{"title":"Cellular retinoic acid-binding protein 1, CRABP1, in thyroid gland aging.","authors":"Fatimah Najjar, Jennifer Nhieu, Natalia Calixto Mancipe, Christy Henzler, Li-Na Wei","doi":"10.1038/s41514-026-00386-6","DOIUrl":"10.1038/s41514-026-00386-6","url":null,"abstract":"<p><p>Aging differentially affects disease risks of various organs<sup>1</sup>. The endocrine organs undergo significant changes along aging. Clinical reports showed increased prevalence of thyroid disorders with age, especially hypothyroidism<sup>2</sup>. Primary hypothyroidism includes congenital, autoimmune, and iatrogenic causes, which can occur throughout the lifespan. But those with unknown aetiology increase dramatically (~5 fold) in the elderly (≥75 years old)<sup>3,4</sup>. In thyrocytes, accumulated thyroglobulin requires efficient protein folding in the endoplasmic reticulum (ER)<sup>5,6</sup>. When ER experiences protein folding defects, it activates the unfolded protein response (UPR), which determines the life-or-death cell fate. The most fundamental mediator in UPR signaling is inositol-requiring enzyme-1 alpha (IRE-1α)<sup>7</sup>. This study reports, for the first time, a highly conserved gene, Cellular retinoic acid binding protein 1 (Crabp1), critical to thyrocyte function in aging. CRABP1 acts by modulating clustering and activation of IRE-1α, thereby reducing thyrocyte ER stress.</p>","PeriodicalId":94160,"journal":{"name":"npj aging","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13265909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147694488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The retina-body axis: proteomic mechanisms linking oculomics and clinical traits in a female aging cohort.","authors":"Selena Wei Zhang, Shunming Liu, Yanxian Chen, Jing Liu, Ying Yao, Xianwen Shang, Honghua Yu, Yu Huang, Mingguang He","doi":"10.1038/s41514-026-00385-7","DOIUrl":"10.1038/s41514-026-00385-7","url":null,"abstract":"<p><p>The retina provides a unique window into systemic health, yet molecular mechanisms linking retinal features (oculomics) to clinical traits in aging remain unclear. In this study, we leveraged the homogeneous Canton 70 s Alumni Cohort (N = 258 females aged ~70 years) to minimize socio-demographic confounders and extracted oculomic features from fundus images using AutoMorph. Linear mixed-effects models identified 129 significant associations between oculomic and clinical features (p < 0.05). Sparse canonical correlation analysis indicated a key phenotypic retina-body axis (r = 0.538, p = 0.047) primarily driven by central retinal venular equivalent (Hubbard, zone b) and mean corpuscular hemoglobin concentration. Permutational Multivariate Analysis of Variance revealed that oculomic categories were significantly associated with systemic conditions like chest pain, dyslipidemia, and stroke. Age differentially impacted retinal features across clinical condition status (adjusted p for interaction < 0.2), with pronounced trends in individuals with health problems but relative stability in healthy controls. Plasma proteomics was integrated to explore potential molecular mechanisms. Weighted gene co-expression network analysis identified shared proteomic modules associated with both oculomic and clinical features. These modules were enriched in pathways including complement and coagulation cascades, cholesterol metabolism, and cytokine-cytokine receptor interaction. This study establishes both phenotypic and molecular connections underlying the retina-body axis in a female aging cohort.</p>","PeriodicalId":94160,"journal":{"name":"npj aging","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13265977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147679777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
npj agingPub Date : 2026-04-09DOI: 10.1038/s41514-026-00376-8
Giulia De Simone, Chiara Stival, Michele Rossi, Annalisa Davin, Alessia Giannetta, Carlotta Micaela Jarach, Mirco Luciano Randazzo, Toshiko Tanaka, Aurelia Morabito, Silvano Gallus, Stefania Bandinelli, Luigi Ferrucci, Antonio Guaita, Alessandra Lugo, Alice Passoni, Laura Brunelli
