Cellular senescence has been implicated in the pathophysiology of radiotherapy-associated bone loss. Based on our previous work, clearance of senescent cells using genetic and pharmacological tools alleviates the anomalies associated with radiation-associated bone deterioration. The pro-inflammatory senescence associated secretome referred to as senescence associated secretory phenotype (SASP), is a hallmark of cellular senescence. The modulation of SASP by senomorphic drugs, potentially can suppress the pro-inflammatory secretome of senescent cells, irrespective of the underlying senescence mechanism. In this study we tested a senomorphic drug, ruxolitinib, a Janus kinase inhibitor (JAKi), during acute and chronic radiotherapy related effects on the bone. Our clinical data indicate an early increase in several pro-inflammatory SASP proteins following radiotherapy of spinal metastasis in prostate cancer patients. Longitudinal assessment of SASP-related genes confirmed this acute elevation in several SASP markers in systemic circulation following irradiation of male mouse femurs. In studies done in male mice, following three preclinical radiotherapy regimens of 30Gy (5 x 6Gy), 60Gy (5 x 12Gy) and a single dose of 24Gy, suppression of SASP by JAKi was efficacious in suppressing radiation-induced bone damage. In comparison and as shown before, the senolytic combination of D+Q was also able to alleviate radiation-associated bone loss. Early and intermittent suppression of SASP using JAK inhibitors in male mice alleviated chronic bone deterioration, diminished telomere dysfunction, lowered senescence and SASP marker expression and reduced bone-marrow adiposity. Overall, our study shows that early targeting of SASP proteins could be a potential therapeutic to prevent radiotherapy-related chronic bone loss and risk of fractures.

Cellular senescence drives aging and age-related dysfunction across multiple tissues, including the brain. Through a high-content, senescent cell-based phenotypic screen of a small panel of natural products, we identified tomatidine, an aglycone of tomatine found in tomatoes, as a previously unrecognized senotherapeutic agent. In senescent human brain microvascular endothelial cells and fibroblasts, tomatidine selectively suppressed SASP expression without affecting p16Ink4a or p21Cip1 levels consistent with a senomorphic effect. In aged mice, tomatidine reduced frailty and improved motor coordination and cognitive performance. These functional benefits were accompanied by reduced senescence markers (p16 Ink4a, p21 Cip1, and telomere-associated DNA damage foci) in liver, skin, and hippocampal neurons, along with decreased neuroinflammation and microglial activation. Tomatidine also diminished brain endothelial cell senescence while enhancing tight junction protein expression, suggesting preserved blood-brain barrier integrity. Together, these findings identify tomatidine as a promising senescence-targeting compound with beneficial effects in aged mice and support its further evaluation in mechanistic and translational studies.

Inflammaging, the aberrant chronic inflammatory state at advanced age, is an immunological phenomenon associated with detrimental long-term health consequences, morbidity, and mortality. Although the precise etiology of inflammaging is elusive, emerging evidence indicates that molecular and cellular changes in immune cells drive inflammaging directly through heightened cytokine production and indirectly via inflammatory cell death and ineffective neutralization of inflammatory cellular waste. Additionally, nonimmune tissue cells, particularly senescent cells, amplify the heightened inflammatory environment with age via their secretome and by modulating the immune system. The systemic concentrations of inflammatory mediators during aging is in the same range as those seen in mild, acute viral infections. Intriguingly, centenarians, who exhibit exceptional health span and longevity do not evade inflammaging but appear to neutralize its downstream effects through negative molecular or cellular feedback mechanisms. Collectively, this review positions inflammaging as a dynamic and multifactorial process arising from coordinated immune and nonimmune dysfunction while outlining opportunities to counter age-related inflammation.

