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Aging is the result of the accumulation of a wide variety of molecular and cellular damages over time, meaning that "the more damage we accumulate, the higher the possibility to develop age-related diseases". Therefore, to reduce the incidence of such diseases and improve human health, it becomes important to find ways to combat such damage. In this sense, geroprotectors have been suggested as molecules that could slow down or prevent age-related diseases. On the other hand, nutraceuticals are another set of compounds that align with the need to prevent diseases and promote health since they are biologically active molecules (occurring naturally in food) that, apart from having a nutritional role, have preventive properties, such as antioxidant, anti-inflammatory and antitumoral, just to mention a few. Therefore, in the present review using the specialized databases Scopus and PubMed we collected information from articles published from 2010 to 2023 in order to describe the role of nutraceuticals during the aging process and, given their role in targeting the hallmarks of aging, we suggest that they are potential geroprotectors that could be consumed as part of our regular diet or administered additionally as nutritional supplements.

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As scientists investigated the molecular mechanisms of the biology of aging, they discovered that these are malleable and can enhance healthy longevity by intervening in the drivers of aging, which are leading to disease, dysfunction and death. These exciting observations gave birth to the field of geroscience. As the mechanisms of aging affect almost all mechanisms of life, detailed molecular mechanistic knowledge must be gained or expanded by considering and integrating as many types of data as possible, from genes and transcripts to socioenvironmental factors. Such a large-scale integration of large amounts of data will in turn profit from "deep" bioinformatics analyses that provide insights beyond contextualizing and interpreting the data in the light of knowledge from databases such as the Gene Ontology. The authors suggest that "deep" bioinformatics, employing methods based on artificial intelligence, will be a key ingredient of future analyses.

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Ginger (Zingiber officinale Roscoe) is broadly used as a traditional remedy and food ingredient, and numerous preclinical and clinical studies have demonstrated health benefits in a range of age-related disorders. Moreover, longevity-promoting effects have been demonstrated in several (preclinical) research models. With this work, we aimed to comprehensively review the reported effects of ginger and its bioactive constituents on the twelve established hallmarks of aging, with the ultimate goal of gaining a deeper understanding of the potential for future interventions in the area of longevity-extension and counteracting of aging-related diseases. The reviewed literature supports the favorable effects of ginger and some of its constituents on all twelve hallmarks of aging, with a particularly high number of animal research studies indicating counteraction of nutrient-sensing dysregulations, mitochondrial dysfunction, chronic inflammation, and dysbiosis. On this background, validation in human clinical trials is still insufficient or is entirely missing, with the exception of some studies indicating positive effects on deregulated nutrient-sensing, chronic inflammation, and dysbiosis. Thus, the existing body of literature clearly supports the potential of ginger to be further studied in clinical trials as a supplement for the promotion of both lifespan and health span.

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While the biological hallmarks of aging are widely recognized as fundamental mechanisms of biological aging, more recently, there have been calls within geroscience to understand the aging process more comprehensively by adding a perspective of the social hallmarks of aging. Social and behavioral factors, such as socioeconomic status, life events or behavior and beliefs can alter the aging process per se and act in complex interactions with biological pathways. In addition, underlying biological pathways have been proposed for various psychosocial concepts, such as views on age and relationship quality. The aim of the present article is to provide narrative insights into theoretical and empirical developments between social and behavioral gerontology and geroscience or biogerontology. This article focuses on the potential of an interdisciplinary aging research but it also sets out the critical perspective that social gerontology provides.

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Psychological stress is a major contributing factor to several health problems (e.g., depression, cardiovascular disease). Around 35 % of the world's population suffers from it, including younger generations. Physiologically, stress manifests through neuroendocrine pathways (Hypothalamic-Pituitary-Adrenal (HPA) axis and Sympathetic-Adrenal-Medullary (SAM) system) which culminate in the production of stress mediators like cortisol, epinephrine and norepinephrine. Stress and its mediators have been associated to body aging, through molecular mechanisms such as telomere attrition, mitochondrial dysfunction, cellular senescence, chronic inflammation, and dysbiosis, among others. Regarding its impact in the skin, stress impacts its structural integrity and physiological function. Despite this review focusing on several hallmarks of aging, emphasis was placed on skin microbiota dysbiosis. In this line, several studies, comprising different age groups, demographic contexts and body sites, have reported skin microbiota alterations associated with aging, and some effects of stress mediators on skin microbiota have also been reviewed in this paper. From a different perspective, since it is not a "traditional" stress mediator, oxytocin, a cortisol antagonist, has been related to glucorticoids inhibition and to display positive effects on cellular aging. This hormone dysregulation has been associated to psychological issues such as depression, whereas its upregulation has been linked to positive social interaction.

