{"title":"Circulating miR-483-5p predicts long term all-cause mortality in hospitalized older adults.","authors":"Silvia Di Valerio, Deborah Ramini, Matilde Sbriscia, Mirko Di Rosa, Dalila Colombaretti, Francesco Piacenza, Giulia Matacchione, Chiara Giordani, Sonia Fantone, Francesca Marchegiani, Rina Recchioni, Iryna Rusanova, Fabrizia Lattanzio, Fabiola Olivieri, Jacopo Sabbatinelli, Angelica Giuliani","doi":"10.1016/j.mad.2026.112190","DOIUrl":"10.1016/j.mad.2026.112190","url":null,"abstract":"<p><p>Accurately predicting long-term mortality in older adults remains challenging, as chronological age and conventional clinical indices incompletely capture biological vulnerability. Circulating microRNAs (miRNAs) have emerged as potential biomarkers of aging-related pathophysiology, but their long-term prognostic value remains poorly defined. In this prospective observational study nested within the Report-AGE cohort, we evaluated whether selected circulating miRNAs predict 10-year all-cause mortality in hospitalized adults aged ≥ 65 years. Baseline circulating levels of miR-483-5p, miR-320b, miR-21-5p, and miR-146a-5p were measured in 648 participants and categorized into tertiles. During follow-up, 525 deaths occurred. Among the four miRNAs examined, higher circulating levels of miR-483-5p were associated with increased mortality. In fully adjusted Cox models accounting for demographic characteristics, comorbidity burden, polypharmacy, renal function, hematological indices, inflammatory parameters, albumin, and calcium, participants in the highest miR-483-5p tertile had significantly higher mortality risk than those in the lowest tertile. This association remained robust after exclusion of individuals with chronic kidney disease. In exploratory analyses, miR-483-5p and miR-320b showed stronger associations with Phenotypic Age acceleration than with chronological age. Addition of miR-483-5p modestly improved mortality discrimination at early and intermediate follow-up. These findings suggest that circulating miR-483-5p is associated with mortality and may reflect biological vulnerability in late life.</p>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":" ","pages":"112190"},"PeriodicalIF":5.1,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839875","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}
Ilia Stambler, Alexander Tietz-Latza, Björn Schumacher, Hartmut Geiger, Helen Morrison, Oliver Tüscher, Georg Fuellen, Roland Meisel, Andreas Simm, Andreas Pfeiffer, Axel Steinhage, Aurel Popa-Wagner, Wolfgang Wagner, Oliver Cornely, Mario Krause, Georgios Mitrou, Marios Kyriazis, Morten Scheibye-Knudsen, Suresh Rattan, Richard Siow, David Weinkove, Shuvarthi Bhattacharjee, Didier Coeurnelle, Niccolò Invidia, Nicola Marino, Maddalena Illario, Calogero Caruso, Ennio Tasciotti, Federico Schena, Francesca Cesaroni, Salvatore De Rosa, Francesco Neri, Dmitry Bulavin, John Rowell, Bruno Vellas, Edouard Debonneuil, Lilia Lens-Pechakova, José Luis Cordeiro, Eduardo Díaz-Rubio, María Cordón Muro, Mayca Marín, Cayetano Santana Gil, Sergio Guillen, Dolores Corella, Pedro Barata, Amelia Pilar Rauter, Mónica Sousa, Linus Petersson, Brun Ulfhake, Valdis Pīrāgs, Svjatoslavs Kistkins, Emīls Sjundjukovs, Dmitrijs Bliznuks, Leonas Valius, Silvija Valdonė Alšauskė, Maria Teresa Arredondo, Marek Postula, Igors Berkovics, Karol Kaminski, Antonella Santuccione Chadha, Evelyne Bischof, Alessandro Puiatti, Raluca Prodan, Ionel Blănculescu, Lacramioara Frasineanu, Anca Andreea Sandu, Milena Georgieva, Angel Marchev, Angel Marchev, Alexander Tchernev, Martin Lipovšek, Dóra Horváth, Harald Sourij, Hana Vankova, Marjolein Visser, Kinga Matuła, Oleh Lushchak, Zoia Dikhtiarenko, Abraham Kebede, Rada Sandic-Spaho, Michelle Adams, Efstathios S Gonos
{"title":"The need to increase support for healthy ageing and longevity research in the EU by establishing a Coordination and Support Programme on Healthy Ageing and Longevity.","authors":"Ilia Stambler, Alexander Tietz-Latza, Björn Schumacher, Hartmut Geiger, Helen Morrison, Oliver Tüscher, Georg Fuellen, Roland Meisel, Andreas Simm, Andreas Pfeiffer, Axel Steinhage, Aurel Popa-Wagner, Wolfgang Wagner, Oliver Cornely, Mario Krause, Georgios Mitrou, Marios Kyriazis, Morten Scheibye-Knudsen, Suresh Rattan, Richard Siow, David Weinkove, Shuvarthi Bhattacharjee, Didier Coeurnelle, Niccolò Invidia, Nicola Marino, Maddalena Illario, Calogero Caruso, Ennio Tasciotti, Federico Schena, Francesca Cesaroni, Salvatore De Rosa, Francesco Neri, Dmitry Bulavin, John Rowell, Bruno Vellas, Edouard