Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder in aging populations, demands minimally invasive biomarkers for early diagnosis and monitoring. Circulating microRNAs (miRNAs) show promise as such biomarkers. In this study, we examined the levels of five selected miRNAs, implicated in neurodegenerative processes, in plasma and neuron-derived extracellular vesicles (EVs) from cognitively healthy controls (n = 5), and patients with mild (n = 10) and moderate AD (n = 10), stratified by Mini-Mental State Examination (MMSE). miR-23a-3p, miR-223a-3p, and miR-132–3p were significantly downregulated in both plasma and EVs of AD patients, with miR-132–3p emerging as the strongest biomarker candidate for mild AD. Plasma miRNA levels strongly correlated with EV cargo, supporting plasma-based assessments. To validate these findings, miR-132–3p levels were analyzed in expanded cohorts, including cognitively healthy subjects (n = 36), mild AD (n = 37), and moderate AD (n = 40), as well as a cohort of subjects with mild cognitive impairment (MCI, n = 31) and an additional external cohort of cognitively healthy subjects (CTR external, n = 37). Results confirmed miR-132–3p downregulation in AD patients and revealed a significant elevation in MCI individuals, suggesting a potential neuroprotective role in AD early stages. These findings highlight miR-132–3p as a promising, minimally invasive biomarker for early AD diagnosis and disease progression monitoring.
{"title":"miR-132–3p is down-regulated in plasma and CD171+ extracellular vesicles isolated from patients with mild Alzheimer’s disease","authors":"Matilde Sbriscia , Tatiana Spadoni , Patrizia Ambrogini , Michele Guescini , Rachele Agostini , Laura Graciotti , Francesco Piacenza , Cinzia Giuli , Monia Cecati , Anna Rita Bonfigli , Salvatore Vaiasicca , Marica Pagliarini , Iryna Rusanova , Francesca Fazioli , Jacopo Sabbatinelli , Maria Cristina Albertini , Fabiola Olivieri , Angelica Giuliani","doi":"10.1016/j.mad.2025.112063","DOIUrl":"10.1016/j.mad.2025.112063","url":null,"abstract":"<div><div>Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder in aging populations, demands minimally invasive biomarkers for early diagnosis and monitoring. Circulating microRNAs (miRNAs) show promise as such biomarkers. In this study, we examined the levels of five selected miRNAs, implicated in neurodegenerative processes, in plasma and neuron-derived extracellular vesicles (EVs) from cognitively healthy controls (n = 5), and patients with mild (n = 10) and moderate AD (n = 10), stratified by Mini-Mental State Examination (MMSE). miR-23a-3p, miR-223a-3p, and miR-132–3p were significantly downregulated in both plasma and EVs of AD patients, with miR-132–3p emerging as the strongest biomarker candidate for mild AD. Plasma miRNA levels strongly correlated with EV cargo, supporting plasma-based assessments. To validate these findings, miR-132–3p levels were analyzed in expanded cohorts, including cognitively healthy subjects (n = 36), mild AD (n = 37), and moderate AD (n = 40), as well as a cohort of subjects with mild cognitive impairment (MCI, n = 31) and an additional external cohort of cognitively healthy subjects (CTR external, n = 37). Results confirmed miR-132–3p downregulation in AD patients and revealed a significant elevation in MCI individuals, suggesting a potential neuroprotective role in AD early stages. These findings highlight miR-132–3p as a promising, minimally invasive biomarker for early AD diagnosis and disease progression monitoring.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"225 ","pages":"Article 112063"},"PeriodicalIF":5.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143850726","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 : 2025-04-16DOI: 10.1016/j.mad.2025.112062
Muhammad Daniel Azlan Mahadzir , Sheryl Tan , Sandalova Elena , Ee Moon Chin , Vandana Garg , Konstantinos Mantantzis , Szabolcs Péter , Andrea B. Maier
Micronutrients are essential for maintaining physiological homeostasis and optimizing healthspan, defined as the years lived in good health without chronic diseases or disabilities. Despite increasing global life expectancy, improvements in healthspan have not kept pace, partly due to subclinical micronutrient deficiencies that often precede clinical symptoms. The triage theory highlights how micronutrient insufficiencies compromise long-term health by prioritizing critical metabolic functions. Micronutrients such as Vitamins B6, B9, B12, D, and K are particularly crucial to optimizing healthspan, by influencing energy metabolism, neurological health, immune regulation, and bone integrity. Traditional tools like Dietary Reference Intakes (DRIs) provide population-level guidelines but fail to account for individual factors such as genetics, lifestyle, and nutrient interactions. Quantitative assessment of micronutrient concentrations using biomarkers offers a more precise approach but faces challenges, including high costs and limited accessibility. National nutrition surveys demonstrate potential in addressing population-level deficiencies and form the basis for advancing precision supplementation strategies to improve health outcomes and extend healthspan by defining optimal micronutrient concentrations. Future efforts should aim to establish evidence-based thresholds for optimal micronutrient concentrations by integrating biomarker data with clinical outcomes, genetic profiles, and lifestyle factors, providing a framework to guide personalized and population-level supplementation strategies.
