Is there a limit to human lifespan? We examine upper-tail lifespan dynamics in 46 countries using reliable period life-table data. The characteristic life ( α ), the model-based upper-tail parameter ( ω ), and their interval ( δ = ω - α ) are estimated annually from the 1990s onward. Across countries, α increases steadily, whereas ω declines or stabilizes and δ narrows, a pattern consistent with postponed and increasingly concentrated late-life mortality rather than unlimited upper-tail expansion. Under the baseline L = 120 projection model, both females and males approach ω ≈ 120 years and α ≈ 103.5 years by 2100. Sensitivity analyses show that the inferred asymptotic boundary is model-dependent, so the projected value near 120 years should be interpreted as a mathematical upper-tail estimate rather than a definitive biological maximum. These findings are consistent with, but do not establish, an increasingly bounded upper-tail survival regime within the present demographic and modeling framework.
Prolonged crises expose older adults to chronic psychological and social stress, irregular nutrition, reduced physical activity, reduced access to health care, and interruptions in treatment of chronic disease. Together, these factors can compound age-related vulnerabilities and increase the risk of metabolic deterioration, multimorbidity and functional decline. This Perspective argues that prolonged crises should be viewed not only as social or psychological events, but also as conditions that may affect stress-related and ageing-related biological pathways. Severe or prolonged stress, however, can make these responses maladaptive and contribute to physiological dysregulation. Under prolonged crisis conditions, such maladaptive stress responses may be linked to abdominal obesity, sarcopenic obesity, physical frailty, and functional decline through chronic activation of the hypothalamic–pituitary–adrenal axis, altered glucocorticoid signalling, sleep disturbance, inflammation, cellular senescence and senescence-associated secretory phenotype, immunometabolic dysregulation, adipose tissue inflammation, insulin resistance, mitochondrial dysfunction and anabolic resistance in skeletal muscle. Ukraine is a timely example of this broader problem, as prolonged war, population ageing, non-communicable diseases, displacement, mental health needs, and new screening initiatives now intersect. Thus, a biologically informed framework for healthy ageing needs to incorporate mental health assessment, metabolic screening, nutritional assessment, muscle function and rehabilitation rather than address these in isolation. Functional ability reflects the combined effects of psychological stress, metabolic ageing, muscle loss, multimorbidity, and changes in the living environment. It should be considered a key indicator for older adults during and after prolonged crises.
Actin is a highly conserved cytoskeletal protein that regulates numerous cellular processes essential for tissue homeostasis and healthy aging. Although genetic studies have established important roles for actin and actin-binding proteins in longevity, pharmacological approaches offer complementary advantages for manipulating conserved cytoskeletal pathways across model systems. Here, we systematically evaluated the effects of small-molecule modulators targeting distinct actin regulatory pathways on lifespan, locomotor function, and tissue-specific actin organization in Caenorhabditis elegans. Animals were treated with compounds targeting the Arp2/3 complex (CK666), tropomyosin-dependent actin regulation (TR100), formins (SMIFH2), cofilin regulation (SZ-3), or actin stabilization (phalloidin). Among the compounds tested, only CK666 consistently produced a dose-dependent reduction in lifespan and exacerbated age-associated muscle actin disorganization, identifying Arp2/3-mediated actin branching as a critical regulator of cytoskeletal integrity during aging. CK666 also transiently disrupted hypodermal actin organization early in adulthood. In contrast, SMIFH2, TR100, phalloidin, and SZ-3 produced little or no detectable disruption of muscle actin organization, despite previous genetic studies demonstrating roles for several of these pathways in aging. Comparison with prior RNAi studies suggests that pharmacological perturbation can reproduce some aspects of actin dysfunction but may be limited by compound stability, drug delivery, or inefficient targeting of proteins in C. elegans. Together, these findings establish a framework for evaluating pharmacological modulation of actin during aging, identify CK666-mediated Arp2/3 inhibition as the most robust pharmacological perturbation under the conditions tested, and highlight important considerations for translating genetic discoveries into pharmacological strategies to target cytoskeletal function during aging.
