Human Healthspan Research Articles

Chili pepper extends lifespan in a concentration-dependent manner and confers cold resistance on Drosophila melanogaster cohorts by influencing specific metabolic pathways.

Chili powder is a widely used spice with pungent taste, often consumed on a daily basis in several countries. Recent prospective cohort studies showed that the regular use of chili pepper improves healthspan in humans. Indeed, chili pepper fruits contain phenolic substances which are structurally similar to those that show anti-aging properties. The objective of our study was to test whether consumption of chili-supplemented food by the fruit fly, Drosophila melanogaster, would prolong lifespan and in which way this chili-supplemented food affects animal metabolism. Chili powder added to food in concentrations of 0.04%-0.12% significantly extended median lifespan in fruit fly cohorts of both genders by 9% to 13%. However, food supplemented with 3% chili powder shortened lifespan of male cohorts by 9%. Lifespan extension was accompanied by a decrease in age-independent mortality (i.e., death in early ages). The metabolic changes caused by consumption of chili-supplemented food had a pronounced dependence on gender. A characteristic of both fruit fly sexes that ate chili-supplemented food was an increased resistance to cold shock. Flies of both sexes had lower levels of hemolymph glucose when they ate food supplemented with low concentrations of chili powder, as compared with controls. However, males fed on food with 3% chili had lower levels of storage lipids and pyruvate reducing activity of lactate dehydrogenase compared with controls. Females fed on this food showed lower activities of hexokinase and pyruvate kinase, as well as lower ADP/O ratios, compared with control flies.

The mTOR-lysosome axis at the centre of ageing.

Age‐related diseases represent some of the largest unmet clinical needs of our time. While treatment of specific disease‐related signs has had some success (for example, the effect of statin drugs on slowing progression of atherosclerosis), slowing biological ageing itself represents a target that could significantly increase health span and reduce the prevalence of multiple age‐related diseases. Mechanistic target of rapamycin complex 1 (mTORC1) is known to control fundamental processes in ageing: inhibiting this signalling complex slows biological ageing, reduces age‐related disease pathology and increases lifespan in model organisms. How mTORC1 inhibition achieves this is still subject to ongoing research. However, one mechanism by which mTORC1 inhibition is thought to slow ageing is by activating the autophagy–lysosome pathway. In this review, we examine the special bidirectional relationship between mTORC1 and the lysosome. In cells, mTORC1 is located on lysosomes. From this advantageous position, it directly controls the autophagy–lysosome pathway. However, the lysosome also controls mTORC1 activity in numerous ways, creating a special two‐way relationship. We then explore specific examples of how inhibition of mTORC1 and activation of the autophagy–lysosome pathway slow the molecular hallmarks of ageing. This body of literature demonstrates that the autophagy–lysosome pathway represents an excellent target for treatments that seek to slow biological ageing and increase health span in humans.

Translational Geroscience: Human Models of Healthy Aging and Longevity

While insulin like growth factor-1 (IGF-1) is a well-established modulator of aging and longevity in model organisms, its role in humans is less well understood. Previous ambiguities in part have been attributed to cohort characteristics and unawareness of interactions between age and IGF-1. Centenarians have emerged as an ideal model of healthy aging because they delay the onset of age-related diseases and often remain disease free for the duration of their lifespan. In cohorts of centenarians and generally healthy older adults, we demonstrated that reduced IGF-1 is associated with extended lifespan and health-span. Additionally, we confirmed that IGF-1 interacts with age to modify risk in a manner consistent with antagonistic pleiotropy: younger individuals with high IGF-1 are protected from dementia, vascular disease, diabetes, cancer, and osteoporosis, while older individuals do not exhibit IGF-1-associated protection from disease. These findings offer evidence for IGF-1 modulating health-span and lifespan in humans.

FOXO3, Telomere Dynamics, and Healthy Brain Aging: A COBRE Study

Human longevity is linked to genetic, cellular, and other complex biological and psychosocial traits. Aging is typically accompanied by gradual brain atrophy and cognitive decline, but the mechanisms are unclear. Cellular aging, characterized by telomere shortening and altered telomerase activity, is related to mortality and brain aging. Decelerated brain aging is associated with greater peripheral blood leukocyte telomere length (LTL) and, we hypothesize, may be linked to FOXO3 genotype. We will use MRI to assess brain structure and function cross-sectionally in 100 Kuakini Honolulu Heart Program Offspring. Atrophy and disrupted functional connectivity, markers of brain aging, will be examined in relation to FOXO3 and LTL. Associations between brain structural and functional differences, FOXO3 genotype and LTL will be investigated over a wide range of ages, controlling for other biological and psychosocial factors. Results may provide insight into mechanisms influencing the rate of brain aging, and may eventually extend human healthspan.