{"title":"Plasma hippuric acid as a marker of frailty influenced by dietary fruit and vegetable consumption: longitudinal analysis in Italian cohorts of older adults.","authors":"Giulia De Simone, Chiara Stival, Michele Rossi, Annalisa Davin, Alessia Giannetta, Carlotta Micaela Jarach, Mirco Luciano Randazzo, Toshiko Tanaka, Aurelia Morabito, Silvano Gallus, Stefania Bandinelli, Luigi Ferrucci, Antonio Guaita, Alessandra Lugo, Alice Passoni, Laura Brunelli","doi":"10.1038/s41514-026-00376-8","DOIUrl":"10.1038/s41514-026-00376-8","url":null,"abstract":"<p><p>Frailty is a geriatric syndrome characterised by loss of function and increased risk of death. Identification of individuals at risk of frailty is crucial for effective preventive interventions. This study aimed to investigate the association between plasma hippuric acid concentrations and frailty across two longitudinal Italian cohorts. Plasma hippuric acid was quantified using European Medicines Agency-validated mass spectrometry methods in plasma samples from InCHIANTI (n = 534; 55.4% females; aged ≥65 years, 1998, 2002, 2004, 2008 follow-ups, FU) and InveCe.Ab (n = 912; 53.8% females; aged ≥70 years, 2010, 2012, 2014, 2018 FU) participants who were non-frail at baseline. Frailty was defined through two different classifications: frailty index (FI) and frailty phenotype (FP). Longitudinal association between hippuric acid and frailty indexes within the two cohorts was assessed by linear mixed models adjusting for sex, age, educational status, renal and liver function, and body mass index. Mediation analyses explored the role of hippuric acid in mediating the fruit and vegetable consumption-frailty relationship. Median values of hippuric acid concentrations were significantly lower in frail compared to non-frail participants (measured by FI) in both (i) InCHIANTI study: non-frail = 1.59 (Q<sub>1</sub>-Q<sub>3</sub>, 0.99-2.74) μg/ml vs frail = 1.18 (0.75-1.88) (μg/mL in 2004 year FU; non-frail = 1.44 (0.87-2.50) μg/ml vs frail = 1.12 (0.63-1.99) μg/ml in 2007 year FU; and (ii) InveCe.Ab study: non-frail = 2.19 (1.26-3.92) μg/ml vs frail = 1.81 (0.87-3.65) μg/ml in 2018 year FU. No statistically significant cross-sectional associations were observed between hippuric acid and FP. Longitudinal association showed that higher plasma hippuric acid levels were significantly associated with a reduced risk of frailty (p = 0.026 InCHIANTI and p = 0.044 InveCe.Ab). Longitudinal mediation analysis indicated that hippuric acid act as mediator of the relationship between fruit and vegetable intake and FI (p < 0.05) in both cohorts. Low plasma hippuric acid levels may serve as a marker of frailty, potentially linked to reduced fruit and vegetable intake.</p>","PeriodicalId":94160,"journal":{"name":"npj aging","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13249886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147648072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
npj agingPub Date : 2026-04-09DOI: 10.1038/s41514-026-00382-w
Paolo Cimaglia, Elisa Mikus, Michele Trichilo, Elisabetta Tonet, Mariafrancesca Fiorentino, Diego Sangiorgi, Simona Brogneri, Jacopo Bonini, Chiara Bianchi, Alberto Sarti, Elena Tremoli, Carlo Savini
{"title":"Correlation between frailty status, surgical access, and outcomes in older adults with valvular heart disease undergoing cardiac surgery.","authors":"Paolo Cimaglia, Elisa Mikus, Michele Trichilo, Elisabetta Tonet, Mariafrancesca Fiorentino, Diego Sangiorgi, Simona Brogneri, Jacopo Bonini, Chiara Bianchi, Alberto Sarti, Elena Tremoli, Carlo Savini","doi":"10.1038/s41514-026-00382-w","DOIUrl":"10.1038/s41514-026-00382-w","url":null,"abstract":"<p><p>Frailty is not routinely assessed nor incorporated into the Euroscore II, and evidence on minimally invasive cardiac surgery (MICS) in older frail adults remains limited. We evaluated whether frailty assessment improves the prognostic performance of the Euroscore II and whether MICS provides benefits in frail patients. Patients aged ≥70 years undergoing valve surgery were assessed for frailty preoperatively. The primary endpoint was the composite of all-cause death or cardiovascular hospitalization at 1 year; the secondary endpoint was 1-year all-cause mortality. A total of 568 patients were included (median age 76 years; median Euroscore II 2.3); 65.3% underwent elective surgery, and 63.4% MICS. For the primary endpoint, the Edmonton Frailty Scale (EFS) provided the greatest improvement when added to Euroscore II (Harrell's C + 0.054, p < 0.05), followed by the Clinical Frailty Scale (+0.013, p < 0.05). For mortality, EFS showed the largest gain (+0.057, p < 0.05), followed by the Essential Frailty Toolset (+0.011, p < 0.05). In frail patients, MICS was protective for mortality but not for the composite endpoint. Frailty assessment, particularly EFS, improves risk stratification, and MICS may reduce mortality in frail older adults.