GeroScience最新文献

{"title":"Adaptations of mitochondrial, autophagy and nutrient sensing pathways in the liver from long-lived mice overexpressing CYB5R3 are sex-dependent and involve inter-organ responses.","authors":"Luz Marina Sánchez-Mendoza,José A González-Reyes,Sandra Rodríguez-López,Cristina García-Caballero,Juan Antonio Moreno,Rafael de Cabo,M Isabel Burón,José M Villalba","doi":"10.1007/s11357-025-01761-z","DOIUrl":"https://doi.org/10.1007/s11357-025-01761-z","url":null,"abstract":"Cytochrome b5 reductase 3 (CYB5R3) overexpression mimics several metabolic benefits of calorie restriction, with sex- and tissue-specific effects. This study aimed to investigate how CYB5R3 overexpression impacts hepatic metabolism in young mice, focusing on mitochondrial biogenesis, lipid metabolism, autophagy and nutrient sensing pathways thus establishing a baseline that allows for subsequent comparisons with older animals. The accrual of CYB5R3 polypeptide exhibited marked sexual dimorphism as it was increased by transgenesis only in females with predominant microsomal targeting but mainly located in the mitochondria in males. Nevertheless, key metabolic markers, including TFAM (biogenesis), p62 and LC3 (autophagy), AKT and mTOR (nutrient sensing), SIRT1/SIRT3 (enzymatic regulation and gene expression) and ACC1/ACAA2 (lipid metabolism), were significantly altered in transgenic males. Wild-type males exhibited higher levels of mitochondrial complexes III and IV than females, and these differences were attenuated by transgenesis. TFAM was increased in transgenic mice of both sexes, indicative of enhanced mitochondrial biogenesis. Changes of lipid metabolism markers indicated reduced hepatic lipid accumulation in females while males showed changes in ACC1 and ACAA2, affecting lipid storage and oxidation. Autophagy markers (p62, LC3I/II) were altered in males, whereas mitophagy markers (PINK1, PARKIN) were upregulated in females, suggesting efficient mitochondrial turnover. In conclusion, CYB5R3 expression is regulated by post-transcriptional and post-translational mechanisms and induces sex-dependent hepatic metabolic adaptations. While females exhibit increased CYB5R3 protein and associated mitochondrial improvements, males respond with distinct metabolic reprogramming despite unchanged CYB5R3 levels, underscoring the relevance of sexual dimorphism and systemic regulatory mechanisms in the response to longevity-promoting interventions.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"653 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144521193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the transformative effects of calorie restriction on the lacrimal gland in adult mice.","authors":"Olivier Mauduit,Prashant Kumar,Kaitlin K Scholand,Emre Aksan,Laura Schaefer,Anmar Abu-Romman,Vanessa Delcroix,Zhiyuan Yu,Aude I Sindikubwabo,Ron Korstanje,Helen P Makarenkova,Cintia S de Paiva","doi":"10.1007/s11357-025-01748-w","DOIUrl":"https://doi.org/10.1007/s11357-025-01748-w","url":null,"abstract":"Advanced age is one of the most recognizable risk factors for dry eye. Dry eye disease affects millions worldwide and can result from age-related lacrimal gland dysfunction, which correlates with a decline in lacrimal gland secretory cell function and chronic inflammation. This study investigated the potential of calorie restriction to maintain lacrimal gland and ocular surface health. Adult female C57BL/6 J mice were subjected to a 40% calorie restriction for 4 months, starting at 6-7 months and continuing until 10-11 months. These mice were compared to controls fed ad libitum. Bulk RNA sequencing of lacrimal glands, conjunctiva, and cornea subjected to calorie restriction compared to ad libitum revealed significant differentially expressed genes (DEGs). Pathways enriched in the upregulated DEGs indicate enhanced circadian rhythm, secretory functions, and lipid metabolism. These findings were confirmed using individual qRT-PCR and western blotting. In contrast, pathways enriched in the downregulated DEGs were associated with immune cell activation, adaptive immune responses, extracellular matrix remodeling, and metalloproteinase activity. Histological sections of calorie-restricted lacrimal glands revealed reduced mononuclear cell infiltration and fewer positive cells for CD4, CD19, and MHC II than in ad libitum lacrimal glands. Calorie restriction also prevented age-related corneal barrier dysfunction and mitigated age-related conjunctival goblet cell loss, hallmarks of dry eye disease. These findings suggest that calorie restriction supports lacrimal gland and ocular surface health by reducing inflammation and extracellular matrix remodeling and by enhancing the lacrimal gland's secretory function.