systemic circulation may increase, especially with the inflammatory process that can lead to dementia. Despite this information, it is not yet known how changes in the gut microbiome and microbiota-related metabolites affect cognitive functions. Confusion due to conflicting findings regarding this relationship between the gut microbiome and dementia also exist. Understanding this bidirectional interaction is essential for discovering the underlying molecular pathogenic mechanisms of many disorders, especially in the neuroscience field. Studies in this field will provide the means to develop personalized treatments and will reveal different biomarkers and help us consider new treatment options. This review highlights the progress that has been made in omics research while noting the gaps in our knowledge.

Gum disease has bacterial causes, but the activities of senescent cells are implicated in the progression of the condition, as well as consequent bone loss and potential for oral cancer. When present in even comparatively small numbers, lingering senescent cells can disrupt tissue structure and function with their pro-growth, pro-inflammatory signaling. Many degenerative conditions characterized by chronic inflammation might be improved by the application of senolytic therapies capable of selectively destroying senescent cells.

The senescence-associated secretory phenotype (SASP), which accumulates over the course of normal aging and in age-related diseases, is a crucial driver of chronic inflammation and aging phenotypes. It is also responsible for the pathogenesis of multiple oral diseases. However, the pathogenic mechanism underlying SASP has not yet been fully elucidated.

Here, relevant articles on SASP published over the last five years (2017-2022) were retrieved and used for bibliometric analysis, for the first time, to examine SASP composition. More than half of the relevant articles focus on various cytokines (27.5%), growth factors (20.9%), and proteases (20.9%). In addition, lipid metabolites (13.1%) and extracellular vesicles (6.5%) have received increasing attention over the past five years, and have been recognized as novel SASP categories.

Based on this, we summarize the evidence demonstrating that SASP plays a pleiotropic role in oral immunity and propose a four-step hypothetical framework for the progression of SASP-related oral pathology - 1) oral SASP development, 2) SASP-related oral pathological alterations, 3) pathological changes leading to oral immune homeostasis disruption, and 4) SASP-mediated immune dysregulation escalating oral disease. By targeting specific SASP factors, potential therapies can be developed to treat oral and age-related diseases.

Link: https://doi.org/10.3389/fimmu.2022.1019313

Researchers here discuss what is know of changes that take place with age in cell membranes in the brain, and how they might negatively affect cell function. Like many aspects of aging, connecting these changes to the set of underlying mechanisms that cause aging is a challenging prospect, yet to be accomplished. Everything changes with age, and drawing connections between any two of those changes in order to demonstrate causation is a hard task.

Aging affects the plasma membrane of all the cells of the body, not only its composition and structure but also the function of its different components. Any change in the lipid composition of the cell membranes will impact the function of membrane receptors and the way the cells sense the environment. Numerous studies have shown the existence of significant differences in the relative amounts of the different lipids in tissues of young and old individuals, and this is mainly evident in the brain, because the blood-brain barrier strictly controls the entrance of lipids to the central nervous system. In particular, an increase in saturated fatty acid content and a decrease in polyunsaturated fatty acid (PUFA) content was found with age starting from 50 years old.

Lipid changes in the old seems to be more pronounced in lipid raft fractions of the plasma membrane. Using lipid rafts isolated from human frontal cortex in nondemented subjects aged from 24 to 85 years, researchers showed that these lipid rafts undergo significant alterations of specific lipid classes with aging. Furthermore, lipid rafts seems to be particularly sensitive to aging and decreased arachidonic acid (AA) and docosahexaenoic acid (DHA) levels in lipid rafts may represent an early event during normal aging, at least in the brain. These results clearly show that lipid remodeling occurs at the plasma membrane with aging. In the brain, some of these changes seem to occur early, at the starting point of the aging process, supporting the hypothesis that reshaping of the plasma membrane may be a very early event in the development of cellular aging, responsible for the occurrence of some of the typical manifestations of aging.