IMPORTANCE AND OBJECTIVE:Aging is a complex biological process uniquely shaped in women by hormonal transitions, particularly across the menopause transition. While chronological age alone fails to capture individual health variability, emerging molecular biomarkers offer tools to quantify biological aging and understand mechanisms underlying age-related decline. This review synthesizes the current landscape of aging biomarkers, including senescence-associated secretory phenotype factors, epigenetic clocks, clonal hematopoiesis of indeterminate potential, and telomere length, with a particular emphasis on their relevance to menopause. METHODS:This narrative review synthesizes human studies, translational research, and foundational basic science identified through PubMed searches through June 2025, examining aging biomarkers in general populations, among women in the menopause transition, and in relation to vasomotor symptoms and hormone therapy. DISCUSSION AND CONCLUSION:Evidence demonstrates that changes in biological aging biomarkers are observed across multiple molecular systems during midlife, including the menopause transition, reflecting broader age-related biological remodeling. Postmenopausal status, particularly following early or surgical menopause, has been associated with biological aging phenotypes, including elevated senescence-associated secretory phenotype factors, epigenetic age acceleration, clonal hematopoiesis, and shorter leukocyte telomere length, likely reflecting a combination of chronological aging, hormonal changes, and individual biological vulnerability. While severe vasomotor symptoms have been linked to higher epigenetic age, hormone therapy may favorably influence certain senescence markers and biological age discrepancy. Despite these advances, significant limitations constrain clinical translation, as current biomarkers capture overlapping biological processes and lack validated thresholds to define biological aging, especially in women. Future research requires large, longitudinal studies across diverse populations to establish clinically meaningful thresholds and sex-specific calibration. Advancing precision health strategies for women requires a better understanding of how reproductive and hormonal factors modify biomarker trajectories to improve risk prediction and to facilitate the development of targeted interventions for age-related diseases.

The 12th Aging Research and Drug Discovery (ARDD) meeting convened at the University of Copenhagen, presenting a comprehensive overview of recent advancements in the biology of aging. A central theme across sessions was the field's gradual shift from descriptive, correlational studies to mechanistic understandings enabling the engineering of personalized therapeutic interventions aimed at extending human healthspan. Key discussions highlighted the convergence of multiple disciplines. Presentations detailed how fundamental biological insights are being integrated with artificial intelligence and machine learning platforms for accelerated target identification and drug development. Furthermore, the development and application of novel preclinical research models were presented as critical for improving the translational pipeline to human clinical trials. Scientific discourse has advanced from cataloging the established hallmarks of aging to identifying and modulating the specific molecular mechanisms that regulate them. This focus is predicated on the hypothesis that aging is not solely a result of stochastic damage accumulation but may be a tractable, modifiable, and potentially reversible biological process amenable to intervention. This report summarizes the principal research directions and conceptual frameworks presented at the conference.

Geroscience research benefits from interdisciplinary approaches, team science, and collaborations, which collectively facilitate the discovery of aging mechanisms and their translation into tangible, clinical interventions. Since its inception in 2019, the Midwest Aging Consortium (MAC) has provided an engaging platform for aging researchers in the United States' Midwest to connect, collaborate, and exchange ideas. The Sixth Annual Research Symposium of the MAC held at the Mayo Clinic in Rochester, Minnesota, in April 2025 highlighted the continued impact of the MAC in bringing together aging researchers, including many trainees and early career investigators, into a collaborative environment. This record-setting event featured interdisciplinary research on key aging mechanisms, including lipid metabolism, mitochondrial dysfunction, stress response, cellular senescence, and immune adaptations across organ systems. New therapeutic concepts and clinical trial approaches were presented. Cutting-edge methodologies including single-cell and spatial transcriptomics, metabolomics, and organoid cultures, to dissect aging process in tissue-specific and systemic contexts also were presented. Overall, the MAC symposium underscored the translational potential of geroscience and reinforced the MAC's mission to accelerate aging research through regional collaborations and innovation.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease with undefined etiology and minimally effective therapies. The greatest risk factor for developing IPF is aging. The central paradigm to developing antifibrotic drugs for the last half century has focused on directly targeting proliferative lung fibroblasts. However, recent high-resolution analyses of IPF patient lungs suggests disease unique populations of resident lung cells are enriched for markers of senescence. Published work by our group and others further supports that senescent cells are key drivers of fibrosis and may provide an opportunity to develop an effective antifibrotic drug. Multiple naturally derived flavonoids can selectively induce apoptosis in senescent cells (senolytic) and improve end points in models of lung fibrosis; however, these natural phytochemicals are not structurally optimized to maximize their translational potential. Inspired by this opportunity we have performed hit-to-lead studies and medicinal chemistry optimization to generate a novel synthetic flavanoid (F-4N) with ∼ 50× greater senolytic potency in vitro- compared to fisetin or quercetin, two naturally derived senolytic flavonols. Furthermore, in bleomycin injury models of lung fibrosis we have shown treatment with F-4N (10 mg/kg-30 mg/kg, daily) promotes reduced senescence burden, resolution of chronic lung fibrosis, and markers of enhanced alveolar epithelial repair.