{"title":"Towards defining optimal concentrations of micronutrients in adults to optimize health","authors":"Muhammad Daniel Azlan Mahadzir , Sheryl Tan , Sandalova Elena , Ee Moon Chin , Vandana Garg , Konstantinos Mantantzis , Szabolcs Péter , Andrea B. Maier","doi":"10.1016/j.mad.2025.112062","DOIUrl":"10.1016/j.mad.2025.112062","url":null,"abstract":"<div><div>Micronutrients are essential for maintaining physiological homeostasis and optimizing healthspan, defined as the years lived in good health without chronic diseases or disabilities. Despite increasing global life expectancy, improvements in healthspan have not kept pace, partly due to subclinical micronutrient deficiencies that often precede clinical symptoms. The triage theory highlights how micronutrient insufficiencies compromise long-term health by prioritizing critical metabolic functions. Micronutrients such as Vitamins B6, B9, B12, D, and K are particularly crucial to optimizing healthspan, by influencing energy metabolism, neurological health, immune regulation, and bone integrity. Traditional tools like Dietary Reference Intakes (DRIs) provide population-level guidelines but fail to account for individual factors such as genetics, lifestyle, and nutrient interactions. Quantitative assessment of micronutrient concentrations using biomarkers offers a more precise approach but faces challenges, including high costs and limited accessibility. National nutrition surveys demonstrate potential in addressing population-level deficiencies and form the basis for advancing precision supplementation strategies to improve health outcomes and extend healthspan by defining optimal micronutrient concentrations. Future efforts should aim to establish evidence-based thresholds for optimal micronutrient concentrations by integrating biomarker data with clinical outcomes, genetic profiles, and lifestyle factors, providing a framework to guide personalized and population-level supplementation strategies.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"225 ","pages":"Article 112062"},"PeriodicalIF":5.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863371","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 : 2025-04-11DOI: 10.1016/j.mad.2025.112060
Zonghao Qian , Yuzhen Huang , Ni Yang , Ziwei Fang , Yucong Zhang , Yi Huang , Mandi Luo , Tianyi Ji , Zuoguan Chen , Shang Gao , Yongjun Li , Jinhua Yan , Dingsheng Jiang , Lei Ruan , Anding Liu , Cuntai Zhang , Le Zhang
Vascular aging is a key driver of age-related cardiovascular and metabolic diseases, with endothelial dysfunction and senescence as a central mechanism. In our recent study, we observed elevated ADAM10 protein levels in senescent endothelial cells, which worsened endothelial dysfunction and senescence. However, the regulatory mechanisms controlling ADAM10 expression are poorly understood. In this study, we show that ADAM10 undergoes post-transcriptional modification in senescent human umbilical vein endothelial cells (HUVECs), with the E3 ubiquitin ligase MARCHF8 predicted to facilitate its ubiquitination-dependent degradation. We also found that MARCHF8 expression was significantly reduced in senescent HUVECs. Knockdown of MARCHF8 in young HUVECs induced endothelial senescence and impaired key endothelial functions, including migration, proliferation, angiogenesis, and nitric oxide production. Conversely, overexpression of MARCHF8 in senescent HUVECs ameliorated senescence-associated dysfunctions. RNA sequencing analysis revealed that MARCHF8 knockdown disrupted pathways linked to cell senescence and atherosclerosis. In vivo, MARCHF8 overexpression in high-fat diet-fed apoE-/- mice reduced plasma interleukin-6 levels and attenuated atherosclerosis progression. Additionally, miR-34a-5p upregulation in senescence inhibited MARCHF8 expression, compromising its protective effects in delaying endothelial senescence. Collectively, these findings reveal a novel miR-34a-5p/MARCHF8/ADAM10 axis in vascular endothelial senescence, positioning MARCHF8 as a potential biomarker and therapeutic target for vascular aging and related diseases.