Link: https://doi.org/10.3389/fcell.2022.1031007

Transthyretin amyloidosis may be a primary component of the present limit on human longevity. Transthyretin is one of the few proteins in the human body that can misfold in ways that encourage other molecules of the same protein to misfold in the same way, joining together form solid aggregates that disrupt cell and tissue function. This is particularly an issue in the cardiovascular system, and while it is presently thought that transthyretin amyloidosis only contributes to a minority of fatal cardiovascular disease in younger old age, autopsies of supercentenarians suggested that it is the major cause of death in the oldest old.

Transthyretin amyloidosis has both normal and accelerated forms, the later resulting from inherited mutations. Most of the work done in developing therapies has focused on treating the rare mutant form of the condition, given the favorable incentives placed on therapies for rare diseases by regulators. Fortunately many of these treatments are also applicable to the age-related normal form of transthyretin amyloidosis. We might hope to see this condition better diagnosed and periodically reversed in its earlier stages, as this part of the industry progresses. Removal of this and other forms of amyloid should be a part of any comprehensive toolkit of rejuvenation therapies in order to prevent its contribution to degenerative aging.

A Review of Transthyretin Cardiac Amyloidosis

Transthyretin cardiac amyloidosis is a progressive disease known to cause heart failure, conduction anomalies, and arrythmias. Due to poor outcomes and mortality from severe cardiomyopathy, prevalence and incident rates are often underreported. As global longevity is increasing and rates of amyloidosis are also increasing, there is a need to improve diagnostic and therapeutic interventions. Previously, symptom management and transplantation were the mainstay of treatment for heart failure symptoms, but studies using RNAi and siRNA technologies have shifted the paradigm of therapeutic strategy in amyloid cardiomyopathy management.

Transthyretin (TTR) stabilizers are a new class of medication which function to selectively bind to TTR tetramers, stabilizer tetramer formation, and preventing dissociation of TTR into monomers, which happens to be the rate-limiting step in the formation of amyloidogenic protein deposits. Tafamidis is currently one of the few FDA-approved medications for cardiac amyloidosis that has shown promising results in clinical trials. Double-blind randomized control trials (n = 87) have shown increased quality of life, decreased or complete resolution of neuropathy, and reduction in all-cause mortality and hospitalization at 30 months. Tafamidis remains a very costly medication, estimated to cost $250,000 per year which may pose limitations for consumers.

Diflunisal, a non-steroidal anti-inflammatory, is another TTR stabilizer that has been FDA-approved for the treatment of musculoskeletal pathologies but is used for off-label purposes to treat cardiac amyloidosis. Like tafamidis, diflunisal also stabilizes the TTR tetramer but does so by binding specifically at the dimer-dimer interface and decreasing dissociation. Fewer studies have been conducted using diflunisal, but it has been shown to reduce progression of neuropathy by around 70% in the span of 24 months from the date of diagnosis.

TTR silencers work by inhibiting translation and reduction production of TTR protein. This can be accomplished either with the use of small-interfering RNA (siRNA) or antisense oligonucleotides (ASO). Patisiran is an siRNA that functions by binding to untranslated regions of TTR mRNA and effectively marking it for degradation to avoid protein production from mutated TTR genes. The Phase III APOLLO-A trial, a randomized placebo-controlled trial of 25 patients, investigated the use of patisiran in the treatment of systemic amyloidosis and showed improvements in polyneuropathy, global longitudinal heart strain, NT-proBNP levels, and numerous echocardiographic parameters. In fact, the study demonstrated a sustained 81% reduction in serum TTR levels after 18 months in patients treated with IV patisiran every 3 weeks.

Vutrisiran is a second-generation siRNA functions like patisiran but has the advantage of enhanced stabilization chemistry enabling longer binding to mRNA sequences and, as a result, infrequent dosing of the medication. Inotersen is also a TTR silencer but acts as an ASO, not an siRNA. This medication is a TTR-directed ASO which binds TTR mRNA, reduces these levels, and hereby reduces tissue deposition. The NEURO-TTR clinical trial, an international, randomized, double-blind, placebo-controlled trial of 172 patients, showed improved course of neurologic disease and quality of life. However, unlike the APOLLO study, it did not demonstrate improvement in echocardiographic parameters.

