Hallmark Of Aging Research Articles

Psychosocial and biological pathways to aging : The role(s) of the behavioral and social sciences in geroscience.

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 aperspective 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.

Can geroscience be translated into healthcare?

As an introduction to this special issue on geroscience, the present work focuses on the complexity of disentangling biomolecular mechanisms of aging from biopsychosocial causes of accelerated aging. Due to this complexity, the biomolecular aging hallmarks of frailty and multimorbidity as predominant aging phenotypes in geriatrics reflect single aspects of the aging process. Apossible approach to facilitate the integration of geroscience into healthcare might be to consider aging as the dynamic ratio between damage accumulation at the molecular and cellular level and resilience as strategies that prevent or repair such damage. There is alarge body of evidence to show that geroscience has the potential to change healthcare; however, reaching aconsensus and translating the best tool to measure aging needs more research on 1)the sensitivity of biomarkers to interventions and 2)the relationship between changes in biomarkers and changes in health trajectories.

Differential Aging Effects on Implicit and Explicit Sensorimotor Learning.

Deterioration in motor control is a hallmark of aging, significantly contributing to a decline in quality of life. More controversial is the question of whether and how aging impacts sensorimotor learning. We hypothesized that the inconsistent picture observed in the current literature can be attributed to at least two factors. First, aging studies tend to be underpowered. Second, the learning assays used in these experiments tend to reflect, to varying degrees, the operation of multiple learning processes, making it difficult to make inferences across studies. We took a two-pronged approach to address these issues. We first performed a meta-analysis of the sensorimotor adaptation literature focusing on outcome measures that provide estimates of explicit and implicit components of adaptation. We then conducted two well-powered experiments to re-examine the effect of aging on sensorimotor adaptation, using behavioral tasks designed to isolate explicit and implicit processes. Convergently, both approaches revealed a striking dissociation: Older individuals exhibited a marked impairment in their ability to discover an explicit strategy to counteract a visuomotor perturbation. However, they exhibited enhanced implicit recalibration. We hypothesize that the effect of aging on explicit learning reflects an age-related decline in reasoning and problem solving, and the effect of aging on implicit learning reflects age-related changes in multisensory integration. Taken together, these findings deepen our understanding of the impact of aging on sensorimotor learning.

O-078 Deletion of interlukin-17A protects against ovarian aging via activating wnt10b/β-catenin signaling

Abstract Study question Is there any compelling evidence to suggest that the deletion of IL17A could potentially ameliorate ovarian aging? Summary answer IL17A is elevated in the follicular fluid of aged women. Knocking out Il17a in mice improves ovarian aging phenotypes by activating Wnt10b/β-catenin signaling. What is known already Inflammation, a hallmark of aging, negatively impacts female fertility. Interleukin 17 (IL-17) cytokines, including IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F, are signature cytokines of T helper 17 cells. IL-17A, the first-discovered and well-explored among them, has been predominantly characterized as a kind of proinflammatory cytokine and a promoter in the pathogenesis of chronic autoimmune diseases such as psoriasis and ankylosing spondylitis. Significant accumulation of CD4-CD8-double-negative T cells in aged mouse ovaries, identified as a crucial source of IL-17, was reported via single-cell RNA sequencing. However, much remains unknown about the IL17 and ovarian aging relationship. Study design, size, duration Follicular fluid was collected from 51 women (age≥35 years) and 37 controls (age <35 years) at the Southern Medical University Southern Hospital's Reproductive Center to measure IL17A levels from March 2022 to August 2023. Additionally, we generated Il-17a knockout (Il17-a KO) mice (42 KO mice and 49 controls) to elucidate the role of Il-17a in ovarian aging in vivo. Further, RNA-seq was employed to explore the mechanism involved in the Il17a-associated ovarian aging. Participants/materials, setting, methods Clinical data were compared from two infertile patient cohorts. IL17A levels in follicular fluid were quantified using ELISA. Pearson correlation analysis explored the relationship between IL17A levels and age, ovarian reserve, and clinical outcomes. We also assessed aging-related phenotypes in Il17a-KO and WT mice at 3, 8, 12, and 15 months of age. Fertility assessment, ovarian reserve, histological analysis, mason staining, western blot analysis, qRT-PCR, IVF, spindle formation, and RNA-seq were used in this study. Main results and the role of chance Elevated IL17A levels in follicular fluid from aged patients were observed and may be used as a sensitive biomarker for advanced age (P < 0.001). Deletion of Il17a not only enhanced fertility and ovarian reserve in mice but also ameliorated inflammation, the senescent associated secretory phenotype (SASP), senescence and fibrosis. RNA-seq analysis identified 705 differentially expressed genes, primarily enriched in the Wnt10b signaling pathway. Validation experiments suggested that IL-17A deficiency may improve ovarian aging by upregulating wnt10b expression, promoting β-catenin nuclear translocation, and activating downstream molecules (c-Myc, Cyclin D1, c-jun). Limitations, reasons for caution This study found a correlation between IL17A and aging. However, how knocking out IL17A promotes the increase of Wnt10b and other potential functions of Il17a in ovarian aging remain to be further explored. Wider implications of the findings This study shows new insights into the mechanisms of IL17A in ovarian aging and provides potential biomarkers and therapeutic targets for the treatment of ovarian aging. In the future, a larger sample of studies are needed to investigate the relationship between IL17A and aged women. Trial registration number not applicable