{"title":"miR-34a-5p/MARCHF8/ADAM10 axis in the regulation of vascular endothelial cell dysfunction and senescence","authors":"Zonghao Qian , Yuzhen Huang , Ni Yang , Ziwei Fang , Yucong Zhang , Yi Huang , Mandi Luo , Tianyi Ji , Zuoguan Chen , Shang Gao , Yongjun Li , Jinhua Yan , Dingsheng Jiang , Lei Ruan , Anding Liu , Cuntai Zhang , Le Zhang","doi":"10.1016/j.mad.2025.112060","DOIUrl":"10.1016/j.mad.2025.112060","url":null,"abstract":"<div><div>Vascular aging is a key driver of age-related cardiovascular and metabolic diseases, with endothelial dysfunction and senescence as a central mechanism. In our recent study, we observed elevated ADAM10 protein levels in senescent endothelial cells, which worsened endothelial dysfunction and senescence. However, the regulatory mechanisms controlling ADAM10 expression are poorly understood. In this study, we show that ADAM10 undergoes post-transcriptional modification in senescent human umbilical vein endothelial cells (HUVECs), with the E3 ubiquitin ligase MARCHF8 predicted to facilitate its ubiquitination-dependent degradation. We also found that MARCHF8 expression was significantly reduced in senescent HUVECs. Knockdown of MARCHF8 in young HUVECs induced endothelial senescence and impaired key endothelial functions, including migration, proliferation, angiogenesis, and nitric oxide production. Conversely, overexpression of MARCHF8 in senescent HUVECs ameliorated senescence-associated dysfunctions. RNA sequencing analysis revealed that MARCHF8 knockdown disrupted pathways linked to cell senescence and atherosclerosis. In vivo, MARCHF8 overexpression in high-fat diet-fed <em>apoE</em><sup>-/-</sup> mice reduced plasma interleukin-6 levels and attenuated atherosclerosis progression. Additionally, miR-34a-5p upregulation in senescence inhibited MARCHF8 expression, compromising its protective effects in delaying endothelial senescence. Collectively, these findings reveal a novel miR-34a-5p/MARCHF8/ADAM10 axis in vascular endothelial senescence, positioning MARCHF8 as a potential biomarker and therapeutic target for vascular aging and related diseases.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"225 ","pages":"Article 112060"},"PeriodicalIF":5.3,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143821078","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 : 2025-04-11DOI: 10.1016/j.mad.2025.112058
Kechuan Lin , Xin Luo , Can Du , Chenzhe Zuo , Zhenyu Li , Guogang Zhang , Chuanchang Li , Lingping Zhu
Vascular aging, marked by endothelial cell (EC) dysfunction and compromised angiogenesis, is a central driver of age-related ischemic diseases. Although lncRNAs have emerged as pivotal regulators of endothelial function, their specific roles in endothelial aging remain enigmatic. In this study, we identify the lncRNA ANRIL as a crucial modulator of endothelial dysfunction during aging. By analyzing publicly available lncRNA sequencing datasets comparing young and old ECs, we pinpointed ANRIL and validated its role through a replicative senescence model in human umbilical vein ECs (HUVECs) and FACS sorting of skeletal muscle ECs from aged mice. While ANRIL showed minimal direct effects on angiogenesis, functional assays and transcriptomic analysis revealed its profound impact on the senescence-associated secretory phenotype (SASP). Remarkably, ANRIL regulates the expression of miR146a in ECs, which is transferred to macrophages, where it inhibits VEGF secretion and disrupts endothelial neovascularization. In vivo, ANRIL downregulation in a murine hindlimb ischemia model significantly enhanced neovascularization and restored blood flow, revealing its therapeutic potential for ischemic diseases. These findings position ANRIL as a novel, potent regulator of endothelial senescence, offering new insights into the molecular basis of vascular aging and suggesting ANRIL as a promising therapeutic target to mitigate age-related vascular dysfunction.
