Mechanisms of Ageing and Development最新文献

{"title":"The impact of a selective androgen receptor modulator (RAD140) on frailty and underlying mechanisms in older male and female C57Bl/6 mice","authors":"Stefan S. Heinze ,&nbsp;Maddison L. Hodgins ,&nbsp;Susan E. Howlett","doi":"10.1016/j.mad.2025.112054","DOIUrl":"10.1016/j.mad.2025.112054","url":null,"abstract":"<div><h3>Background</h3><div>Androgen receptors (AR) are promising therapeutic targets for mechanisms of aging, including chronic inflammation, lean mass loss, and worsening bone health. We investigated the impact of RAD140, a selective AR modulator that activates ARs, on frailty and underlying mechanisms in older C57BL/6 mice.</div></div><div><h3>Methods</h3><div>Mice (23.7–25.5 months; N = 21 males; 15 females) received RAD140 (5 mg/kg/day) or placebo (DMSO) daily for 6-weeks. Frailty (clinical and lab-based), body composition, circulating inflammatory markers, grip strength, and genes relating to function/hypertrophy in quadriceps femoris muscles were assessed.</div></div><div><h3>Results</h3><div>Despite no differences in frailty between treatment and control, there were positive effects in male, but not female mice. RAD140 treated male mice had preserved lean mass (p = 0.024) and bone mineral density (p = 0.004) and lower serum interleukin-6 (p = 0.043) versus controls. In contrast, benefits to body composition and inflammatory markers were not seen in females. In either sex, grip strength, fat mass, and skeletal muscle genes were unaffected.</div></div><div><h3>Conclusion</h3><div>Six-weeks of RAD140 treatment did not affect frailty in older male or female mice. The beneficial effects in lean mass, bone mineral density, and systemic inflammation warrant longer treatments to explore any positive impact on frailty in males. RAD140 may not be ideal for achieving these in females.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"225 ","pages":"Article 112054"},"PeriodicalIF":5.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Induction of epithelial cell senescence by SERPINE1 derived from fibroblasts in the amnion at parturition","authors":"Li-Jun Ling ,&nbsp;Meng-Die Li ,&nbsp;Jiang-Wen Lu ,&nbsp;Fan Zhang ,&nbsp;Fan Pan ,&nbsp;Yao Su ,&nbsp;Leslie Myatt ,&nbsp;Wang-Sheng Wang ,&nbsp;Kang Sun ,&nbsp;Hao Ying","doi":"10.1016/j.mad.2025.112053","DOIUrl":"10.1016/j.mad.2025.112053","url":null,"abstract":"<div><div>Senescence of amnion epithelial cells not only disrupts the fetal membrane structure, but also becomes a source of proinflammatory signals contributing to membrane inflammation at parturition. However, the trigger initiating their senescence awaits identification. In this study, we found that SERPINE1 abundance was significantly increased in the amnion at parturition, where SERPINE1 was found predominantly expressed in amnion fibroblasts. SERPINE1 from amnion fibroblasts induced amnion epithelial cell senescence by causing vitronectin shedding from the cells thereby interrupting the association of vitronectin with integrin subunit αV, which led to the inhibition of the cell survival-associated focal adhesion pathway. In turn, proinflammatory cytokines such as interleukin-1β from senescent amnion epithelial cells enhanced SERPINE1 expression in amnion fibroblasts, thus forming a feed-forward loop between SERPINE1 production in amnion fibroblasts and epithelial cell senescence at parturition. Studies in the pregnant mice showed that intra-amniotic injection of SERPINE1 induced preterm birth with increased cellular senescence in the fetal membranes, which could be reversed by co-administration of vitronectin. Our findings indicate that SERPINE1 derived from amnion fibroblasts participates in the induction of amnion epithelial cell senescence at parturition. Intervening in the interaction of SERPINE1 with vitronectin may have therapeutic benefit in the treatment of preterm birth.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"225 ","pages":"Article 112053"},"PeriodicalIF":5.3,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular signatures of cellular senescence in cancer: a critical review of prognostic implications and therapeutic opportunities","authors":"Débora C. Santos-Sousa ,&nbsp;Solon da Rosa ,&nbsp;Eduardo Filippi-Chiela","doi":"10.1016/j.mad.2025.112052","DOIUrl":"10.1016/j.mad.2025.112052","url":null,"abstract":"<div><div>Cellular senescence is a state of permanent loss of proliferative capacity. Therefore, cells that reach a senescent state prevent tumor initiation, acting as an anti-tumor mechanism. However, despite not being proliferative, senescent cells have high secretory activity, constituting the Senescence-Associated Secretory Phenotype (SASP). SASP includes thousands of soluble