Antecedent Metabolic Health and Metformin (ANTHEM) Aging Study: Rationale and Study Design for a Randomized Controlled Trial.

The antidiabetic medication metformin has been proposed to be the first drug tested to target aging and extend healthspan in humans. While there is extensive epidemiological support for the health benefits of metformin in patient populations, it is not clear if these protective effects apply to those free of age-related disease. Our previous data in older adults without diabetes suggest a dichotomous change in insulin sensitivity and skeletal muscle mitochondrial adaptations after metformin treatment when co-prescribed with exercise. Those who entered the study as insulin-sensitive had no change to detrimental effects while those who were insulin-resistant had positive changes. The objective of this clinical trial is to determine if (a) antecedent metabolic health and (b) skeletal muscle mitochondrial remodeling and function mediate the positive or detrimental effects of metformin monotherapy, independent of exercise, on the metabolism and biology of aging. In a randomized, double-blind clinical trial, adults free of chronic disease (n = 148, 40-75 years old) are stratified as either insulin-sensitive or resistant based on homeostatic model assessment of insulin resistance (≤2.2 or ≥2.5) and take 1 500 mg/day of metformin or placebo for 12 weeks. Hyperinsulinemic-euglycemic clamps and skeletal muscle biopsies are performed before and after 12 weeks to assess primary outcomes of peripheral insulin sensitivity and mitochondrial remodeling and function. Findings from this trial will identify clinical characteristics and cellular mechanisms involved in modulating the effectiveness of metformin treatment to target aging that could inform larger Phase 3 clinical trials aimed at testing aging as a treatment indication for metformin. Clinical Trials Registration Number: NCT04264897.

No limit to maximal lifespan in humans: how to beat a 122-year-old record.

Although average human life expectancy is rising, the maximum lifespan is not increasing. Leading demographers claim that human lifespan is fixed at a natural limit around 122 years. However, there is no fixed limit in animals. In animals, anti-aging interventions (dietary restrictions, rapamycin, genetic manipulations) postpone age-related diseases and thus automatically extend maximum lifespan. In humans, anti-aging interventions have not been yet implemented. Instead, by treating individual diseases, medical interventions allow a patient to live longer (despite morbidity), expanding morbidity span. In contrast, slowly aging individuals (centenarians) enter very old age in good health, but, when diseases finally develop, they do not receive thorough medical care and die fast. Although the oldest old die from age-related diseases, death certificates often list “old age”, meaning that diseases were not even diagnosed and even less treated. The concept of absolute compression of morbidity is misleading in humans (in truth, there is no other way to compress morbidity as by denying thorough medical care) and false in animals (in truth, anti-aging interventions do not condense morbidity, they postpone it). Anti-aging interventions such as rapamycin may potentially extend both healthspan and maximal lifespan in humans. Combining anti-aging medicine with cutting-edge medical care, regardless of chronological age, will extend maximal lifespan further.

Rodent diet aids and the fallacy of caloric restriction

Understanding the molecular mechanisms of normal aging is a prerequisite to significantly improving human health span. Caloric restriction (CR) can delay aging and has served as a yardstick to evaluate interventions extending life span. However, mice given unlimited access to food suffer severe obesity. Health gains from CR depend on control mice being sufficiently overweight and less obese mouse strains benefit far less from CR. Pharmacologic interventions that increase life span, including resveratrol, rapamycin, nicotinamide mononucleotide and metformin, also reduce body weight. In primates, CR does not delay aging unless the control group is eating enough to suffer from obesity-related disease. Human survival is optimal at a body mass index achievable without CR, and the above interventions are merely diet aids that shouldn’t slow aging in healthy weight individuals. CR in humans of optimal weight can safely be declared useless, since there is overwhelming evidence that hunger, underweight and starvation reduce fitness, survival, and quality of life. Against an obese control, CR does, however, truly delay aging through a mechanism laid out in the following tumor suppression theory of aging.

Cell and Cell-Free Therapies to Counteract Human Premature and Physiological Aging: MSCs Come to Light.