An expedited screening platform for the discovery of anti-ageing compounds in vitro and in vivo

BackgroundRestraining or slowing ageing hallmarks at the cellular level have been proposed as a route to increased organismal lifespan and healthspan. Consequently, there is great interest in anti-ageing drug discovery. However, this currently requires laborious and lengthy longevity analysis. Here, we present a novel screening readout for the expedited discovery of compounds that restrain ageing of cell populations in vitro and enable extension of in vivo lifespan.MethodsUsing Illumina methylation arrays, we monitored DNA methylation changes accompanying long-term passaging of adult primary human cells in culture. This enabled us to develop, test, and validate the CellPopAge Clock, an epigenetic clock with underlying algorithm, unique among existing epigenetic clocks for its design to detect anti-ageing compounds in vitro. Additionally, we measured markers of senescence and performed longevity experiments in vivo in Drosophila, to further validate our approach to discover novel anti-ageing compounds. Finally, we bench mark our epigenetic clock with other available epigenetic clocks to consolidate its usefulness and specialisation for primary cells in culture.ResultsWe developed a novel epigenetic clock, the CellPopAge Clock, to accurately monitor the age of a population of adult human primary cells. We find that the CellPopAge Clock can detect decelerated passage-based ageing of human primary cells treated with rapamycin or trametinib, well-established longevity drugs. We then utilise the CellPopAge Clock as a screening tool for the identification of compounds which decelerate ageing of cell populations, uncovering novel anti-ageing drugs, torin2 and dactolisib (BEZ-235). We demonstrate that delayed epigenetic ageing in human primary cells treated with anti-ageing compounds is accompanied by a reduction in senescence and ageing biomarkers. Finally, we extend our screening platform in vivo by taking advantage of a specially formulated holidic medium for increased drug bioavailability in Drosophila. We show that the novel anti-ageing drugs, torin2 and dactolisib (BEZ-235), increase longevity in vivo.ConclusionsOur method expands the scope of CpG methylation profiling to accurately and rapidly detecting anti-ageing potential of drugs using human cells in vitro, and in vivo, providing a novel accelerated discovery platform to test sought after anti-ageing compounds and geroprotectors.

Linking Aging to Cancer: The Role of Chromatin Biology.

Epigenetic changes have been established to be a hallmark of aging, which implies that aging science requires collaborating with the field of chromatin biology. DNA methylation patterns, changes in relative abundance of histone post-translational modifications, and chromatin remodeling are the central players in modifying chromatin structure. Aging is commonly associated with an overall increase in chromatin instability, loss of homeostasis, and decondensation. However, numerous publications have highlighted that the link between aging and chromatin changes is not nearly as linear as previously expected. This complex interplay of these epigenetic elements during the lifetime of an organism likely contributes to cellular senescence, genomic instability, and disease susceptibility. Yet, the causal links between these phenomena still need to be fully unraveled. In this perspective article, we discuss potential future directions of aging chromatin biology.

