npj aging最新文献

{"title":"Modifiable traits and genetic associations with grey matter volume in mid-to-late adulthood: a population-based study in the UK biobank.","authors":"Guoqing Pan, Yi Zhang, Ju-Jiao Kang, Yuchao Jiang, Wei Zhang, Peng Ren, Jia You, Weikang Gong, Jin-Tai Yu, Jian-Feng Feng, Xuejuan Zhang, Wei Cheng, Linbo Wang","doi":"10.1038/s41514-025-00255-8","DOIUrl":"10.1038/s41514-025-00255-8","url":null,"abstract":"<p><p>Given the growing global elderly population and the accelerating decrease in grey matter volume (GMV) with age, understanding healthy brain aging is increasingly important. This study investigates whether variations in modifiable traits can account for differences in GMV and whether these traits can inform strategies to mitigate risks of future brain disorders. We identified 66 traits significantly associated with total GMV. Further, we examined the joint contributions of different domain traits to the GMV variance, finding that blood biomarkers and physical measurements accounted for the largest proportion of GMV variance. Some traits mediated the relationship between the genetic risk for brain disorders and GMV. Moreover, the identified traits divided the population into two subgroups, with significant differences in GMV and incidences of brain disorders. Our findings underscore the importance of modifiable traits in supporting healthy brain aging and reducing the risk of brain disorders, suggesting potential targets for intervention.</p>","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"11 1","pages":"67"},"PeriodicalIF":4.1,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12271401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144661479","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":"Interpretable deep learning framework for understanding molecular changes in human brains with Alzheimer's disease: implications for microglia activation and sex differences.","authors":"Maitry Ronakbhai Trivedi, Amogh Manoj Joshi, Jay Shah, Benjamin P Readhead, Melissa A Wilson, Yi Su, Eric M Reiman, Teresa Wu, Qi Wang","doi":"10.1038/s41514-025-00258-5","DOIUrl":"10.1038/s41514-025-00258-5","url":null,"abstract":"<p><p>The utilization of artificial intelligence in studying the dysregulation of gene expression in Alzheimer's disease (AD) affected brain tissues remains underexplored, particularly in delineating common and specific transcriptomic signatures across different brain regions implicated in AD-related cellular and molecular processes, which could help illuminate novel disease biology for biomarker and target discovery. Herein we developed a deep learning framework, which consisted of multi-layer perceptron (MLP) models to classify neuropathologically confirmed AD versus controls, using bulk tissue RNA-seq data from the RNAseq Harmonization Study of the Accelerating Medicines Project for Alzheimer's Disease (AMP-AD) consortium. The models were trained based on data from three distinct brain regions, including dorsolateral prefrontal cortex (DLPFC), posterior cingulate cortex (PCC), and head of the caudate nucleus (HCN), obtained from the Religious Orders Study/Memory and Aging Project (ROSMAP). Subsequently, we inferred a disease progression trajectory for each brain region by applying unsupervised dimensionality transformation to the distribution of the subjects' expression profiles. To interpret the MLP models, we employed an interpretable method for deep neural network models, obtaining SHapley Additive exPlanations (SHAP) values and identified the most significantly AD-implicated genes for gene co-expression network analysis. Our models demonstrated robust performance in classification and prediction across two other external datasets from the Mayo RNA-seq (MAYO) cohort and the Mount Sinai Brain Bank (MSBB) cohort of AMP-AD. By interpreting the models both mechanistically and biologically, our study elucidated subtle molecular alterations in various brain regions, uncovering shared transcriptomic signatures activated in microglia and sex-specific modules in neurons relevant to AD. Notably, we identified, for the first time, a sex-linked transcription factor pair (ZFX/ZFY) associated with more pronounced neuronal loss in AD females, shedding light on a novel mechanism for sex dimorphism in AD. This study lays the groundwork for leveraging artificial intelligence methodologies to investigate AD at the molecular level, which is not readily achievable from conventional analysis approaches such as differential gene expression (DGE) analysis. The transcription factor implicated in sex difference also underpins a new molecular mechanistic basis of women's greater neurodegeneration in AD warranting further study.