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Social gradients in health and aging have been reported in studies across many human populations, and - as the papers included in this special collection highlight - also occur across species. This paper serves as a general introduction to the special collection of Neuroscience and Biobehavioral Reviews entitled "Social dimensions of health and aging: population studies, preclinical research, and comparative research using animal models". Authors of the fourteen reviews are primarily members of a National Institute of Aging-supported High Priority Research Network on "Animal Models for the Social Dimensions of Health and Aging". The collection is introduced by a foreword, commentaries, and opinion pieces by leading experts in related fields. The fourteen reviews are divided into four sections: Section 1: Biodemography and life course studies; Section 2: Social behavior and healthy aging in nonhuman primates; Section 3: Social factors, stress, and hallmarks of aging; Section 4: Neuroscience and social behavior.

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Aging probably is the most complexed process in biology. It is manifested by a variety of hallmarks. These hallmarks weave a network of aging; however, each hallmark is not uniformly strong for the network. It is the weakest link determining the strengthening of the network of aging, or the maximum lifespan of an organism. Therefore, only improvement of the weakest link has the chance to increase the maximum lifespan but not others. We hypothesize that mitochondrial dysfunction is the weakest link of the network of aging. It may origin from the innate intramitochondrial immunity related to the activities of pathogen DNA recognition receptors. These receptors recognize mtDNA as the PAMP or DAMP to initiate the immune or inflammatory reactions. Evidence has shown that several of these receptors including TLR9, cGAS and IFI16 can be translocated into mitochondria. The potentially intramitochondrial presented pathogen DNA recognition receptors have the capacity to attack the exposed second structures of the mtDNA during its transcriptional or especially the replicational processes, leading to the mtDNA mutation, deletion, heteroplasmy colonization, mitochondrial dysfunction, and alterations of other hallmarks, as well as aging. Pre-consumption of the intramitochondrial presented pathogen DNA recognition receptors by medical interventions including development of mitochondrial targeted small molecule which can neutralize these receptors may retard or even reverse the aging to significantly improve the maximum lifespan of the organisms.

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Aging is the result of several complex and multifactorial processes, where several agents contribute to an increased intrinsic vulnerability and susceptibility to age-related diseases. The hallmarks of aging are a set of biological mechanisms that are finely regulated and strictly interconnected, initiating or contributing to biological changes and anticipating several age-related diseases. The complex network of cellular and intercellular connections between the hallmarks might represent a possible target for the research of agents with pleiotropic effects. Vitamin D (VitD) is known to have a positive impact not only on muscle and bone health but also on several extra-skeletal districts, due to the widespread presence of Vitamin D Receptors (VDRs). VitD and VDR could be molecules potentially targeting the hallmarks of the aging network. To date, evidence about the potential effects of VitD on the hallmarks of aging is scarce in humans and mainly based on preclinical models. Although underpowered and heterogeneous, in-human studies seem to confirm the modulatory effect of VitD on some hallmarks of aging and diseases. However, more investigations are needed to clarify the pleiotropic effects of VitD and its impact on the hallmark of aging, hopefully highlighting the courses for translational applications and potential clinical conclusions.

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Aging is characterized by a progressive loss of cellular functions that increase the risk of developing chronic diseases, vascular dysfunction, and neurodegenerative conditions. The field of geroscience has identified cellular and molecular hallmarks of aging that may serve as targets for future interventions to reduce the risk of age-related disease and disability. These hallmarks include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Several studies show that exercise may favorably affect these processes and thereby have antiaging properties. The primary mechanisms through which exercise confers protective benefits in the brain are still incompletely understood. To better understand these effects and leverage them to help promote brain health, we present current findings supporting the notion that adaptive responses to exercise play a pivotal role in mitigating the hallmarks of aging and their effects on the aging cerebrovasculature, and ultimately contribute to the maintenance of brain function across the healthspan.

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Magnesium is an essential ion in the human body that regulates numerous physiological and pathological processes. Magnesium deficiency is very common in old age. Age-related chronic diseases and the aging process itself are frequently associated with low-grade chronic inflammation, called 'inflammaging'. Because chronic magnesium insufficiency has been linked to excessive generation of inflammatory markers and free radicals, inducing a chronic inflammatory state, we formerly hypothesized that magnesium inadequacy may be considered among the intermediaries helping us explain the link between inflammaging and aging-associated diseases. We show in this review evidence of the relationship of magnesium with all the hallmarks of aging (genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, disabled autophagy, dysbiosis, and chronic inflammation), which may positively affect the human healthspan. It is feasible to hypothesize that maintaining an optimal balance of magnesium during one's life course may turn out to be a safe and economical strategy contributing to the promotion of healthy aging. Future well-designed studies are necessary to further explore this hypothesis.