Obesity and risk of diseases associated with hallmarks of cellular ageing: a multicohort study

Obesity and risk of diseases associated with hallmarks of cellular ageing: a multicohort study

Psychosocial Disadvantage During Childhood and Midlife Health

Low childhood socioeconomic status (SES) is a social hallmark of aging that contributes to adult health disparities and earlier morbidity and mortality. Childhood perceptions of stress are associated with child health outcomes and may contribute to premature biological aging into adulthood. To describe the association of childhood SES and perceived stress with midlife insulin resistance and epigenetic age and to explore whether late adolescent adiposity mediates the observed associations. The longitudinal cohort National Heart, Lung, and Blood Institute Growth and Health Study enrolled girls aged 10 years from January 1987 to May 1988, and followed them up to 19 years of age. Participants from Richmond, California, were recruited again at midlife in 2016 to assess insulin resistance and epigenetic age. Analyses were conducted from August 2, 2023, to March 18, 2024. A total of 433 participants were eligible and included in the analyses (specific sample sizes ranged across analyses from 303 to 391). Childhood levels of SES at 10 years of age (parental educational level and income) and perceived stress at 11 years of age. The hypotheses tested were formulated after data collection. Outcomes included the homeostatic model assessment of insulin resistance (HOMA-IR) and the GrimAge and DunedinPACE epigenetic clocks. Waist circumference in late adolescence was tested as a mediator. Among the 433 participants, the mean (SD) age was 39.4 (1.2) years; 218 (50.3%) were Black and 215 (49.7%) were White; and 135 (31.2%) had parents with a college degree or higher. Higher parental educational level was associated with lower HOMA-IR (B = -0.22 [95% CI, -0.41 to -0.02]; P = .03), lower midlife GrimAge (B = -1.76 [95% CI, -2.85 to -0.66] years; P = .002), and slower midlife DunedinPACE (B = -0.03 [95% CI, -6.29 to -0.002]; P = .04). Childhood perceived stress was indirectly associated through late adolescent adiposity with midlife HOMA-IR (B = 0.01 [95% CI, 0.001-0.01]; P = .02) and midlife GrimAge (B = 0.02 [95% CI, 0.003-0.04] years; P = .01). In this longitudinal cohort study of midlife health and aging, childhood social hallmarks of aging were associated with midlife insulin resistance and epigenetic age (GrimAge and DunedinPACE). Future studies should identify malleable factors that may slow the impact of social hallmarks of aging.

Stimuli-Specific Senescence of Primary Human Lung Fibroblasts Modulates Alveolar Stem Cell Function.

Aging is the main risk factor for chronic lung diseases (CLDs) including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Accordingly, hallmarks of aging like cellular senescence are increased in these patients in different lung cell types including fibroblasts. However, little is known about the different triggers that induce a senescence phenotype in different disease backgrounds and its role in CLD pathogenesis. Therefore, we characterized senescence in primary human lung fibroblasts (phLF) from control, IPF, or COPD patients at baseline and after exposure to disease-relevant insults (H2O2, bleomycin, TGF-β1) and studied their capacity to support progenitor cell potential in a lung organoid model. Bulk-RNA sequencing revealed that phLF from IPF and COPD activate different transcriptional programs but share a similar senescence phenotype at baseline. Moreover, H2O2 and bleomycin but not TGF-β1 induced senescence in phLF from different disease origins. Exposure to different triggers resulted in distinct senescence programs in phLF characterized by different SASP profiles. Finally, co-culture with bleomycin- and H2O2-treated phLF reduced the progenitor cell potential of alveolar epithelial progenitor cells. In conclusion, phLF from COPD and IPF share a conserved senescence response that varies depending on the insult and impairs alveolar epithelial progenitor capacity ex vivo.

Modulating in vitro lung fibroblast activation via senolysis of senescent human alveolar epithelial cells.

