Bone mechanosensitivity declines with age, resulting in a reduced anabolic response to mechanical stimulation. Although the mechanosensitive ion channel Piezo1 plays a critical role in bone mechanoresponsiveness, its mechanisms of mechanotransduction in aged bone remain incompletely understood. Here, we report that aged tibiae from 19-month-old male mice exhibit a blunted anabolic response to axial cyclic compressive loading or administration of the Piezo1 agonist Yoda1 alone. However, chemical activation of osteocytic Piezo1 by Yoda1 effectively rescues the anabolic response of aged cortical bone to mechanical loading. Mechanistically, Yoda1-induced Piezo1 activation promotes its co-localization with connexin 43 (Cx43) on the osteocyte membrane in response to mechanical stimulation. This Piezo1-Cx43 interaction enhances Cx43 hemichannel (HC) activity via the PI3K-Akt signaling pathway. Subsequent HC opening facilitates the release of the anabolic factor prostaglandin E2 (PGE2) and suppresses the catabolic factor sclerostin (SOST), thereby promoting bone formation and inhibiting bone resorption on the endosteal surface, which ultimately increases cortical bone mass during mechanical loading. Collectively, our findings reveal a mechanism whereby Piezo1 mediates the skeletal anabolic response to mechanical loading in aged bone via Cx43 HCs, offering new perspectives for combating age-related osteoporosis.

The increase in life expectancy over the past century has been accompanied by the recognition of age as the primary risk factor for a wide range of pathologies, including cardiovascular and neurodegenerative diseases, as well as cancer. Thus, the development of interventions that slow the underlying biological processes of aging could have beneficial effects on the prevention or progression of these diseases. To evaluate such geroprotective interventions, quantifying biological damage via aging clocks-particularly those based on transcriptomic biomarkers-has become highly relevant, as they provide estimations with strong biological interpretability. However, the limited availability of transcriptomic clocks for murine experimental models has hindered the implementation of these tools in aging research and their use in evaluating interventions that may have geroprotective effects. Here, we have developed an accurate, accessible, and ready-to-use murine transcriptomic clock that provides robust age predictions for healthy mice using hepatic RNA-seq data. Applying the clock to accelerated-aging models revealed an increased transcriptomic age in progeroid syndromes, demonstrating its ability to capture aging-related biological processes. Finally, considering the main interest of these tools, we show that well-established interventions with geroprotective potential, both genetic (Snell Dwarf, Ames Dwarf, and growth hormone receptor-deficient mice) and environmental (caloric, protein, or methionine restriction, as well as rapamycin supplementation in specific contexts), reduce the transcriptomic age estimated by the clock. These findings indicate that the proposed transcriptomic clock could be a valuable tool for studying the biology of aging and for designing and evaluating potential geroprotective interventions.

Cellular senescence is a fundamental hallmark of aging and represents a major barrier to the scalable and reproducible application of mesenchymal stromal cell (MSC)-derived small extracellular vesicles (sEVs). Senescent human umbilical cord mesenchymal stromal cells (hUCMSCs) exhibit impaired proliferative capacity, disrupted mitochondrial homeostasis, and altered secretory phenotypes, which may compromise the biological activity and therapeutic reliability of sEVs. Here, we investigated whether overexpression of human telomerase reverse transcriptase (hTERT) attenuates senescence-associated deterioration and stabilizes sEV functional properties. Late-passage hUCMSCs displayed canonical senescence features and mitochondrial dysfunction, all of which were markedly alleviated by hTERT expression. Functionally, sEVs derived from senescent cells exhibited impaired immunomodulatory activity, whereas sEVs from hTERT-expressing cells largely restored this function. Mechanistically, senescence was associated with altered sEV cargo, including enrichment of miR-217-5p, which contributed to diminished immunomodulatory potency, at least in part through modulation of SIRT1-associated inflammatory signaling in recipient macrophages. Proteomic profiling further showed that H11-sEVs retained a young-like protein cargo profile, particularly for proteins associated with immune and inflammatory regulation. In parallel, sEVs from all three groups retained primordial follicle-activating capacity, consistent with the broad retention of PI3K-Akt pathway-related proteins in their proteomic profiles and PI3K-Akt pathway activation in ovarian tissues. In aged female mice, H11-sEVs exhibited young-like ovarian protective activity. Collectively, these findings demonstrate that hTERT uncouples cellular senescence from sEV functional decline, supporting the development of potency-stabilized sEV sources for aging-related and regenerative applications and providing insight into the biological roles of senescent cell-derived sEVs.