</p>","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"11 1","pages":"66"},"PeriodicalIF":4.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12267417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651669","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":"Sirtuins and their role in ovarian aging-related fibrosis predisposing to ovarian cancer.","authors":"Arkadiusz Grzeczka, Agnieszka Skowronska, Sara Sepe, Mariusz T Skowronski, Paweł Kordowitzki","doi":"10.1038/s41514-025-00256-7","DOIUrl":"10.1038/s41514-025-00256-7","url":null,"abstract":"<p><p>The pursuit of understanding early genetic or protein markers for ovarian aging has garnered considerable attention in the realm of reproductive medicine. Sirtuins (SIRTs) are a group of proteins that are NAD⁺-dependent, and thanks to their properties, they are able to change the acetylation profile of proteins and post-translationally modify their functions, too. Previous research provided evidence that SIRTs influence fibrosis levels in several organs. With regard to ovaries, fibrosis is one of the features of aged ovaries and also creates a metastasis-friendly environment, thus can also be a seedbed for the development of primary cancerous lesions. Ovarian cancer remains a formidable challenge in oncology due to its high prevalence, insidious onset, and frequent recurrence. Noteworthy, ovarian cancer is the seventh most common cancer among women and the eighth leading cause of cancer death worldwide. Ovarian fibrosis runs concurrently with the activation of TGF-β/Smads signaling, as well as inflammasome (NLRP3), nuclear factor kB (NFkB) and forkhead box O (FOXO) attenuation. Reduced levels of certain sirtuins resulting from decreased nicotinamide adenine dinucleotide (NAD + ) may underlie the dysregulation of the aforementioned signaling pathways and therefore represent a potential therapeutic target. This review elucidates the role of SIRTs in ovarian aging-related fibrosis as a process that predisposes to tumorigenesis.</p>","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"11 1","pages":"65"},"PeriodicalIF":4.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144644465","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 Rab3 family proteins in age-related neurodegeneration: unraveling molecular pathways and potential therapeutic targets.","authors":"Haijun He, Ruixue Ai, Evandro Fei Fang, Konstantinos Palikaras","doi":"10.1038/s41514-025-00257-6","DOIUrl":"10.1038/s41514-025-00257-6","url":null,"abstract":"<p><p>The Rab3 protein family is composed of a series of small GTP-binding proteins, including Rab3a, Rab3b, Rab3c, and Rab3d, termed Rab3s. They play crucial roles in health, including in brain function, such as through the regulation of synaptic transmission and neuronal activities. In the high-energy-demanding and high-traffic neurons, the Rab3s regulate essential cellular processes, including trafficking of synaptic vesicles and lysosomal positioning, which are pivotal for the maintenance of synaptic integrity and neuronal physiology. Emerging findings suggest that alterations in Rab3s expression are associated with age-related neurodegenerative pathologies, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, among others. Here, we provide an overview of how Rab3s dysregulation disrupts neuronal homeostasis, contributing to impaired autophagy, synaptic dysfunction, and eventually leading to neuronal death. We highlight emerging questions on how Rab3s safeguards the brain and how their dysfunction contributes to the different neurodegenerative diseases. We propose fine-tuning the Rab3s signaling directly or indirectly, such as via targeting their upstream protein AMPK, holding therapeutic potential.</p>","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"11 1","pages":"64"},"PeriodicalIF":4.1,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12260062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639143","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":"Nothobranchius furzeri: a vertebrate model for studying cardiac aging and cellular senescence.","authors":"Xueling Ma, Yonghe Ding, David Mondaca-Ruff, Xinyue Zhang, Yu Lu, Baul Yoon, Feixiang Yan, Yanyan Liang, Maryam Moossavi, Xiaolei Xu","doi":"10.1038/s41514-025-00253-w","DOIUrl":"10.1038/s41514-025-00253-w","url":null,"abstract":"<p><p>African turquoise killifish (Nothobranchius furzeri) is the shortest-lived vertebrate that can be bred in captivity, making it an ideal model organism for aging studies. However, whether the animal can be used for studying cardiac aging