Idiopathic pulmonary fibrosis (IPF) is an age-related disease with poor prognosis and limited therapeutic options. Activation of lung fibroblasts and differentiation to myofibroblasts are the principal effectors of disease pathology, but damage and senescence of alveolar epithelial cells, specifically type II (ATII) cells, has recently been identified as a potential trigger event for the progressive disease cycle. Targeting ATII senescence and the senescence-associated secretory phenotype (SASP) is an attractive therapeutic strategy; however, translatable primary human cell models that enable mechanistic studies and drug development are lacking. Here, we describe a novel system of conditioned medium (CM) transfer from bleomycin-induced senescent primary alveolar epithelial cells (AEC) onto normal human lung fibroblasts (NHLF) that demonstrates an enhanced fibrotic transcriptional and secretory phenotype compared to non-senescent AEC CM treatment or direct bleomycin damage of the NHLFs. In this system, the bleomycin-treated AECs exhibit classical hallmarks of cellular senescence, including SASP and a gene expression profile that resembles aberrant epithelial cells of the IPF lung. Fibroblast activation by CM transfer is attenuated by pre-treatment of senescent AECs with the senolytic Navitoclax and AD80, but not with the standard of care agent Nintedanib or senomorphic JAK-targeting drugs (e.g., ABT-317, ruxolitinib). This model provides a relevant human system for profiling novel senescence-targeting therapeutics for IPF drug development.

Life-Course Pathways to Exceptional Longevity: Evidence From the Lothian Birth Cohort of 1921.

Longevity, a hallmark of successful aging, is a multifactorial trait with influences from birth onwards. However, limited evidence exists on the pathways linking diverse life-course exposures to longevity, especially within a single cohort. We investigated associations between life-course factors and longevity among community-dwelling adults aged 79 (N = 547) from the Lothian Birth Cohort 1921 with a mortality follow-up of 24 years. Cox proportional hazards and structural equation (path) models were used to explore how factors from early life (social class, childhood intelligence quotient [IQ], education), midlife (social class), and later life (health, lifestyle, psychosocial well-being), as well as sex, personality, and apolipoprotein E e4 status, influence survival time in days. During follow-up (1999-2023), 538 participants (98%) died (mean age of death = 89.3 years) and 9 survived (mean age = 101.6 years). Factors associated with lower mortality risk in the multivariable Cox model were higher cognitive function (hazard ratio [HR] = 0.72; 95% confidence interval [CI]: 0.59-0.88), better physical function (HR = 0.61; 95% CI: 0.44-0.85), and greater physical activity (HR = 0.81; 95% CI: 0.71-0.92), while history of cancer was associated with higher mortality risk (HR = 1.84; 95% CI: 1.22-2.77). The life-course path model identified the same direct predictors, with additional contributions from female sex and nonsmoking status, to greater longevity. Early- and midlife factors (IQ, education, social class), and emotional stability, conscientiousness, and female sex, were indirectly and positively associated with survival trajectories via multiple dimensions of adult health. In understanding why people live to very old ages it is necessary to consider factors from throughout the life course, and to include demographic, psychosocial, and health variables.

FRMD6 determines the cell fate towards senescence: involvement of the Hippo-YAP-CCN3 axis

Cellular senescence, a hallmark of aging, is pathogenically linked to the development of aging-related diseases. This study demonstrates that FRMD6, an upstream component of the Hippo/YAP signaling cascade, is a key regulator of senescence. Proteomic analysis revealed that FRMD6 is upregulated in senescent IMR90 fibroblasts under various senescence-inducing conditions. Silencing FRMD6 mitigated the senescence of IMR90 cells, suggesting its requirement in senescence. Conversely, the overexpression of FRMD6 alone induced senescence in cells and in lung tissue, establishing a causal link. The elevated FRMD6 levels correlated well with increased levels of the inhibitory phosphorylated YAP/TAZ. We identified cellular communication network factor 3 (CCN3), a key component of the senescence-associated secretory phenotype regulated by YAP, whose administration attenuated FRMD6-induced senescence in a dose-dependent manner. Mechanistically, FRMD6 interacted with and activated MST kinase, which led to YAP/TAZ inactivation. The expression of FRMD6 was regulated by the p53 and SMAD transcription factors in senescent cells. Accordingly, the expression of FRMD6 was upregulated by TGF-β treatment that activates those transcription factors. In TGF-β-treated IMR90 cells, FRMD6 mainly segregated with p21, a senescence marker, but rarely segregated with α-SMA, a myofibroblast marker, which suggests that FRMD6 has a role in directing cells towards senescence. Similarly, in TGF-β-enriched environments, such as fibroblastic foci (FF) from patients with idiopathic pulmonary fibrosis, FRMD6 co-localized with p16 in FF lining cells, while it was rarely detected in α-SMA-positive myofibroblasts that are abundant in FF. In sum, this study identifies FRMD6 as a novel regulator of senescence and elucidates the contribution of the FRMD6-Hippo/YAP-CCN3 axis to senescence.