</p>","PeriodicalId":94160,"journal":{"name":"npj aging","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13249931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147648074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Aging effects on emotionality, cognition and brain mononuclear cells in Sprague-Dawley rats of both sexes.","authors":"Jasmina Djuretić, Jana Ivanović, Kristina Jezdić, Vanja Todorović, Biljana Bufan, Anja Santrač, Jovana Aranđelović Ilić","doi":"10.1038/s41514-026-00364-y","DOIUrl":"10.1038/s41514-026-00364-y","url":null,"abstract":"<p><p>Aging impairs the function of immune cells and increases susceptibility to diseases such as anxiety and dementia. Nevertheless, some individuals exhibit resilience to age-related impairments, although the mechanisms are still unclear. This study investigated alterations in brain mononuclear cells and their association with age-related behavioral deficits in male and female rats. Flow cytometry was used to analyze the expression of CD45, CX3CR1, and CD163 on brain CD11b+ cells. Aging rats demonstrated reduced anxiety-like behavior, spatial learning, and social play, with certain sex differences. Young adult females showed hyperactivity and higher cognitive flexibility than same-aged males. Aging increased CD45 and CD163 expression within CD11b+ cells. Furthermore, sex-dependent correlations were observed between expression of CD163 and CX3CR1 within CD11b+ cells and locomotor activity in aging. Females might appear to be more susceptible to aging, suggesting microglial activation as a compensatory mechanism. These results suggest immune cell dynamics underlying sex-specific aging behavior.</p>","PeriodicalId":94160,"journal":{"name":"npj aging","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13233918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147635385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
npj agingPub Date : 2026-04-06DOI: 10.1038/s41514-026-00370-0
Bin Yu, Yajuan Zhang, Yong Tang, Meiling Hu, Jinfen Wei
{"title":"HCCaging: a liver physiological aging-related biomarker for hepatocellular carcinoma diagnosis based on transcriptome data.","authors":"Bin Yu, Yajuan Zhang, Yong Tang, Meiling Hu, Jinfen Wei","doi":"10.1038/s41514-026-00370-0","DOIUrl":"10.1038/s41514-026-00370-0","url":null,"abstract":"<p><p>Aging is a fundamental biological process that influences cancer development in a context-dependent manner; however, how aging-related programs manifest in hepatocellular carcinoma (HCC) remains incompletely understood. Here, we systematically characterized aging-associated features in HCC by establishing a liver cancer-specific aging signature, termed HCCaging, across more than 2,000 tumor samples from 16 independent cohorts. We comprehensively evaluated its heterogeneity and associations with clinical outcomes, tumor stage, immune infiltration, and therapeutic response. The HCCaging score increased with chronological age, was higher in normal liver than tumor tissues, and elevated in early- versus late-stage tumors. In contrast, 13 previously reported aging- or senescence-related gene sets failed to show consistent patterns across these conditions in HCC. Machine learning models, including gradient boosting machines and random forests, achieved higher accuracy in distinguishing tumor from non-tumor samples using the HCCaging score compared with other 13 aging- or senescence-gene sets across eight independent HCC cohorts. Single-cell transcriptomic profiling revealed that HCCaging increased with age, particularly within epithelial compartments, reaching its highest levels in hepatocytes. Notably, although the proportion of T/NK cells declined with aging, their functional programs, including activated effector function, chemokine/chemokine receptor signaling, cytolytic activity, and pro-inflammatory pathways, were