molecules and extracellular vesicles, through which senescent cells can affect other cells and the extracellular matrix. In advanced tumors, the enrichment of senescent cells can have anti- or pro-tumor effects depending on features like SASP composition, tumor microenvironment (TME) composition, the anatomic site, histopathologic characteristics of malignancy, and tumor molecular background. We reviewed the studies assessing the impact of the senescence status, measured by mRNA or lncRNA molecular signatures, in the prognosis and other clinically relevant information in cancer, including anti-tumor immunity and response to therapy. We discussed the pros and cons of different strategies to define those molecular signatures and the main limitations of the studies. Finally, we also raised clinical challenges regarding the crossroad between cellular senescence and cancer prognosis, including some therapeutic opportunities in the field.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"225 ","pages":"Article 112052"},"PeriodicalIF":5.3,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143686789","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":"Exosomal dynamics: Bridging the gap between cellular senescence and cancer therapy","authors":"Babu Santha Aswani ,&nbsp;Anjana Sajeev ,&nbsp;Mangala Hegde ,&nbsp;Anamika Mishra ,&nbsp;Mohamed Abbas ,&nbsp;Thafasalijyas Vayalpurayil ,&nbsp;Gautam Sethi ,&nbsp;Ajaikumar B. Kunnumakkara","doi":"10.1016/j.mad.2025.112045","DOIUrl":"10.1016/j.mad.2025.112045","url":null,"abstract":"<div><div>Cancer remains one of the most devastating diseases, severely affecting public health and contributing to economic instability. Researchers worldwide are dedicated to developing effective therapeutics to target cancer cells. One promising strategy involves inducing cellular senescence, a complex state in which cells exit the cell cycle. Senescence has profound effects on both physiological and pathological processes, influencing cellular systems through secreted factors that affect surrounding and distant cells. Among these factors are exosomes, small extracellular vesicles that play crucial roles in cellular communication, development, and defense, and can contribute to pathological conditions. Recently, there has been increasing interest in engineering exosomes as precise drug delivery vehicles, capable of targeting specific cells or intracellular components. Studies have emphasized the significant role of exosomes from senescent cells in cancer progression and therapy. Notably, chemotherapeutic agents can alter the tumor microenvironment, induce senescence, and trigger immune responses through exosome-mediated cargo transfer. This review explores the intricate relationship between cellular senescence, exosomes, and cancer, examining how different therapeutics can eliminate cancer cells or promote drug resistance. It also investigates the molecular mechanisms and signaling pathways driving these processes, highlighting current challenges and proposing future perspectives to uncover new therapeutic strategies for cancer treatment.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"225 ","pages":"Article 112045"},"PeriodicalIF":5.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143616222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of cytomegalovirus serostatus with ELOVL2 methylation: Implications for lipid metabolism, inflammation, DNA damage, and repair capacity in the MARK-AGE study population","authors":"Robertina Giacconi ,&nbsp;Chiara Pirazzini ,&nbsp;Maria Giulia Bacalini ,&nbsp;Paolo Garagnani ,&nbsp;Miriam Capri ,&nbsp;Claudio Franceschi ,&nbsp;Carlo Fortunato ,&nbsp;Gretta Veronica Badillo Pazmay ,&nbsp;Alexander Bürkle ,&nbsp;María Moreno Villanueva ,&nbsp;Maurizio Cardelli ,&nbsp;Francesco Piacenza ,&nbsp;Monia Cecati ,&nbsp;Laura Cianfruglia ,&nbsp;Martijn E.T. Dollé ,&nbsp;Eugène Jansen ,&nbsp;Tilman Grune ,&nbsp;Efstathios S. Gonos ,&nbsp;Birgit Weinberger ,&nbsp;Ewa Sikora ,&nbsp;Marco Malavolta","doi":"10.1016/j.mad.2025.112043","DOIUrl":"10.1016/j.mad.2025.112043","url":null,"abstract":"<div><div>Cytomegalovirus (CMV) infection has been linked to accelerated biological aging, potentially increasing the risk of cardiovascular disease. DNA methylation of the gene Elongation Of Very Long Chain Fatty Acids-Like 2 (<em>ELOVL2</em>) is a molecular biomarker for aging, and its gene product is involved in polyunsaturated fatty acid synthesis, which impacts immune and inflammatory responses. This study, conducted in the MARK-AGE population, aimed to investigate the relationship between CMV infection and ELOVL2 methylation in adults aged 35–75, as well as the influence of CMV IgG levels on lipid metabolism, inflammation, DNA