Miscarriage and abnormal embryonic development in women of advanced maternal age (AMA) are often associated with impaired decidualization. mTORC2 is an evolutionarily conserved protein kinase. As a core component of mTORC2, RICTOR has been implicated in nutrient sensing and is closely linked to implantation disorders; however, its role in regulating age-related decidualization disorders remains unreported. In this study, we identified pronounced decidualization defects in AMA foster mice, accompanied by a significant reduction in RICTOR in the decidual tissues of AMA women. Uterine-specific genetic deletion of Rictor in mice resulted in pregnancy loss and impaired decidualization. Notably, Rictor knockdown led to attenuated Akt3-FoxO1 signaling and impaired nuclear export of FoxO1. Molecular and histological analyses demonstrated that the specific RICTOR activator MHY1485 effectively rescued decidualization defects in vivo and in vitro. These findings indicate that RICTOR plays an essential role in the aging decidual microenvironment and may serve as a potential biomarker for uterine stromal cell decidualization. Furthermore, therapeutic activation of RICTOR represents a promising strategy to counteract senescent decidual impairment in AMA women and improve pregnancy outcomes.

Mammalian cochlear hair cells convert acoustic stimuli into electrical signals, which are relayed to the central auditory pathway via auditory neurons. Progressive loss of hair cells and their synapses is a characteristic of age-related hearing loss (ARHL), but the underlying mechanisms remain poorly understood. In this study, we tested the hypothesis that hair cell physiological properties change with age in CBA/CaJ mice, a strain known for its slow ARHL progression. We found that hair cell size began to decrease from 10 months of age, well before detectable increase in hearing thresholds from auditory brainstem responses. This structural change was associated with a significant decrease in the size of the basolateral membrane current, in particular that carried by the large conductance calcium-activated potassium (BK) channel currents (IK,f) in the apical inner hair cells (IHCs). However, the size of the mechanoelectrical transducer (MET) current measured in the IHCs remained unaffected at least up to 22 months of age. Our results provide clear evidence of an early change in the physiological properties of apical IHCs with age, which precedes measurable hearing loss, suggesting that these cellular deficits might define a distinct pathological route in the CBA/CaJ mice.

Redox imbalances and mitochondrial dysfunction are key contributors to age-related declines in skeletal muscle and may contribute to impaired exercise responsiveness. Here, we investigated the influence of aging on skeletal muscle redox at rest and in response to acute exercise, examining how mitochondrial quality and quantity relate to skeletal muscle redox status. Skeletal muscle biopsies were obtained from 12 young (22 ± 4 years) and 10 older adults (66 ± 7 years) before and immediately after 60-min of high-intensity knee-extension exercise. We assessed mitochondrial respiration, mitochondrial DNA (mtDNA) copy number and deletion mutation frequency at baseline, while skeletal muscle redox proteomics was performed on pre- and post-exercise biopsies in a subset of participants. Mitochondrial respiration was preserved with age (max respiration, p = 0.123). However, the older adults had a lower mtDNA copy number (p = 0.046) and higher mtDNA deletion frequency (p = 0.001), with widespread remodeling of the skeletal muscle redox proteome, including altered thiol occupancy of proteins involved in metabolism, immune function, and extracellular matrix organization. In response to exercise, young skeletal muscle exhibited predominantly reversible peptide reductions, whereas preferential oxidation of mitochondrial antioxidant proteins, including PRDX3, occurred in older muscle. Both mtDNA deletion frequency and mitochondrial respiration were strongly associated with exercise-induced redox modifications in mitochondrial proteins. These findings suggest that aging alters both the regulation and resolution of exercise-induced redox signaling, with mitochondrial genomic instability and respiration shaping redox responsiveness.