Cellular senescence is an irreversible form of cell-cycle arrest caused by excessive stress or damage. While various biomarkers of cellular senescence have been proposed, there are currently no universal, stand-alone indicators of this condition. The field largely relies on the combined detection of multiple biomarkers to differentiate senescent cells from non-senescent cells. Here we introduce a new approach: unbiased cell culture selections to identify senescent cell-specific folded DNA aptamers from vast libraries of trillions of random 80-mer DNAs. Senescent mouse adult fibroblasts and their non-senescent counterparts were employed for selection. We demonstrate aptamer specificity for senescent mouse cells in culture, identify a form of fibronectin as the molecular target of two selected aptamers, show increased aptamer staining in naturally aged mouse tissues, and demonstrate decreased aptamer staining when p16 expressing cells are removed in a transgenic INK-ATTAC mouse model. This work demonstrates the value of unbiased cell-based selections to identify new senescence-specific DNA reagents.

Background/objectives: Falls are a leading cause of traumatic injury and hospitalization for adults over the age of 65. While common, bed-related falls are relatively understudied when compared to ambulatory falls. The aim of this study is to characterize the risk factors for the hospitalization of older adults presenting to U.S. emergency departments (EDs) after a fall from bed. Methods: This was a cross-sectional study using publicly available data from the U.S. Consumer Product Safety Commission’s National Electronic Injury Surveillance System (NEISS) from 2014 to 2023, including all adults over the age of 65 presenting to the NEISS’s participating EDs with bed-related fall injuries. We identified fall injuries using a keyword search of the NEISS narratives and determined how the fall occurred by manually reviewing a randomized 3% sample of the narratives. We summarized demographics and injury patterns with descriptive statistics. We constructed a multivariable logistic regression model to identify risk factors for hospitalization and used Poisson regression to assess temporal trends in fall incidence and hospital admissions. Results: An estimated average of 320,751 bed-related fall injuries presented to EDs annually from 2014 to 2023. ED visits increased by 2.85% per year, while hospital admissions rose by 5.67% per year (p < 0.001). The most common injury patterns were superficial injuries (contusions, abrasions, lacerations, avulsions, and punctures) (28.6%), fractures (21.7%), and internal injuries (including concussions) (21.6%). Most of the falls occurred while transitioning into or out of bed (34.4%) or falling out of bed (56.8%). Hospitalization was required in 34.1% of cases and was associated with male sex, medication use at time of injury, and fracture injuries. Conclusions: Bed-related falls and associated hospitalizations are increasing among older adults. ED providers should understand risk factors for hospitalization in these common injuries such as male sex, medication use at time of injury, and high-risk injury patterns. Additionally, prevention efforts should focus on helping older adults remain safely in bed and then assisting with transitions into or out of bed.

Obesity accelerates the onset and progression of age-related conditions. In preclinical models, obesity drives cellular senescence, a cell fate that compromises tissue health and function, in part through a robust and diverse secretome. In humans, components of the secretome have been used as senescence biomarkers that are predictive of age-related disease, disability, and mortality. Here, using biospecimens and clinical data from two large and independent cohorts of older adults, we tested the hypothesis that the circulating concentrations of senescence biomarkers are influenced by body mass index. After adjusting for age, sex, and race, we observed significant increases in activin A, Fas, MDC, PAI1, PARC, TNFR1, and VEGFA, and a significant decrease in RAGE, from normal weight, to overweight, to obesity body mass index categories by linear regression in both cohorts (all p < .05). These results highlight the influence of body mass index on circulating concentrations of senescence biomarkers.

As Earth's magnetic field weakens, space radiation begins to pose a significant threat to the health of not only space travelers, but the world's population. Space radiation, comprising high-energy and high-charge ions, creates distinct clusters of DNA damage and dense macromolecular damage that result in the accumulation of senescent cells (SnCs) known to play a critical role in promoting multimorbidity. Here, we demonstrate that human fibroblasts exposed to different forms of space radiation acquire senescence-associated phenotypes including morphological alterations and the accumulation of SA-ß-gal+ cells to a greater extent than what is observed following γ-irradiation. Bulk and single cell RNA (scRNAseq) sequencing analysis revealed that space irradiated human fibroblasts up-regulated senescent-like phenotypes to a greater extent compared to γ-irradiation and enriched pathways associated with chronic activation and adaptation of the integrated stress response and NADPH-coupled redox metabolism. Healthy cells treated with conditioned media from irradiated SnCs manifested pro-inflammatory transcriptional profiles dependent on both radiation and cell type. Finally, treatment with known senotherapeutics demonstrated radiation-specific effects in primary dermal fibroblasts. Our data demonstrate that space radiation differentially induces senescent phenotypes in human cells compared to γ-irradiation, which may play a key role in the pathogenic effects of space travel.