Kinetic stabilizers are yet another class of medications that have the potential to control cardiac amyloidosis disease progression. Acoramidis, which is currently under development, is an orally deliverable TTR designed to strengthen interactions between amyloid dimers and prevent tetramer dissociation. One Phase II randomized, double-blind, placebo-controlled trial with 49 patients is assessing the use of placebo versus 400 mg of acoramidis versus 800 mg of acoramidis and preliminary results have shown an increase in serum TTR with treatment, which is a marker for TTR stabilization. Tolcapone is another stabilizer which is typically used in the management of Parkinson's disease but has the potential to cross the blood brain barrier and treat systemic amyloidosis patients with leptomeningeal involvement. There is currently a Phase IIA proof-of-concept trial of two phases with 17 subjects showing significant stabilization of TTR with administration of tolcapone.

By targeting loose, floating pathogenic amyloid fibrils, fibril disruptors have the potential to prevent further deposition and tissue damage. Doxycycline, which belongs to the class of tetracycline antibiotics, is interestingly being considered as a fibril disruptor. Research has shown that, when combined with ambiphilic bile acid supplements like tauro-ursodeoxycholic acid (TUDCA), doxycycline can disrupt amyloid components. While studies thus far have shown decreased cardiac involvement, many study participants have voluntarily dropped out of studies due to poor tolerability and adverse effects like sun sensitivity. Currently, there is limited evidence supporting the use of doxycycline for the indication of cardiac amyloidosis, but it has shown some signs of effectiveness.

Numerous other avenues are being explored to treat TTR cardiac amyloidosis. Antibody therapies are being developed to target certain epitopes and have been increasingly studied for their role in removing ATTR amyloid or misfolded fibrils. Studies are now showing that the antibodies did not react with native tetramers in vivo but did appropriately react with TTR deposits in vivo and in vitro. In fact, a Phase I open-label three-phase clinical trial PRX004 involving 36 subjects has shown that antibodies targeting TTR89-97 residues improved neuropathy, reassuring drug tolerability, and favorable side effect profile at various dosages. There is a lot of promise in the science behind antibodies targeting amyloid genes.

The CRISPR-Cas9 system is a well-known gene editing treatment which has been engineered to identify and knock out TTR gene in a single administration. Pilot studies with less than 10 subjects have demonstrated reduced serum TTR by up to 87% in the span of just four weeks. Further studies are needed to assess tolerability and drug safety, but this system serves as an excellent example of translational science and the use of gene editing technologies to treat amyloidosis.

Age-related hearing loss correlates with the risk of onset and progression of neurodegenerative conditions such as Alzheimer's disease. There is some question as to whether this correlation exists because similar processes of neurodegeneration produce both outcomes, or whether one drives the other, or whether there is a bidirectional relationship. It seems plausible that reduced sensory input can accelerate decline of neural networks that run on a "use it or lose it" basis, though current thinking is also focused on reduced quality of sensory input causing functional issues in neural processing. Either way, the question remains as to whether that can account for a meaningful fraction of the loss of cognitive function and related issues, versus other more blunt mechanisms, such as the chronic inflammation in brain tissue that is characteristic of neurodegenerative diseases.

Evidence suggests that hearing loss (HL), even at mild levels, increases the long-term risk of cognitive decline and incident dementia. Hearing loss is one of the modifiable risk factors for dementia, with approximately 4 million of the 50 million cases of dementia worldwide possibly attributed to untreated HL. This paper describes four possible mechanisms that have been suggested for the relationship between age-related hearing loss (ARHL) and Alzheimer's disease (AD), which is the most common form of dementia.