Cardiac aging: from hallmarks to therapeutic opportunities.

Cardiac aging is an intricate and multifaceted process with considerable impact on public health, especially given the global demographic shift towards aged populations. This review discusses structural, cellular and functional changes associated with cardiac aging and heart failure with preserved ejection fraction (HFpEF). Key molecular mediators are considered within the framework of the established hallmarks of aging, with particular attention to promising therapeutic candidates. We further delineate the differential impacts of aging on cardiac structure and function in men and women, addressing hormonal and chromosomal influences. The protective and mitigating effects of exercise in cardiac aging and HFpEF in particular are discussed, as an inspiration for the identification of pathways that mitigate biological aging. We also emphasize how much remains to be learned and the importance of these efforts in enhancing the cardiac health of aging populations worldwide.

The impact of telomere length on the risk of idiopathic normal pressure hydrocephalus: a bidirectional Mendelian randomization study

Idiopathic normal pressure hydrocephalus (iNPH) affects mainly aged populations. The gradual shortening of telomere length (TL) is one of the hallmarks of aging. Whereas the genetic contribution of TL to the iNPH is incompletely understood. We aimed to investigate the causal relationship between TL and iNPH through the Mendelian randomization (MR) analysis. We respectively obtained 186 qualified single nucleotide polymorphisms (SNPs) of TL and 20 eligible SNPs of iNPH for MR analysis. The result of MR analysis showed that genetically predicted longer TL was significantly associated with a reduced odd of iNPH (odds ratio [OR] = 0.634 95% Confidence interval [CI] 0.447–0.899, p = 0.011). The causal association remained consistent in multivariable MR (OR = 0.530 95% CI 0.327–0.860, p = 0.010). However, there was no evidence that the iNPH was causally associated with the TL (OR = 1.000 95% CI 0.996–1.004, p = 0.955). Our study reveals a potential genetic contribution of TL to the etiology of iNPH, that is a genetically predicted increased TL might be associated with a reduced risk of iNPH.

Genome-wide CRISPR screen identifies neddylation as a regulator of neuronal aging and AD neurodegeneration

Aging is the biggest risk factor for the development of Alzheimer's disease (AD). Here, we performed a whole-genome CRISPR screen to identify regulators of neuronal age and show that the neddylation pathway regulates both cellular age and AD neurodegeneration in a human stem cell model. Specifically, we demonstrate that blocking neddylation increased cellular hallmarks of aging and led to an increase in Tau aggregation and phosphorylation in neurons carrying the APPswe/swe mutation. Aged APPswe/swe but not isogenic control neurons also showed a progressive decrease in viability. Selective neuronal loss upon neddylation inhibition was similarly observed in other isogenic AD and in Parkinson's disease (PD) models, including PSENM146V/M146V cortical and LRRK2G2019S/G2019S midbrain dopamine neurons, respectively. This study indicates that cellular aging can reveal late-onset disease phenotypes, identifies new potential targets to modulate AD progression, and describes a strategy to program age-associated phenotypes into stem cell models of disease.