OBJECTIVE:Aging alters mesenchymal stromal cell (MSC) function, leading to dysregulated adipogenesis across tissues through biased lineage commitment. Fat redistribution from adipose depots to skeletal muscle and bone marrow is common in aging, but the underlying mechanisms remain unclear. This study investigates how MSC senescence modulates adipogenesis. METHODS:Primary MSCs were isolated from mouse skeletal muscle (FAPs), adipose tissue (APCs), and bone marrow (BMSCs). Single-cell RNA sequencing was performed to compare transcriptional profiles among these populations. In vitro adipogenic differentiation and DNA damage-induced senescence assays were conducted, and the effects of autologous conditioned media from senescent MSCs on adipogenesis were assessed. RESULTS:Transcriptional analyses revealed that FAPs and APCs share greater similarity with each other than with BMSCs. All MSC types exhibited adipogenic potential and developed a robust senescence-associated secretory phenotype (SASP) upon senescence induction. Conditioned media from senescent MSCs enhanced adipogenesis in BMSCs but inhibited adipogenesis in FAPs and APCs, revealing tissue-specific paracrine effects. CONCLUSIONS:MSC senescence reprograms adipogenic bias in a tissue-dependent, non-cell autonomous manner, contributing to age-related fat redistribution among adipose tissue, skeletal muscle, and bone marrow. Understanding these mechanisms may provide new therapeutic approaches for improving tissue composition and function in the context of aging.

OBJECTIVES:To study whether a history of premenopausal bilateral oophorectomy (PBO) may influence circulating concentrations of cellular senescence biomarkers and their associations with measures of physical and cognitive function later in life. STUDY DESIGN:The plasma concentrations of 29 candidate senescence biomarkers and parameters of physical and cognitive function were measured in 510 older women, comprising 273 with a history of PBO and 237 referents. MAIN OUTCOME MEASURES:Plasma concentrations of senescence biomarkers and their associations with measures of physical and cognitive function. RESULTS:In participants with a history of PBO compared to referents, only the plasma levels of tumor necrosis factor alpha (TNFα) and tumor necrosis factor receptor 2 (TNFR2) were statistically significantly higher than they were in the referent group, whereas matrix metalloproteinase 2 (MMP2) was lower. Overall, measures of physical and cognitive function did not differ between those with and without PBO. In an exploratory analysis, several senescence-related biomarkers were associated with chronological age, body mass index, and measures of physical function, including 6-minute walk distance and muscle strength and power. Only few biomarkers were associated with measures of cognitive function. Using machine learning, subsets of biomarkers in combination with demographic and clinical covariates exhibited higher value than the covariates alone in predicting most of the physical and cognitive function outcomes in cross-sectional analyses. CONCLUSIONS:The circulating concentrations of several candidate senescence biomarkers were associated with physical and cognitive function in a cohort of older women, but only a few biomarkers differed between participants with a history of PBO and referents. Additional research is needed to better understand the influence of PBO on the biology of aging.

