Search Results (297)

The “unexplained failure” of rotator cuff repair is multifactorial, but its structural endpoint is anatomically consistent, i.e., the failure of the tendon-to-bone interface (enthesis) to heal. The native enthesis is a four-zone fibrocartilaginous gradient that does not regenerate but heals as a mechanically inferior fibrovascular scar, so the outcome of repair hinges on the interface’s healing capacity—which chronological age predicts poorly. This review organizes the aging biology governing bone-to-tendon healing capacity into eight domains: progenitor competence, cellular senescence and the SASP, immune aging, extracellular-matrix and collagen aging via advanced glycation end-product cross-linking, footprint angiogenesis, morphogen signaling, mechanotransduction, and bone quality. We then precisely define the DNA-methylation epigenetic clock—a continuous value produced by weighted CpG methylation, with defined units, reproducibility, and effect sizes—and propose it as a candidate quantitative readout of these domains; whether or not it truly integrates them into a single biologically meaningful measure at the enthesis is a hypothesis of this review, not an established mechanism. In 1087 twins, epigenetic age acceleration predicted fracture and osteoporosis risk, with hazard ratios of 1.29–3.17 per standard deviation; moreover, aging is tissue-specific, so the enthesis may run ahead of blood. Critically, the clock provides a single axis on which current regenerative-medicine strategies—stem cells, exosomes, immunomodulation, biomimetic gradient scaffolds, growth factors, senolytics, and epigenetic reprogramming—can be systematically categorized by how far each shifts biological age toward a healing-competent state; partial reprogramming, which rewinds the clock directly, shows that the clock is simultaneously the readout and the therapeutic target. We integrate this into a “hidden biological age of bone-to-tendon healing”, explicitly stating that this remains an unvalidated hypothesis requiring prospective validation. Full article

Aging is the strongest risk factor for chronic diseases such as cardiovascular diseases, cancer, diabetes, and neurodegenerative disorders. Advances in geroscience indicate that pharmacological modulation of conserved molecular pathways may extend healthspan and delay multimorbidity. A structured narrative review of the PubMed, Scopus, and Web of Science literature published between January 2010 and May 2026 was conducted, with seminal earlier studies retained where relevant. The review focused on molecular pathways implicated in aging, pharmacological interventions targeting these pathways, and their preclinical and clinical evaluation. Particular emphasis was placed on translational evidence, including human biomarker studies and randomized clinical trials, and on the distinction between biomarker modulation and clinically meaningful outcomes. Repurposed drugs such as metformin and rapamycin have among the most extensive preclinical and translational evidence, although clinical evidence for broadly applicable geroprotection remains limited. Statins, SGLT2 inhibitors, GLP-1 receptor agonists, and menopausal hormone therapy have established disease-specific or cardiometabolic benefits that may have indirect relevance to geroprotection, but direct effects on biological aging and healthspan remain unproven. Other candidates, including senolytics, NAD⁺ precursors, taurine, and epigenetic reprogramming approaches, are at different stages of translational development, with evidence ranging from promising preclinical findings to early human studies. Across interventions, a substantial gap remains between mechanistic plausibility and clinically validated geroprotection. Geroprotective pharmacology represents a promising but incompletely validated approach to extending healthspan. Major uncertainties include the absence of universally accepted biomarkers and clinical endpoints of biological aging, heterogeneity in treatment response, optimal timing and duration of interventions, and long-term safety. Future research should prioritize adequately powered randomized clinical trials integrating standardized measures of biological aging with clinically meaningful outcomes, alongside biomarker-guided patient selection, appropriate treatment timing, and careful assessment of long-term safety. The future of geroprotective medicine will depend not only on identifying additional pharmacological targets, but on demonstrating that their modulation produces durable and clinically meaningful benefits in humans. Full article