The progressive loss of the regenerative potential of tissues is one of the most obvious consequences of aging, driven by altered intercellular communication, cell senescence and niche-specific stem cell exhaustion, among other drivers. Mesenchymal tissues, such as bone, cartilage and fat, which originate from mesenchymal stem cell (MSC) differentiation, are especially affected by aging. Senescent MSCs show limited proliferative capacity and impairment in key defining features: their multipotent differentiation and secretory abilities, leading to diminished function and deleterious consequences for tissue homeostasis. In the past few years, several interventions to improve human healthspan by counteracting the cellular and molecular consequences of aging have moved closer to the clinic. Taking into account the MSC exhaustion occurring in aging, advanced therapies based on the potential use of young allogeneic MSCs and derivatives, such as extracellular vesicles (EVs), are gaining attention. Based on encouraging pre-clinical and clinical data, this review assesses the strong potential of MSC-based (cell and cell-free) therapies to counteract age-related consequences in both physiological and premature aging scenarios. We also discuss the mechanisms of action of these therapies and the possibility of enhancing their clinical potential by exposing MSCs to niche-relevant signals.

Exercise and Sestrin Mediate Speed and Lysosomal Activity in Drosophila by Partially Overlapping Mechanisms.

Chronic exercise is widely recognized as an important contributor to healthspan in humans and in diverse animal models. Recently, we have demonstrated that Sestrins, a family of evolutionarily conserved exercise-inducible proteins, are critical mediators of exercise benefits in flies and mice. Knockout of Sestrins prevents exercise adaptations to endurance and flight in Drosophila, and similarly prevents benefits to endurance and metabolism in exercising mice. In contrast, overexpression of dSestrin in muscle mimics several of the molecular and physiological adaptations characteristic of endurance exercise. Here, we extend those observations to examine the impact of dSestrin on preserving speed and increasing lysosomal activity. We find that dSestrin is a critical factor driving exercise adaptations to climbing speed, but is not absolutely required for exercise to increase lysosomal activity in Drosophila. The role of Sestrin in increasing speed during chronic exercise requires both the TORC2/AKT axis and the PGC1α homolog spargel, while dSestrin requires interactions with TORC1 to cell-autonomously increase lysosomal activity. These results highlight the conserved role of Sestrins as key factors that drive diverse physiological adaptations conferred by chronic exercise.

Extending human healthspan and longevity: a symposium report.

For many years, it was believed that the aging process was inevitable and that age-related diseases could not be prevented or reversed. The geroscience hypothesis, however, posits that aging is, in fact, malleable and, by targeting the hallmarks of biological aging, it is indeed possible to alleviate age-related diseases and dysfunction and extend longevity. This field of geroscience thus aims to prevent the development of multiple disorders with age, thereby extending healthspan, with the reduction of morbidity toward the end of life. Experts in the field have made remarkable advancements in understanding the mechanisms underlying biological aging and identified ways to target aging pathways using both novel agents and repurposed therapies. While geroscience researchers currently face significant barriers in bringing therapies through clinical development, proof-of-concept studies, as well as early-stage clinical trials, are underway to assess the feasibility of drug evaluation and lay a regulatory foundation for future FDA approvals in the future.

The San Diego Nathan Shock Center: tackling the heterogeneity of aging.

Understanding basic mechanisms of aging holds great promise for developing interventions that prevent or delay many age-related declines and diseases simultaneously to increase human healthspan. However, a major confounding factor in aging research is the heterogeneity of the aging process itself. At the organismal level, it is clear that chronological age does not always predict biological age or susceptibility to frailty or pathology. While genetics and environment are major factors driving variable rates of aging, additional complexity arises because different organs, tissues, and cell types are intrinsically heterogeneous and exhibit different aging trajectories normally or in response to the stresses of the aging process (e.g., damage accumulation). Tackling the heterogeneity of aging requires new and specialized tools (e.g., single-cell analyses, mass spectrometry-based approaches, and advanced imaging) to identify novel signatures of aging across scales. Cutting-edge computational approaches are then needed to integrate these disparate datasets and elucidate network interactions between knownaging hallmarks. There is also a need for improved, human cell-based models of aging to ensure that basic research findings are relevant to human aging and healthspan interventions. The San Diego Nathan Shock Center (SD-NSC) provides access to cutting-edge scientific resources to facilitate the study of the heterogeneity of aging in general and to promote the use of novel human cell models of aging. The center also has a robust Research Development Core that funds pilot projects on the heterogeneity of aging and organizes innovative training activities, including workshops and a personalized mentoring program, to help investigators new to the aging field succeed. Finally, the SD-NSC participates in outreach activities to educate the general community about the importance of aging research and promote the need for basic biology of aging research in particular.