Aged skeletal muscle is impaired at every phase of post-injury repair that has been examined, with myeloid recruitment delayed and skewed in composition, debris degradation lagging behind uptake, and muscle stem cell (MuSC) activation following a conserved trajectory at delayed kinetics. Deficits inside a phase may be differences of degree that a longer window absorbs, whereas the transition between phases offers no comparable slack. Each transition is triggered by a defined switch in signal, either the fall in damage input after debris degradation, the TNF/TGF-β balance that permits fibro-adipogenic progenitor (FAP) apoptosis, or the Ly6Chigh→Ly6Clow monocyte conversion. Because positive feedback operates beyond each switch, a compartment arriving late meets a microenvironment already committed to a self-maintaining alternative state that its later output appears unable to reverse. Retained mitochondrial lesions in postmitotic myofibers are one proposed input holding the first switch open. MuSCs face pool contraction, skewed fate allocation, and cell-autonomous defects uncorrected by a young host. FAPs resist clearance past their support phase while a stiffening matrix keeps them fibrogenic, and aged myeloid cells reach the pro-repair switch late and with attenuated output. None of these lesions need be primary for the sequence to fail. Interventions should instead be judged on whether inflammation declines, matrix remodeling closes, myogenic output yields mature fibers, and reserve survives repeated injury. Aging may therefore be read as a loss of temporal coordination, in which sub-threshold delays accumulate between compartments that must act in sequence, until a failed transition settles the tissue into an inflammatory-fibrotic endpoint.
Cellular senescence, a hallmark of aging, entails the irreversible cessation of cell division in response to intrinsic and extrinsic stressors. Though metabolically active, senescent cells lose their replicative capacity and resist apoptotic signals, accumulating tissues with advancing age and contributing to age-related pathologies. Senescence is characterized by the acquisition of a senescence-associated secretory phenotype (SASP), releasing a myriad of bioactive molecules. SASP not only influences intracellular processes but also orchestrates the modification of neighboring cells and the surrounding microenvironment. In the context of aging, the proportion of senescent cells escalates, ranging from 1 to 15
Berberine has been widely used in traditional and folk medicine for many years. The molecular mechanisms of berberine's action are pleiotropic and have been fairly well studied. Its applications are generally limited to cardiometabolic diseases and cancer therapy, and a focused critical evaluation of berberine and its derivatives in the specific context of immunosenescence remains limited. Immunosenescence represents an age-associated remodeling of the innate and adaptive immune systems, closely linked to impaired immunometabolism, chronic inflammation, and shifts in the AMPK/mTOR, NF-κB, autophagy, and inflammasome pathways; therefore, berberine is a logical candidate for the role of a multi-target regulator of these processes. In this review, we examine the molecular mechanisms of immunosenescence and their biomarkers, and critically evaluate the effects of berberine on these parameters. Here we provide a detailed examination of the rationale for using berberine as a modulator of immunosenescence and proposes a design for future studies.
Ageing is an independent, non-modifiable risk factor for myocardial infarction (MI). It is also characterized by chronic, low-grade inflammation (inflammaging) and progressive cardiovascular senescence. These ageing-associated processes alter cytokine networks and innate and adaptive immune-cell function, promote endothelial dysfunction, and compromise post-infarction repair, thereby increasing myocardial susceptibility to ischaemia and adverse cardiac remodelling in the elderly. Lifestyle modifications, including regular physical activity, reduce inflammaging by facilitating the release of anti-inflammatory cytokines and counteract cellular senescence. This review compiles current mechanistic and translational evidence connecting inflammaging to age-related myocardial infarction, focusing on cytokine-mediated immune interactions. Additionally, this review also examines age-related cytokine dysregulation in myocardial infarction, pro-inflammatory and anti-inflammatory cytokine networks, inflammasome-mediated pyroptosis, senescence-associated secretory phenotypes, and emerging cytokine and extracellular vesicle-based biomarkers. It further discusses translational advances in cytokine-targeted, senescence-directed, and precision immunology-guided therapeutic strategies for the ageing population. In conclusion, inflammaging is closely linked to age-related myocardial infarction, with the IL-6/IL-1 signalling axis supported by the most direct interventional evidence to date including outcome evidence from canakinumab (CANTOS) and phase 2 STEMI myocardial-salvage evidence from tocilizumab (ASSAIL-MI). Cytokine-based immunotherapies targeting this axis represent a promising therapeutic approach for age-related myocardial infarction, although their efficacy and safety in older populations remain to be established in dedicated clinical trials.