The clinical outcomes of trabeculectomy, a standard glaucoma filtration surgery (GFS), have dramatically improved with the introduction of mitomycin C (MMC), an antimetabolite widely used to inhibit postoperative scarring. MMC exerts anti-scarring effects primarily by promoting apoptosis and suppressing fibroblast proliferation at the surgical site. However, despite these beneficial effects, MMC also induces the production of inflammatory cytokines, and its full mechanism of action remains incompletely understood. Moreover, a subset of patients continues to experience poor surgical outcomes even after MMC application, highlighting the need for complementary therapeutic strategies. Comprehensive transcriptomic analysis of postoperative GFS tissues revealed that MMC promoted the expression of genes associated with cellular senescence and inflammatory responses. Supporting this, in vitro experiments suggested that the transcriptional changes were associated with MMC-induced senescence-associated secretory phenotype (SASP)-like changes in the fibroblasts. Single-cell RNA sequencing (scRNA-Seq) analyses of postoperative GFS tissues also revealed that fibroblasts after GFS with MMC secrete SASP factors. Furthermore, Cell-Cell communication analysis identified CCL7 as one of the key molecules involved in inflammatory cell migration and the promotion of fibrosis. Importantly, we demonstrated that fibroblasts exhibiting SASP-like features can be selectively eliminated by a specific senolytic agent, suggesting a novel and promising therapeutic approach that may improve long-term surgical outcomes after GFS.

Age-related taste dysfunction impairs nutrition and quality of life, contributing to metabolic disorders and frailty in the elderly, yet its cellular and molecular basis remains poorly understood. By integrating single-cell RNA and spatial transcriptomics sequencing, we systematically mapped murine taste bud aging across five developmental stages from neonatal to aged. Our findings reveal that age-associated taste impairment is driven by the progressive depletion of stem/progenitor cell differentiation capacity, predominantly characterized in the posterior tongue, and mediated by inflamm-aging responses and micro-environmental alterations. Specifically, we identified macrophage infiltration and polarization shifts in aged circumvallate and foliate papillae, underscoring the crucial role of macrophages in age-related taste decline. A co-culture model using taste organoids with conditioned media from polarized macrophage revealed that M1-polarized cells suppress taste organoid proliferation and differentiation. Mechanistically, this inhibition may be mediated by macrophage-derived Thbs1, as recombinant Thbs1 treatment directly suppressed taste progenitor cell expansion in vitro. Together, this study provides the first comprehensive spatiotemporal atlas of taste bud aging and identifies novel therapeutic targets for the treatment of age-related taste disorders.

Ageing impairs immune function, increasing susceptibility to infection, autoimmunity and inflammation. The thymus undergoes involution during childhood, and thymocyte and thymic epithelial cell (TEC) numbers decline. Given that adaptive immunity depends on T-cells recognising diverse antigens via their unique T-cell receptor (TCR), the precise age-related changes in TCR repertoire composition are key to understand immunity. To investigate the influence of age on the thymic TCR repertoire we sequenced TCRα and TCRβ transcripts from developmentally defined thymocyte populations from 4-week, 12-month and 18-month-old mice, and from thymocytes recovering from hydrocortisone-treatment, and athymic recipients of RAG1-deficient thymus transplants. The 18-month thymus selected TCR repertoires with distinctive patterns of VxJ and CDR3 k-mer usage compared to young thymus, indicating it had a qualitatively different repertoire with different specificity. It also selected a less diverse TCRβ repertoire with more expanded clones than young thymus. On recovery from hydrocortisone-treatment, both 4-week and 12-month thymus showed bias towards foetal-like 3'TRAVx5'TRAJ rearrangements, but 12-month thymus also produced less diverse and evenly distributed TCRβ repertoires, with increased expansion of TCRβ clones at the CD4[-]CD8[-]CD25[+]CD44[-]intracellularTCRβ[+] stage, increased TRBJ-1-cluster usage and distinctive patterns of combinatorial VxJ usage. Transplantation of athymic nude recipients with old RAG1-deficient thymus generated less diverse, less evenly distributed TCR repertoires with different combinatorial VxJ usage than those generated by young transplants. Taken together our experiments show that the old thymus generates qualitatively different TCR repertoires than young thymus and the non-lymphoid compartment of the thymus contributes strongly to these changes and to age-associated decline in TCR repertoire diversity.

