The Journals of Gerontology Series A: Biological Sciences and Medical Sciences最新文献

{"title":"Predicting One-Year Mortality in Older Cancer Patients: Performance of G8, SPPB, and IF-VIG in the PROFIT Study.","authors":"Maria Cristina Ferrara,Fabricio Zambom-Ferraresi,Aida Ribera,Idoia Morilla-Ruiz,Sofia Espinoza-Tofalos,Carmina Castellano-Tejedor,Josep Majó-Llopart,Oriol Planesas-Pérez,Eva Heras,Francisco José Tarazona-Santabalbina,Hugo Badani,Nicolàs Martínez-Velilla,Marco Inzitari","doi":"10.1093/gerona/glag099","DOIUrl":"https://doi.org/10.1093/gerona/glag099","url":null,"abstract":"BACKGROUNDFrailty is a prognostic determinant in older patients, yet the most effective tools to predict survival remain unclear. This study aimed to assess the predictive performance of different frailty assessment tools for one-year mortality in oncogeriatric population.METHODSA multicenter cohort study (PROFIT Study) involved patients aged ≥65 with cancer, evaluated in oncology clinics and post-acute oncogeriatric units. Frailty was measured using the Geriatric 8 questionnaire (G8), Short Physical Performance Battery (SPPB), and the Frailty Index Indice Frágil-Valoración Integral Geriátrica (IF-VIG). One-year mortality was monitored. Predictive ability was analyzed using ROC curves with optimized cut-offs, and covariate-adjusted Cox regression models were used to evaluate the association between frailty and mortality.RESULTSAmong 229 patients (mean age 75.1 ± 6.4 years; 68.6% male; cancer type: 47.2% lung cancer, 17.9% colorectal, 25.3% other gastrointestinal, 9.6% prostate; tumoral stage IV: 85.2%), 146 (63.7%) died within one year. All tools showed predictive value, with IF-VIG demonstrating the highest sensitivity and SPPB the highest specificity. Optimized cut-offs improved performance compared to standard thresholds (G8: 12.5 vs. 14; SPPB: 8 vs. 9; IF-VIG: 0.16 vs. 0.25). Adjusted Cox models confirmed significant associations with one-year mortality: hazard ratio [HR] 1.97 (95% CI 1.30-2.99) for G8, 2.35 (95% CI 1.52-3.64) for SPPB, and 2.42 (95% CI 1.50-3.90) for IF-VIG.CONCLUSIONSAll frailty tools were significantly associated with one-year mortality. SPPB and IF-VIG outperformed G8 in prognostic accuracy, highlighting their potential utility in clinical decision-making for older patients with cancer.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147695248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteome-wide association study of cortical proteins that may provide resilience for late-life disability","authors":"Brittney S Lange-Maia, Ricardo A Vialle, Tianhao Wang, Andrea R Zammit, Jose Farfel, Nicholas T Seyfried, David A Bennett, Aron S Buchman","doi":"10.1093/gerona/glag101","DOIUrl":"https://doi.org/10.1093/gerona/glag101","url":null,"abstract":"Disabilities are common and untreatable in many older adults. This proteome-wide discovery study identified cortical proteins that may provide resilience for disabilities in older adults. Participants were 850 decedents (mean age 89.3 years [SD: 6.6] at death, 67% female) from two longitudinal cohort studies with proteome-wide data collected from the dorsal lateral prefrontal cortex, indices of 10 Alzheimer’s disease and related dementia (ADRD) pathologies, and measures of mobility disability, instrumental activities of daily living (IADLs), and activities of daily living (ADLs) prior to death. Linear regression models adjusting for demographics identified proteins related to each disability phenotype correcting for multiple comparisons (p < 5 × 10−6). Resilience proteins—operationalized as proteins related to residual disability after adjusting for ADRD pathologies—were aggregated into resilience index scores for each disability instrument and their associations with adverse health outcomes were tested. Exploratory functional enrichment analyses identified molecular pathways associated with resilience proteins. We identified 12 resilience proteins related to mobility disability, 215 for IADL and 291 for ADL disability. Models with resilience index scores accounted for an additional 2.7%, 3.3%, and 3.5% of the variance of mobility, IADL, and ADL disability, respectively, compared to 1.7%, 2.7% and 2.0%, for ADRD pathologies. In exploratory analyses, key enriched Gene Ontology terms were predominantly related to mitochondrial function. Further work targeting these cortical proteins is needed to demonstrate that they provide resilience for disability in older adults and can facilitate functional independence in old age, though future work is needed to demonstrate protective mechanisms. Ultimately, targeting these proteins may lead to therapies that maintain functional independence in aging adults.