Cellular senescence is one of the major risk factors for the onset and progression of chronic pulmonary diseases. Cellular senescence can be induced by diverse stressors, including genotoxic damage, oncogenic signaling, and therapeutic interventions. These senescent cells communicate via the release of multiple inflammatory molecules known as the Senescence-Associated Secretory Phenotype (SASP), which induces persistent low-grade inflammation and contributes to various chronic inflammatory lung diseases. This review summarizes the basic concepts of cell senescence, its hallmarks, SASP, and the mechanisms of cell senescence in the lung, and its consequences in the development and progression of chronic pulmonary diseases. Current therapeutic strategies include senolytics (e.g., BCL-2 family inhibitors and dasatinib–quercetin) and senomorphics that suppress SASP activity. Future directions in the development of cell- and stage-specific therapies are critical for targeting age-related lung disease with desired outcomes. Full article

Skeletal muscle retains adaptive information from previous mechanical loading, enabling faster responses to subsequent training and regenerative challenges. This review synthesizes current evidence on the cellular and epigenetic mechanisms underlying skeletal muscle memory and examines how these mechanisms are modified by aging and post-injury regeneration. Muscle memory emerges from complementary structural and molecular components, including myonuclear retention, persistent DNA methylation changes, chromatin remodeling, transcriptional priming, non-coding RNA regulation, and mitochondrial epigenetic adaptations. These mechanisms interact with muscle satellite cells (MuSCs), fibro-adipogenic progenitors (FAPs), immune cells, and extracellular matrix remodeling to maintain regenerative competence. During aging, epigenetic drift, chronic low-grade inflammation, altered macrophage states, MuSC dysfunction, persistent FAP activity, fibrosis, mitochondrial impairment, and anabolic resistance progressively reduce this plasticity, thereby contributing to sarcopenia. Training–detraining–retraining studies indicate that parts of the exercise-induced epigenetic landscape remain detectable after training cessation and can be reactivated during renewed loading, although the persistence and functional importance of individual molecular signatures remain incompletely defined. Physical exercise remains the most established intervention for preserving muscle function and epigenetic responsiveness, whereas caloric restriction, modulation of nutrient-sensing pathways, senolytic strategies, and direct targeting of epigenetic regulators remain promising but translationally less mature approaches. Overall, the preservation of epigenetic plasticity may be a key determinant of healthy skeletal muscle aging and effective regeneration. Full article

Senotherapeutic agents targeting senescent cell (SnC) accumulation represent a promising frontier in aging research. These agents encompass senolytics that selectively eliminate accumulated SnCs and senomorphics that suppress the pathological persistence of the senescence-associated secretory phenotype (SASP). Concerns regarding off-target effects of synthetic senolytics have intensified interest in plant-derived alternatives that offer multitargeted mechanisms and favorable safety profiles. This scoping review was conducted following Joanna Briggs Institute guidelines and PRISMA-ScR, mapped preclinical evidence on plant-derived senotherapeutics published between 2015 and 2025 across PubMed, Scopus, Web of Science, Wiley Library and Google Scholar. Of 1355 identified articles, 111 studies met inclusion criteria. Most characterized compound classes included flavonoids, non-flavonoid polyphenols and stilbenes, terpenoids and alkaloids, and combination and complex plant extracts. Mechanistically, BCL-2/BCL-XL apoptosis, PI3K/AKT/mTOR and p53/p21/p16^INK4a modulation emerged as senolytic mechanisms, while NF-κB-mediated SASP suppression predominated among senomorphic agents. Ginkgetin-mediated cyclic GMP-AMP-synthase–stimulator of interferon genes (cGAS-STING) inhibition was identified as a mechanistically novel target within natural senotherapy. Metabolomics demonstrated dual utility in guiding compound discovery from complex plant matrices (e.g., phenolamides from Allium hookeri) and mechanistic validation by characterizing senescence-associated metabolic remodeling, including retinoic acid metabolism restoration, lipotoxic metabolites attenuation, tricarboxylic acid (TCA) cycle, and choline-betaine-TCA cascade regulation. However, challenges in pharmacokinetic optimization, methodological heterogeneity in senescence induction and biomarker panels persist. Plant-derived senotherapy characterized through metabolomics-guided pipelines provides a compelling foundation for their progression toward clinical validation and functional food applications as accessible interventions for healthy aging and age-related disease management. Full article