damage, and DNA repair. Our data revealed a higher prevalence of ischemic heart disease, atrial fibrillation, hypertension, and diabetes in CMV-positive individuals. CMV IgG levels were positively associated with <em>ELOVL2</em> methylation at specific CpG sites and with increased expression of DNA methyltransferase-1 (DNMT1). CMV IgG was linked to lipid imbalances, such as increased BMI, VLDL-cholesterol, triglycerides, and HDL1-cholesterol. Additionally, <em>ELOVL2</em> methylation was associated with systemic inflammation markers, lipid parameters and altered T-cell subsets. A negative correlation was observed between CMV IgG levels and both baseline DNA integrity and repair capacity. These results suggest that CMV infection might promote cardiovascular disease through <em>ELOVL2</em> hypermethylation, lipid dysregulation, inflammation, and DNA damage.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"225 ","pages":"Article 112043"},"PeriodicalIF":5.3,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537227","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":"Heart of the matter: Mitochondrial dynamics and genome alterations in cardiac aging","authors":"Claudie Gabillard-Lefort ,&nbsp;Théophile Thibault ,&nbsp;Guy Lenaers ,&nbsp;Rudolf J. Wiesner ,&nbsp;Jeanne Mialet-Perez ,&nbsp;Olivier R. Baris","doi":"10.1016/j.mad.2025.112044","DOIUrl":"10.1016/j.mad.2025.112044","url":null,"abstract":"<div><div>Cardiac pathological aging is a serious health issue, with cardiovascular diseases still being a leading cause of deaths worldwide. Therefore, there is an urgent need to identify culprit factors involved in this process. In the last decades, mitochondria, which are crucial for cardiac function, have emerged as major contributors. Mitochondria are organelles involved in a plethora of metabolic pathways and cell processes ranging from ATP production to calcium homeostasis or regulation of apoptotic pathways. This review provides a general overview of the pathomechanisms involving mitochondria during cardiac aging, with a focus on the role of mitochondrial dynamics and mitochondrial DNA (mtDNA). These mechanisms involve imbalanced mitochondrial fusion and fission, loss of mtDNA integrity leading to tissue mosaic of mitochondrial deficiency, as well as mtDNA release in the cytoplasm, promoting inflammation via the NLRP3, cGAS/STING and TLR9 pathways. Potential links between mtDNA, mitochondrial damage and the accumulation of senescent cells in the heart are also discussed. A better understanding of how these factors impact on heart function and accelerate its pathological aging should lead to the development of new therapies to promote healthy aging and restore age-induced cardiac dysfunction.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"224 ","pages":"Article 112044"},"PeriodicalIF":5.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143512363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The relationship between physical activity and telomere length in women: A systematic review","authors":"Jeni Page ,&nbsp;Catherine Stephens ,&nbsp;Melissa Richard ,&nbsp;Elizabeth Lyons ,&nbsp;Elizabeth Baumler ,&nbsp;M. Terese Verklan ,&nbsp;Elizabeth Lorenzo","doi":"10.1016/j.mad.2025.112042","DOIUrl":"10.1016/j.mad.2025.112042","url":null,"abstract":"<div><div>Telomere length (TL) is a biomarker of cellular aging with variations observed by sex, age, race, and ethnicity. Prior studies have suggested that physical activity (PA) may positively impact TL by potentially elongating telomeres and slowing cellular aging. However, research examining the optimal type and intensity of PA needed to elicit these changes specific to women remains limited. This systematic review aimed to investigate variations in TL in response to PA among women, exploring how these effects differ by age, race, or ethnicity. Following PRISMA guidelines, searches across five databases identified 17 relevant studies published from 2008 to 2022. A narrative synthesis of study findings indicated PA did not have a significant relationship with TL in women. However, a possible positive relationship was noted between specific types of PA and TL, specific to combined aerobic and strength-training PA and high intensity interval training interventions. The impact of PA on TL appeared to be age-dependent as well, showing significant positive relationships between PA and TL in early and later adulthood but not in middle adulthood. Findings related to race or ethnicity were inconclusive due to limited analyses from the included studies. The studies varied greatly by PA type, intensity, duration, and frequency, which, along with the reliance on self-reported PA measures in the observational studies, impacted the ability to draw firm conclusions. This review underscores the necessity for future research in large cohort studies using objectively measured PA interventions to further clarify the complex associations between PA and TL in women.