TERT activation targets DNA methylation and multiple aging hallmarks

Insufficient telomerase activity, stemming from low telomerase reverse transcriptase (TERT) gene transcription, contributes to telomere dysfunction and aging pathologies. Besides its traditional function in telomere synthesis, TERT acts as a transcriptional co-regulator of genes pivotal in aging and age-associated diseases. Here, we report the identification of a TERT activator compound (TAC) that upregulates TERT transcription via the MEK/ERK/AP-1 cascade. In primary human cells and naturally aged mice, TAC-induced elevation of TERT levels promotes telomere synthesis, blunts tissue aging hallmarks with reduced cellular senescence and inflammatory cytokines, and silences p16INK4a expression via upregulation of DNMT3B-mediated promoter hypermethylation. In the brain, TAC alleviates neuroinflammation, increases neurotrophic factors, stimulates adult neurogenesis, and preserves cognitive function without evident toxicity, including cancer risk. Together, these findings underscore TERT's critical role in aging processes and provide preclinical proof of concept for physiological TERT activation as a strategy to mitigate multiple aging hallmarks and associated pathologies.

A new gene signature for endothelial senescence identifies self-RNA sensing by retinoic acid-inducible gene I as a molecular facilitator of vascular aging.

The number of senescent vascular endothelial cells increases during aging and their dysfunctional phenotype contributes to age-related cardiovascular disease. Identification of senescent cells is challenging as molecular changes are often tissue specific and occur amongst clusters of normal cells. Here, we established, benchmarked, and validated a new gene signature called EndoSEN that pinpoints senescent endothelial cells. The EndoSEN signature was enriched for interferon-stimulated genes (ISG) and correlated with the senescence-associated secretory phenotype (SASP). SASP establishment is classically attributed to DNA damage and cyclic GMP-AMP synthase activation, but our results revealed a pivotal role for RNA accumulation and sensing in senescent endothelial cells. Mechanistically, we showed that endothelial cell senescence hallmarks include self-RNA accumulation, RNA sensor RIG-I upregulation, and an ISG signature. Moreover, a virtual model of RIG-I knockout in endothelial cells underscored senescence as a key pathway regulated by this sensor. We tested and confirmed that RIG-I knockdown was sufficient to extend the lifespan and decrease the SASP in endothelial cells. Taken together, our evidence suggests that targeting RNA sensing is a potential strategy to delay vascular aging.

A global view of altered ligand-receptor interactions in bone marrow aging based on single-cell sequencing

Altered cell-cell communication is a hallmark of aging, but its impact on bone marrow aging remains poorly understood. Based on a common and effective pipeline and single-cell transcriptome sequencing, we detected 384,124 interactions including 2575 ligand-receptor pairs and 16 non-adherent bone marrow cell types in old and young mouse and identified a total of 5560 significantly different interactions, which were then verified by flow cytometry and quantitative real-time PCR. These differential ligand-receptor interactions exhibited enrichment for the senescence-associated secretory phenotypes. Further validation demonstrated supplementing specific extracellular ligands could modify the senescent signs of hematopoietic stem cells derived from old mouse. Our work provides an effective procedure to detect the ligand-receptor interactions based on single-cell sequencing, which contributes to understand mechanisms and provides a potential strategy for intervention of bone marrow aging.

Towards Healthy Longevity: Comprehensive Insights from Molecular Targets and Biomarkers to Biological Clocks.

Aging is a complex and time-dependent decline in physiological function that affects most organisms, leading to increased risk of age-related diseases. Investigating the molecular underpinnings of aging is crucial to identify geroprotectors, precisely quantify biological age, and propose healthy longevity approaches. This review explores pathways that are currently being investigated as intervention targets and aging biomarkers spanning molecular, cellular, and systemic dimensions. Interventions that target these hallmarks may ameliorate the aging process, with some progressing to clinical trials. Biomarkers of these hallmarks are used to estimate biological aging and risk of aging-associated disease. Utilizing aging biomarkers, biological aging clocks can be constructed that predict a state of abnormal aging, age-related diseases, and increased mortality. Biological age estimation can therefore provide the basis for a fine-grained risk stratification by predicting all-cause mortality well ahead of the onset of specific diseases, thus offering a window for intervention. Yet, despite technological advancements, challenges persist due to individual variability and the dynamic nature of these biomarkers. Addressing this requires longitudinal studies for robust biomarker identification. Overall, utilizing the hallmarks of aging to discover new drug targets and develop new biomarkers opens new frontiers in medicine. Prospects involve multi-omics integration, machine learning, and personalized approaches for targeted interventions, promising a healthier aging population.

Exploring the interplay between stress mediators and skin microbiota in shaping age-related hallmarks: A review

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.