Annual killifishes of the genus Nothobranchius compress a vertebrate life cycle into a few months, which is what makes them useful in aging research, yet no broad biochemical description of ageing exists for N. guentheri. In a cross-sectional design, we measured 27 clinical chemistry analytes in whole-body homogenates of male and female fish sampled at 3, 6 and 9 months of age (20 analytical samples). Age trends were assessed by Spearman rank correlation, and age, sex and their interaction by two-way ANOVA. Twenty-four of the 27 analytes fell with age. Calcium declined most steeply (r = − 0.573, p = 0.008), followed by fructose (r = − 0.507, p = 0.023), albumin (r = − 0.486, p = 0.030) and magnesium (r = − 0.479, p = 0.033); potassium fell just short of significance (r = − 0.422, p = 0.064). Only adenosine deaminase, C-reactive protein and HDL cholesterol trended upward, none of them significantly. Males had higher creatinine, carbon dioxide and HDL cholesterol than females. The picture is one of generalised decline rather than the selective elevations of glucose, lipids and nitrogenous waste seen in long-lived mammals, and is most simply read as progressive loss of metabolically active tissue. We suggest, as a hypothesis for testing, that the abrupt terminal mortality familiar to killifish keepers follows the crossing of a threshold after months of subclinical decline. Sample sizes were small and p-values uncorrected, so individual associations need confirmation, but the panel offers endpoints that can be read out within one generation of this species.
Reproductive aging in the ovary, endometrium, and testis is characterized by progressive decline in regenerative capacity, yet the upstream mechanisms coordinating stem cell dysfunction across these tissues remain incompletely understood. Emerging evidence suggests that alterations in extracellular matrix (ECM) mechanics, particularly age and disease associated increases in tissue stiffness, may contribute to impaired stem cell function through mechanotransductive signaling pathways. In the testis, increased matrix stiffness has been associated with activation of mechanosensitive pathways such as Piezo1, leading to calcium influx, mitochondrial stress, and downstream effects on steroidogenic and stem cell populations. In the ovary, age-related fibrosis and cortical stiffening correlate with disrupted follicular development and altered signaling through Hippo-YAP/TAZ pathways. Similarly, the endometrium exhibits stiffness-dependent functional changes, where excessive ECM remodeling is associated with impaired decidualization and reduced regenerative potential. Across these reproductive tissues, mechanotransduction pathways involving calcium signaling, reactive oxygen species generation, and YAP/TAZ activity appear to integrate biomechanical cues with cellular stress responses, potentially contributing to stem cell exhaustion. However, current evidence remains largely correlative, and direct causal links between tissue stiffness and stem cell failure in human reproductive tissues are still limited. We propose the “Hardened Ground” framework as a unifying working model suggesting that increased ECM stiffness may represent a contributory biomechanical factor influencing stem cell function across the reproductive axis. Importantly, this model does not replace established molecular and hormonal mechanisms of aging but instead integrates mechanical properties of the tissue microenvironment as an additional regulatory layer. Notably, clinical observations such as preserved follicular reserve in polycystic ovary syndrome despite increased ovarian stiffness, and dynamic changes in endometrial stiffness across the menstrual cycle, indicate that mechanotransduction outcomes are context-dependent and influenced by hormonal and inflammatory states. Future studies integrating quantitative elastography with stem cell and molecular markers in human tissues are needed to clarify the causal role of stiffness in reproductive aging. This framework generates testable predictions and highlights potential therapeutic avenues targeting extracellular matrix remodeling and mechanosensitive signaling pathways to preserve reproductive tissue function.