enhanced in older individuals. The HCCaging score, together with key genes ACAA1 and ESR1, were negatively correlated with T/NK cell infiltration, anti-inflammatory activity, and anti-apoptotic signatures, but positively correlated with pro-apoptotic, pro-inflammatory, chemokine, and cytolytic pathways. Furthermore, increased expression of XCL1 and XCL2 in T/NK cells with aging correlated positively with HCCaging, ACAA1, and ESR1, suggesting preserved or even enhanced antitumor potential of T/NK cells in older patients. Collectively, these findings highlight the dual role of aging in liver tumorigenesis. Hepatic aging and enhanced T/NK cell effector function may confer tumor-protective effects, whereas the concomitant decline in overall T/NK cell infiltration likely compromises immunosurveillance, thereby increasing carcinogenic susceptibility in the aging liver. This study provides new insights into the heterogeneity of hepatic aging and its complex interplay with the HCC tumor microenvironment and clinical outcomes.</p>","PeriodicalId":94160,"journal":{"name":"npj aging","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13230847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147629644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
npj agingPub Date : 2026-04-06DOI: 10.1038/s41514-026-00372-y
Magdalena Sepúlveda, Iván Palomo, Felipe Lagos, Ximena Pardo, Camilo López-Alarcón, Felipe Ávila, Eduardo Fuentes
{"title":"Biomarkers of oxidative damage as a tool to investigate frailty syndrome in older women.","authors":"Magdalena Sepúlveda, Iván Palomo, Felipe Lagos, Ximena Pardo, Camilo López-Alarcón, Felipe Ávila, Eduardo Fuentes","doi":"10.1038/s41514-026-00372-y","DOIUrl":"10.1038/s41514-026-00372-y","url":null,"abstract":"<p><p>Frailty syndrome (FS) is a critical factor associated with several oxidative stress and age-related diseases. In this work, we investigated the connection between frailty, defined at early stages using a new cut-off value of the Frailty Trait Scale (FTS-5), and plasma biomarkers of oxidative stress. Plasma samples of 76 older women were analyzed to determine free and protein-bounded tryptophan (Trp), kynurenine (Kyn), N-formylKynurenine (N-Kyn), advanced glycation end products, and protein carbonylation. A subgroup of 30 subjects was selected from the entire group to determine malondialdehyde (MDA), free methionine (Met), phenylalanine (Phe), Trp, and Kyn. In the whole group (N = 76), Kyn and the Kyn/Trp ratio were higher in women with a Romberg test altered (p-values = 0.0439, and 0.0472, respectively) and BMI < 25.3 kg/m<sup>2</sup> (p-values = 0.0008, and 0.0011, respectively). Increased protein carbonylation was found for subjects with BMI ≥ 25.3 kg/m<sup>2</sup>. For the subgroup, an increase in the Kyn/Trp ratio was observed in subjects with an altered Romberg test, concomitant with decreased levels of Trp, Met, Phe, and MDA (p-values = 0.0255, 0.0427, 0.0459, and 0.0173, respectively) when data were grouped according to the modified FTS-5. These results highlight the relevance of oxidative biomarkers as a tool for an early diagnosis of FS and its related complications.</p>","PeriodicalId":94160,"journal":{"name":"npj aging","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13230943/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147629618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Elevated trimethylamine levels characterize impaired muscle mass response to leucine-enriched protein supplementation in older adults at risk of sarcopenia.","authors":"Hsiang-Yu Tang, Chi-Jen Lo, Hung-Yao Ho, Cheng-Hung Yang, Chen-Yu Chang, Yu-Hsuan Ho, Ji-Tseng Fang, Chih-Ming Lin, Mei-Ling Cheng","doi":"10.1038/s41514-026-00375-9","DOIUrl":"10.1038/s41514-026-00375-9","url":null,"abstract":"<p><p>Leucine-enriched supplementation is a primary intervention for sarcopenia, yet individual responses vary. We integrated <sup>1</sup>H-NMR metabolomics with clinical assessments in 47 older adults at high sarcopenia risk to identify metabotypes associated with improvements in muscle mass and strength. Following a 12-week intervention, distinct metabolic trajectories emerged between responders and non-responders. Notably, urinary levels of the gut-derived metabolite trimethylamine (TMA) and phenylpyruvic acid exhibited divergent trends across outcome-defined groups. Elevated TMA was associated with a blunted muscle mass response to leucine supplementation and with impaired myogenic differentiation and compromised myotube integrity in vitro, supporting a potential role in limiting myogenic capacity. These findings highlight the gut-muscle axis as a key modulator of heterogeneous responses to nutritional intervention and provide a metabolic framework for stratifying individuals in sarcopenia prevention strategies.