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147702428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the Genetic Association Between Synaptic Genes and Parkinson's Disease Risk.","authors":"Qiyuan Sun,Zhedong Zheng,Qiong Wu,Min Zhong,Mingmin Wu,Runxia Xie,Lingfeng Lai,Qiujie Chen,Xuena Pan,Jitian Guan","doi":"10.1093/gerona/glag100","DOIUrl":"https://doi.org/10.1093/gerona/glag100","url":null,"abstract":"Recent research indicates a strong link between synaptic dysfunction and Parkinson's disease (PD). This study utilizes summary data-based Mendelian randomization (SMR) to explore genetic associations and causal relationships between synaptic genes and the risk of developing PD. This study utilized the GeneCards database to gather synaptic genes. Subsequently, we integrated QTL data related to these genes, encompassing DNA methylation (mQTLs), gene expression (eQTLs), and protein expression (pQTLs). GWAS data on PD were acquired from the GWAS catalog, with validation datasets from FinnGen dataset. The SMR method was used to assess potential causal relationships, and colocalization analysis was performed to verify that the signals were due to shared genetic variants, thereby enhancing the robustness of the findings. Furthermore, five tissue eQTL datasets were used for tissue-specific validation. Through SMR and colocalization analyses, we identified 67 methylation sites corresponding to 33 genes in mQTLs, 10 genes in eQTLs, and 4 proteins in pQTLs associated with PD. Integration of multi-omics evidence highlighted Adhesion Molecule With Ig Like Domain 1 (AMIGO1) as potentially key gene in the association between synapses and PD, with positive SMR results in both mQTL-eQTL analysis and eQTL-pQTL analysis. The tissue-specific validation results further underscores the critical role of AMIGO1 in the disease. Our study emphasizes the importance of synaptic genes, particularly AMIGO1, in the pathogenesis of PD. Future research should build on these findings by elucidating the specific mechanisms of these genes through functional experiments, with the ultimate goal of developing effective prevention and treatment strategies.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147680437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Frailty and Genetics: Linking Molecular Aging to Clinical Vulnerability.","authors":"Jhuliana Castillo,Natalia García,Fernando Gómez","doi":"10.1093/gerona/glag088","DOIUrl":"https://doi.org/10.1093/gerona/glag088","url":null,"abstract":"Aging is a multifactorial process involving cumulative cellular and molecular damage, directly affecting physiological reserve and homeostasis. In this context, frailty emerges as a complex, dynamic, and potentially reversible geriatric syndrome, associated with inflammatory dysregulation, immunosenescence, and genetic alterations. This narrative review presents the most recent findings linking frailty to genetic factors, including genome-wide association studies and specific polymorphisms related to inflammation. The genetic relationship between frailty and various chronic comorbidities is also explored. This genetic perspective provides a promising framework for a better understanding of the etiopathogenesis of frailty and highlights new opportunities for individualized interventions.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147663863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycemic Control Targets in Older Adults with Type 2 Diabetes and Chronic Kidney Disease: A Trajectory-Based Survival Analysis of HbA1c.","authors":"Wang Xiaolong,Yang Jian,Shuang Liang,Zheyi Dong","doi":"10.1093/gerona/glag097","DOIUrl":"https://doi.org/10.1093/gerona/glag097","url":null,"abstract":"BACKGROUNDThe optimal glycemic target for older adults with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) remains controversial. This study analyzed longitudinal HbA1c trajectories to compare glycemic-mortality associations between older and younger adults, providing real-world evidence for individualized glycemic management.METHODSThis retrospective multicenter cohort study utilized the Tianjin Health and Medical Big Data Super Platform (2000-2025), including 2,037 older adults as the primary cohort and 6,075 younger adults as controls. Group-based trajectory modeling (GBTM) identified latent HbA1c evolution patterns. LASSO regression, multivariate Cox proportional hazards models, and Kaplan-Meier curves assessed mortality associations. A five-trajectory model refined the optimal glycemic range, with robustness confirmed through subgroup and sensitivity analyses.RESULTSOver a median follow-up of 4.56 years, 213 deaths (10.5%) occurred in older adults. Three trajectories were identified: Low-stable (38.5%, mean HbA1c 5.12%), Medium-declining (40.9%, 6.62%), and High-stable (20.6%, 8.50%). In younger adults, both High-stable and Medium-declining trajectories were associated with increased mortality risk; in older adults, only the High-stable trajectory significantly elevated risk (HR 1.73, P = 0.006). Five-trajectory analysis demonstrated that maintaining HbA1c between approximately 6.66%-7.94% did not increase mortality risk, whereas progressive hyperglycemia ≥8.20% significantly increased risk (HR 1.75, P = 0.021). Effective glycemic reduction mitigated hyperglycemia-associated harm.CONCLUSIONOlder adults with T2DM and CKD exhibit distinct glycemic-mortality patterns compared to younger patients. Maintaining HbA1c between 6.5%-8% was associated with optimal survival outcomes, whereas sustained hyperglycemia exceeding 8% warrants active intervention. Individualized relaxed glycemic targets may optimize the balance between survival benefit and treatment burden in this population.