Aging is influenced by both genetic and environmental factors, yet comparative studies across species with different natural lifespans remain limited. We examined how reduced ambient temperature (18 °C vs 25 °C) and constant darkness, compared with a 12 h light/12 h dark cycle (DD vs LD), affect lifespan, age-related physiological traits, and gene expression in three Drosophila species with contrasting natural lifespans and climatic adaptations (tropical, short‑lived D. kikkawai, tropical, intermediate‑lived D. melanogaster, and temperate, long‑lived D. virilis). Low temperature extended lifespan in all three species, with the largest relative gains occurring in the shortest‑lived D. kikkawai males, yet the longest absolute lifespans were consistently attained by the long‑lived D. virilis. Constant darkness moderately increased lifespan at 25 °C, particularly in males, but its combination with low temperature became antagonistic in D. virilis, revealing that the interaction between photoperiod and temperature depends on both baseline longevity and sex. Longer lifespan correlated with lower metabolic rate, greater body mass, and sustained late‑life activity. Gene expression analyses in D. melanogaster revealed that low temperature induced a youthful metabolic and immune profile, whereas DD often counteracted these changes. Our findings do not support a simple inverse or direct relationship between baseline longevity and geroprotective efficacy. Instead, these results suggest that the responses to low temperature and darkness are species‑ and sex‑specific and reflect each species’ evolutionary and ecological background.
As global population aging accelerates, maintaining locomotor function in later life has become a critical biomedical challenge. This study investigates the effects of three bioactive compounds—Luteolin (Lut), Glycitein (Gly), and α-Spinasterol (α-Spin)—isolated from the traditional Chinese medicinal herb Codonopsis pilosula (Dangshen), on age-related locomotor decline using the Caenorhabditis elegans (C.elegans) model. We demonstrate that Lut and Gly significantly ameliorate the deterioration of body bend and thrashing frequencies in aged nematodes. Further analysis reveals that both compounds mitigate age-associated sarcopenia by reducing abnormalities in muscle structure and mitochondrial morphology. Mechanistically, we found that the beneficial effects of Lut and Gly on locomotion are dependent on the transcription factor DAF-16/FOXO, as both compounds promote DAF-16 nuclear translocation and the effects are abolished upon daf-16 knockdown. However, these compounds diverge in their regulation of autophagy: Lut improves locomotion through an lgg-1-dependent autophagy-related process, whereas Gly exerts its effects independently of the autophagic pathway. In contrast, α-Spin, despite altering autophagosome levels, did not improve locomotor capacity. These findings elucidate the distinct pharmacological mechanisms of Codonopsis pilosula constituents, highlighting their potential as modulators of healthspan via DAF-16-dependent but mechanistically distinct pathways.
Background: Aging disrupts bone remodeling by increasing osteoclast activity, reducing osteogenic capacity, and elevating inflammation. Toll-like receptor 4 (TLR4)–mediated inflammatory signaling has been implicated in bone degeneration, yet its role in age-related skeletal decline remains incompletely understood. Isoorientin, a plant-derived flavonoid with reported anti-inflammatory properties, has not been evaluated in the context of skeletal aging. Methods: Bone aging was first assessed in C57BL/6 J mice using micro-computed tomography (μCT), histology, TRAP staining, and immunofluorescence. The effects of isoorientin on osteogenesis were examined in senescent hBMSCs by alkaline phosphatase (ALP) activity, mineralization assays, and expression of osteogenesis-related genes. LPS-stimulated RAW264.7 cells were used to evaluate inflammatory responses and M1/M2 polarization. To assess TLR4/ mitogen-activated protein kinase (MAPK)/ nuclear factor-κB (NF-κB) regulation, RAW264.7 cells were treated with TAK-242 or TAK-242 plus isoorientin. Finally, aged mice were treated with isoorientin, TAK-242, or both to evaluate in vivo pathway modulation and bone protection. Results: Aged mice exhibited reduced trabecular mass, elevated osteoclast activity, and increased osteoclast-associated markers. Isoorientin treatment improved trabecular structure, decreased osteoclast numbers, and lowered osteoclast-associated proteins. In senescent hBMSCs, isoorientin restored ALP activity, enhanced mineral deposition, and increased osteogenic marker expression. Isoorientin also reduced pro-inflammatory cytokines, suppressed M1 polarization, and inhibited TLR4/MAPK/NF-κB activation. The combination of isoorientin and TAK-242 exhibited the most potent suppression of inflammatory signaling and the most significant enhancement in bone microarchitecture. Conclusion: Isoorientin alleviates age-related bone loss by suppressing TLR4-mediated inflammation, reducing osteoclast activation, and restoring impaired osteogenesis. These findings identify isoorientin as a promising therapeutic candidate for age-associated osteoporosis.