Debonneuil, Lilia Lens-Pechakova, José Luis Cordeiro, Eduardo Díaz-Rubio, María Cordón Muro, Mayca Marín, Cayetano Santana Gil, Sergio Guillen, Dolores Corella, Pedro Barata, Amelia Pilar Rauter, Mónica Sousa, Linus Petersson, Brun Ulfhake, Valdis Pīrāgs, Svjatoslavs Kistkins, Emīls Sjundjukovs, Dmitrijs Bliznuks, Leonas Valius, Silvija Valdonė Alšauskė, Maria Teresa Arredondo, Marek Postula, Igors Berkovics, Karol Kaminski, Antonella Santuccione Chadha, Evelyne Bischof, Alessandro Puiatti, Raluca Prodan, Ionel Blănculescu, Lacramioara Frasineanu, Anca Andreea Sandu, Milena Georgieva, Angel Marchev, Angel Marchev, Alexander Tchernev, Martin Lipovšek, Dóra Horváth, Harald Sourij, Hana Vankova, Marjolein Visser, Kinga Matuła, Oleh Lushchak, Zoia Dikhtiarenko, Abraham Kebede, Rada Sandic-Spaho, Michelle Adams, Efstathios S Gonos","doi":"10.1016/j.mad.2026.112187","DOIUrl":"https://doi.org/10.1016/j.mad.2026.112187","url":null,"abstract":"<p><p>Europe faces rapidly accelerating population ageing, driving multimorbidity and unsustainable healthcare costs. This paper calls for the establishment of an EU Coordination and Support Programme on Healthy Ageing and Longevity to integrate research, innovation, regulation, and capacity‑building across Member States.</p>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"231 ","pages":"112187"},"PeriodicalIF":5.1,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839872","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}
Lavinia Attili, Marianna Nicoletta Rossi, Rachele Di Santo, Guglielmo Duranti, Roberta Ceci, Manuela Cervelli
{"title":"Polyamines and autophagy as a dynamic regulatory network in skeletal muscle regeneration and aging.","authors":"Lavinia Attili, Marianna Nicoletta Rossi, Rachele Di Santo, Guglielmo Duranti, Roberta Ceci, Manuela Cervelli","doi":"10.1016/j.mad.2026.112188","DOIUrl":"10.1016/j.mad.2026.112188","url":null,"abstract":"<p><p>Autophagy is a core cellular mechanism that preserves tissue homeostasis by removing damaged proteins and organelles. In skeletal muscle, proper regulation of autophagic flux is essential for maintaining metabolic and structural integrity, whereas its disruption contributes to muscle atrophy, metabolic dysfunction, and age-related functional decline. Increasing evidence identifies polyamines, particularly spermidine (Spd), as important modulators of autophagy and cellular resilience, with beneficial effects on stress responses, metabolic regulation, and lifespan extension. Physical exercise likewise acts as a physiological inducer of autophagy, promoting muscle remodelling, mitochondrial quality control, and adaptive responses to stress. Within this framework, spermine oxidase (SMOX) has emerged as a relevant regulator of muscle homeostasis. SMOX expression is maintained in healthy muscle but declines in atrophic conditions. By converting spermine into spermidine, SMOX may help sustain autophagy-related pathways and support muscle mass under physiological conditions. This review explores the interplay between exercise, spermidine, and SMOX, highlighting autophagy as a unifying regulatory axis. We summarize current evidence on their individual and combined roles in preserving muscle function and discuss their potential relevance for promoting healthy muscle aging and counteracting sarcopenia.</p>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":" ","pages":"112188"},"PeriodicalIF":5.1,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839936","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":"Mechanistic Insights into the Neuroprotective Potential of Gut Microbiota-Derived Urolithins in Alzheimer's Disease.","authors":"Mehdi Alami, Hicham Berrougui, Mojgan Morvaridzadeh, Kaoutar Boumezough, Ikram Salih, Nada Zoubdane, Jamal Oubaouz, Oualid Abboussi, Khalid Sadki, Tamas Fülöp, Abdelouahed Khalil","doi":"10.1016/j.mad.2026.112189","DOIUrl":"https://doi.org/10.1016/j.mad.2026.112189","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) aggregation, tau pathology, synaptic failure, and progressive neuronal loss. In addition to these classical hallmarks, chronic neuroinflammation, oxidative stress, and mitochondrial dysfunction have gained recognition as central to disease pathogenesis. Dietary polyphenols and their microbial metabolites have emerged as promising modulators of these processes. Among them, urolithins, bioactive gut-derived compounds produced from ellagitannins, exhibit notable neuroprotective potential both in vitro and in vivo. Urolithins readily cross the blood-brain barrier and modulate key pathways implicated in AD, including tau-mediated axonal degeneration, microglial activation, redox imbalance, and impaired mitophagy in cellular and animal models. In the present narrative review, we discuss the mechanistic basis of urolithin's actions in established cellular models and in the ageing animal brains, highlighting in vitro and preclinical evidence that positions these metabolites at the intersection of nutrition, microbiota, and neurodegeneration. We propose that targeting urolithin-sensitive pathways may offer a novel, multifaceted strategy against AD-related brain dysfunction and slow disease progression.