Mechanisms of Ageing and Development最新文献

{"title":"Targeting mitophagy in the heart: Exploring the therapeutic potential of MicroRNAs","authors":"Amin Javadifar ,&nbsp;Masoud Tahani ,&nbsp;Sorousha Khayat ,&nbsp;Shiva Rakhshani Nasab ,&nbsp;Sercan Karav ,&nbsp;Prashant Kesharwani ,&nbsp;Amirhossein Sahebkar","doi":"10.1016/j.mad.2025.112082","DOIUrl":"10.1016/j.mad.2025.112082","url":null,"abstract":"<div><div>Mitophagy, a selective form of autophagy, plays an indispensable role in preserving mitochondrial integrity by eliminating dysfunctional mitochondria, thereby sustaining cellular homeostasis. This process is particularly critical in cardiomyocytes, which rely heavily on high-quality mitochondria to meet their substantial energy demands. Impaired mitophagy has been implicated in the pathogenesis of various cardiovascular diseases, including ischemic heart disease, heart failure, and cardiomyopathy. Emerging evidence highlights the pivotal regulatory role of microRNAs (miRNAs)—small non-coding RNA molecules—in modulating mitophagy by targeting key genes such as PINK1, Parkin, and FUNDC1, which are integral to mitochondrial quality control. This review comprehensively examines the dual capacity of miRNAs to either enhance or suppress mitophagy and evaluates the implications of these regulatory actions for cardiovascular health. For instance, miRNAs such as miR-24–3p and miR-125a-5p modulate mitophagy pathways, influencing cardiac function in distinct ways. Additionally, miRNAs like miR-34a and miR-330–3p may exert broader effects on mitochondrial homeostasis in cardiac tissue. This paper further explores the therapeutic potential of targeting miRNAs to restore mitophagy equilibrium and mitigate mitochondrial dysfunction, offering novel avenues for cardiovascular disease management. By synthesizing recent findings, this review underscores the promise of miRNA-based interventions and identifies critical directions for future research.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"226 ","pages":"Article 112082"},"PeriodicalIF":5.3,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144230352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of aging and biological sex on cardiac collagen metabolism","authors":"Kalyani Pandya ,&nbsp;Annabel Menendez ,&nbsp;Mark G. MacAskill ,&nbsp;Gillian A. Gray ,&nbsp;Adriana A.S. Tavares","doi":"10.1016/j.mad.2025.112079","DOIUrl":"10.1016/j.mad.2025.112079","url":null,"abstract":"<div><div>Age and sex exert profound influences on the heart, shaping its structure, function, and susceptibility to disease. Among the myriad of changes driven by age and sex, alterations in the extracellular matrix (ECM), particularly collagen influence myocardial health in aging. Collagen, the predominant ECM protein, upholds tissue integrity and function through tightly regulated processes. Aging, a significant cardiovascular risk factor, is linked to increased collagen deposition, left ventricular remodelling, and fibrosis. Similarly, sex differences affect cardiovascular disease progression, with notable variations in the deposition of collagen types I and III between males and females. While collagen accumulation is present in aging in both sexes, females exhibit a tempered response until menopause, primarily due to oestrogen-mediated suppression of excessive collagen remodelling. This review focuses on the mechanisms underlying age- and sex-related changes in cardiac collagen metabolism and their implications for myocardial health. Aging-associated fibrosis and collagen accumulation appear mechanistically distinct from those seen with injury or dysfunction, occurring without increased collagen synthesis despite elevated degradation enzymes. Factors such as senescence, inflammation, oxidative stress, and enhanced ECM crosslinking are identified as key drivers of these metabolic shifts. While studies in ovariectomized rodent models have highlighted the role of sex in collagen metabolism, evidence suggests that aging exerts a more dominant influence overall. Additionally, this review emphasizes a critical gap in the field: the limited availability of longitudinal aging fibrosis studies that include both sexes. This scarcity hampers a comprehensive understanding of how aging and sex collectively shape collagen turnover and myocardial health. By assessing these knowledge gaps, the review aims to define current perspectives and may provide insights to help inform the development of more effective, targeted therapeutic approaches.