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.
{"title":"Human oral microbiome in aging: A systematic review","authors":"Elena Carbone , Elisa Fabrizi , Roberto Rivabene , Marisa Cappella , Paola Fortini , Lucia Conti , Nicoletta Locuratolo , Patrizia Lorenzini , Eleonora Lacorte , 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}
Pub Date : 2025-06-02DOI: 10.1016/j.mad.2025.112081
C.M. Donado-Pestana , L. Rodrigues , M. Rundle , E.L. Thomas , S. Wopereis , T.E. Gundersen , J.P. Trezzi , D. Bunzel , Y. Kiselova-Kaneva , D. Sonntag , S.E. Kulling , D. Ivanova , K. Hiller , C.A. Drevon , L. Brennan , J.D. Bell , B. van Ommen , G. Frost , H. Daniel , J. Fiamoncini
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 < 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 < 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.
{"title":"Plasma metabolomic profiles reveal sex-specific response to an oral glucose tolerance test in late middle-aged adults","authors":"C.M. Donado-Pestana , L. Rodrigues , M. Rundle , E.L. Thomas , S. Wopereis , T.E. Gundersen , J.P. Trezzi , D. Bunzel , Y. Kiselova-Kaneva , D. Sonntag , S.E. Kulling , D. Ivanova , K. Hiller , C.A. Drevon , L. Brennan , J.D. Bell , B. van Ommen , G. Frost , H. Daniel , 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 < 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 < 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}
Pub Date : 2025-05-24DOI: 10.1016/j.mad.2025.112076
Yuping Dai , Ni Boussaguet , Jérôme Teulière , Hugo Bonnefous , Elphège Budzinski , Philippe Lopez , Louis-Patrick Haraoui , Eric Bapteste
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. Salmonella, Escherichia and Shigella 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 Salmonella, Escherichia and Shigella 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.
{"title":"Interspecific interactions and aging: Prediction of gerogenic bacteria and critical human protein targets of microbial infections","authors":"Yuping Dai , Ni Boussaguet , Jérôme Teulière , Hugo Bonnefous , Elphège Budzinski , Philippe Lopez , Louis-Patrick Haraoui , 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}
Pub Date : 2025-05-06DOI: 10.1016/j.mad.2025.112067
Xinchen Huang , Xiaoling Kui , Jiyao Ma , Jiaxin Chen , Yilong Huang , Bo He
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. In vitro, 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.
{"title":"Cyr61 promotes D-gal-induced aging C2C12 cell fibrosis by modulating Wnt/β-catenin signaling pathways","authors":"Xinchen Huang , Xiaoling Kui , Jiyao Ma , Jiaxin Chen , Yilong Huang , 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}
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.
{"title":"Role of stem cells in ageing and age-related diseases","authors":"Jitendra Kumar Chaudhary , Ajay Kumar Danga , Anita Kumari , Akshay Bhardwaj , 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}
Pub Date : 2025-05-03DOI: 10.1016/j.mad.2025.112068
John T. González , Olivia H. Scharfman , Wanling Zhu , Jessica Kasamoto , Victoria Gould , Rachel J. Perry , Albert T. Higgins-Chen
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.
{"title":"Transcriptomic and epigenomic signatures of liver metabolism and insulin sensitivity in aging mice","authors":"John T. González , Olivia H. Scharfman , Wanling Zhu , Jessica Kasamoto , Victoria Gould , Rachel J. Perry , 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}
Aging is a key risk factor for sarcopenia, a progressive disorder affecting skeletal muscle. One hallmark of aging is cellular senescence. To investigate cellular senescence in mouse skeletal myoblasts, we attempted to induce cellular senescence by HRasV12. Unexpectedly, HRasV12 did not induce the expression of senescence markers such as p16 and p21, and no SA-β-gal-positive cells were observed in the myoblasts. Instead, HRasV12 elevated the levels of apoptotic markers such as cleaved caspase-3, cleaved caspase-8, and the ratio of Bax to Bcl-2 in the myoblasts. These findings suggested that HRasV12 does not induce senescence, but triggers apoptotic cell death in mouse skeletal myoblasts.