</p>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":" ","pages":"112189"},"PeriodicalIF":5.1,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839928","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}
Linghuan Wang , Yan Ma , Tianhu Wang , Weiwei Zhang , Zhiyi Fang , Tingting Lu , Yingjie Zhang , Yan Fang , Ting Sun , Dong Han , Feng Cao
{"title":"SRC suppression attenuates vascular aging by activating FUNDC1-dependent mitophagy","authors":"Linghuan Wang , Yan Ma , Tianhu Wang , Weiwei Zhang , Zhiyi Fang , Tingting Lu , Yingjie Zhang , Yan Fang , Ting Sun , Dong Han , Feng Cao","doi":"10.1016/j.mad.2026.112156","DOIUrl":"10.1016/j.mad.2026.112156","url":null,"abstract":"<div><div>Vascular smooth muscle cell senescence contributes critically to vascular remodeling and atherosclerosis, with mitochondrial dysfunction and impaired mitophagy recognized as major contributors. SRC, a stress-responsive tyrosine kinase, has been linked to aging, yet its role in vascular aging remains unclear. Here, we examined the role of SRC in regulating autophagy/mitophagy using <em>in vitro</em> and <em>in vivo</em> models. An accelerated vascular aging model was established using a high-fat diet and streptozotocin injection in ApoE<sup>-/-</sup> mice, while senescence in mouse aortic vascular smooth muscle cells (MOVASs) was induced by doxorubicin. Elevated expression of SRC and phosphorylated SRC (Tyr418) was confirmed in both models. Pharmacological inhibition of SRC with KX2–391 partially mitigated features of vascular aging, improved mitochondrial morphology, reduced plaque burden, and enhanced fibrous cap stability. In senescent MOVASs, SRC knockdown decreased FUNDC1 Tyr18 phosphorylation, enhanced mitophagic flux, and reduced senescence, whereas SRC overexpression produced opposite effects and impaired KX2–391–mediated protection. Moreover, FUNDC1 knockdown abolished the anti-senescence effects of KX2–391, confirming that FUNDC1 is essential for SRC-mediated regulation. Together, these findings establish the SRC–FUNDC1 axis as an important regulator of mitophagy and vascular aging, suggesting that SRC inhibition may offer therapeutic benefit against vascular senescence and atherosclerosis.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"230 ","pages":"Article 112156"},"PeriodicalIF":5.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994313","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}
Peizhi Deng , Siyu Tang , Jinron Zeng , Jianyun Lu
{"title":"Inflammatory and genetic mechanisms mediate the association between frailty and incident atopic dermatitis in middle-aged and elderly adults","authors":"Peizhi Deng , Siyu Tang , Jinron Zeng , Jianyun Lu","doi":"10.1016/j.mad.2025.112148","DOIUrl":"10.1016/j.mad.2025.112148","url":null,"abstract":"<div><div>Frailty is linked to many chronic conditions, but its relationship with atopic dermatitis (AD) remains insufficiently defined. We assessed whether frailty predisposes to incident AD and explored inflammatory and genetic mechanisms. Baseline frailty was ascertained using both the physical frailty phenotype and a multidimensional frailty index, classifying participants as non-frail, pre-frail, or frail. Cox proportional hazards models with stratified analyses quantified associations with AD onset. To probe causality, we performed two-sample Mendelian randomization (TSMR) and generalized summary-data-based MR (GSMR). We further integrated circulating inflammatory markers and plasma proteomic data to illuminate biological pathways. Compared with non-frail participants, pre-frail and frail individuals had higher risks of incident AD after adjustment for established confounders; associations were stronger in adults < 65 years. TSMR and GSMR supported a potential causal effect of frailty on AD. Neutrophil count, eosinophil count, and C-reactive protein partially mediated the frailty-AD relationship. Proteomic analyses highlighted MMP12 as a promising AD-specific biomarker in frail individuals. Overall, frailty confers an elevated long-term risk of AD, with middle-aged adults displaying the greatest vulnerability. Several inflammatory cell measures and circulating proteins-including MMP12-may serve as early indicators of AD risk, informing earlier diagnosis and targeted monitoring in pre-frail and frail populations.