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"226 ","pages":"Article 112079"},"PeriodicalIF":5.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional significance of extracellular vesicles as mediators of cardiometabolic and cardiorenal diseases upon aging","authors":"Wing Yan Chung ,&nbsp;Sabrina Lam ,&nbsp;Brooke Pernari ,&nbsp;Yoojung Kim ,&nbsp;Ssang-Goo Cho ,&nbsp;Dylan Burger ,&nbsp;Gary Sweeney","doi":"10.1016/j.mad.2025.112078","DOIUrl":"10.1016/j.mad.2025.112078","url":null,"abstract":"<div><div>Aging increases the risk of cardiometabolic and cardiorenal disease and this is associated with cellular dysregulation including oxidative stress, chronic inflammation, insulin resistance and senescence. Extracellular vesicles (EV) facilitate inter-organ communication and are now well established as important pathophysiological mediators in many aging-associated diseases. Our knowledge of EV biosynthesis, cargo composition, cellular targeting and functional effects has expanded significantly over the past decade. Here we provide a comprehensive review on the characteristics and functional significance of EV in cardiometabolic and cardiorenal diseases in the context of aging. Specifically, we focus on heart failure, type 2 diabetes, metabolic dysfunction-associated steatohepatitis (MASH), hypertension, and chronic kidney disease and discuss aging-associated changes in bioactive molecules transferred via EV and how these are associated with healthspan. Furthermore, we summarize current potential therapeutic applications of EV. Overall, this review summarizes current knowledge indicating an important role for EV in aging-related cardiometabolic and cardiorenal diseases, and how insights from basic research can potentially be translated to the clinic in order to combat aging-associated metabolic decline and improve longevity and healthspan.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"226 ","pages":"Article 112078"},"PeriodicalIF":5.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The combination of GDF15, FGF21, sRAGE and NfL plasma levels can identify frailty in community-dwelling people across old age","authors":"Maria Conte ,&nbsp;Federica Sevini ,&nbsp;Giuseppe Conte ,&nbsp;Monica Tognocchi ,&nbsp;Erika Ciurca ,&nbsp;Lorenzo Trofarello ,&nbsp;Antonio Chiariello ,&nbsp;Miriam Capri ,&nbsp;Claudio Franceschi ,&nbsp;Daniela Monti ,&nbsp;Mirko Di Rosa ,&nbsp;Antonio Cherubini ,&nbsp;Fabiola Olivieri ,&nbsp;Stefano Salvioli","doi":"10.1016/j.mad.2025.112077","DOIUrl":"10.1016/j.mad.2025.112077","url":null,"abstract":"<div><div>Frailty is a complex medical condition characterized by decline in physiological functions and global health of older people, representing a strong risk factor for disability, hospitalization, and mortality. The identification of biomarkers reliably associated with frailty could provide more information on the actual health status and outcome of older subjects. To this aim, we investigated possible associations of four biomarkers related to age and age-related diseases, namely GDF15, FGF21, sRAGE, and NfL, with frailty, measured using frailty index (FI), in community-dwelling subjects of different age. The study was conducted on a cohort of 463 subjects (50–113 years) enrolled before the Covid-19 pandemic and categorized as frail and non-frail, based on a 45-item FI, according to the deficit accumulation model. Plasma levels of the four biomarkers were analysed by Ella Automated ELISA and investigated for their possible association with FI. A Random Forest Decision model was used to assess the biomarkers’ discrimination power with respect to FI. In our cohort, FI was associated with plasma levels of GDF15, NfL and FGF21, but not sRAGE. The first two were also associated with survival. The model based on those four biomarkers estimated frailty with 82 % accuracy. Moreover, frailty estimate obtained with this model led to a more refined prediction of survival on a 3-year follow-up. Our data suggest that GDF15, NfL, FGF21 and sRAGE plasma levels can be proposed as parameters to provide additional information about frailty status and survival with respect to FI in community-dwelling subjects.