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"224 ","pages":"Article 112042"},"PeriodicalIF":5.3,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472653","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":"Vascular participation in bone healing: Implications related to advancing age and morbidity","authors":"Rhonda D. Prisby","doi":"10.1016/j.mad.2025.112041","DOIUrl":"10.1016/j.mad.2025.112041","url":null,"abstract":"<div><div>Fracture non-union and the related morbidities represent a global health concern. While many factors are necessary for proper bone healing following fracture, the vascular system is requisite. Important considerations include vascular morphology in bone and marrow and the regulation of tissue blood flow. This review discusses the types of fracture management and associated bone repair (i.e., intramembranous vs. endochondral), the phases of bone healing, and the role of the bone vascular network. Finally, fracture healing is considered in the context of advanced age and morbidity.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"224 ","pages":"Article 112041"},"PeriodicalIF":5.3,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143429479","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":"Aging: A struggle for beneficial to overcome negative factors made by muscle and bone","authors":"Steven S. Welc ,&nbsp;Marco Brotto ,&nbsp;Kenneth E. White ,&nbsp;Lynda F. Bonewald","doi":"10.1016/j.mad.2025.112039","DOIUrl":"10.1016/j.mad.2025.112039","url":null,"abstract":"<div><div>Musculoskeletal health is strongly influenced by regulatory interactions of bone and muscle. Recent discoveries have identified a number of key mechanisms through which soluble factors released during exercise by bone exert positive effects on muscle and by muscle on bone. Although exercise can delay the negative effects of aging, these beneficial effects are diminished with aging. The limited response of aged muscle and bone tissue to exercise are accompanied by a failure in bone and muscle communication. Here, we propose that exercise induced beneficial factors must battle changes in circulating endocrine and inflammatory factors that occur with aging. Furthermore, sedentary behavior results in the release of negative factors impacting the ability of bone and muscle to respond to physical activity especially with aging. In this review we report on exercise responsive factors and evidence of modification occurring with aging.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"224 ","pages":"Article 112039"},"PeriodicalIF":5.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143422506","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 EZH2/MCM Complex/hTERT axis facilitates hepatocellular carcinoma progression by inhibiting cellular senescence","authors":"Ziyi Shen ,&nbsp;Yuanhui Wang ,&nbsp;Jie Gao ,&nbsp;Wei Gu ,&nbsp;Ziyi Ren ,&nbsp;Luanqi Xu ,&nbsp;Rui Qian ,&nbsp;Qinyi Miao ,&nbsp;Xiaomeng Hu ,&nbsp;Yan Wu ,&nbsp;Wei Liu ,&nbsp;Yi Cai ,&nbsp;Chunpeng (Craig) Wan ,&nbsp;Yansong Zhu ,&nbsp;Lei Sun ,&nbsp;Tingdong Yan","doi":"10.1016/j.mad.2025.112040","DOIUrl":"10.1016/j.mad.2025.112040","url":null,"abstract":"<div><div>The complex pathogenesis of hepatocellular carcinoma (HCC) limits the effectiveness of current therapies. Through RNA sequencing of cancerous and adjacent non-cancerous tissues from six HCC patients, we identified a significant upregulation of MCM2–7 genes, which encode proteins that form the MCM complex, a DNA helicase involved in DNA replication and cell cycle progression. We focused on MCM2, MCM3, and MCM7, and observed that knockdown of these proteins inhibited HCC cell proliferation. Further analysis revealed a critical regulatory axis involving EZH2, the MCM complex, and hTERT. EZH2 was found to be highly correlated with MCM complex gene expression and directly bound to the MCM gene promoters, regulating their expression. This EZH2/MCM complex/hTERT axis may play a key role in suppressing cellular senescence, thereby promoting HCC progression. Knocking down MCM complex genes reduced hTERT expression, inducing HCC cell senescence and enhancing the therapeutic efficacy of sorafenib. These findings suggest that the EZH2/MCM complex/hTERT axis could serve as a novel therapeutic target for HCC.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"224 ","pages":"Article 112040"},"PeriodicalIF":5.3,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388112","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}