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"25 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144521024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma lipidomic fingerprinting enables high-accuracy biomarker discovery for Alzheimer's disease: a targeted LC-MRM/MS approach.","authors":"Xia Gao, Xiaoqin Cheng, Peipei Chen, Ling Lin, Xiaoyu Wang, Runbing Xu, Huali Shen, Qian Yang","doi":"10.1007/s11357-025-01777-5","DOIUrl":"https://doi.org/10.1007/s11357-025-01777-5","url":null,"abstract":"<p><p>Dysregulation of lipid metabolism is increasingly recognized as a key factor in the pathogenesis of Alzheimer's disease (AD). Unfortunately, an accurate lipidomic fingerprints in AD patients' biofluids remains challenging. A comprehensive analysis of plasma samples from 26 patients with AD and 30 healthy individuals was performed using untargeted and targeted lipidomics techniques with strict lipid annotation criteria. By monitoring characteristic fragments per precursor, we achieved precise lipid characterization and quantification for approximately 270 lipid species. Multivariate statistical analysis revealed a distinct lipid profile between AD patients and controls, with 72 lipids significantly altered (FC > 1.5 or < 0.667, VIP > 1, P < 0.05). Notably, a biomarker analysis based on the multivariate exploratory receiver operating characteristic (ROC) curve identified a comprehensive panel consisting of 10 novel lipids as potential markers for AD, achieving 98.2% accuracy with a favorable auxiliary diagnostic value (area under curve of 0.995). Additionally, the higher levels of SM(d18:1/16:0), SM(d18:1/18:1), and LPE 18:0 were strongly correlated with the clinical dementia rating (CDR) and mini-mental state examination (MMSE) scores, underscoring the therapeutic potential of lipid modulation in AD. These findings reveal the intricate relationship between lipid alterations and AD pathology and emphasize the necessity for LC-MRM/MS lipidomics with rigorous criteria in the discovery of reliable biomarkers, enriching our understanding of lipid roles in neurodegenerative processes and informing future mechanistic investigations and drug target development.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep learning predicts onset acceleration of 38 age-associated diseases from blood and body composition biomarkers in the UK Biobank.","authors":"Mica Xu Ji, Marjola Thanaj, Léna Nehale-Ezzine, Brandon Whitcher, E Louise Thomas, Jimmy D Bell","doi":"10.1007/s11357-025-01702-w","DOIUrl":"https://doi.org/10.1007/s11357-025-01702-w","url":null,"abstract":"<p><p>A major challenge in multimorbid aging is understanding how diseases co-occur and identifying high-risk groups for accelerated disease development, but to date associations in the relative onset acceleration of disease diagnoses have not been used to characterize disease patterns. This study presents the development and evaluation of a neural network Cox model for predicting onset acceleration risk for age-associated conditions, using demographic, anthropomorphic, imaging, and blood biomarker traits from 60,396 individuals and 218,530 outcome events from the UK Biobank. Risk prediction was evaluated with Harrell's concordance index (C-index). The model performed well on internal (C-index <math><mrow><mn>0.6830</mn> <mo>±</mo> <mn>0.0902</mn></mrow> </math> , <math><mrow><mi>n</mi> <mo>=</mo> <mn>8</mn> <mo>,</mo> <mn>931</mn></mrow> </math> ) and external (C-index <math><mrow><mn>0.6461</mn> <mo>±</mo> <mn>0.1264</mn></mrow> </math> , <math><mrow><mi>n</mi> <mo>=</mo> <mn>855</mn></mrow> </math> ) test sets, attaining C-index <math><mrow><mo>≥</mo> <mn>0.6</mn></mrow> </math> on 38 out of 47 ( <math><mrow><mn>80.9</mn> <mo>%</mo></mrow> </math> ) conditions. Inclusion of body composition and blood biomarker input traits was independently important for predictive performance. Kaplan-Meier curves for predicted risk quartiles (log-rank <math><mrow><mi>p</mi> <mo>≤</mo> <mn>1.16</mn> <mi>E</mi> <mo>-</mo> <mn>16</mn></mrow> </math> ) indicated robust stratification of individuals into high and low risk groups. Analysis of risk quartiles revealed cardiometabolic, vascular-neuropsychiatric, and digestive-neuropsychiatric disease clusters with strong statistically significant inter-correlated onset acceleration ( <math><mrow><mi>r</mi> <mo>≥</mo> <mn>0.6</mn></mrow> </math> , <math><mrow><mi>p</mi> <mo>≤</mo> <mn>3.46</mn> <mi>E</mi> <mo>-</mo> <mn>5</mn></mrow> </math> ), while 13 and 19 conditions were strongly associated with onset acceleration of all-cause mortality and all-cause morbidity, respectively. In prognostic survival analysis, the proportional hazards assumption was met (Schoenfeld residual <math><mrow><mi>p</mi> <mo>></mo> <mn>0.05</mn></mrow> </math> ) in 435 out of 435 or 100% (1238 out of 1334 or 92.8%) of cases across outcomes, <math><mrow><mi>a</mi> <mi>H</mi> <mi>R</mi> <mo>=</mo> <mn>6.11</mn> <mo>±</mo> <mn>9.00</mn></mrow> </math> ( <math><mrow><mi>a</mi> <mi>H</mi> <mi>R</mi> <mo>=</mo> <mn>3.67</mn> <mo>±</mo> <mn>5.78</mn></mrow> </math> ) with (without) Bonferroni correction. The neural architecture of OnsetNet was interpreted with saliency analysis, and several significant body composition and blood biomarkers were identified. The results demonstrate that neural network survival models are able to estimate prognostically informative onset acceleration risk, which could be used to improve understanding of synchronicity in the onset of age-associated diseases and reprioritize patients based on disease-specific risk.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PCSK9 expression and cancer survival: a prognostic biomarker at the intersection of oncology and geroscience.","authors":"Zoltan Ungvari, Otília Menyhart, Andrea Lehoczki, Monika Fekete, Giampaolo Bianchini, Balázs Győrffy","doi":"10.1007/s11357-025-01733-3","DOIUrl":"https://doi.org/10.1007/s11357-025-01733-3","url":null,"abstract":"<p><p>Proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily recognized for its role in cholesterol metabolism; however, emerging evidence suggests it plays a broader role in the regulation of cellular aging mechanisms and the pathogenesis of age-related diseases. Given that cancer is an age-related disease, PCSK9 has garnered attention for its potential impact on tumor progression and patient survival. In this study, we conducted a comprehensive analysis of PCSK9 expression across multiple tumor types, assessing its prognostic significance using RNA sequencing data from The Cancer Genome Atlas (TCGA) and gene expression microarray data from the Gene Expression Omnibus (GEO). Cox proportional hazards regression models and Kaplan-Meier survival analyses were employed to evaluate overall survival (OS) associations. Our findings reveal that elevated PCSK9 expression is associated with improved OS in breast and ovarian cancers, particularly in Luminal B breast cancer subtypes. Conversely, high PCSK9 expression correlates with worse OS in bladder cancer, renal clear cell carcinoma, melanoma, and pancreatic cancer. Notably, while PCSK9 expression is significantly upregulated in melanoma and bladder tumors, it is downregulated in renal clear cell carcinoma, yet relatively higher expression among renal tumors still predicts poorer survival. No significant associations between PCSK9 expression and OS were observed in colon, liver, gastric, lung, prostate, head and neck cancers, or low-grade gliomas in the available datasets.In conclusion, our study identifies PCSK9 as a prognostic biomarker with distinct, tumor-specific survival implications. Its dual role-associating with improved survival in some cancers while correlating with worse outcomes in others-suggests that PCSK9 may influence cancer progression through context-dependent mechanisms. Future research should focus on elucidating the mechanistic underpinnings of these associations and exploring the diagnostic and therapeutic potential of targeting PCSK9 in oncology.