Telomere length (TL) is a well-established biomarker of biological ageing, sensitive to cumulative physiological and psychosocial stress. This review synthesises current evidence on how pregnancy, postpartum stressors, and reproductive history shape maternal biological ageing, integrating findings from telomere biology and emerging epigenetic ageing measures. Pregnancy represents a period of substantial metabolic, hormonal, and immunological demand and is increasingly conceptualised as a transient state of accelerated biological ageing. While telomere shortening is not consistently detectable during gestation, epigenetic clocks indicate a temporary increase in biological age, which is only partially reversible postpartum. Across the life course, higher parity is associated with shorter TL, with evidence suggesting a cumulative effect that becomes most apparent in later life and around the menopausal transition. However, this relationship is heterogeneous and modified by factors including age at last birth, breastfeeding, and socioeconomic context. Postpartum represents a critical and underexplored window in which sleep deprivation, psychological stress, and social factors converge to influence telomere dynamics. In particular, poor sleep quality and postpartum depression (PPD) are consistently linked to accelerated telomere attrition and epigenetic ageing, with emerging evidence of a bidirectional relationships whereby shorter TL may also predispose to PPD. Overall, evidence supports a model in which reproductive events impose are associated with measurable transient and cumulative costs to cellular ageing biomarkers. These findings highlight the importance of incorporating postpartum health, particularly sleep and mental health support, into life-course models of ageing and underscore the need for longitudinal, mechanistic, and intervention-focused research in maternal populations.
Aging is a multifactorial process affects different tissues and organs and is modulated by genetic and environmental factors. In aging, the frequency of DNA repair errors and genomic instability are augmented. Depletion of endogenous antioxidant capacity during aging promotes the development of oxidative stress which triggers oxidative stress-induced DNA injury. Brain aging is manifested by cognitive impairment and memory disorders. Development of neuronal senescence is the major pathway in the progression of brain aging. Silent information regulator sirtuin 1 (SIRT1) is a class III histone deacetylase plays a critical role in genomic stability during aging. SIRT1 is highly expressed in specific brain regions involved in energy expenditure and metabolic activity that is necessary for brain development and control of brain senescence. Therefore, SIRT1 may have neuroprotective effects against brain aging and related neurodegenerative diseases. This narrative review aims to critically evaluate the role of SIRT1 in brain aging and to summarize current evidence on compounds that directly or indirectly modulate SIRT1 activity, with a focus on their mechanistic pathways and potential therapeutic implications. Findings of the present review highlighted that SIRT1 activators such as resveratrol, metformin and statins have neuroprotective effects against brain aging by regulating inflammatory and oxidative stress disorders through modulation of downstream signaling pathways.
In recent decades, there has been active research into how ionizing radiation at low doses, an inevitable factor in human activity, affects aging processes and which molecular genetic mechanisms underlie this influence. This study investigates the effects of mutations in PIWI subfamily genes (piwi and aub), which regulate transposable elements, on the lifespan of Drosophila melanogaster under conditions of genome instability induced by hobo transposons and chronic low-intensity irradiation (20 cGy). It is shown that dysfunction of piwi and aub modulates the activity of hobo transposons, increasing the frequency of their excisions/transpositions and recombinogenic activity, as confirmed by phenotypic and PCR analyses. The presence of hobo transposons in the genome elevates the spontaneous level of DNA fragmentation in ovarian cells, and chronic irradiation enhances this effect, leading to increased DNA damage in somatic and germline cells of most studied strains. Despite increased genetic instability and reduced fertility in some genotypes, the combined presence of mutations and hobo transposons paradoxically increases lifespan both under control conditions and after irradiation. Analysis of the interaction between genetic factors reveals a predominantly antagonistic, and in one case synergistic, effect on lifespan, depending on the type of mutation, the structure of the hobo transposons (full-size or defective copies), sex, and irradiation conditions. These results demonstrate the complex interplay between systems controlling transpositional activity and stress-induced processes that affect key viability parameters.