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"226 ","pages":"Article 112077"},"PeriodicalIF":5.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144242954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human oral microbiome in aging: A systematic review","authors":"Elena Carbone ,&nbsp;Elisa Fabrizi ,&nbsp;Roberto Rivabene ,&nbsp;Marisa Cappella ,&nbsp;Paola Fortini ,&nbsp;Lucia Conti ,&nbsp;Nicoletta Locuratolo ,&nbsp;Patrizia Lorenzini ,&nbsp;Eleonora Lacorte ,&nbsp;Paola Piscopo","doi":"10.1016/j.mad.2025.112080","DOIUrl":"10.1016/j.mad.2025.112080","url":null,"abstract":"<div><div>Studying aging and risk factors associated with chronic non-communicable diseases is increasingly relevant due to the progressive aging of the global population. Risk factors have focused on diet, physical exercise, cognitive activity, and lifestyle habits; however, recent research has begun to explore how the oral microbiome may influence health and contribute to chronic diseases. The aim of our systematic review is to evaluate the link between human oral microbiome and aging. This SR was carried out using PubMed, Cochrane Library, and Embase, identifying 3490 records, of which 6 met our inclusion/exclusion criteria. These studies were qualitatively assessed using the Revised Risk of Bias Assessment Tool for Nonrandomized Studies of Interventions. Overall, the evidence suggests that while the bacterial and fungal communities remain similar across age groups, there is an increased presence of periodontal pathogens in older subjects. Moreover, bacterial species richness and alpha-diversity decrease with advancing age, though no clear age clustering was observed. Although the reviewed studies offer insights into the association between aging and changes in the oral microbiome, further research is required to address confounding factors, limitations in sample size, and gender differences, in order to better elucidate the role of microbiome alterations in general health.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"226 ","pages":"Article 112080"},"PeriodicalIF":5.3,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma metabolomic profiles reveal sex-specific response to an oral glucose tolerance test in late middle-aged adults","authors":"C.M. Donado-Pestana ,&nbsp;L. Rodrigues ,&nbsp;M. Rundle ,&nbsp;E.L. Thomas ,&nbsp;S. Wopereis ,&nbsp;T.E. Gundersen ,&nbsp;J.P. Trezzi ,&nbsp;D. Bunzel ,&nbsp;Y. Kiselova-Kaneva ,&nbsp;D. Sonntag ,&nbsp;S.E. Kulling ,&nbsp;D. Ivanova ,&nbsp;K. Hiller ,&nbsp;C.A. Drevon ,&nbsp;L. Brennan ,&nbsp;J.D. Bell ,&nbsp;B. van Ommen ,&nbsp;G. Frost ,&nbsp;H. Daniel ,&nbsp;J. Fiamoncini","doi":"10.1016/j.mad.2025.112081","DOIUrl":"10.1016/j.mad.2025.112081","url":null,"abstract":"<div><div>Sex is a key determinant of human phenotype, with males and females exhibiting distinct anthropometric and metabolic features that influence disease susceptibility. This study investigated sex-specific metabolic differences in late middle-aged adults without diagnosed metabolic diseases, both in the fasting state and during an oral glucose tolerance test (OGTT). Using data from the NutriTech project, we analyzed plasma metabolomic responses during the OGTT, along with detailed assessments of body composition and fasting clinical parameters. Females exhibited 28 % greater total adipose tissue, mainly subcutaneous, whereas males had more intra-abdominal fat and higher energy expenditure. Females showed elevated fasting levels of fatty acids—particularly very-long-chain fatty acids— leptin, and adiponectin. Males had slightly higher fasting glycemia (∼ 5 %) and a more pronounced glycemic increase during the OGTT (17 %), along with elevated insulin levels. In both fasting and postprandial states, males showed higher circulating levels (p &lt; 0.05) of aromatic and branched-chain amino acids (BCAA) and their catabolites. Conversely, females had higher sphingomyelins levels during fasting and throughout the OGTT, and increased postprandial levels of secondary bile acids (p &lt; 0.05). These sex-specific metabolic features in late middle-aged adults may enhance our understanding of metabolic disease risk and support the development of more targeted prevention strategies.