and whether cellular senescence contribute to this ageing process remain unclear. Here, we conducted a longitudinal study on the GRZ strain, aiming to identify phenotypic and functional markers for cardiac aging. We found that cardiac ageing in GRZ fish can be measured by comparing fish at 16 weeks to 8 weeks of age, using systemic markers such as body/fin coloration, body weight, BMI, cardiac ageing markers such as EF, E/A ratio, and swimming capacity, and cellular senescence markers such as SA-β-gal staining, p15/p16, γ-H2A.X, and SASP markers. Senolytic treatment with D (Dasatinib) and Q (Quercetin) from 12 to 16 weeks mitigated senescence and decelerated cardiac ageing. Together, our findings established GRZ as a useful vertebrate model for studying cardiac ageing and related cardiac senescence.</p>","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"11 1","pages":"63"},"PeriodicalIF":4.1,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12254275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144621634","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":"p300 inhibition delays premature cellular senescence.","authors":"Elisabetta Di Fede, Esi Taci, Silvia Castiglioni, Stefano Rebellato, Silvia Ancona, Paolo Grazioli, Chiara Parodi, Elisa Adele Colombo, Clara Bernardelli, Elena Lesma, Ian Daniel Krantz, Stefania Corti, Alberto Priori, Grazia Fazio, Cristina Gervasini, Valentina Massa, Antonella Lettieri","doi":"10.1038/s41514-025-00251-y","DOIUrl":"10.1038/s41514-025-00251-y","url":null,"abstract":"<p><p>Cellular senescence represents a permanent state of cell cycle arrest, also observed in neurodegenerative disorders. As p300 has been identified as an epigenetic driver of replicative senescence, we aimed to investigate whether in vitro p300 inhibition could rescue the stress-induced premature senescence (SIPS) phenotype. We exploited 2D and 3D (brain organoids) in vitro models of SIPS using two different stressor agents. In addition, we combined the treatment with a p300 inhibitor and validated p300 role in SIPS by analyzing different senescence markers and the transcriptome in our models. Interestingly, p300 inhibition can counteract the DNA damage and SIPS phenotype, detecting a dysregulation of gene expression and protein translation associated with the senescence program. These findings highlight both the molecular mechanisms underlying senescence and p300 as a possible pharmacological target. Thus, targeting p300 and, by extension, senescent cells could represent a promising therapeutic strategy for age-related diseases such as neurodegenerative disorders.</p>","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"11 1","pages":"62"},"PeriodicalIF":4.1,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12246142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144610700","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-associated alterations in gene regulatory networks associate with risk, prognosis and response to therapy in lung adenocarcinoma.","authors":"Enakshi Saha, Marouen Ben Guebila, Viola Fanfani, Katherine H Shutta, Dawn L DeMeo, John Quackenbush, Camila M Lopes-Ramos","doi":"10.1038/s41514-025-00247-8","DOIUrl":"10.1038/s41514-025-00247-8","url":null,"abstract":"<p><p>Aging is the primary risk factor for many cancer types, including lung adenocarcinoma (LUAD). To understand how aging-related alterations in the regulation of key cellular processes might affect LUAD risk and survival, we built individual-specific gene regulatory networks integrating gene expression, transcription factor protein-protein interaction, and sequence motif data, using PANDA/LIONESS algorithms, for non-cancerous lung samples from GTEx project and LUAD samples from TCGA. In healthy lung, pathways involved in cell proliferation and immune response were increasingly targeted with age; these aging-associated alterations were accelerated by smoking and resembled oncogenic shifts observed in LUAD. Aging-associated genes showed greater aging-biased targeting patterns in individuals with LUAD compared to healthier counterparts, a pattern suggestive of age acceleration. Using drug repurposing tool CLUEreg, we found small molecule drugs that may potentially alter the accelerating aging profiles we found. We defined a network-informed aging signature that was associated with survival in LUAD.