{"title":"ANRIL modulates endothelial senescence and angiogenesis through SASP-driven miR146a regulation in age-related vascular dysfunction","authors":"Kechuan Lin , Xin Luo , Can Du , Chenzhe Zuo , Zhenyu Li , Guogang Zhang , Chuanchang Li , Lingping Zhu","doi":"10.1016/j.mad.2025.112058","DOIUrl":"10.1016/j.mad.2025.112058","url":null,"abstract":"<div><div>Vascular aging, marked by endothelial cell (EC) dysfunction and compromised angiogenesis, is a central driver of age-related ischemic diseases. Although lncRNAs have emerged as pivotal regulators of endothelial function, their specific roles in endothelial aging remain enigmatic. In this study, we identify the lncRNA ANRIL as a crucial modulator of endothelial dysfunction during aging. By analyzing publicly available lncRNA sequencing datasets comparing young and old ECs, we pinpointed ANRIL and validated its role through a replicative senescence model in human umbilical vein ECs (HUVECs) and FACS sorting of skeletal muscle ECs from aged mice. While ANRIL showed minimal direct effects on angiogenesis, functional assays and transcriptomic analysis revealed its profound impact on the senescence-associated secretory phenotype (SASP). Remarkably, ANRIL regulates the expression of miR146a in ECs, which is transferred to macrophages, where it inhibits VEGF secretion and disrupts endothelial neovascularization. <em>In vivo</em>, ANRIL downregulation in a murine hindlimb ischemia model significantly enhanced neovascularization and restored blood flow, revealing its therapeutic potential for ischemic diseases. These findings position ANRIL as a novel, potent regulator of endothelial senescence, offering new insights into the molecular basis of vascular aging and suggesting ANRIL as a promising therapeutic target to mitigate age-related vascular dysfunction.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"225 ","pages":"Article 112058"},"PeriodicalIF":5.3,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143835203","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 : 2025-04-10DOI: 10.1016/j.mad.2025.112057
James Cole , Andrew Overall , Jennifer C. French , Matt Grove , Nicolas J.W. Rattray , Nicholas A. Stewart , Richard G.A. Faragher
Growing old is the major risk factor for hundreds of distinct conditions. Thus, ageing of the global population will pose major social, medical, and economic challenges unless this ill health can be ameliorated or reversed. Accordingly, it is increasingly clear that cross-disciplinary approaches to understanding ageing, although not essential, allow collaborative teams to develop new methodologies which can accelerate translation of research into interventions. Co-creation of new concepts and technologies also brings reciprocal benefits to the individual disciplines involved. The evolution of human ageing is a case in point. Whilst there is broad consensus concerning the process and factors shaping the evolution of ageing in general their relative contributions to the evolution of human ageing remain less clear. This is due to three distinct factors. The extended genetic bottlenecks to which H. sapiens was exposed until the termination of the last ice age which sharply distinguishes our species from almost all current ageing models. Sociality, which humans share with many, but not all, living primate species; and finally, an extended post reproductive menopausal period which is extremely rare in the biosphere and uniquely long in humans. Accordingly, a symposium on the physiology and demography of early human evolution was organised by the authors at which palaeodemographers, archaeologists, population biologists and geroscientists discussed human ageing. This has generated important interdisciplinary research priorities which could accelerate the development of treatments for older people in the present and transform key aspects of our understanding of the ageing process in the past.
{"title":"Ageing, metabolomics and palaeoanthropology: What can the fields learn from each other?","authors":"James Cole , Andrew Overall , Jennifer C. French , Matt Grove , Nicolas J.W. Rattray , Nicholas A. Stewart , Richard G.A. Faragher","doi":"10.1016/j.mad.2025.112057","DOIUrl":"10.1016/j.mad.2025.112057","url":null,"abstract":"<div><div>Growing old is the major risk factor for hundreds of distinct conditions. Thus, ageing of the global population will pose major social, medical, and economic challenges unless this ill health can be ameliorated or reversed. Accordingly, it is increasingly clear that cross-disciplinary approaches to understanding ageing, although not essential, allow collaborative teams to develop new methodologies which can accelerate translation of research into interventions. Co-creation of new concepts and technologies also brings reciprocal benefits to the individual disciplines involved. The evolution of human ageing is a case in point. Whilst there is broad consensus concerning the process and factors shaping the evolution of ageing in general their relative contributions to the evolution of human ageing remain less clear. This is due to three distinct factors. The extended genetic bottlenecks to which <em>H. sapiens</em> was exposed until the termination of the last ice age which sharply distinguishes our species from almost all current ageing models. Sociality, which humans share with many, but not all, living primate species; and finally, an extended post reproductive menopausal period which is extremely rare in the biosphere and uniquely long in humans. Accordingly, a symposium on the physiology and demography of early human evolution was organised by the authors at which palaeodemographers, archaeologists, population biologists and geroscientists discussed human ageing. This has generated important interdisciplinary research priorities which could accelerate the development of treatments for older people in the present and transform key aspects of our understanding of the ageing process in the past.