</div></div><div><h3>Clinical trial registration number</h3><div>NCT01684917</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"226 ","pages":"Article 112081"},"PeriodicalIF":5.3,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interspecific interactions and aging: Prediction of gerogenic bacteria and critical human protein targets of microbial infections","authors":"Yuping Dai ,&nbsp;Ni Boussaguet ,&nbsp;Jérôme Teulière ,&nbsp;Hugo Bonnefous ,&nbsp;Elphège Budzinski ,&nbsp;Philippe Lopez ,&nbsp;Louis-Patrick Haraoui ,&nbsp;Eric Bapteste","doi":"10.1016/j.mad.2025.112076","DOIUrl":"10.1016/j.mad.2025.112076","url":null,"abstract":"<div><div>Bacteria permeate every niche of the human body with major consequences on our health and senescence that have not been fully described. Here, we predict which bacteria and which bacterial proteins could interfere with proteins associated with human aging using bipartite networks showing interspecific protein interactions coupled with investigations of published experimental evidence and transcriptomic data. We introduce the term of “gerogenic” bacteria, literally bacteria that could induce some aging in their host and discuss the mechanisms by which such bacteria could serve as age-distorters of humans. <em>Salmonella</em>, <em>Escherichia</em> and <em>Shigella</em> appear as major candidate age-distorters, characterized by a higher experimentally demonstrated potential than other bacteria to interact with human proteins associated with human aging and human cellular senescence. Our analysis also highlights an evolutionary convergence among bacterial and viral candidate age-distorting proteins, since 14 human proteins associated with aging can be commonly targeted by bacteria and viruses in case of microbial infection. Since infections are common and <em>Salmonella</em>, <em>Escherichia</em> and <em>Shigella</em> are frequently found as pathogens in our microbiomes, characterizing bacterial influence on our aging and our cellular senescence through molecular hijacking could enhance the understanding of the causes of aging and suggest new anti-aging therapies.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"226 ","pages":"Article 112076"},"PeriodicalIF":5.3,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144139653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cyr61 promotes D-gal-induced aging C2C12 cell fibrosis by modulating Wnt/β-catenin signaling pathways","authors":"Xinchen Huang ,&nbsp;Xiaoling Kui ,&nbsp;Jiyao Ma ,&nbsp;Jiaxin Chen ,&nbsp;Yilong Huang ,&nbsp;Bo He","doi":"10.1016/j.mad.2025.112067","DOIUrl":"10.1016/j.mad.2025.112067","url":null,"abstract":"<div><div>Sarcopenia is characterized by age-related muscle mass/function loss and fibrosis. Satellite cell (SC) dysfunction during aging promotes fibrotic transdifferentiation and extracellular matrix (ECM) deposition. Cyr61, a pro-fibrotic matricellular protein, and Wnt/β-catenin signaling pathway are implicated in muscle regeneration-fibrosis balance, but their interaction in sarcopenia remains unclear. This study first compared the expression of Cyr61 and fibrosis markers (TGF-β1, collagen type I and III) in skeletal muscle of young and old mice. <em>In vitro</em>, D-gal-induced C2C12 aging models were used to assess Cyr61 and Wnt signaling pathway by proliferation/apoptosis assays, ECM analysis, and detecting the changes of myogenic/fibrotic markers (MyoD, α-SMA). Pathway modulation (FH535 inhibitor/LiCl activator) and combined with Cyr61 overexpression and knockout experiments defined mechanistic roles. Cyr61 was upregulated in skeletal muscle of aged mice, which was positively correlated with increased TGF-β1 and collagen deposition. In D-gal-induced C2C12 cells showed suppressed cell proliferation, increased apoptosis and enhanced ECM deposition, accompanied by elevated Cyr61. Cyr61 knockdown or Wnt signaling pathway inhibition (FH535) reversed fibrosis (α-SMA, collagen) and restored myogenesis (MyoD).This study reveals for the first time that Cyr61 drives sarcopenic fibrosis via Wnt/β-catenin activation, promoting myocyte-to-fibrotic transition. Targeting the Cyr61-Wnt axis may ameliorate age-related muscle degeneration, warranting translational validation in preclinical models.