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"230 ","pages":"Article 112148"},"PeriodicalIF":5.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145915215","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":"Senescent cancer-associated fibroblasts in cancer progression: From formation to therapeutic opportunities","authors":"Yingying Feng, Xiaochen Zhi, Ting Xiao, Lin Feng","doi":"10.1016/j.mad.2026.112158","DOIUrl":"10.1016/j.mad.2026.112158","url":null,"abstract":"<div><div>Cancer-associated fibroblasts (CAFs) are a key cellular component of the tumor microenvironment (TME), which comprises distinct subtypes, each exhibiting unique and significant roles in cancer development. Senescent cancer-associated fibroblasts (senCAFs) are a newly identified subset of CAFs characterized by high expression of senescence-associated markers. Notably, senCAFs significantly promote tumor malignancy through the secretion of diverse senescence-associated secretory phenotype (SASP) factors, such as interleukin-6 (IL-6), interleukin-8 (IL-8), matrix metalloproteinases (MMPs), and transforming growth factor-β (TGF-β), thereby facilitating tumor cell proliferation, invasion, angiogenesis, immunosuppression, and resistance to cancer therapy. Consequently, targeting senCAFs—either through selective clearance of this cell subset or suppression of their SASP—represents a promising approach for cancer treatment. Emerging therapies include pharmacological inhibition of key SASP regulatory pathways (e.g., JAK/STAT3 and NF-κB) and antagonists targeting individual SASP components. Additionally, senolytic agents and therapies targeting senCAF-specific markers (e.g., TSPAN8) are being actively explored. Furthermore, immunotherapies, including CAR-T cells targeting senescence-associated surface proteins, provide intriguing avenues. These advances highlight senCAFs as attractive therapeutic targets and underscore the potential for integrating SASP inhibitors and senolytic agents into precision oncology paradigms.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"230 ","pages":"Article 112158"},"PeriodicalIF":5.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035545","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}
Jee Hee Yoon , Yun Haeng Lee , Sekyung Oh , Kyeong Seon Lee , Ji Ho Park , Yoo Jin Lee , Byeonghyeon So , Duyeol Kim , Minseon Kim , Hyung Wook Kwon , Youngjoo Byun , Ki Yong Lee , Joon Tae Park
{"title":"Vitisin B rejuvenates senescence via WBP2NL regulation","authors":"Jee Hee Yoon , Yun Haeng Lee , Sekyung Oh , Kyeong Seon Lee , Ji Ho Park , Yoo Jin Lee , Byeonghyeon So , Duyeol Kim , Minseon Kim , Hyung Wook Kwon , Youngjoo Byun , Ki Yong Lee , Joon Tae Park","doi":"10.1016/j.mad.2026.112159","DOIUrl":"10.1016/j.mad.2026.112159","url":null,"abstract":"<div><div>One of the main factors contributing to aging is reactive oxygen species (ROS), which are produced by dysfunctional mitochondria. Reducing ROS generation is considered an essential treatment for senescence, but no effective treatment has been developed yet. In this study, vitisin B, a tetramer of resveratrol, was found to be an efficient reagent that reduces mitochondrial ROS generation after screening phenylpropanoids (PPs), metabolites produced to overcome ROS-mediated stress in plants. Vitisin B induced mitochondrial functional recovery by activating mitophagy and removing dysfunctional mitochondria. Mitochondrial functional recovery by vitisin B decreased mitochondrial ROS, a by-product generated from dysfunctional mitochondria. In addition, ROS reduction by vitisin B restored senescence-associated phenotypes. RNA sequencing identified <em>WBP2 N-Terminal Like</em> (<em>WBP2NL</em>) as a gene essential for vitisin B-mediated senescence rejuvenation. Knockdown of <em>WBP2NL</em> exhibited effects similar to those of vitisin B, reducing mitochondrial ROS generation and consequently reversing senescence-associated phenotypes. This study elucidates a novel mechanism by which vitisin B reverses senescence by lowering mitochondrial ROS generation. This discovery opens the way to new therapeutic options to control aging by modulating mitochondrial ROS production.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"230 ","pages":"Article 112159"},"PeriodicalIF":5.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035490","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}