The first mechanism suggests mitochondrial dysfunction and altered signal pathways due to aging as a possible link between ARHL and AD. The second mechanism proposes that sensory degradation in hearing impaired people could explain the relationship between ARHL and AD. The occupation of cognitive resource (third) mechanism indicates that the association between ARHL and AD is a result of increased cognitive processing that is required to compensate for the degraded sensory input. The fourth mechanism is an expansion of the third mechanism, i.e., the function and structure interaction involves both cognitive resource occupation (neural activity) and AD pathology as the link between ARHL and AD.

Exploring the specific mechanisms that provide the link between ARHL and AD has the potential to lead to innovative ideas for the diagnosis, prevention, and/or treatment of AD. This paper also provides insight into the current evidence for the use of hearing treatments as a possible treatment/prevention for AD, and if auditory assessments could provide an avenue for early detection of cognitive impairment associated with AD.

Link: https://doi.org/10.3233/ADR-220035

Researchers continue to investigate the fundamental biology of cellular senescence, and every so often they turn up new targets that might be the basis for development of novel senolytic therapies. First generation senolytic treatments, that provoke a sizable fraction of senescent cells in aged tissues into self-destruction, have produced impressive results in aged mice, extending life, but more importantly rapidly reversing many measures of aging and age-related disease. While many different forms of senolytic treatment are presently under preclinical and clinical development, there will always be room for more, given that every human much over the age of 50 is a potential repeat customer.

Cellular senescence is characterized by cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP) whereby cells secrete pro-inflammatory and tissue-remodeling factors. Given that the SASP exacerbates age-associated pathologies, some aging interventions aim at selectively eliminating senescent cells. In this study, a drug library screen uncovered TrkB (NTRK2) inhibitors capable of triggering apoptosis of several senescent, but not proliferating, human cells.

Senescent cells expressed high levels of TrkB, which supported senescent cell viability, and secreted the TrkB ligand BDNF. The reduced viability of senescent cells after ablating BDNF signaling suggested an autocrine function for TrkB and BDNF, which activated ERK5 and elevated BCL2L2 levels, favoring senescent cell survival. Treatment with TrkB inhibitors reduced the accumulation of senescent cells in aged mouse organs. We propose that the activation of TrkB by SASP factor BDNF promotes cell survival and could be exploited therapeutically to reduce the senescent-cell burden.

Link: https://doi.org/10.1038/s41467-022-33709-8

The record for mouse life span is held by growth hormone receptor knockout lineages, approaching a 70% gain, but a lot of that increase is due to early life effects. These animals are very small in comparison to their peers. In comparison, growth hormone receptor knockout in adulthood has a greater impact on female mice than on male mice, and the gain in life span is much reduced. In today's open access paper, researchers demonstrate another approach, generating a lineage of mice in which growth hormone receptor is only disabled in fat tissue. Again, the outcomes are different in male and female mice, and smaller than those produced by full knockout.

While the effect size of full growth hormone knockout in mice is larger than that produced by most other interventions, this seems unlikely to be a viable approach to greatly extend human life span. The life span of short-lived species is more plastic in response to changes in environment and metabolism than is the case for long-lived species such as our own.

We can make direct comparisons between mice and humans for the practice of calorie restriction, and see that while mouse life span can be extended by up to 40%, adding more than a few years of human life span is just not in the cards. We can also directly compare interference in growth hormone receptor function, as a human lineage analogous to the growth hormone receptor knockout mice exists. Those individuals born with Laron syndrome inherit a loss-of-function mutation in growth hormone receptor. They may be resistant to some age-related conditions, but don't appear to live longer than the rest of us.

Disruption of Growth Hormone Receptor in Adipocytes Improves Insulin Sensitivity and Lifespan in Mice

Growth hormone receptor knockout (GHRKO) mice have been used for 25 years to uncover some of the many actions of growth hormone (GH). Since they are extremely long-lived with enhanced insulin sensitivity and protected from multiple age-related diseases, they are often used to study healthy aging. To determine the effect that adipose tissue has on the GHRKO phenotype, our laboratory recently created and characterized adipocyte-specific GHRKO (AdGHRKO) mice, which have increased adiposity but appear healthy with enhanced insulin sensitivity.