A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan.

The numerous beneficial health outcomes associated with the use of metformin to treat patients with type 2 diabetes (T2DM), together with data from pre-clinical studies in animals including the nematode, C. elegans, and mice have prompted investigations into whether metformin has therapeutic utility as an anti-aging drug that may also extend lifespan. Indeed, clinical trials, including the MILES (Metformin In Longevity Study) and TAME (Targeting Aging with Metformin), have been designed to assess the potential benefits of metformin as an anti-aging drug. Preliminary analysis of results from MILES indicate that metformin may induce anti-aging transcriptional changes; however it remains controversial as to whether metformin is protective in those subjects free of disease. Furthermore, despite clinical use for over 60 years as an anti-diabetic drug, the cellular mechanisms by which metformin exerts either its actions remain unclear. In this review, we have critically evaluated the literature that has investigated the effects of metformin on aging, healthspan and lifespan in humans as well as other species. In preparing this review, particular attention has been placed on the strength and reproducibility of data and quality of the study protocols with respect to the pharmacokinetic and pharmacodynamic properties of metformin. We conclude that despite data in support of anti-aging benefits, the evidence that metformin increases lifespan remains controversial. However, via its ability to reduce early mortality associated with various diseases, including diabetes, cardiovascular disease, cognitive decline and cancer, metformin can improve healthspan thereby extending the period of life spent in good health. Based on the available evidence we conclude that the beneficial effects of metformin on aging and healthspan are primarily indirect via its effects on cellular metabolism and result from its anti-hyperglycemic action, enhancing insulin sensitivity, reduction of oxidative stress and protective effects on the endothelium and vascular function.

Friends and foes: Extracellular vesicles in aging and rejuvenation.

Extracellular vesicles (EVs) are released by many different cell types throughout the body and play a role in a diverse range of biological processes. EVs circulating in blood as well as in other body fluids undergo dramatic alterations over an organism's lifespan that are only beginning to be elucidated. The exact nature of these changes is an area of active and intense investigation, but lacks clear consensus due to the substantial heterogeneity in EV subpopulations and insufficiencies in current technologies. Nonetheless, emerging evidence suggests that EVs regulate systemic aging as well as the pathophysiology of age‐related diseases. Here, we review the current literature investigating EVs and aging with an emphasis on consequences for the maintenance of human healthspan. Intriguingly, the biological utility of EVs both in vitro and in vivo and across contexts depends on the states of the source cells or tissues. As such, EVs secreted by cells in an aged or pathological state may impose detrimental consequences on recipient cells, while EVs secreted by youthful or healthy cells may promote functional improvement. Thus, it is critical to understand both functions of EVs and tip the balance toward their beneficial effects as an antiaging intervention.

Hormesis: Transforming disciplines that rely on the dose response.

This article tells the story of hormesis from its conceptual and experimental origins, its dismissal by the scientific and medical communities in the first half of the 20th century, and its rediscovery over the past several decades to be a fundamental evolutionary adaptive strategy. The upregulation of hormetic adaptive mechanisms has the capacity to decelerate the onset and reduce the severity of a broad spectrum of common age-related health, behavioral, and performance decrements and debilitating diseases, thereby significantly enhancing the human health span. Incorporation of hormetic-based lifestyle options within the human population would have profoundly positive impacts on the public health, significantly reducing health care costs.

Reproductive aging and telomeres: Are women and men equally affected?

Successful reproduction is very important for individuals and for society. Currently, the human health span and lifespan are the object of intense and productive investigation with great achievements, compared to the last century. However, reproduction span does not progress concomitantly with lifespan. Reproductive organs age, decreasing the levels of sexual hormones, which are protectors of health through their action on several organs of the body. Thus, this is the starting point of the organismal decay and infertility. This starting point is easily detected in women. In men, it goes under the surface, undetected, but it goes, nevertheless.Regarding fertility, aging alters the hormonal equilibrium, decreases the potential of reproductive organs, diminishes the quality of the gametes and worsen the reproductive outcomes. All these events happen at a different pace and affecting different organs in women and men. The question is what molecular pathways are involved in reproductive aging and if there is a possible halting or even reversion of the aging events. Answers to all these points will be explained in the present review.

Sarcopenia: What Is the Origin of This Aging-Induced Disorder?