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"90 4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147663866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Particulate Air Pollution and Constituents Exacerbate 10-year ASCVD Risk: Estimating Effects of Hypothetical Interventions.","authors":"Boxiang Wang,Shouxin Peng,Zhongyang Chen,Hanxiang Cai,Feifei Liu","doi":"10.1093/gerona/glag096","DOIUrl":"https://doi.org/10.1093/gerona/glag096","url":null,"abstract":"BACKGROUNDLong-term exposure to fine particulate matter (PM2.5) increases atherosclerotic cardiovascular disease (ASCVD) risk, but evidence on its components' effects and the potential benefits achievable through PM2.5 interventions remains limited.METHODSWe used data from participants in the China Health and Retirement Longitudinal Study (CHARLS) with low ASCVD risk at baseline. The associations between PM2.5, its components (black carbon, ammonium, nitrate, sulfate, organic matter), and 10-year ASCVD risk were evaluated using the generalized linear regression. Co-exposure effects of PM2.5 components were estimated using weighted quantile sum (WQS) regression and quantile g-computation. Effects of hypothetical PM2.5 interventions (reducing annual averages to 35, 25, and 15 μg/m3) on ASCVD risk were assessed using the parametric g-formula.RESULTSEach 10 μg/m3 increase in PM2.5 raised 10-year ASCVD risk by 18.3% (RR = 1.183, 95% CI: 1.099-1.267). Each 0.1 μg/m3 increase in black carbon and 1 μg/m3 increase in ammonium, nitrate, sulfate, and organic matter increased risks by 18.4%, 10.7%, 6.8%, 9.0%, and 6.7%, respectively. Nitrate contributed most (46.3%). Parametric g-formula estimated that reducing PM2.5 to 35, 25, and 15 μg/m3 lowered ASCVD risk by 2.78%, 3.15%, and 3.43%, respectively. Psychological conditions (e.g. depression) mediated 10-year ASCVD risk. Interaction analysis showed females were more susceptible to PM2.5 and its components.CONCLUSIONLong-term exposure to PM2.5 and its components elevates ASCVD risk in Chinese adults, with greater susceptibility in females. Reducing PM2.5 concentrations significantly mitigates ASCVD risk.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"48 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147663864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Interplay Between Osteosarcopenia and Intrinsic Capacity: Insights and Associations With All-Cause Mortality in the Toledo Study for Healthy Aging.","authors":"Ivan Baltasa R-Fernandez,Pedro L Valenzuela,Irene Rodríguez-Gómez,Fabio Quiñonez-Bareiro,Luis M Alegre,Konstantinos Prokoipidis,Leocadio Rodriguez-Mañas,Ignacio Ara,Oscar Rosas-Carrasco,Lana Williams,Robinson Ramirez-Vélez,Julie Pasco,Guy Hajj-Boutros,Raman Agnihotram,Marc Sim,Wayne Lok,Mahdi Imani,Ana Maria Ayala-Copete,Julia Chabot,Miguel G Borda,Nailton J Neto,Claire Godard-Sebillotte,Howard Bergman,Anna Andrianova,Hidenori Arai,Pierrette Gaudreau,Liang Kung Chen,Hussein Samhat,Tiago da Silva Alexandre,Ricardo Guerra,Andréa Faust,Alexandra Papaioannou,Harmehr Sekhon,Emma Connolly,Gustavo Duque,Francisco José García-García, ","doi":"10.1093/gerona/glag090","DOIUrl":"https://doi.org/10.1093/gerona/glag090","url":null,"abstract":"BACKGROUNDOsteosarcopenia-the coexistence of osteopenia/osteoporosis and sarcopenia-is associated with numerous adverse health outcomes, but its association with intrinsic capacity (IC) remains unknown. We aimed to explore the associations of osteosarcopenia with IC and all-cause mortality in older adults.METHODSWe conducted a cross-sectional analysis of IC and a prospective analysis of all-cause mortality in 1142 participants from the Toledo Study for Healthy Aging (75.1±6.0 years, 53.1% women). Participants were classified as having no musculoskeletal disorders, osteopenia/osteoporosis, sarcopenia, or osteosarcopenia (DXA- and EWGSOP2-based criteria). IC was operationalized as a composite score integrating locomotion, cognition, psychological, vitality, and sensory domains.RESULTSOlder adults with osteosarcopenia exhibited lower total IC (76.6±1.1 points) than those without musculoskeletal disorders (83.7±0.5 points; p<0.001) or with osteopenia/osteoporosis (81.3±0.3 points; p<0.001), with significant differences also found between the latter groups (p<0.001). Specifically, osteosarcopenia was associated with poorer results in the locomotion, cognition, vitality, and sensory domains (all p<0.01), but not in the psychological domain. Over a median 6.2-year follow-up, osteosarcopenia-but not osteopenia/osteoporosis-was associated with higher risk of mortality compared to those without musculoskeletal disorders [HR (95%CI)=1.96 (1.02-3.77); p=0.045]. In joint analyses with IC status (high vs. low, segregated by the median), this association was specifically observed among participants with osteosarcopenia and low IC [HR = 2.55 (1.31-4.96); p=0.004].CONCLUSIONSOsteosarcopenia is associated with lower total IC and impairments across most IC domains. This finding is of clinical relevance, as the combination of this condition and low IC is associated with an increased mortality risk.