Background: Chronic morphine consumption induces oxidative stress and renal dysfunction, effects that may be exacerbated by aging-related declines in adaptive capacity. Regular endurance exercise enhances antioxidant defense and mitochondrial regulation; however, its ability to counteract morphine-induced renal alterations across different stages of aging remains insufficiently characterized. Methods: Male wistar rats, categorized as young and aged based on chronological age and body weight, were allocated to control, morphine, exercise, and morphine plus exercise groups within each age category. Morphine was administered via drinking water for four weeks. Concurrently, animals in the exercise groups performed moderate-intensity continuous training on a treadmill. At study completion, serum and renal tissues were collected for assessment of oxidative stress markers (MDA, TAC, SOD), MPO, renal function indices (BUN and creatinine), and renal expression of sirtuin 1 (SIRT1) and Klotho, Mitochondrial compatibility markers (Citrate synthase activity and TFAM). Results: Chronic morphine exposure was associated with increased oxidative stress markers and decreased antioxidant capacity in kidney tissue, and simultaneously increased serum urea and creatinine levels in young and old mice, indicating impaired renal functional status. Chronic morphine administration also decreased SIRT1 and Klotho levels in young and old animals. In contrast, 4 weeks of endurance training improved markers of mitochondrial adaptation, oxidative balance, and renal function, which were associated with increased expression of SIRT1 and Klotho in kidney tissue. These changes could indicate a potential link between exercise training and molecular pathways involved in the regulation of oxidative stress and renal homeostasis. However, these findings suggest an association, and causal or mechanistic interpretations will require further investigation in future studies. Conclusion: These findings indicate that endurance training is associated with more favorable renal biomarker profiles in the context of chronic opioid exposure. Effects of chronic morphine exposure and moderate-intensity continues training (MICT) on renal functional and molecular adaptations in young and aged male rats.
Aging-related neurological disorders, including stroke, Alzheimer’s disease (AD), Parkinson’s disease (PD), epilepsy, and various neuroinflammatory conditions, affect over three billion individuals worldwide and constitute leading causes of morbidity, disability, and socioeconomic burdens. Aging contributes not only to the increased incidence of these disorders but also to their progression through interconnected mechanisms, including endothelial dysfunction, oxidative stress, chronic inflammation, mitochondrial dysfunction, cellular senescence, metabolic imbalance, and gut microbiota dysbiosis. These processes collectively impair neuronal survival, synaptic plasticity, and cognitive and motor functions. Traditional Chinese medicine (TCM), with its characteristic multi-component and multi-target therapeutic strategies, has emerged as a promising approach to counteract age-associated neurological decline. Accumulating preclinical studies suggest that TCM interventions may exert neuroprotective, anti-inflammatory, and antioxidant effects, modulate autophagy, restore metabolic homeostasis, and potentially delay cellular senescence. However, high-quality clinical evidence on safety and efficacy remains limited. This review summarizes current insights into the molecular interplay between aging and neurological disorders and highlights the therapeutic potential of TCM in targeting hallmarks of aging, providing perspectives for integrative prevention and treatment strategies for neurodegenerative and neurovascular diseases.