</p>","PeriodicalId":94160,"journal":{"name":"npj aging","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13230888/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147619280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
npj agingPub Date : 2026-04-04DOI: 10.1038/s41514-026-00379-5
Gangcai Xie
{"title":"scAgeClock: a single-cell transcriptome-based human aging clock model using gated multi-head attention neural networks.","authors":"Gangcai Xie","doi":"10.1038/s41514-026-00379-5","DOIUrl":"10.1038/s41514-026-00379-5","url":null,"abstract":"<p><p>Aging clock models have emerged as a crucial tool for measuring biological age, with significant implications for anti-aging interventions and disease risk assessment. However, human aging clock models that offer single-cell resolution and account for cell and tissue heterogeneities remain underdeveloped. This study introduces scAgeClock, a novel gated multi-head attention neural network-based single-cell aging clock model. Leveraging a large-scale dataset of over 16 million single-cell transcriptome profiles from more than 40 human tissues and 400 cell types, scAgeClock demonstrates improved age prediction accuracy compared to baseline methods. Nearly half of the tissue-level cell types exhibit mean absolute errors of <10 years, with substantial variability in prediction accuracy observed across different cell types. Feature importance analysis reveals enrichment of aging clock genes related to ribosome, translation, defense response, viral life cycle, programmed cell death, and COVID-19 disease. A novel metric, the aging deviation index proposed by this study, revealed deceleration of ages in cells with higher differentiation potencies and tumor cells in higher phases or under metastasis, while acceleration of ages was observed in skin cells. Furthermore, scAgeClock is publicly available to facilitate future research and potential implementations.</p>","PeriodicalId":94160,"journal":{"name":"npj aging","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13230536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147619327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Extracellular matrix: new insights into its role in female reproductive aging and potential therapeutic strategies.","authors":"Ning Lu, Jing Wang, Yi-Hui Li, Xu-Hui Fang, Yu-Ting Peng, Qing-Peng Luo, Ai-Hua Liao","doi":"10.1038/s41514-026-00371-z","DOIUrl":"10.1038/s41514-026-00371-z","url":null,"abstract":"<p><p>Extracellular matrix (ECM), once regarded as a passive structural scaffold, is now recognized as a key hallmark of aging. In the context of female reproductive aging, ECM remodeling acts as a pivotal driver of functional deterioration. This review outlines how age-associated ECM alterations, including collagen cross-linking, elastin degradation, and perturbed biomechanics, orchestrate ovarian aging through the mechanical activation of Hippo signaling, compromise endometrial receptivity via dysregulated matrix metalloproteinase activity, and impair embryo invasion by altering ligand presentation. We also discuss emerging ECM-targeted strategies, such as decellularized scaffolds, engineered hydrogels, and 3D-bioprinted matrices, which have demonstrated potential for rejuvenating reproductive function in preclinical models. Furthermore, matrisome-based biomarkers provide novel prognostic insights into reproductive outcomes. Collectively, these advances identify the ECM as a promising target for innovative, non-hormonal interventions aimed at extending female reproductive longevity.</p>","PeriodicalId":94160,"journal":{"name":"npj aging","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13230844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147619283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}