To test the hypothesis that removal of GH action in adipocytes might partially replicate the increased lifespan and healthspan observed in global GHRKO mice, we assessed adiposity, cytokines/adipokines, glucose homeostasis, frailty, and lifespan in aging AdGHRKO mice of both sexes. Our results show that disrupting the GH receptor gene in adipocytes improved insulin sensitivity at advanced age and increased lifespan in male AdGHRKO mice. AdGHRKO mice also exhibited increased fat mass, reduced circulating levels of insulin, c-peptide, adiponectin, resistin, and improved frailty scores with increased grip strength at advanced ages.

Comparison of published mean lifespan data from GHRKO mice to that from AdGHRKO and muscle-specific GHRKO mice suggests that approximately 23% of lifespan extension in male GHRKO is due to GHR disruption in adipocytes vs approximately 19% in muscle. Females benefited less from GHR disruption in these two tissues with approximately 19% and approximately 0%, respectively. These data indicate that removal of GH's action, even in a single tissue, is sufficient for observable health benefits that promote long-term health, reduce frailty, and increase longevity.

Raised blood pressure produces damage to tissues throughout the body. That control of blood pressure via antihypertensive drugs, forcing better function without addressing any of the underlying causative damage of aging, does in fact reduce mortality in later life is a compelling indication of the degree to which raised blood pressure is directly harmful. In the brain, manifestations of this harm include an acceleration of the processes of atherosclerosis, disruption of the blood-brain barrier leading to brain inflammation, and an increase in the pace at which capillaries and other small vessels rupture, all of this damage contributing to the onset and progression of neurodegeneration and loss of cognitive function.

Dementia is fast becoming a global epidemic, currently affecting an estimated 50 million people worldwide. While many trials have looked at the health benefits of lowering blood pressure, not many included dementia outcomes and even fewer were placebo-controlled - considered to provide the best level of evidence. "Most trials were stopped early because of the significant impact of blood pressure lowering on cardiovascular events, which tend to occur earlier than signs of dementia."

To examine the relationship between blood pressure and dementia more closely, researchers analysed five double-blind placebo-controlled randomised trials that used different blood pressure lowering treatments and followed patients until the development of dementia. A total of 28,008 individuals with an average age of 69 and a history of high blood pressure from 20 countries were included. Across these studies, the mid-range of follow up was just over four years. After a median follow-up of 4.3 years, there were 861 cases of incident dementia. Regression analysis reported an adjusted odds ratio 0.87 in favour of antihypertensive treatment reducing risk of incident dementia with a mean blood pressure lowering of 10/4 mmHg.

"Our results imply a broadly linear relationship between blood pressure reduction and lower risk of dementia, regardless of which type of treatment was used. Our study provides the highest grade of available evidence to show that blood pressure lowering treatment over several years reduces the risk of dementia, and we did not see any evidence of harm. But what we still don't know is whether additional blood pressure lowering in people who already have it well-controlled or starting treatment earlier in life would reduce the long-term risk of dementia."

Link: https://www.georgeinstitute.org.au/media-releases/best-evidence-yet-that-lowering-blood-pressure-can-prevent-dementia

Alex Zhavoronkov founded one of the earlier companies in the now growing longevity industry, In Silico Medicine. There is a cycle in every industry, in which founders of successful companies tend to invest a fraction of their gains in new startups, either directly or via industry-focused funds, and act as philanthropists in support of relevant academic research. This reinforces and accelerates growth. The early longevity industry contains a good number of zealots willing to do more than invest only a fraction of their wealth. Thinking a great deal about health, aging, mortality, and medicine tends to focus the mind on what one truly gains from holding on to wealth in a world in which everyone becomes sick, aged, and dies.

What frustrates me is that most people do not pay enough attention to the inevitable decline, frailty, loss of function, diseases, and death that are associated with aging and choose to be distracted and spend their time on attention-grabbing causes that only provide a temporary reward. The problem is here, right now, and every individual contributor can make a difference. Like climate change or poverty, aging research requires everyone on the planet to become involved. But unlike climate change, aging is causing millions of casualties and suffering worldwide today and right now.