</p>","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"11 1","pages":"61"},"PeriodicalIF":4.1,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12241614/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602684","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":"Psilocybin treatment extends cellular lifespan and improves survival of aged mice.","authors":"Kosuke Kato, Jennifer M Kleinhenz, Yoon-Joo Shin, Cristian Coarfa, Ali J Zarrabi, Louise Hecker","doi":"10.1038/s41514-025-00244-x","DOIUrl":"10.1038/s41514-025-00244-x","url":null,"abstract":"<p><p>Psilocybin, the naturally occurring psychedelic compound produced by hallucinogenic mushrooms, has received attention due to considerable clinical evidence for its therapeutic potential to treat various psychiatric and neurodegenerative indications. However, the underlying molecular mechanisms remain enigmatic, and few studies have explored its systemic impacts. We provide the first experimental evidence that psilocin (the active metabolite of psilocybin) treatment extends cellular lifespan and psilocybin treatment promotes increased longevity in aged mice, suggesting that psilocybin may be a potent geroprotective agent.</p>","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"11 1","pages":"55"},"PeriodicalIF":4.1,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593279","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":"Walking into aging: real-world mobility patterns and digital benchmarks from the InCHIANTI Study.","authors":"Jose Albites-Sanabria, Pierpaolo Palumbo, Stefania Bandinelli, Ilaria D'Ascanio, Sabato Mellone, Anisoara Paraschiv-Ionescu, Arne Küderle, Andrea Cereatti, Silvia Del Din, Felix Kluge, Eran Gazit, Carl-Philipp Jansen, Laura Delgado-Ortiz, Judith Garcia-Aymerich, Lynn Rochester, Jochen Klenk, Luigi Ferrucci, Clemens Becker, Lorenzo Chiari, Luca Palmerini","doi":"10.1038/s41514-025-00245-w","DOIUrl":"10.1038/s41514-025-00245-w","url":null,"abstract":"<p><p>Mobility is a cornerstone of health and quality of life, particularly in older adults. Digital mobility outcomes (DMOs) from real-world walking data offer crucial insights into the functional status and early markers of mobility decline. This study provides reference values for walking activity, pace, rhythm, and gait bout-to-bout variability in community-dwelling older adults and evaluates the effects of age, sex, height, and weight on these parameters. Using data from 200 older adults (aged 65-94 years) from the InCHIANTI Study and applying the Mobilise-D computational pipeline, we analyzed real-world walking over a week. Significant differences by sex and age were found, with males showing higher walking activity in younger age groups (65-74 and 75-84 years) but not in the oldest group (85-94 years). Additionally, we observed non-linear trends in mobility metrics with age, indicating an accelerated reduction in mobility at certain age ranges. These findings underscore the importance of monitoring real-world walking data to pinpoint critical periods of mobility decline and guide targeted interventions. This work offers valuable benchmarks for clinical assessments and future research.</p>","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"11 1","pages":"60"},"PeriodicalIF":4.1,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12227531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565591","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":"Years since menopause and its metabolomic signature with biological aging in women at midlife: a population-based study.","authors":"Bo Xie, Meiling Li, Qi Wang, Chunying Fu, Xiaoyi Wang, Dongshan Zhu","doi":"10.1038/s41514-025-00249-6","DOIUrl":"10.1038/s41514-025-00249-6","url":null,"abstract":"<p><p>This study analyzed UK Biobank data from 46,463 postmenopausal women to investigate metabolic changes linked to years since menopause (YSM) and their impact on aging biomarkers. Elastic net regression identified 115 YSM-associated metabolites, forming a metabolic signature strongly correlated with YSM (r = 0.30, P < 0.001). Each standard deviation increase in this metabolic signature was associated with decreased odds of long telomere length (0.94, 0.92-0.96), increased odds of high allostatic load (1.53, 1.50-1.56) and high PhenoAge (2.30, 2.17-2.44). Mediation analysis indicated that the metabolic signature explained 43.5% of the association between YSM and allostatic load, 9.09% between YSM and telomere length, and 89.3% between YSM and PhenoAge. These findings reveal how menopause-related metabolic shifts drive biological aging, highlighting potential intervention targets for postmenopausal health.</p>","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"11 1","pages":"58"},"PeriodicalIF":4.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12216968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546708","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}