Cellular senescence is a context-dependent cellular state characterised by persistent cell-cycle arrest, epigenetic remodelling, metabolic reprogramming and acquisition of a senescence-associated secretory phenotype. Transient senescence contributes to embryogenesis, tissue repair and tumour suppression, whereas persistent senescent cell populations accumulate with advancing age across multiple tissues, in part owing to declining immune-mediated clearance and intrinsic resistance to apoptosis, thereby promoting chronic systemic inflammation, tissue fibrosis, stem-cell dysfunction and propagation of secondary senescence. Experimental genetic and pharmacological evidence supports a contributory and in several contexts causal role for senescent cells in cardiovascular, metabolic, musculoskeletal, fibrotic and neurodegenerative disorders. These findings have accelerated the development of senotherapeutic strategies, including senolytics, senomorphics and immune-mediated clearance approaches, with early clinical studies showing preliminary evidence of functional benefit in idiopathic pulmonary fibrosis and diabetic kidney disease. However, clinical translation remains constrained by senescence heterogeneity, limited biomarker specificity and unresolved long-term safety concerns. Improved molecular, spatial and functional resolution of senescent states will be essential for developing biomarker-guided and tissue-specific interventions that preserve the beneficial functions of transient senescence while limiting its chronic deleterious effects.
Aging is characterized by a progressive decline in cellular and tissue function, shaped in part by disruptions in communication between the extracellular matrix (ECM) and intracellular signaling networks. The cell surface receptor CD44 functions as a molecular hub, integrating signals from a remodeled ECM to regulate core aging programs including senescence, inflammation, and metabolic balance. This review synthesizes evidence that CD44, through its structural domains, isoform diversity, and proteolytic processing, integrates extracellular cues to modulate key pathways such as STAT3, NF-κB, and the class III PI3K complex. Mechanistically, HA-fragment engagement of CD44 activates the CD44-STAT3 axis in vascular tissue, suppressing autophagic flux and promoting endothelial senescence. Concurrently, ECM-derived ligand binding to CD44 drives NF-κB signaling that amplifies chronic inflammation in a tissue and context-dependent manner, contributing to inflammaging. Functional outcomes are context-dependent, shaped by isoform switching and γ-secretase-mediated release of CD44-ICD, which may drive degeneration or support repair and proteostasis. Emerging single-cell and spatial transcriptomics reveal spatiotemporal CD44 dysregulation across vasculature, brain, adipose tissue, kidney, and liver. This review establishes CD44 as a mechanistic link connecting ECM remodeling to nuclear responses in aging and outlines therapeutic strategies including ligand competition, antibody blockade, and γ-secretase modulation to mitigate age-related pathology and extend health span. These insights provide a coherent framework for understanding aging biology and guiding future translational interventions targeting CD44 signaling pathways effectively.
Hypertension affects one-third of adults and is a major comorbidity of neurocognitive disorders. The causal relationship, shared genetic architecture, and upstream mechanisms linking hypertension to brain aging remain unclear. Hypertension GWAS datasets from MVP and FinnGen R12 were meta-analyzed as the exposure, and a European-ancestry brain age gap (BAG) GWAS derived from the UK Biobank and LIFE-Adult cohorts was used as the outcome. MR and GSMR assessed causality. LDSC, HDL, and S-LDSC estimated genetic correlation. Four TWAS methods (MAGMA, FUSION, JTI-PrediXcan, FOCUS) mapped associations to genes, followed by SMR for causal validation and PoPS for prioritization. GSMAP with spatial transcriptomics characterized regional and cell-type enrichment. Hypertension and brain aging were genetically correlated, and MR and GSMR analyses suggested a causal effect of hypertension on increased brain age gap. TWAS identified 15 shared Hypertension–BAG genes, 10 supported by SMR. PoPS prioritized TRIM47 as the core gene. Shared signals were enriched in meninges, fiber tracts, cortical layer 1, and CA1 stratum lacunosum/radiatum, with cell-type enrichment in meninges, smooth muscle cells, oligodendrocytes, and astrocyte subtypes. Hypertension is genetically correlated with, and shows evidence of a causal effect on, accelerated brain aging. TRIM47 is a core gene bridging hypertension and BAG. GSMAP-based spatial enrichment provides a hypothesis-generating framework for understanding vascular, meningeal, and myelin-related pathways linking hypertension to increased brain age gap.