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"225 ","pages":"Article 112057"},"PeriodicalIF":5.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859970","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 : 2025-04-10DOI: 10.1016/j.mad.2025.112059
Abhishek Chandra , Susan F. Law , Robert J. Pignolo
Aging profoundly impacts mesenchymal and hematopoietic lineage cells, including their progenitors—the skeletal stem cells (SSCs) and hematopoietic stem cells (HSCs), respectively. SSCs are crucial for skeletal development, homeostasis, and regeneration, maintaining bone integrity by differentiating into osteoblasts, adipocytes, and other lineages that contribute to the bone marrow (BM) microenvironment. Meanwhile, HSCs sustain hematopoiesis and immune function. With aging, SSCs and HSCs undergo significant functional decline, partly driven by cellular senescence—a hallmark of aging characterized by irreversible growth arrest, secretion of pro-inflammatory factors (senescence associated secretory phenotype, SASP), and impaired regenerative potential. In SSCs, senescence skews lineage commitment toward adipogenesis at the expense of osteogenesis, contributing to increased bone marrow adiposity , reduced bone quality, and osteoporosis. Similarly, aged HSCs exhibit diminished self-renewal, biased differentiation, and heightened inflammation, compromising hematopoietic output and immune function. In this review, we examine the age-related cellular and molecular changes in SSCs and HSCs, their lineage decisions in the aging microenvironment, and the interplay between skeletal and hematopoietic compartments. We also discuss the role of senescence-driven alterations in BM homeostasis and how targeting cellular aging mechanisms may offer therapeutic strategies for mitigating age-related skeletal and hematopoietic decline.
{"title":"Changing landscape of hematopoietic and mesenchymal cells and their interactions during aging and in age-related skeletal pathologies","authors":"Abhishek Chandra , Susan F. Law , Robert J. Pignolo","doi":"10.1016/j.mad.2025.112059","DOIUrl":"10.1016/j.mad.2025.112059","url":null,"abstract":"<div><div>Aging profoundly impacts mesenchymal and hematopoietic lineage cells, including their progenitors—the skeletal stem cells (SSCs) and hematopoietic stem cells (HSCs), respectively. SSCs are crucial for skeletal development, homeostasis, and regeneration, maintaining bone integrity by differentiating into osteoblasts, adipocytes, and other lineages that contribute to the bone marrow (BM) microenvironment. Meanwhile, HSCs sustain hematopoiesis and immune function. With aging, SSCs and HSCs undergo significant functional decline, partly driven by cellular senescence—a hallmark of aging characterized by irreversible growth arrest, secretion of pro-inflammatory factors (senescence associated secretory phenotype, SASP), and impaired regenerative potential. In SSCs, senescence skews lineage commitment toward adipogenesis at the expense of osteogenesis, contributing to increased bone marrow adiposity , reduced bone quality, and osteoporosis. Similarly, aged HSCs exhibit diminished self-renewal, biased differentiation, and heightened inflammation, compromising hematopoietic output and immune function. In this review, we examine the age-related cellular and molecular changes in SSCs and HSCs, their lineage decisions in the aging microenvironment, and the interplay between skeletal and hematopoietic compartments. We also discuss the role of senescence-driven alterations in BM homeostasis and how targeting cellular aging mechanisms may offer therapeutic strategies for mitigating age-related skeletal and hematopoietic decline.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"225 ","pages":"Article 112059"},"PeriodicalIF":5.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143816689","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 : 2025-04-06DOI: 10.1016/j.mad.2025.112056
Anastasia Conti , Raffaella Di Micco
The selective eradication of senescent cells using senolytic compounds represents a promising strategy to treat senescence-associated diseases like aging and cancer. However, many senolytics may cause systemic toxicity. Magkouta et al., writing in Nature Aging, introduced mGL392, an advanced senolytic platform utilizing a lipofuscin-binding domain scaffold conjugated with a senolytic drug (e.g., dasatinib). mGL392 effectively eliminates senescent cells in vitro and in vivo, reducing tumor size in melanoma models while minimizing systemic toxicity. Compared to existing senolytics, it offers improved specificity, reducing off-target effects. This innovation presents a safer and more effective approach for treating senescence-related diseases.