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PCSK9 expression and cancer survival: a prognostic biomarker at the intersection of oncology and geroscience.","authors":"Zoltan Ungvari,Otília Menyhart,Andrea Lehoczki,Monika Fekete,Giampaolo Bianchini,Balázs Győrffy","doi":"10.1007/s11357-025-01733-3","DOIUrl":"https://doi.org/10.1007/s11357-025-01733-3","url":null,"abstract":"Proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily recognized for its role in cholesterol metabolism; however, emerging evidence suggests it plays a broader role in the regulation of cellular aging mechanisms and the pathogenesis of age-related diseases. Given that cancer is an age-related disease, PCSK9 has garnered attention for its potential impact on tumor progression and patient survival. In this study, we conducted a comprehensive analysis of PCSK9 expression across multiple tumor types, assessing its prognostic significance using RNA sequencing data from The Cancer Genome Atlas (TCGA) and gene expression microarray data from the Gene Expression Omnibus (GEO). Cox proportional hazards regression models and Kaplan-Meier survival analyses were employed to evaluate overall survival (OS) associations. Our findings reveal that elevated PCSK9 expression is associated with improved OS in breast and ovarian cancers, particularly in Luminal B breast cancer subtypes. Conversely, high PCSK9 expression correlates with worse OS in bladder cancer, renal clear cell carcinoma, melanoma, and pancreatic cancer. Notably, while PCSK9 expression is significantly upregulated in melanoma and bladder tumors, it is downregulated in renal clear cell carcinoma, yet relatively higher expression among renal tumors still predicts poorer survival. No significant associations between PCSK9 expression and OS were observed in colon, liver, gastric, lung, prostate, head and neck cancers, or low-grade gliomas in the available datasets.In conclusion, our study identifies PCSK9 as a prognostic biomarker with distinct, tumor-specific survival implications. Its dual role-associating with improved survival in some cancers while correlating with worse outcomes in others-suggests that PCSK9 may influence cancer progression through context-dependent mechanisms. Future research should focus on elucidating the mechanistic underpinnings of these associations and exploring the diagnostic and therapeutic potential of targeting PCSK9 in oncology.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"652 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The CAIDE dementia risk score indicates elevated cognitive risk in late adulthood: a structural and functional neuroimaging study.","authors":"Katalin Farkas,Timea Lazar,Melinda Becske,Janos Andras Zsuffa,Viktoria Rosenfeld,Dalida Borbala Berente,Gergo Bolla,Janos Negyesi,Andras Attila Horvath","doi":"10.1007/s11357-025-01766-8","DOIUrl":"https://doi.org/10.1007/s11357-025-01766-8","url":null,"abstract":"While the CAIDE score is an established mid-life risk assessment tool for the longitudinal prediction of dementia, its application as a measure of elevated cognitive risk in late adulthood is unclear. One hundred one healthy individuals (aged > 55) were tested using detailed neuropsychological assessments, as well as structural and functional MRI. Participants were divided into a low-risk group (CAIDE < 7) and a high-risk group (CAIDE > 6). High-risk participants had significantly worse cognitive performance in the Trail-Making Test results (TMT-B: t = -4.03, p = 0.0001), and significantly smaller global brain volumes (e.g., brain segmentation volume: t = 2.898, p = 0.0485) and regional volumes (e.g., accumbens volumes: tleft = 3.928, p = 0.036, Cohen's d = 0.828; tright = 3.151, p= 0.0485, Cohen's d = 0.656). High-risk participants also showed a trend for reduced functional connectivity in the default mode, salience, and central attention networks. Overall, the CAIDE score might help identify cognitively high-risk individuals in a late adulthood population.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"46 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Osteoimmunology and aging - a frontier to explore.","authors":"Mihailo Ille,Iannis E Adamopoulos,Mindy J Fain,Janko Ž Nikolich","doi":"10.1007/s11357-025-01744-0","DOIUrl":"https://doi.org/10.1007/s11357-025-01744-0","url":null,"abstract":"Osteoimmunology is an interdisciplinary branch of immunology which studies the interplay of skeletal and immune systems. Both spatial and functional connections exist between the two systems, as most immune cells are generated in the bone marrow microenvironment, which facilitates the communication between the two systems. Moreover, immune cytokines such as RANKL (receptor activating Nf-kB