Naturally derived bioactive compounds that modulate aging-associated mechanisms have attracted growing research interest, yet few reviews examine how such compounds might act together. This narrative review examines four mechanistically distinct compounds, namely spermidine, fisetin, berberine, and urolithin A, as emerging functional food ingredients with scientifically supported effects on key hallmarks of human aging. Spermidine, a dietary polyamine from wheat germ and fermented foods, induces autophagy through EP300 inhibition and is associated with reduced all-cause mortality in prospective studies. Fisetin, a flavonoid from strawberries and apples, exerts senolytic activity by selectively eliminating senescent cells via PI3K/AKT and Bcl-2/Bcl-xL inhibition, with emerging clinical evidence. Berberine, an isoquinoline alkaloid from Berberis species, modulates metabolic dysfunction via AMP-activated protein kinase (AMPK) activation and reshapes gut microbiota composition through direct high intraluminal exposure, with the most extensive clinical dataset of the four compounds. Urolithin A, a gut microbiome-derived postbiotic from ellagitannins in pomegranates and nuts, induces mitophagy via PINK1/Parkin and has been evaluated in a growing number of registered human clinical trials. Together, the four compounds primarily target distinct but complementary aging-associated pathways (autophagy, senolysis, metabolic regulation, mitophagy), suggesting rational potential for combined functional food formulations. Limited direct evidence for their combined use and the need for dedicated co-administration studies are discussed, alongside bioavailability, safety, and regulatory considerations. Full article

Cardiac senescence is not an isolated organ decline but a systemic consequence driven by pathological crosstalk between the heart and its peripheral metabolic organs. In this review, we discard the traditional organ–centric perspective and construct an integrated framework around multi-organ crosstalk axes, including the epicardial adipose tissue–heart axis, the skeletal muscle–heart axis, the gut–heart axis, and the kidney–heart axis. For each axis, we dissect the local molecular mediators—inflammatory cytokines, lipotoxic metabolites, microbiota-derived compounds such as trimethylamine N-oxide (TMAO), renin-angiotensin-aldosterone system (RAAS) effectors, and extracellular vesicle (EV) cargoes—and illustrate how they converge onto common pathways of oxidative stress, impaired autophagy, and cellular senescence. Importantly, we emphasize that these signals do not operate in isolation; they act synergistically through the circulation, converting local organ dysfunction into systemic cardiac aging via convergence onto shared senescence pathways. By redefining aging as a potentially modifiable multi-organ crosstalk, we propose emerging nodal points—senolytics, myokine mimetics, gut microbiota modulation, RAAS/sodium–glucose cotransporter 2 (SGLT2) inhibitors, and integrated lifestyle strategies—to block pathological crosstalk and delay cardiovascular aging. This framework shifts the research focus from isolated organs to systemic multi-organ crosstalk, providing new insights into cardiometabolic aging. Full article