OBJECTIVES:Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN:The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a "successful aging" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING:Recruitment occurred at eight centers in the United States. PARTICIPANTS:We included 1,373 participants enrolled in the study with baseline measures of 27 biomarkers of cellular senescence and adjudication of mild cognitive impairment (MCI) and dementia at baseline and 24-month follow-up. At baseline, participants were aged 70-80, sedentary, and at high risk of mobility disability. MEASUREMENTS:A neuropsychological assessment was administered at baseline and 24 months post-randomization. At both timepoints, a clinical adjudication committee determined whether individuals had a diagnosis of cognitively normal, MCI, or dementia; individuals with dementia at baseline were excluded. The concentrations of 26 of the 27 plasma proteins identified as components of the SASP were measured with commercially available Luminex xMAP multiplex magnetic bead-based immunoassays analyzed on the MAGPIX System while 1 protein (Activin A) was measured using an enzyme-linked immunosorbent assay. RESULTS:Logistic regression models were used to examine the associations of each senescence biomarker, in quartiles, with baseline or incident MCI. Models stratified by clinical site and adjusted for intervention assignment, age, gender, race, and education. Among 1,373 participants, 117 (8.5%) were diagnosed with MCI at baseline. Increasing quartiles of myeloperoxidase (MPO) was associated with higher odds of MCI compared to quartile 1 (Q2: OR = 1.34, 95% CI: 0.74-2.45; Q3: OR = 1.43, 95% CI: 0.80-2.59; Q4: OR = 1.79, 95% CI: 1.02-3.22). Additionally, matrix metalloproteinase 1 (MMP1) quartiles 2-4 had lower odds of MCI compared to quartile 1 (Q2: OR = 0.61, 95% CI: 0.35-1.02; Q3: OR = 0.58, 95% CI: 0.33-0.98; Q4: OR = 0.64, 95% CI: 0.37-1.08). Of the 1,256 cognitively unimpaired participants at baseline, 141 (11.2%) were diagnosed with incident MCI or dementia at the 24-month follow-up. Compared to quartile 1, increasing baseline quartiles of MPO (Q2: OR = 1.10, 95% CI: 0.63-1.92; Q3: OR = 1.36, 95% CI: 0.80-2.33; Q4: OR = 1.92, 95% CI: 1.16-3.25) and matrix metalloproteinase 7 (MMP7, Q2: OR = 0.88, 95% CI: 0.47-1.62; Q3: OR = 1.46, 95% CI: 0.85-2.55; Q4: OR = 2.14, 95% CI: 1.28-3.65) were associated with increased odds of MCI or dementia at 24 months. CONCLUSIONS:Among older adults at high risk of mobility disability, high plasma MPO was cross-sectionally and, along with MMP7, longitudinally associated with increased odds of MCI and dementia. In contrast, high MMP1 was cross-sectionally associated with reduced odds of MCI.

Rats share a significant amount of genetic and physiological similarity with humans. Many biological processes and pathways are conserved between rats and humans, making rats a suitable model for studying various aspects of human health and disease. Using rats as an aging model offers a more ethical alternative to using larger, longer-lived animals like primates. Rats are easier to handle in laboratory settings, as compared to non-human primates, both of which have physiological functions like humans. To date, there are very few studies which have comprehensively studied age-related changes in rat physiology. Here we present a longitudinal assessment of several aspects of Brown-Norway rat physiology and histopathology using molecular and functional assessments at 6-, 17- and 27 months of age. Our studies thus provide age-related healthspan parameters, which can be used as reference for genetic or pharmacological rat models of aging.

There is an increasing need for biomarkers of senescent cell burden to facilitate the selection of participants for clinical trials. p16Ink4a is encoded by the CDKN2A locus, which produces five variant transcripts in humans, two of which encode homologous p16 proteins: p16Inka4a, encoded by p16_variant 1, and p16ɣ, encoded by p16_variant 5. While distinct quantitative polymerase chain reaction primers can be designed for p16_variant 5, primers for p16_variant 1 also measure p16_variant 5 (p16_variant 1 + 5). In a recent clinical trial evaluating the effects of the senolytic combination, dasatinib + quercetin (D + Q), on bone metabolism in postmenopausal women, we found that women in the highest tertile for T-cell expression of p16_variant 5 had the most robust skeletal responses to D + Q. Importantly, the assessment of p16_variant 5 was more predictive of these responses than p16_variant 1 + 5. Here, we demonstrate that in vitro, p16_variant 1 + 5 increased rapidly (Week 1) following the induction of DNA damage, whereas p16_variant 5 increased later (Week 4), suggesting that p16_variant 5 becomes detectable only when the abundance of senescent cells reaches some threshold. Further analysis identified a SASP panel in plasma that performed as well in identifying postmenopausal women with a positive skeletal response to D + Q. Collectively, our findings provide further support for the T-cell p16_variant 5 assay as a biomarker for selecting participants in clinical trials of senolytic interventions. In addition, our data indicate that correlated plasma SASP markers could be used in lieu of the more technically challenging T-cell p16 assay. Trial Registration: ClinicalTrials.gov identifier: NCT04313634.