{"title":"A novel platform for precise senolysis","authors":"Anastasia Conti , Raffaella Di Micco","doi":"10.1016/j.mad.2025.112056","DOIUrl":"10.1016/j.mad.2025.112056","url":null,"abstract":"<div><div>The selective eradication of senescent cells using senolytic compounds represents a promising strategy to treat senescence-associated diseases like aging and cancer. However, many senolytics may cause systemic toxicity. Magkouta et al., writing in <em>Nature Aging</em>, introduced mGL392, an advanced senolytic platform utilizing a lipofuscin-binding domain scaffold conjugated with a senolytic drug (e.g., dasatinib). mGL392 effectively eliminates senescent cells <em>in vitro</em> and <em>in vivo</em>, reducing tumor size in melanoma models while minimizing systemic toxicity. Compared to existing senolytics, it offers improved specificity, reducing off-target effects. This innovation presents a safer and more effective approach for treating senescence-related diseases.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"225 ","pages":"Article 112056"},"PeriodicalIF":5.3,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811752","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 : 2025-04-03DOI: 10.1016/j.mad.2025.112055
Joanna Czarnecka-Herok , Kexin Zhu , Emmanuelle Leblanc , Kristell Lazou , Carine Nizard , Anne-Laure Bulteau , Nadine Martin , David Bernard
Elastic fibers are well-known extracellular matrix components that are essential for elastic properties and thus function of many tissues. Tropoelastin is encoded by the ELN gene which is the main component of the elastic fibers. Elastic fibers decrease with aging and this decrease is proposed to contribute to this process. Senescent cells, cells that stop to proliferate and that instruct their microenvironment, accumulate with aging and promote it. Until recently, whether ELN expression and function is linked to cellular senescence was unknown. Here we will comment and extend recent results supporting a function of the ELN gene in protecting cells from cellular senescence. We will also discuss hypotheses on mechanisms by which ELN could regulate cellular senescence, and especially a hypothesis that involves a non-canonical function of ELN regulating the mitochondrial respiratory chain activity, thereby controlling oxidative stress and cellular senescence. These findings provide critical insights into the molecular and cellular processes potentially underlying the phenotypes driven by ELN deletion in the context of aging.
{"title":"ELN regulates cellular senescence: Emerging hypothesis for a non-canonical role","authors":"Joanna Czarnecka-Herok , Kexin Zhu , Emmanuelle Leblanc , Kristell Lazou , Carine Nizard , Anne-Laure Bulteau , Nadine Martin , David Bernard","doi":"10.1016/j.mad.2025.112055","DOIUrl":"10.1016/j.mad.2025.112055","url":null,"abstract":"<div><div>Elastic fibers are well-known extracellular matrix components that are essential for elastic properties and thus function of many tissues. Tropoelastin is encoded by the <em>ELN</em> gene which is the main component of the elastic fibers. Elastic fibers decrease with aging and this decrease is proposed to contribute to this process. Senescent cells, cells that stop to proliferate and that instruct their microenvironment, accumulate with aging and promote it. Until recently, whether <em>ELN</em> expression and function is linked to cellular senescence was unknown. Here we will comment and extend recent results supporting a function of the <em>ELN</em> gene in protecting cells from cellular senescence. We will also discuss hypotheses on mechanisms by which <em>ELN</em> could regulate cellular senescence, and especially a hypothesis that involves a non-canonical function of <em>ELN</em> regulating the mitochondrial respiratory chain activity, thereby controlling oxidative stress and cellular senescence. These findings provide critical insights into the molecular and cellular processes potentially underlying the phenotypes driven by <em>ELN</em> deletion in the context of aging.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"225 ","pages":"Article 112055"},"PeriodicalIF":5.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788602","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 : 2025-03-28DOI: 10.1016/j.mad.2025.112054
Stefan S. Heinze , Maddison L. Hodgins , Susan E. Howlett
Background
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.
Methods
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.
Results
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.
Conclusion
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.
{"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 , Maddison L. Hodgins , 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}
Pub Date : 2025-03-23DOI: 10.1016/j.mad.2025.112053
Li-Jun Ling , Meng-Die Li , Jiang-Wen Lu , Fan Zhang , Fan Pan , Yao Su , Leslie Myatt , Wang-Sheng Wang , Kang Sun , Hao Ying
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.
{"title":"Induction of epithelial cell senescence by SERPINE1 derived from fibroblasts in the amnion at parturition","authors":"Li-Jun Ling , Meng-Die Li , Jiang-Wen Lu , Fan Zhang , Fan Pan , Yao Su , Leslie Myatt , Wang-Sheng Wang , Kang Sun , 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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号