Background/Objectives: Long COVID is characterised by persistent symptoms such as fatigue, pain, cognitive impairment, sleep disturbances, and reduced quality of life (QoL) following SARS-CoV-2 infection. Proposed mechanisms include persistent immune activation, chronic inflammation, oxidative stress, endothelial dysfunction, mitochondrial disturbances, and virus-induced cellular senescence. Current management is largely supportive, highlighting the need for complementary strategies targeting these pathways. Natural polyphenols such as quercetin and curcumin possess anti-inflammatory, antioxidant, immunomodulatory, and potential senolytic properties that may modulate multiple pathways implicated in Long COVID. This study aimed to explore the potential complementary effects of oral quercetin–curcumin co-supplementation, administered alongside usual symptomatic management, in adults with persistent Long COVID symptoms. Methods: This single-centre, open-label, single-arm, pragmatic exploratory study enrolled 15 adults with Long COVID in an outpatient real-life clinical practice setting. Participants received a nutraceutical formulation containing quercetin (65 mg) and Curcuma longa extract standardised to provide 42 mg curcumin (Nasafytol^®), administered as two capsules twice daily for 8 weeks in addition to standard care. The primary endpoint was change in overall symptom burden assessed using the COVID-19 Yorkshire Rehabilitation Scale (C19-YRS). Secondary outcomes included fatigue (Fatigue Severity Scale, FSS), pain (Brief Pain Inventory—Short Form, BPI-SF), cognitive function (Patient-Reported Outcomes Measurement Information System Cognitive Function Short Form 8a, PROMIS-CF-8a), mood (Hospital Anxiety and Depression Scale, HADS), sleep quality (Pittsburgh Sleep Quality Index, PSQI), autonomic symptoms (Composite Autonomic Symptom Score-31, COMPASS-31), and health-related QoL (Medical Outcomes Study 36-Item Short-Form Health Survey, SF-36). Results: After 8 weeks, overall symptom burden significantly decreased (C19-YRS median 50 to 32; q = 0.018). Significant reductions were observed in patient-reported fatigue (q = 0.006), pain severity and interference (q = 0.006), and improved physical health-related QoL (SF-36 PCS; q = 0.025). Numerically favourable changes were also observed in cognitive function, anxiety, sleep quality, and autonomic symptoms, although these did not reach statistical significance. The supplementation was generally well tolerated with no serious adverse events. Conclusions: Quercetin–curcumin co-supplementation was associated with lower patient-reported symptom burden, fatigue, and pain and better physical health-related QoL after 8 weeks of supplementation in adults with Long COVID. These observed findings represent treatment-associated changes within this uncontrolled exploratory study and should be interpreted cautiously. Further evaluation in adequately powered randomised placebo-controlled trials is warranted. Trial registration: ClinicalTrials.gov (ID NCT06974058). Full article

Cellular senescence, characterized by stable cell cycle arrest, drives organismal aging and functional decline. Senescent cells (SnCs) increase in multiple tissues with age and contribute to pathology by resisting apoptosis, impairing regeneration, and releasing senescence-associated secretory phenotype (SASP) factors. Senotherapeutics, including senolytics and senomorphics, aim to reduce the impact of SnCs by selectively clearing SnCs or suppressing SASP production. Natural terpenoids are structurally diverse plant- and fungus-derived metabolites with antioxidant, anti-inflammatory, and cytoprotective properties. Growing evidence supports their ability to counteract senescence-associated phenotypes, including senescence-associated β-galactosidase (SA-β-gal) activity and the expression of p53, p21, and p16. In this review, we examine mono-, sesqui-, di-, and triterpenoids that modulate cell cycle regulation, SASP attenuation, redox homeostasis, mitochondrial function, autophagy, and apoptosis-related mechanisms. We also outline the principal pathways underlying these anti-senescence activities and highlight natural terpenoids as emerging modulators of cellular senescence. Full article

Background/Objectives: Fisetin (3,3′,4′,7-tetrahydroxyflavone) is a naturally occurring flavonol present in strawberries, apples, grapes, onions, cucumbers, and other plant sources. It has attracted considerable interest because of its antioxidant, anti-inflammatory, antimicrobial, anticancer, neuroprotective, cardioprotective, and senolytic properties. This review comprehensively evaluated the pharmacological activities, mechanisms of action, translational challenges, and global research trends associated with fisetin. Methods: A comprehensive literature review was conducted to synthesise evidence on the traditional uses, pharmacological properties, molecular mechanisms, and therapeutic applications of fisetin. Bibliometric analysis of publications from 2005 to 2024 was performed using the Web of Science Core Collection. A total of 664 records were retrieved using the keywords “fisetin” and “3,3′,4′,7-tetrahydroxyflavone”. Following refinement using Bibliometrix (version 5.0) and the Biblioshiny interface in RStudio, 658 publications were included in the final analysis. Results: Fisetin exhibited diverse biological activities through modulation of oxidative stress, inflammation, apoptosis, autophagy, mitochondrial function, and cellular senescence. Experimental evidence supports its therapeutic potential against cancer, cardiovascular, neurodegenerative, metabolic, and infectious diseases. However, poor aqueous solubility, low oral bioavailability, rapid metabolism, and limited clinical evidence continue to impede its clinical translation. Nanotechnology-based delivery systems, computational modelling, and multi-omics approaches show promise for improving its pharmacokinetic profile and therapeutic efficacy. Bibliometric findings revealed substantial growth in fisetin research, with China leading scientific output and Africa contributing comparatively few publications. Conclusions: Fisetin is a promising multifunctional phytochemical with broad therapeutic potential. Future research should emphasise advanced formulations, rigorous clinical trials, and international collaboration to accelerate its translation into evidence-based clinical practice. Full article