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Current research on human aging has largely been guided by the milestone paper "hallmarks of aging," which were first proposed in the seminal 2013 paper by Lopez-Otin et al. Most studies have focused on one aging hallmark at a time, asking whether the underlying molecular perturbations are sufficient to drive the aging process and its associated phenotypes. More recently, researchers have begun to investigate whether aging phenotypes are driven by concurrent perturbations in molecular pathways linked to not one but to multiple hallmarks of aging and whether they present different patterns in organs and systems over time. Indeed, preliminary results suggest that more complex interactions between aging hallmarks must be considered and addressed, if we are to develop interventions that successfully promote healthy aging and/or delay aging-associated dysfunction and diseases. Here, we summarize some of the latest work and views on the interplay between hallmarks of aging, with a specific focus on mitochondrial dysfunction. Indeed, this represents a significant example of the complex crosstalk between hallmarks of aging and of the effects that an intervention targeted to a specific hallmark may have on the others. A better knowledge of these interconnections, of their cause-effect relationships, of their spatial and temporal sequence, will be very beneficial for the whole aging research field and for the identification of effective interventions in promoting healthy old age.

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As aging and tumorigenesis are tightly interconnected biological processes, targeting their common underlying driving pathways may induce dual-purpose anti-aging and anti-cancer effects. Our transcriptomic analyses of 16,740 healthy samples demonstrated tissue-specific age-associated gene expression, with most tumor suppressor genes downregulated during aging. Furthermore, a large-scale pan-cancer analysis of 11 solid tumor types (11,303 cases and 4431 control samples) revealed that many cellular processes, such as protein localization, DNA replication, DNA repair, cell cycle, and RNA metabolism, were upregulated in cancer but downregulated in healthy aging tissues, whereas pathways regulating cellular senescence were upregulated in both aging and cancer. Common cancer targets were identified by the AI-driven target discovery platform-PandaOmics. Age-associated cancer targets were selected and further classified into four groups based on their reported roles in lifespan. Among the 51 identified age-associated cancer targets with anti-aging experimental evidence, 22 were proposed as dual-purpose targets for anti-aging and anti-cancer treatment with the same therapeutic direction. Among age-associated cancer targets without known lifespan-regulating activity, 23 genes were selected based on predicted dual-purpose properties. Knockdown of histone demethylase KDM1A, one of these unexplored candidates, significantly extended lifespan in Caenorhabditis elegans. Given KDM1A's anti-cancer activities reported in both preclinical and clinical studies, our findings propose KDM1A as a promising dual-purpose target. This is the first study utilizing an innovative AI-driven approach to identify dual-purpose target candidates for anti-aging and anti-cancer treatment, supporting the value of AI-assisted target identification for drug discovery.

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Old age is associated with a greater burden of disease, including neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease, as well as other chronic diseases. Coincidentally, popular lifestyle interventions, such as caloric restriction, intermittent fasting, and regular exercise, in addition to pharmacological interventions intended to protect against age-related diseases, induce transcription factor EB (TFEB) and autophagy. In this review, we summarize emerging discoveries that point to TFEB activity affecting the hallmarks of aging, including inhibiting DNA damage and epigenetic modifications, inducing autophagy and cell clearance to promote proteostasis, regulating mitochondrial quality control, linking nutrient-sensing to energy metabolism, regulating pro- and anti-inflammatory pathways, inhibiting senescence and promoting cell regenerative capacity. Furthermore, the therapeutic impact of TFEB activation on normal aging and tissue-specific disease development is assessed in the contexts of neurodegeneration and neuroplasticity, stem cell differentiation, immune responses, muscle energy adaptation, adipose tissue browning, hepatic functions, bone remodeling, and cancer. Safe and effective strategies of activating TFEB hold promise as a therapeutic strategy for multiple age-associated diseases and for extending lifespan.