On the positive side, after two decades of hard work, my commercial ventures have started yielding financial returns. It would be logical to donate part of my wealth to charitable foundations focusing on aging research. Over the past two decades, I supported many projects in longevity, saw many failures, analyzed a massive number of grants, and learned how to evaluate the impact of the various longevity initiatives. In addition to capital, I can now bring years of experience, and multiple partner organizations to the most impactful projects. Therefore, I would like to pledge everything I have now, and what I will get in the future, to only one cause - extending healthy productive longevity for all human beings. Instead of donating just a portion of my wealth and energy to this cause, I would like to do more.

I pledge to spend 100% of my time and personal resources to accelerate research and clinical deployment of longevity technologies. At present, I do not plan to leave an inheritance, and I will invest everything I have into projects and companies that extend healthy, productive life for everyone on the planet.

Link: https://www.longevitypledge.org/

Microglia are innate immune cells of the brain, akin to macrophages elsewhere in the body, but with a larger portfolio of tasks, extending beyond defense against pathogens and aiding in tissue repair to include assisting in neural function and maintenance of synaptic networks. A sizable body of evidence points to increasing inflammatory activation of microglia as an important factor in the development of age-related neurodegeneration. Microglia react to signals, such as DNA debris from stressed and dying cells, or the secreted cytokines produced by senescent cells, that become more common with advancing age. When this inflammatory reaction becomes chronic, it harms the brain, diverting microglia from necessary tasks and amplifying the state of inflammation and disruption of tissue function.

Therapies that selectively destroy senescent cells, particularly senescent microglia, and therapies that clear microglia are thus of considerable interest. They have been demonstrated to reduce inflammation and the progression of brain tissue dysfunction in mice engineered to exhibit features of human neurodegenerative conditions. Today's open access paper reports on a similar but less drastic approach, in which a small molecule drug is used to reduce the inflammatory reaction of microglia to their age-damaged environment. The result is a slowing of the early progression of neurodegenerative disease, again pointing to microglial dysfunction as an important factor in the aging of the brain.

Prevention of microgliosis halts early memory loss in a mouse model of Alzheimer's disease

Microglia are the main tissue-resident macrophages of the brain and are important players in Alzheimer's disease (AD). There is abundant evidence for the reactivity of microglia (microgliosis) in the pathogenesis of AD. In people with AD and in AD mice there is a clear change in microglia transcriptome, showing immune activation. Reactive microglia release cytokines causing damage to healthy brain structure. Via complement-dependent pathways, reactive microglia show increased pruning of synapses leading to excessive synapse loss early in AD and ultimately cognitive impairment.

Several recent studies on AD aimed to inhibit microgliosis, and associated AD pathology, using the tetracycline derivative minocycline. Minocycline decreases the inflammatory activation of microglia, and was shown to inhibit microgliosis and alleviate defects in synaptic plasticity and cognitive behavior in mouse models of AD. Although these studies applied minocycline treatment at a relative early pathological phase, gliosis, and amyloid-β (Aβ) plaques were already apparent. The efficacy of a preventive treatment with minocycline, before the onset of gliosis and amyloid pathology has not yet been determined. This is particularly relevant because a recent clinical study on patients with mild AD, showed that minocycline treatment was not successful in slowing disease progression. This implies that a too late treatment is not successful, but leaves the possibility that inhibition of microgliosis can be effective when targeted at an early AD stage, before microgliosis becomes apparent.

The APP/PS1 mouse is a transgenic model for increased amyloidosis, resulting from the introduction of human disease-related mutations, one in amyloid precursor protein (APP) and one in presenilin 1 (PSEN1). Whereas these transgenic mouse models do not reproduce the full spectrum of pathological and clinical symptoms observed in AD, they are useful in studying early pre-pathological memory and plasticity impairments due to increased amyloidosis. Here, we determined the temporal onset of microgliosis, in relation to other AD pathological parameters, in APP/PS1 mice. Subsequently, the outcome of preventive inhibition of microgliosis on AD-related disease progression was investigated.