Cellular senescence contributes to skin aging through the accumulation of senescent cells and the secretion of senescence-associated secretory phenotype (SASP) factors. Although numerous botanical flavonoids have been reported to possess antioxidant and anti-aging properties, the relationship between phytochemical composition, antioxidant capacity, and senolytic activity in complex botanical extracts remains poorly understood. In this study, twenty botanical extracts were systematically compared using a standardized screening platform that integrated total flavonoid quantification, UPLC-Q-TOF-MS phytochemical profiling, antioxidant evaluation, cytotoxicity assessment, and phenotypic senolytic screening in oxidative-stress-induced human foreskin fibroblast (HFF) senescence models. Among the tested extracts, chlorella, water lily, green tea, and rosemary exhibited the most pronounced senolytic-associated activities while maintaining minimal cytotoxicity toward non-senescent fibroblasts. UPLC-Q-TOF-MS analysis revealed that these extracts possessed distinct flavonoid-enriched phytochemical fingerprints despite producing comparable biological responses. Notably, green tea extract exhibited the strongest antioxidant activity, whereas its phytochemical composition differed substantially from those of the other highly active extracts, indicating that antioxidant capacity alone does not predict senolytic efficacy. Collectively, the findings demonstrate that total flavonoid content, antioxidant activity, and senolytic activity are not necessarily directly correlated and highlight the importance of comprehensive phytochemical characterization combined with phenotypic biological screening for identifying botanical resources with senescence-modulating potential. These results provide a practical comparative strategy for discovering multifunctional botanical ingredients applicable to oxidative-stress-associated skin aging. Full article

The pathogenesis of knee osteoarthritis (KOA) involves bone homeostasis imbalance induced by inflammation, metabolism, age, mechanical stress, joint injury and other factors. Recently, Type H vessels (CD31^hiEMCN^hi endothelial cells) have emerged as a specialized endothelial cell subset that couples angiogenesis with osteogenesis. Type H angiogenesis in the diaphysis was found to be beneficial for maintaining bone homeostasis, while the abnormal proliferation of type H vessels in subchondral bone can lead to chondrocyte hypertrophy and osteophyte formation. However, the mechanism by which the abnormal proliferation of type H vessels induces KOA has not been elucidated in detail. In this review, we summarize the latest evidence on the role of type H endothelial cell function in the pathogenesis and progression of osteoarthritis (OA). We review the role of type H angiogenesis at different sites in the development and progression of OA and focus on the potential mechanisms that regulate type H angiogenesis in OA and the potential therapeutic value and significance of targeting type H angiogenesis in promoting bone regeneration and maintaining bone homeostasis. Finally, we discuss key obstacles and future directions for studying type H vessel regulation in KOA, offering an endothelial cell-based framework for understanding bone homeostasis and improving OA. Full article