ligand) and non-immune soluble mediators such as osteoprotegrin (OPG), made by immune and bone cells, respectively, interact to influence differentiation and activation of each other. The above interactions become of particular importance in the old age, when dysregulation of both systems yields changes affecting both length and quality of life. This perspective paper will outline both our current understanding as well as general gaps in knowledge, on geriatric osteoimmunology. We will also specifically address two highly prevalent diseases of aging, osteoarthritis and osteoporosis, as major sources of disability, loss of independence and increased morbidity and mortality in older adults, because cellular senescence appears to play a substantial pathogenetic role in both conditions, potentially opening new avenues for diagnosis and treatment.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"11 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144487966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Misalignment of age clocks.","authors":"Xiaoyue Mei, Hannaneh Kabir, Michael J Conboy, Irina M Conboy","doi":"10.1007/s11357-025-01750-2","DOIUrl":"https://doi.org/10.1007/s11357-025-01750-2","url":null,"abstract":"<p><p>Biological aging is a complex non-linear process, with markedly distinct starting and end points, yet the biomarkers of its progression remain elusive. A key assumption of most machine learning (ML) approaches for age clocks is that predictive biomedical features can be identified via mathematical transformations of data to favor a linear transition from start to end, even if they erase any natural biological pattern. It is given that expected correlations, e.g., time lived (age) and time left to live (mortality), would persist in such mathematically optimized models, biologically meaningful or not. Here, we further clarify the workings of the clocks, explain the trade-off between mathematical optimization and biological interpretability, and discuss a hallmark of aging, inflammaging, that age clocks struggle to detect. We expand on the negative consequences of incoherence in linear models where some DNA methylation (DNAm) features increase with aging and disease, while others correspondingly decrease, yet positive weights are assigned to both. We quantify the misalignment between major DNAm clocks and actual changes in DNAm, providing an interactive visualization of these errors for each model. We demonstrate that major conventional age clocks are both incoherent and skewed toward leukocyte fractions and that rectifying incoherence makes the model balanced and not skewed toward neutrophils and better detects inflammaging. We briefly outline non-linear ML age clocks and the advantages of identifying a natural trajectory of aging directly from the primary data.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quinacrine and rimonabant prolong the life span of Caenorhabditis elegans.","authors":"Qin He,Shupan Guo,Aolan Zhou,Xin Gong,Wei Cheng,Haiyan Ren","doi":"10.1007/s11357-025-01729-z","DOIUrl":"https://doi.org/10.1007/s11357-025-01729-z","url":null,"abstract":"Aging and age-related disorders are significant global health concerns, driving interest in potential preventative strategies. In this study, we established a high-throughput screening system to reveal the effects of quinacrine and rimonabant on lifespan extension in C. elegans. Mechanistically, quinacrine influences the metabolic and immune pathways through the insulin/insulin-like growth factor (IIS) pathway, as it fails to prolong longevity in IIS pathway mutants while boosting the expression of the downstream gene sod-3. Metabolomic profiling revealed a significant elevation of phosphatidylserine in quinacrine-treated worms. Parallel investigations showed that rimonabant exerts its lifespan-extending effects via the IIS pathway, specifically through the DAF-2/HSF-1 regulatory axis. It promotes longevity of C. elegans by enhancing antioxidant defense and detoxification pathways. Our findings position both quinacrine and rimonabant as promising anti-aging candidates, offering novel mechanistic insights for developing interventions against age-related disorders.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"235 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144487962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}