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Aging is characterized by functional decline occurring alongside changes to several hallmarks of aging. One of the hallmarks includes attrition of repeated DNA sequences found at the ends of chromosomes called telomeres. While telomere attrition is linked to morbidity and mortality, whether and how it causally contributes to lifelong rates of functional decline is unclear. In this review, we propose the shelterin-telomere hypothesis of life history, in which telomere-binding shelterin proteins translate telomere attrition into a range of physiological outcomes, the extent of which may be modulated by currently understudied variation in shelterin protein levels. Shelterin proteins may expand the breadth and timing of consequences of telomere attrition, e.g., by translating early life adversity into acceleration of the aging process. We consider how the pleiotropic roles of shelterin proteins provide novel insights into natural variation in physiology, life history, and lifespan. We highlight key open questions that encourage the integrative, organismal study of shelterin proteins that enhances our understanding of the contribution of the telomere system to aging.

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Primary cilia are specialized organelles that sense changes in extracellular milieu, and their malfunction is responsible for several disorders (ciliopathies). Increasing evidence shows that primary cilia regulate tissue and cellular aging related features, which led us to review the evidence on their role in potentiating and/or accelerating the aging process. Primary cilia malfunction is associated with some age-related disorders, from cancer to neurodegenerative and metabolic disorders. However, there is limited understanding of molecular pathways underlying primary cilia dysfunction, resulting in scarce ciliary-targeted therapies available. Here, we discuss the findings on primary cilia dysfunction as modulators of the health and aging hallmarks, and the pertinence of ciliary pharmacological targeting to promote healthy aging or treat age-related diseases.

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Age-related declines in immune response pose a challenge in combating diseases later in life. Influenza (flu) infection remains a significant burden on older populations and often results in catastrophic disability in those who survive infection. Despite having vaccines designed specifically for older adults, the burden of flu remains high and overall flu vaccine efficacy remains inadequate in this population. Recent geroscience research has highlighted the utility in targeting biological aging to improve multiple age-related declines. Indeed, the response to vaccination is highly coordinated, and diminished responses in older adults are likely not due to a singular deficit, but rather a multitude of age-related declines. In this review we highlight deficits in the aged vaccine responses and potential geroscience guided approaches to overcome these deficits. More specifically, we propose that alternative vaccine platforms and interventions that target the hallmarks of aging, including inflammation, cellular senescence, microbiome disturbances, and mitochondrial dysfunction, may improve vaccine responses and overall immunological resilience in older adults. Elucidating novel interventions and approaches that enhance immunological protection from vaccination is crucial to minimize the disproportionate effect of flu and other infectious diseases on older adults.

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We aimed to investigate the effect of chronic D-galactose exposure on the mimicking of natural aging processes based upon the hallmarks of aging. Seven-week-old male Wistar rats (n = 12) were randomly assigned to receive either normal saline solution as a vehicle (n = 6) or 150 mg/kg/day of D-galactose subcutaneously for 28 weeks. Seventeen-month-old rats (n = 6) were also included as the chronologically aged controls. At the end of week 28 of the experiment (when the rats reach 35 weeks old and 24 months old), all rats were sacrificed for brain and heart collection. Our results showed that chronic D-galactose exposure mimicked natural aging characteristics of the brain and the heart in terms of deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, and functional impairment. All of which highlight the potential of D-galactose as a substance for inducing brain and cardiac aging in animal experiments.

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The hallmarks of aging constitute an interconnected network of basic mechanisms that modulate aging and can be modulated by lifestyle factors, including dietary strategies. This narrative review aimed to summarize the evidence on promoting dietary restriction or adherence to specific dietary patterns on hallmarks of aging. Studies with preclinical models or humans were considered. Dietary restriction (DR), usually operationalized as a reduction in caloric intake, is the main strategy applied to study the axis diet-hallmarks of aging. DR has been shown to modulate mainly genomic instability, loss of proteostasis, deregulating nutrient sensing, cellular senescence, and altered intercellular communication. Much less evidence exists on the role of dietary patterns, with most of the studies evaluating the Mediterranean Diet and other similar plant-based diets, and the ketogenic diet. Potential benefits are described in genomic instability, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, and altered intercellular communication. Given the predominant place of food in human life, it is imperative to determine the impact of nutritional strategies on the modulation of lifespan and healthspan, considering applicability, long-term adherence, and side effects.

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Protein translation is an essential cellular process playing key roles in growth and development. Protein translation declines over the course of age in multiple animal species, including nematodes, fruit flies, mice, rats, and even humans. In all these species, protein translation transiently peaks in early adulthood with a subsequent drop over the course of age. Conversely, lifelong reductions in protein translation have been found to extend lifespan and healthspan in multiple animal models. These findings raise the protein synthesis paradox: age-related declines in protein synthesis should be detrimental, but life-long reductions in protein translation paradoxically slow down aging and prolong lifespan. This article discusses the nature of this paradox and complies an extensive body of work demonstrating protein translation as a modulator of lifespan and healthspan.