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"210 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147641661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hot flashes, cold feet: a cautious embrace of regulatory reform.","authors":"Raya Elfadel Kheirbek,Stephen N Davis","doi":"10.1093/gerona/glag080","DOIUrl":"https://doi.org/10.1093/gerona/glag080","url":null,"abstract":"","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"51 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147663865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of aging on rat testicular interstitial compartment: functional losses in endothelial and mesenchymal cells and activation of immune cells.","authors":"Zhenni Li,Zhaobo Xia,Yun Hu,Enhui Wu,Liang Minhui,Jingwen Liu,Hanmin Cai,Niu Xinyu,Xiaoju Guan,Zhijian Su,Congde Chen,Haolin Chen","doi":"10.1093/gerona/glag089","DOIUrl":"https://doi.org/10.1093/gerona/glag089","url":null,"abstract":"Human aging is associated with testosterone decline and spermatogenic defects, impacting fertility and health, yet the underlying cellular mechanisms remain poorly understood. This study aimed to establish a regulatory cell atlas of Leydig cells in aging rat testes and characterize intercellular interactions. Using single-cell RNA sequencing and immunohistochemistry, interstitial cells from young (3-month) and aged (21-month) BN rat testes were analyzed. Among eight identified interstitial cell types, aging was not synchronous, but with remarkable heterogeneity and stochasticity. Mesenchymal cells exhibited reduced expression of genes involved in detoxification and extracellular matrix maintenance, alongside increased immune regulation genes. Endothelial cells, the most communicatively active population, showed decreased angiogenesis and cell adhesion/migration but enhanced immune responses and leukocyte chemotaxis. In immune populations, dendritic cells decreased while lymphocytes increased, with no significant change in macrophages. Transcriptomic shifts indicated a transition from innate to adaptive immunity. The loss of dendritic cells and gain of lymphocytes may be linked to CCL7 and CXCL9-12, as receptors Ccr1/Ccr5 and Cxcr3 were upregulated in lymphocytes but downregulated in dendritic cells. Overall, inflammatory activation and functional losses occurred in both immune and non-immune cells during testicular aging. This innate-to-adaptive immune shift may further compromise non-immune cell functions, accelerating testicular aging.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"113 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147641659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The ISG15 Axis: A Central Mediator and Therapeutic Target in Vascular Inflammaging.","authors":"Ziwei Fang,Shuyi Nie,Hualin Chen,Chenxin Deng,Cuntai Zhang,Le Zhang","doi":"10.1093/gerona/glag087","DOIUrl":"https://doi.org/10.1093/gerona/glag087","url":null,"abstract":"Vascular aging, which is characterized by the progressive decline in the structure and function of blood vessels, is a primary driver of cardiovascular morbidity and mortality in older adults. Although chronic low-grade inflammation (inflammaging) and cellular senescence are central to this process, the molecular nodes that integrate these pathways are not well understood. This review proposes that interferon-stimulated gene 15 (ISG15), a well-established ubiquitin-like modifier in antiviral defense, acts as a critical nexus linking these pathological hallmarks in vascular aging. ISG15 is proposed to function through a dual mechanism: extracellularly, it propagates pro-inflammatory signaling; intracellularly, its covalent conjugation to target proteins (ISGylation) disrupts core homeostatic processes. The review presents evidence demonstrating that the ISG15 system, when activated by sterile triggers via the cGAS-STING pathway, drives endothelial dysfunction and vascular smooth muscle cell phenotypic switching by exacerbating oxidative stress, inducing cellular senescence, and disrupting proteostasis. Consequently, the ISG15 axis is established as a compelling therapeutic target. The rationale behind strategies that range from the direct inhibition of ISGylation and the neutralization of extracellular ISG15, to the repurposing of existing upstream interferon-pathway inhibitors, is discussed. Key outstanding questions are outlined to guide future research, paving the way for novel diagnostics and interventions aimed at preserving vascular health during aging.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"32 2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147641660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}