Vascular aging, not only a victim of vascular cell senescence but also a driving hub of systemic aging, is a complex process in which both anti-aging and pro-aging proteins are involved. Thus, the ideal anti-aging medication should have multiple protein targets; in this case, an lncRNA might be a good choice. AK050834 is a conserved lncRNA, but its roles in vascular biology and vascular aging are currently unknown. Here, we identified that AK050834 was highly expressed in vascular walls and in vascular smooth muscle cells (VSMCs). Notably, AK050834 expression was remarkably increased in aged vessels. By using gain-of-function, loss-of-function, and gene knockout approaches, we identified that AK050834 is a strong regulator of VSMC senescence and vascular aging. In terms of the mechanisms, we found that AK050834 suppressed the expression of the anti-aging protein ATF3 via direct interaction with its promoter, which was further confirmed by a rescue experiment. In addition, AK050834 increased the expression of the pro-aging protein p21 by stabilizing its mRNA. Finally, we found that AK050834 deficiency could effectively prevent vascular aging in mice in vivo. The interesting dual and opposite effects of AK050834 on the anti-aging protein ATF3 and the pro-aging protein p21 suggest that AK050834 might be a novel diagnostic marker as well as an ideal therapeutic and preventive target for vascular aging and many related diseases.

Metabolic aging underlies a cluster of chronic conditions-type 2 diabetes, cardiovascular disease, sarcopenia, and neurodegeneration-that account for a substantial share of global morbidity and mortality. A common feature is progressive mitochondrial dysfunction: impaired bioenergetics, disrupted quality control, and loss of metabolic resilience. Reduced mitochondrial DNA copy number in peripheral blood leukocytes is associated with cardiometabolic disease and mortality, but pre-analytical variability, dependence on blood-cell composition, and uncertain relationship to tissue-level function mean it should be regarded as a candidate risk-associated biomarker rather than a validated measure of mitochondrial integrity. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), developed for glycemic control, engage pathways implicated in mitochondrial biogenesis, dynamics, and mitophagy; whether these effects reflect direct receptor signaling, indirect consequences of weight loss, or secondary mediators such as interleukin-6 remains debated and appears tissue-dependent. In SELECT, semaglutide reduced major adverse cardiovascular events by 20% in obesity without diabetes, and a 2025 multi-omic study in aged male mice found GLP-1 RA treatment attenuated age-associated molecular signatures despite only modest changes in food intake and body weight. No trial, however, has incorporated a prespecified mitochondrial endpoint, human mechanistic evidence remains limited, and access to these therapies remains uneven worldwide. Here we synthesize mechanistic, preclinical, and clinical evidence for a proposed GLP-1-mitochondria axis, classify this evidence by receptor dependence and translational stage, distinguish disease-specific treatment effects from evidence for aging modification, examine four major controversies, and outline a research and policy agenda for responsible, evidence-graded development of GLP-1-based geroscience interventions.

Ischemic postconditioning (I/Post), which is an effective intervention by activating endogenous cardioprotective pathways, recovers ischemia/reperfusion injury. However, this intervention is not as effective in older patients, and its mechanism needs to be further investigated. In this study, we found that myocardial telomeric repeat binding factor 2 (TRF2) protein expression in male aged mice (18 months of age) was lower than that in male adult mice (4 months of age). After ligation of the anterior descending branch of the heart to establish an in vivo model of ischemia/reperfusion injury, we found that TRF2 expression was further decreased after I/Post. To investigate the role of TRF2 in cardioprotection in I/Post in the senescent heart, we performed echocardiography, blood biochemical testing, and apoptosis-related detection after injecting adeno-associated virus type 9 overexpressing TRF2 into aged mice. We found that TRF2 improved myocardial I/Post protection in vivo. Knockdown of TRF2 in a cardiomyocyte cell line (HL-1) increased inflammatory factor release and aggravated mitochondrial and DNA damage in senescent myocardiocytes following hypoxic postconditioning (H/Post). TRF2 also inhibited activation of the cGAS/STING pathway by increasing mitophagy during H/Post in aged myocardiocytes. Moreover, TRF2 interacted with casein kinase 2 alpha 2 polypeptide (CSNK2A2) to regulate the dephosphorylation of FUN14 domain-containing protein 1 (FUNDC1), which contributed to the protective effect of hypoxic postconditioning.