{"title":"HRasV12 induces apoptosis, not cellular senescence in mouse skeletal myoblasts","authors":"Shinichiro Suzuki , Takuya Fukunaga , Tatsuya Hayashi , Tatsuro Egawa","doi":"10.1016/j.mad.2025.112066","DOIUrl":"10.1016/j.mad.2025.112066","url":null,"abstract":"<div><div>Aging is a key risk factor for sarcopenia, a progressive disorder affecting skeletal muscle. One hallmark of aging is cellular senescence. To investigate cellular senescence in mouse skeletal myoblasts, we attempted to induce cellular senescence by HRasV12. Unexpectedly, HRasV12 did not induce the expression of senescence markers such as p16 and p21, and no SA-β-gal-positive cells were observed in the myoblasts. Instead, HRasV12 elevated the levels of apoptotic markers such as cleaved caspase-3, cleaved caspase-8, and the ratio of Bax to Bcl-2 in the myoblasts. These findings suggested that HRasV12 does not induce senescence, but triggers apoptotic cell death in mouse skeletal myoblasts.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"225 ","pages":"Article 112066"},"PeriodicalIF":5.3,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143899212","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}
Pub Date : 2025-04-24DOI: 10.1016/j.mad.2025.112064
Marta Daniela Costa , Jorge Diogo Da Silva , Dulce Almeida , Joana Pereira-Sousa , Daniela Vilasboas-Campos , Jorge Humberto Fernandes , Andreia Teixeira-Castro , Patrícia Maciel
Aging is a natural biological process, but evidence suggests that some aspects of aging can be delayed and reduce the prevalence of neurodegenerative diseases, for which aging is a key risk factor. In a neuronal Caenorhabditis elegans model of a Polyglutamine disease-Spinocerebellar Ataxia Type 3 (SCA3), or Machado-Joseph disease (MJD)- we assessed the hypothesis that delaying aging is neuroprotective, investigating the effect of genetically manipulating multiple lifespan-determinant mechanisms. Lifespan-increasing mutations causing insulin/IGF-1 signaling downregulation, mitochondrial dysfunction, germline ablation and dietary restriction/innate immune activation had distinct impacts on MJD/SCA3 phenotypes, suggesting that not all genetic strategies of stalling aging are equally neuroprotective and challenging the idea that delaying aging is a guaranteed therapy for these diseases. Lifespan-extension improved the SCA3/MJD motor phenotype only when induced by altered nutrient-sensing pathways such as those mediated by insulin/IGF-1 and eat-2 signaling, but their effects on neuronal aggregation differed. These pathways exhibited differential proteostasis profiles, but both activated the heat shock response suggesting that they operate through partially independent mechanisms to confer neuroprotection. The therapeutic value of the insulin/IGF-1 downregulation was demonstrated through the chronic treatment of the SCA3/MJD model with an insulin/IGF-1 signaling inhibitor, underscoring the relevance of aging manipulations in guiding therapeutic strategies for these diseases.
{"title":"Differential effects of lifespan-extending genetic manipulations in an animal model of MJD/SCA3","authors":"Marta Daniela Costa , Jorge Diogo Da Silva , Dulce Almeida , Joana Pereira-Sousa , Daniela Vilasboas-Campos , Jorge Humberto Fernandes , Andreia Teixeira-Castro , Patrícia Maciel","doi":"10.1016/j.mad.2025.112064","DOIUrl":"10.1016/j.mad.2025.112064","url":null,"abstract":"<div><div>Aging is a natural biological process, but evidence suggests that some aspects of aging can be delayed and reduce the prevalence of neurodegenerative diseases, for which aging is a key risk factor. In a neuronal <em>Caenorhabditis elegans</em> model of a Polyglutamine disease-Spinocerebellar Ataxia Type 3 (SCA3), or Machado-Joseph disease (MJD)- we assessed the hypothesis that delaying aging is neuroprotective, investigating the effect of genetically manipulating multiple lifespan-determinant mechanisms. Lifespan-increasing mutations causing insulin/IGF-1 signaling downregulation, mitochondrial dysfunction, germline ablation and dietary restriction/innate immune activation had distinct impacts on MJD/SCA3 phenotypes, suggesting that not all genetic strategies of stalling aging are equally neuroprotective and challenging the idea that delaying aging is a guaranteed therapy for these diseases. Lifespan-extension improved the SCA3/MJD motor phenotype only when induced by altered nutrient-sensing pathways such as those mediated by insulin/IGF-1 and <em>eat-2</em> signaling, but their effects on neuronal aggregation differed. These pathways exhibited differential proteostasis profiles, but both activated the heat shock response suggesting that they operate through partially independent mechanisms to confer neuroprotection. The therapeutic value of the insulin/IGF-1 downregulation was demonstrated through the chronic treatment of the SCA3/MJD model with an insulin/IGF-1 signaling inhibitor, underscoring the relevance of aging manipulations in guiding therapeutic strategies for these diseases.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"225 ","pages":"Article 112064"},"PeriodicalIF":5.3,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143899211","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}