We found that the appearance of microgliosis, synaptic dysfunction and behavioral impairment coincided with increased soluble Aβ42 levels, and occurred well before the presence of Aβ plaques. Inhibition of microglial activity by treatment with minocycline reduced gliosis, synaptic deficits, and cognitive impairments at early pathological stages and was most effective when provided preventive, i.e., before the onset of microgliosis. Our data establish that microglial reactivity is driving early-phase AD pathology and that early treatment is effective in preventing the resulting cognitive impairments.

An interesting effect of intermittent fasting is here demonstrated in mice. Given a rotator cuff injury, mice undergoing intermittent fasting exhibit improved regeneration, but only in the early stages following injury. The researchers provide evidence for this effect to be mediated by changes in the gut microbiome. Various microbial populations generate metabolites that are connected to a range of cellular activities, so the microbiome is a reasonable place to search for mechanisms related to effects of fasting.

Mice underwent rotator cuff injury were treated with intermittent fasting or fed ad libitum. Fasting began one month before surgery and continued until euthanasia. Fresh feces were collected at 2 weeks before surgery, on the day of surgery, and 2, 4, 8 weeks postoperatively for 16S rRNA microbiome sequencing. Supraspinatus tendon-humerus ​(SSTH) complex was collected at 2, 4 and 8 weeks after surgery. Biomechanical, radiological and histological analysis indicated that intermittent fasting significantly promoted the repair of rotator cuff injury in the early postoperative period, but significantly inhibited the repair of rotator cuff injury at 4 weeks postoperatively.

16S rRNA microbiome sequencing result showed that P. distasonis was the species with the most obvious reduction in intestinal flora of mice after fasting. Then live P. distasonis was used for repair of rotator cuff injury, with equal amount of pasteurized P. distasonis (KPD) or sterile anaerobic phosphate buffer saline (PBS) as control. Biomechanical, radiological, histological analysis were used to assess the effect of rotator cuff repair. The results indicated that the live P. distasonis (LPD) significantly impaired the biomechanical properties, bone regeneration and fibrocartilage regeneration postoperatively.

Link: https://doi.org/10.1016/j.jot.2022.09.006

Microglia are innate immune cells of the central nervous system. They are analogous to macrophages in the rest of the body, but undertake additional duties relating to the function of neurons and in brain tissue. Microglia become overly active and inflammatory with age, reacting to the molecular damage of aging and growing numbers of senescent cells. Numerous lines of evidence suggest that this change in microglia behavior is a significant contributing cause of neurodegeneration. Fortunately, microglia can be near entirely cleared via CSF1R inhibitor drugs, triggering repopulation of the brain with new microglia that exhibit fewer issues, even in later life. This may be the basis for therapies for a range of issues in the aging brain, including sleep disruption, as noted here.

Changes in wake/sleep architecture have been observed in both aged human and animal models, presumably due to various functional decay throughout the aging body particularly in the brain. Microglia have emerged as a modulator for wake/sleep architecture in the adult brain, and displayed distinct morphology and activity in the aging brain. However, the link between microglia and age-related wake/sleep changes remains elusive. In this study, we systematically examined the brain vigilance and microglia morphology in aging mice (3, 6, 12, and 18 months old), and determined how microglia affect the aging-related wake/sleep alterations in mice.

We found that from young adult to aged mice there was a clear decline in stable wakefulness at nighttime, and a decrease of microglial processes length in various brain regions involved in wake/sleep regulation. The decreased stable wakefulness can be restored following the time course of microglia depletion and repopulation in the adult brain. Microglia repopulation in the aging brain restored age-related decline in stable wakefulness. Taken together, our findings suggest a link between aged microglia and deteriorated stable wakefulness in aged brains.

Link: https://doi.org/10.3389/fnagi.2022.988166