The aging process is universal, and it is characterized by a progressive deterioration and decrease in physiological function leading to decline on the organismal level. Nevertheless, a number of genetic and non-genetic interventions have been described, which successfully extend healthspan and lifespan in different species. Furthermore, a number of clinical trials have been evaluating the feasibility of different interventions to promote human health. The goal of the annual Biological Sciences Section of the Gerontological Society of America meeting was to share current knowledge of different topics in aging research and provide a vision of the future of aging research. The meeting gathered international experts in diverse areas of aging research including basic biology, demography, and clinical and translational studies. Specific topics included metabolism, inflammaging, epigenetic clocks, frailty, senescence, neuroscience, stem cells, reproductive aging, inter-organelle crosstalk, comparative transcriptomics of longevity, circadian clock, metabolomics, and biodemography.

Cellular senescence is an aging mechanism characterized by cell cycle arrest and a senescence-associated secretory phenotype (SASP). Preclinical studies demonstrate that senolytic drugs, which target survival pathways in senescent cells, can counteract age-associated conditions that span several organs. The comparative efficacy of distinct senolytic drugs for modifying aging and senescence biomarkers in vivo has not been demonstrated. Here, we established aging- and senescence-related plasma proteins and tissue transcripts that changed in old versus young female and male mice. We investigated responsivity to acute treatment with venetoclax, navitoclax, fisetin or luteolin versus transgenic senescent cell clearance in aged p16-InkAttac mice. We discovered that age-dependent changes in plasma proteins, including IL-23R, CCL5 and CA13, were reversed by senotherapeutics, which corresponded to expression differences in tissues, particularly in the kidney. In plasma from humans across the lifespan, IL-23R increased with age. Our results reveal circulating factors as candidate mediators of senescence-associated interorgan signal transduction and translationally impactful biomarkers of systemic senescent cell burden.

Senescent cells drive age-related tissue dysfunction via the induction of a chronic senescence-associated secretory phenotype (SASP). The cyclin-dependent kinase inhibitors p21Cip1 and p16Ink4a have long served as markers of cellular senescence. However, their individual roles remain incompletely elucidated, particularly in vivo. Thus, we conducted a comprehensive examination of multiple single-cell RNA sequencing datasets spanning both murine and human tissues during aging. Our analysis revealed that p21Cip1 and p16Ink4a transcripts demonstrate significant heterogeneity across distinct cell types and tissues, frequently exhibiting a lack of co-expression. Moreover, we identified tissue-specific variations in SASP profiles linked to p21Cip1 or p16Ink4a expression. Using RNA velocity and pseudotime analyses, we discovered that p21+ and p16+ cells follow independent trajectory dynamics, with no evidence of direct transitions between these two states. Despite this heterogeneity, we identified a limited set of shared "core" SASP factors that may drive common senescence-related functions. Our study underscores the substantial diversity of cellular senescence and the SASP, emphasizing that these phenomena are inherently cell- and tissue-dependent.

Skin aging is an inherent biological component of human aging. As the global population ages, the incidence of age-related skin conditions has become increasingly prevalent. Both intrinsic and extrinsic factors, collectively known as the skin “exposome,” contribute to visible and physiological changes. The skin’s layers, including the epidermis, dermis, and hypodermis, function both independently and interdependently in these aging processes. Intrinsic factors such as hormonal fluctuations, genetic predispositions, and cellular senescence, defined as an irreversible cell cycle arrest, drive physiological age-related skin changes. These changes are underpinned by several interconnected hallmarks of aging, including genomic instability, telomere attrition, epigenetic alterations, and loss of proteostasis, all of which impair cell renewal and dermal structure. Stem cell exhaustion and mitochondrial dysfunction reduce the skin’s capacity to regenerate and adapt to stress, whereas altered intercellular communication and chronic low-grade inflammation ("inflammaging") further accelerate aging phenotypes such as loss of elasticity, epidermal thinning, and delayed wound healing. Extrinsic factors, including ultraviolet radiation, air pollution, smoking, and poor nutrition, compound these effects by increasing oxidative stress, DNA damage, and activating senescence-associated secretory phenotypes. Lifelong sun protection, nutritious dietary habits, regular physical activity, and topical interventions such as sunscreen and moisturizers help maintain a resilient skin microenvironment. This review highlights the urgent need to recognize, prevent, and treat skin aging. Emerging therapies targeting root-cause mechanisms may revolutionize dermatologic care and extend skin healthspan — now known as skinspan.