Pub Date : 2025-04-24DOI: 10.1016/j.mad.2025.112065
Edward J. Calabrese , Peter Pressman , A. Wallace Hayes , Linda Baldwin , Evgenios Agathokleous , Harshita Kapoor , Gaurav Dhawan , Rachna Kapoor , Vittorio Calabrese
Kaempferol is a polyphenol in various fruits and vegetables. It is also commercially developed and sold to consumers as a supplement. It has been extensively assessed in clinical trials for clinical utility based upon its numerous experimentally based chemopreventive properties. Kaempferol has been evaluated at the levels of molecule, cell, and individual animal, showing a broad spectrum of biological effects. Kaempferol-induced hormetic concentration responses are common, being reported in many cell types and biological models for numerous endpoints. While the hormetic effects of kaempferol are biologically diverse, there has been a strong focus on age-related endpoints affecting numerous organ systems and endpoints, indicating that kaempferol is a senolytic agent, showing similar properties as quercetin and fisetin. This paper offers the first integrated evaluation of kaempferol-induced hormetic dose responses, their quantitative characteristics, mechanistic explanations, extrapolative strengths or limitations, and related experimental design, biomedical, therapeutic, ageing, and public health, including ageing related applications.
{"title":"Kaempferol, a widely ingested dietary flavonoid and supplement, enhances biological performance via hormesis, especially for ageing-related processes","authors":"Edward J. Calabrese , Peter Pressman , A. Wallace Hayes , Linda Baldwin , Evgenios Agathokleous , Harshita Kapoor , Gaurav Dhawan , Rachna Kapoor , Vittorio Calabrese","doi":"10.1016/j.mad.2025.112065","DOIUrl":"10.1016/j.mad.2025.112065","url":null,"abstract":"<div><div>Kaempferol is a polyphenol in various fruits and vegetables. It is also commercially developed and sold to consumers as a supplement. It has been extensively assessed in clinical trials for clinical utility based upon its numerous experimentally based chemopreventive properties. Kaempferol has been evaluated at the levels of molecule, cell, and individual animal, showing a broad spectrum of biological effects. Kaempferol-induced hormetic concentration responses are common, being reported in many cell types and biological models for numerous endpoints. While the hormetic effects of kaempferol are biologically diverse, there has been a strong focus on age-related endpoints affecting numerous organ systems and endpoints, indicating that kaempferol is a senolytic agent, showing similar properties as quercetin and fisetin. This paper offers the first integrated evaluation of kaempferol-induced hormetic dose responses, their quantitative characteristics, mechanistic explanations, extrapolative strengths or limitations, and related experimental design, biomedical, therapeutic, ageing, and public health, including ageing related applications.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"225 ","pages":"Article 112065"},"PeriodicalIF":5.3,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143885996","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}
Pub Date : 2025-04-19DOI: 10.1016/j.mad.2025.112061
G. Sophie Ngana , Mercedes A. Di Bernardo , Michael G. Surette , Lesley T. MacNeil
Parkinson’s Disease is characterized by selective degeneration of dopaminergic neurons, primarily in the substantia nigra pars compacta, as well as accumulation of alpha-synuclein enriched protein aggregates within neurons. The pathogenesis of PD is still not completely understood, and no treatments exist that alter disease progression. Obvious genetic causes are detected in only a small number of PD patients (5–10 %), suggesting that environmental factors play a significant role the development of PD. Correlative studies suggest that the microbiota could be an important environmental modifier of neurodegeneration. We identified a microbiotal isolate, Actinomyces viscosus, that reduced neurodegeneration in C. elegans expressing a pathological mutant form (G2019S) of leucine-rich repeat kinase 2 (LRRK2) in dopaminergic neurons. A. viscosus also suppressed autophagic dysfunction in these animals and reduced alpha-synuclein aggregation in a synucleinopathy model. Global gene expression analysis revealed increased expression of aspartic cathepsins in response to A. viscosus. Consistent with the involvement of these proteins in neuroprotection, we found that reducing aspartic cathepsin function increased neurodegeneration in the LRRK2 transgenic model. Our findings contribute to the current understanding of how the gut microbiota may influence PD, elucidating one potential mechanism of microbiota-mediated neuroprotection.
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