Cheng-Yun Ma , Sheng-Rong Yeh , Yi-Hsuan Huang , Wei-Sheng Lin , Yi-Chung Lee , Ting-Fen Tsai , Shou-Zen Fan , Pei-Yu Wang
{"title":"Dietary restriction mitigates cognitive impairments in a mouse model of SCA19/22","authors":"Cheng-Yun Ma , Sheng-Rong Yeh , Yi-Hsuan Huang , Wei-Sheng Lin , Yi-Chung Lee , Ting-Fen Tsai , Shou-Zen Fan , Pei-Yu Wang","doi":"10.1016/j.mad.2026.112157","DOIUrl":"10.1016/j.mad.2026.112157","url":null,"abstract":"<div><div>Spinocerebellar ataxia types 19 and 22 (SCA19/22) are neurodegenerative disorders caused by mutations in <em>KCND3</em> (potassium voltage-gated channel subfamily D member 3). Previous studies have developed <em>Kcnd3</em> F227del knock-in (KI) mice that successfully recapitulate the motor deficits and molecular pathogenesis observed in patients. However, the broader neurobehavioral consequences of the humanized <em>Kcnd3</em> F227del mutation, and whether these phenotypes depend on functional <em>Kcnd3</em>, remain unclear. In this study, we employed a battery of behavioral assessments and found that the <em>Kcnd3</em> F227del mutation may not only result in a loss of function but also act as a dominant, toxic gain-of-function variant associated with both ataxia and memory impairments. In contrast, <em>Kcnd3</em> null mice exhibited primarily hyperactivity without major cognitive deficits. Furthermore, we demonstrated that dietary restriction (DR) effectively attenuates memory deficits but does not improve locomotor impairments in <em>Kcnd3</em> F227del KI mice at behavioral, cellular, and neurostructural levels. Specifically, DR preserved neuronal survival, maintained dendritic architecture and spine density, and reduced neuroinflammation in the hippocampus. These findings offer new insights into the etiology of SCA19/22-related symptoms and suggest that DR may serve as a potential therapeutic strategy targeting cognitive deficits in patients carrying the <em>KCND3</em> F227del mutation.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"230 ","pages":"Article 112157"},"PeriodicalIF":5.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003649","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}
Rui Jiang , Hao Wang , Weina Zhang , Jiaxi Li , Shiqi Huang , Lingjiang Chen , Yuhan Min , Zhaohui Ouyang , Ying Jiang , Zhiyong Mao , Guizhu Wu , Ke Wei , Yu Chen
{"title":"DHT ameliorates cardiac aging in progeroid mice by XRCC4-mediated genome stabilization","authors":"Rui Jiang , Hao Wang , Weina Zhang , Jiaxi Li , Shiqi Huang , Lingjiang Chen , Yuhan Min , Zhaohui Ouyang , Ying Jiang , Zhiyong Mao , Guizhu Wu , Ke Wei , Yu Chen","doi":"10.1016/j.mad.2025.112141","DOIUrl":"10.1016/j.mad.2025.112141","url":null,"abstract":"<div><div>Cardiovascular compromise is the primary cause of death in Hutchinson-Gilford Progeria Syndrome (HGPS), a lethal segmental premature aging disorder; however, no therapies directly target its underlying cardiac pathology. Our prior work established that non-homologous end joining (NHEJ)—the dominant pathway for double-strand break repair and genomic stabilization in cardiomyocytes—is impaired in HGPS mice, triggering cardiac atrophy via a CHK2-AMPKα-FOXO3A signaling axis. While forced cardiac hypertrophy can ameliorate pathology, whether restoring DNA repair capacity constitutes a viable therapeutic strategy remains unknown. Here, utilizing dihydrotestosterone (DHT), we demonstrate that NHEJ activation stabilizes the cardiomyocyte genome, increases cardiomyocyte size, and enhances contractile function. Furthermore, DHT administration reduces DNA damage accumulation and promotes structural and functional recovery in HGPS hearts. Transcriptome analysis further demonstrates that DHT treatment rejuvenates HGPS hearts, upregulates pathways linked to heart function and downregulates inflammatory responses, a key driver of cardiac aging and disease. Collectively, our findings support NHEJ activation as a promising therapeutic approach for mitigating HGPS-associated cardiac degeneration and ameliorating cardiac aging.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"229 ","pages":"Article 112141"},"PeriodicalIF":5.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687579","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}
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