Cell therapies represent a promising frontier in modern medicine. Mesenchymal stromal cells (MSCs) constitute a valuable source due to their minimal ethical concerns, low immunogenicity, negligible tumorigenicity in vivo, and robust paracrine activity mediated by the secretion of anti-inflammatory and angiogenic factors. Despite these advantages, MSCs undergo rapid replicative senescence accompanied by a progressive loss of stemness markers and functional potency. In this context, cellular rejuvenation has been emerging as a pivotal strategy to restore their original biological features. These approaches aim to modulate the hallmarks of aging; as these processes are highly interconnected, multiple and complementary targets have been proposed. This review aims to discuss and analyze the main rejuvenation strategies reported in the literature for MSCs, with particular attention to approaches that can enhance their functionality and translational potential. In this context, the review focuses on five key categories of interventions: epigenetic modifications, metabolic reprogramming, modulation of cellular senescence, telomere biology, and extracellular vesicles. These strategies represent the fundamental axes through which cellular aging can be counteracted and the efficacy of cell-based therapies improved.

Adipose tissue senescence is increasingly recognized as a key driver of systemic aging and age-related functional decline, yet the endocrine regulators that actively promote this process remain poorly defined. Angiopoietin-like protein 8 (ANGPTL8) is a metabolic factor implicated in lipid metabolism and inflammation and has been associated with multiple aging-related disorders. However, its direct role in adipose tissue senescence and organismal aging remains unclear. Here, we identify ANGPTL8 as a previously unrecognized regulator of adipose tissue aging through integrative analyzes of human cohorts, animal models, transcriptomics, and cellular studies. In a large human cohort, circulating ANGPTL8 levels were strongly associated with biological aging and mortality risk and significantly improved machine learning-based models for age and survival prediction. Consistent with these findings, genetic deletion of Angptl8 in mice extended lifespan, attenuated aging-associated functional decline, and reduced senescence markers in adipose tissue. Transcriptomic analyzes revealed age-dependent upregulation of ANGPTL8 in adipocytes accompanied by activation of pro-senescent transcriptional programs. Mechanistically, ANGPTL8 directly interacted with AKT2 and activated the AKT-mTOR-S6K signaling pathway, thereby promoting cell-autonomous adipocyte senescence. Genetic or pharmacological inhibition of this pathway abolished the pro-senescent effects of ANGPTL8. Collectively, our findings identify ANGPTL8 as an endocrine regulator linking metabolic dysfunction to adipose tissue senescence and systemic aging, highlighting the ANGPTL8-AKT2-mTOR axis as a potential therapeutic target for delaying age-associated functional decline.

One of the defining phenotypes of a senescent cell is the senescence-associated secretory phenotype (SASP), which can propagate senescence in neighboring cells both in vitro and in vivo. Importantly, this paracrine spreading of senescence can act in a cell non-autonomous manner, influencing neighboring cell populations and contributing to immune cell recruitment. As cellular senescence has recently been linked to both age-related neurodegenerative phenotypes and local inflammation and is more clearly defined across brain cell types in a cell-type-dependent manner, an urgent question remains regarding how a cell-type-specific paracrine spreading of senescence occurs in the brain. Here, we set out to profile the cell-type-specific features of the SASP and characterize the directionality of paracrine senescence-spreading between major brain cell types. Through this analysis, we identified key SASP ligand-receptor pairs involved in this paracrine dissemination. Targeting selected factors with specific inhibitors, we ameliorated some aspects of the paracrine spreading of senescence in a brain cell-type-dependent manner. Taken together, we identified specific SASP targets for therapeutic intervention in the context of human brain cells and thereby informed the SASP-dependent reaction of immune cells and age-related tissue dysfunction across both normal aging and models of neurodegenerative disease.