We here review the loss of muscle function and mass (sarcopenia) in the framework of human healthspan and lifespan, and mechanisms involved in aging. The rapidly changing composition of the human population will impact the incidence and the prevalence of aging-induced disorders such as sarcopenia and, henceforth, efforts to narrow the gap between healthspan and lifespan should have top priority. There are substantial knowledge gaps in our understanding of aging. Heritability is estimated to account for only 25% of lifespan length. However, as we push the expected lifespan at birth toward those that we consider long-lived, the genetics of aging may become increasingly important. Linkage studies of genetic polymorphisms to both the susceptibility and aggressiveness of sarcopenia are still missing. Such information is needed to shed light on the large variability in clinical outcomes between individuals and why some respond to interventions while others do not. We here make a case for the concept that sarcopenia has a neurogenic origin and that in manifest sarcopenia, nerve and myofibers enter into a vicious cycle that will escalate the disease progression. We point to gaps in knowledge, for example the crosstalk between the motor axon, terminal Schwann cell, and myofiber in the denervation processes that leads to a loss of motor units and muscle weakness. Further, we argue that the operational definition of sarcopenia should be complemented with dynamic metrics that, along with validated biomarkers, may facilitate early preclinical diagnosis of individuals vulnerable to develop advanced sarcopenia. We argue that preventive measures are likely to be more effective to counter act aging-induced disorders than efforts to treat manifest clinical conditions. To achieve compliance with a prescription of preventive measures that may be life-long, we need to identify reliable predictors to design rational and convincing interventions.

Responsible biology, aging populations and the 50th anniversary of the "War on Cancer".

The 50th Anniversary of the National Cancer Act of 1971 is the opportune time to critically reflect on the determinates of what the philosopher of science Philip Kitcher calls “responsible biology”. Responsible biology entails that scientists have an obligation to reflect on the ends, and not just the means, of scientific research and to conceive of themselves as artisans working for the public good. Taking stock of the successes and limits of the half a century “war on cancer” reveals the importance of attending to the most significant risk factor for cancer and other chronic diseases- aging itself. The case is made for considering the biology of aging, and the aspiration to slow the rate of biological aging, as critical components of responsible biology in an aging world. As growing numbers of humans survive into late life, the primacy the goal of disease elimination occupies within biomedical research must be revised, and greater effort should be directed towards the goal of increasing the human healthspan and delaying and compressing disease, frailty and disability in late life.

The Journal of Ageing and Longevity: Taking a Holistic View of the Human Healthspan

It is our pleasure to inaugurate the new open access journal, the Journal of Ageing and Longevity (JAL, ISSN 2673-9259) [...]

Natural products as geroprotectors: An autophagy perspective.

Over the past decade, significant attention has been given to repurposing Food and Drug Administration approved drugs to treat age-related diseases. In contrast, less consideration has been given to natural bioactive compounds. Consequently, there have been limited attempts to translate these compounds. Autophagy is a fundamental biological pathway linked to aging, and numerous strategies to enhance autophagy have been shown to extend lifespan. Interestingly, there are a number of natural products that are reported to modulate autophagy, and here we describe a number of them that activate autophagy through diverse molecular and cellular mechanisms. Among these, Urolithin A, Spermidine, Resveratrol, Fatty Acids and Phospholipids, Trehalose and Lithium are featured in detail. Finally, we outline possible strategies to optimise and increase the translatability of natural products, with the overall aim of delaying the ageing process and improving human healthspan.

Regional Diets Targeting Gut Microbial Dynamics to Support Prolonged Healthspan.

In the last 150 years, we have seen a significant increase in average life expectancy, associated with a shift from infectious to non-communicable diseases. The rising incidence of these diseases, for which age is often the largest risk factor, highlights the need for contemporary societies to improve healthy ageing for their growing silver generations. As ageing is an inevitable, non-reversing and highly individualised process, we need to better understand how non-genetic factors like diet choices and commensal gut microbes can modulate the biology of ageing. In this review, we discuss how geographical and ethnic variations influence habitual dietary patterns, nutrient structure, and gut microbial profiles with potential impact on the human healthspan. Several gut microbial genera have been associated with healthy elderly populations but are highly variable across populations. It seems unlikely that a universal pro-longevity gut microbiome exists. Rather, the optimal microbiome appears to be conditional on the microbial functionality acting on regional- and ethnicity-specific trends driven by cultural food context. We also highlight dietary and microbial factors that have been observed to elicit individual and clustered biological responses. Finally, we identify next generation avenues to modify otherwise fixed host functions and the individual ageing trajectory by manipulating the malleable gut microbiome with regionally adapted, personalised food intervention regimens targeted at prolonging human healthspan.