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"225 ","pages":"Article 112067"},"PeriodicalIF":5.3,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143935158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of stem cells in ageing and age-related diseases","authors":"Jitendra Kumar Chaudhary ,&nbsp;Ajay Kumar Danga ,&nbsp;Anita Kumari ,&nbsp;Akshay Bhardwaj ,&nbsp;Pramod C. Rath","doi":"10.1016/j.mad.2025.112069","DOIUrl":"10.1016/j.mad.2025.112069","url":null,"abstract":"<div><div>Stem cell functions and ageing are deeply interconnected, continually influencing each other in multiple ways. Stem cells play a vital role in organ maintenance, regeneration, and homeostasis, all of which decline over time due to gradual reduction in their self-renewal, differentiation, and growth factor secretion potential. The functional decline is attributed to damaging extrinsic environmental factors and progressively worsening intrinsic genetic and biochemical processes. These ageing-associated deteriorative changes have been extensively documented, paving the way for the discovery of novel biomarkers of ageing for detection, diagnosis, and treatment of age-related diseases. Age-dependent changes in adult stem cells include numerical decline, loss of heterogeneity, and reduced self-renewal and differentiation, leading to a drastic reduction in regenerative potential and thereby driving the ageing process. Conversely, ageing also adversely alters the stem cell niche, disrupting the molecular pathways underlying stem cell homing, self-renewal, differentiation, and growth factor secretion, all of which are critical for tissue repair and regeneration. A holistic understanding of these molecular mechanisms, through empirical research and clinical trials, is essential for designing targeted therapies to modulate ageing and improve health parameters in older individuals.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"225 ","pages":"Article 112069"},"PeriodicalIF":5.3,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143935159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic and epigenomic signatures of liver metabolism and insulin sensitivity in aging mice","authors":"John T. González ,&nbsp;Olivia H. Scharfman ,&nbsp;Wanling Zhu ,&nbsp;Jessica Kasamoto ,&nbsp;Victoria Gould ,&nbsp;Rachel J. Perry ,&nbsp;Albert T. Higgins-Chen","doi":"10.1016/j.mad.2025.112068","DOIUrl":"10.1016/j.mad.2025.112068","url":null,"abstract":"<div><div>Age-related declines in insulin sensitivity and glucose metabolism contribute to metabolic disease. Despite the liver’s central role in glucose homeostasis, a comprehensive phenotypic characterization and concurrent molecular analysis of insulin resistance and metabolic dysfunction in the aging liver is lacking. We characterized hepatic insulin resistance and mitochondrial metabolic defects through metabolic cage, hyperinsulinemic-euglycemic clamp, and tracer studies paired with transcriptomic and DNA methylation analyses in young and aged male mice. Aged mice exhibited benchmark measures of whole body and liver insulin resistance. Aged mice showed lower pyruvate dehydrogenase flux, decreased fatty acid oxidation and citrate synthase fluxes, and increased pyruvate carboxylase flux under insulin-stimulated conditions. Molecular analysis revealed age-related changes in metabolic genes Pck1, Socs3, Tbc1d4, and Enpp1. Unsupervised network analysis identified an intercorrelated phenotype module (ME-Glucose), RNA module, and DNA methylation module. The DNA methylation module was enriched for lipid metabolism pathways and TCF-1 binding, while the RNA module was enriched for MZF-1 binding and regulation by miR-155–5p. Protein-protein interaction network analysis revealed interactions between module genes and canonical metabolic pathways, highlighting genes including Ets1, Ppp1r3b, and Enpp3. This study reveals novel genes underlying age-related hepatic insulin resistance as potential targets for metabolic interventions to promote healthy aging.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"225 ","pages":"Article 112068"},"PeriodicalIF":5.3,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143924720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}