(1) Background: Reactive oxygen species (ROS) act as physiological signaling mediators but contribute to oxidative damage, cellular dysfunction, and age-related disease when redox homeostasis fails. Forkhead box O4 (FOXO4) has emerged as a redox-sensitive regulator linking stress adaptation, antioxidant defense, and cellular senescence. This structured narrative review critically evaluates which redox- and aging-related conclusions are supported directly for FOXO4 and which remain inferred from other FOXO isoforms. (2) Methods: PubMed/MEDLINE, Scopus, and Web of Science were searched from inception to May 2026; Google Scholar was used only for supplementary citation tracking and did not contribute a separate platform-level count. Of 420 records, 300 remained after deduplication, 110 full texts were assessed, and 89 publications were retained. FOXO4-related evidence was classified as directly FOXO4-specific (n = 18), FOXO-family/conserved (n = 24), or extrapolated predominantly from FOXO1/FOXO3/DAF-16 (n = 20); 27 contextual publications on redox biology, senescence, disease, and NRF2 were tracked separately. (3) Results: The strongest FOXO4-specific evidence supports three mechanistic axes: cysteine-dependent redox sensing, stress-regulated nuclear trafficking and coactivator engagement through transportin-1 and p300/CBP, and FOXO4–p53-mediated survival of senescent cells. By contrast, direct FOXO4 regulation of commonly cited antioxidant targets, including SOD2, catalase, sestrins, and GADD45, remains insufficiently demonstrated and is inferred mainly from FOXO3 or broader FOXO-family studies. FOXO4-DRI has shown senolytic activity in preclinical models, including vascular endothelium, but has not been clinically validated. (4) Conclusions: FOXO4 is a redox-responsive transcriptional regulator with well-supported roles in cysteine-based signaling and senescent-cell survival, whereas its target-gene-level antioxidant program remains incompletely resolved. Clinical translation of FOXO4–p53 disruption requires isoform- and tissue-specific validation, pharmacokinetic and delivery studies, long-term toxicology, and explicit assessment of p53-dependent tumor surveillance. Full article

Background/Objectives: Cardiovascular disease increases with ageing and remains the leading cause of death worldwide. Cellular senescence contributes to cardiac dysfunction in the older population by secreting the senescence-associated secretory phenotype (SASP). Cardiac injury models induced by surgery have been shown to induce senescence in young adult rodents. However, surgical models are complex and associated with high mortality. Methods: We established a rat model of injury and senescence using isoproterenol (ISO). Male SD rats received ISO (100 mg/kg) for five days, then hearts were collected on days 10 and 28 after the first ISO dose. Results: ISO administration caused cardiac injury, manifested by inflammatory infiltration, fibrosis, and increased cardiomyocyte cross-sectional area. Cardiac injury was accompanied by an increase in the senescence markers SA-β-gal, p16 and p21, and DNA damage marker γH2AX. Moreover, the mRNA levels of p21 increased on day 10, along with several SASP factors, whereas the mRNA levels of p16 increased on day 28. Fibrosis, hypertrophy, and senescence persisted until day 28, indicating long-lasting cardiac remodeling and senescent cell accumulation. Conclusions: These findings suggest that ISO can provide a simple, cost-effective platform for studying senescence and cardiac injury. This model facilitates the study of timing, dosage, mechanisms and efficacy of senolytic interventions and may contribute to the development of senescence-targeted therapies. Full article

Chronic inflammation accelerates the aging process, and targeted clearance of senescent cells shows potential in alleviating age-related decline. PCC1, a potent senescent cell clearance agent in grape seed extract (GSE), has limited applications due to its low oral bioavailability. This study introduced a novel GSE formulation, Natural Senolytics PCC1 (NSPCC1), which significantly enhanced PCC1 absorption and metabolic characteristics. Validation in two mouse aging models demonstrated that oral administration of NSPCC1 markedly extended lifespan and promoted healthy aging. The formulation improved the capacity for hematopoietic stem/progenitor cell differentiation and reduced age-related myeloid cell bias. Comprehensive histological analysis revealed attenuated aging phenotypes in bone marrow and skin, improved peripheral blood erythroid parameters, and a partial increase in blood antioxidant capacity, alongside reduced M1 macrophage infiltration and fibrosis in liver, kidney, and lung tissues. These effects were validated through histological assessments, including H&E, Masson, F4/80, and iNOS staining. This study highlighted the pivotal role of hematopoietic stem cells in aging and established NSPCC1 as a promising natural intervention for age-related pathologies. Its enhanced efficacy lays the groundwork for deeper exploration of natural products in aging biology and provides crucial support for the development of safe and effective anti-aging therapies. Full article