Mechanisms of Ageing and Development最新文献

{"title":"Challenges of infectious diseases in older adults: From immunosenescence and inflammaging through antibiotic resistance to management strategies","authors":"Francesca Mancinetti ,&nbsp;Anna Marinelli ,&nbsp;Virginia Boccardi ,&nbsp;Patrizia Mecocci","doi":"10.1016/j.mad.2024.111998","DOIUrl":"10.1016/j.mad.2024.111998","url":null,"abstract":"<div><div>Infectious diseases in older adults present a significant challenge to the healthcare system, marked by increased morbidity, mortality, and rising costs of care. Age-related changes (ARCs) in the immune system, including immunosenescence and inflammaging, contribute to heightened susceptibility to severe infections and reduced vaccine responsiveness. Additionally, alterations in the normal microbial flora due to aging and factors such as antibiotic therapy predispose older individuals to infections and age-related diseases. Changes in body composition also affect the pharmacokinetics and pharmacodynamics of drugs, complicating the management of antibiotics and leading to potential overdoses, adverse drug reactions, or underdoses that foster antibiotic resistance. The inappropriate use of antibiotics has exacerbated the emergence of multidrug-resistant pathogens, posing a critical global concern. This narrative review provides an overview of immunosenescence and inflammaging and focuses on three major infectious diseases affecting older adults: bacterial pneumonia, urinary tract infections, and Clostridium difficile infections. Through this exploration, we aim to highlight the need for targeted approaches in managing infectious diseases in the aging population.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"222 ","pages":"Article 111998"},"PeriodicalIF":5.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142503540","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":"Impact of senescence cell signature in patients with non-small cell carcinoma and melanoma receiving PD-L1/PD-1 inhibitors","authors":"Young Wha Koh ,&nbsp;Jae-Ho Han ,&nbsp;Seokjin Haam ,&nbsp;Hyun Woo Lee","doi":"10.1016/j.mad.2024.111999","DOIUrl":"10.1016/j.mad.2024.111999","url":null,"abstract":"<div><div>Tumor cell senescence plays a crucial role in tumor immunity. We investigated whether the senescent cell signature (SCS) could predict prognosis in non-small cell carcinoma (NSCLC) and melanoma datasets treated with PD-L1/PD-1 inhibitors. Patients with high SCS expression exhibited elevated levels of interferon-gamma and T cell-inflamed signatures in three lung adenocarcinomas (LUAD), two squamous cell carcinoma (LUSC) and three melanoma datasets. The high SCS group was associated with PD-L1-related pathways such as IL6/JAK/STAT3 and TNF-alpha signaling via NF-kB in LUAD, LUSC, and melanoma datasets. A positive correlation was observed between several immune checkpoint markers and the SCS, indicating an immunosuppressive state in LUAD, LUSC and melanoma datasets. In patients treated with PD-1/PD-L1 inhibitors, a higher SCS was associated with a better prognosis, and a positive correlation between SCS and PD-L1 was observed in six independent NSCLC and three independent melanoma datasets. We used the LASSO Cox regression model to build a risk model focusing on the SCS genes that particularly predict prognosis. We confirmed that the model accurately predicts prognosis. However, the senescent immunohistochemical markers p16 and p21 could predict the response to PD-1/PD-L1 inhibitors in patients with LUSC and melanoma but not in patients with LUAD. SCS could serve as a valuable biomarker to complement PD-L1 expression in patients receiving PD-L1/PD-1 inhibitors.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"222 ","pages":"Article 111999"},"PeriodicalIF":5.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142469475","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":"Deciphering Osteosarcopenia through the hallmarks of aging","authors":"Francisca Franulic ,&nbsp;Felipe Salech ,&nbsp;Daniel Rivas ,&nbsp;Gustavo Duque","doi":"10.1016/j.mad.2024.111997","DOIUrl":"10.1016/j.mad.2024.111997","url":null,"abstract":"<div><div>Osteosarcopenia is a major driver of functional loss and a risk factor for falls, fractures, disability and mortality in older adults, urgently requiring the development of effective interventions to address it. The hallmarks of aging provide a theoretical and practical framework that allows for the structured organization of current knowledge and the planning of new development lines. This article comprehensively reviews the currently available literature on the role of the hallmarks of aging in the development of osteosarcopenia, thereby offering a panoramic view of the state of the art and knowledge gaps in this field.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"222 ","pages":"Article 111997"},"PeriodicalIF":5.3,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sirtuin 3 drives sex-specific responses to age-related changes in mouse embryonic fibroblasts","authors":"Ena Šimunić ,&nbsp;Iva I. Podgorski ,&nbsp;Marija Pinterić ,&nbsp;Marijana Popović Hadžija ,&nbsp;Robert Belužić ,&nbsp;Mladen Paradžik ,&nbsp;Lucija Dončević ,&nbsp;Tihomir Balog ,&nbsp;Marta Kaloper ,&nbsp;Hansjörg Habisch ,&nbsp;Tobias Madl ,&nbsp;Aleksandra Korać ,&nbsp;Sandra Sobočanec","doi":"10.1016/j.mad.2024.111996","DOIUrl":"10.1016/j.mad.2024.111996","url":null,"abstract":"<div><div>The aging process is a complex phenomenon characterised by a gradual decline in physiological functions and an increased susceptibility to age-related diseases. An important factor in aging is mitochondrial dysfunction, which leads to an accumulation of cellular damage over time. Mitochondrial Sirtuin 3 (Sirt3), an important regulator of energy metabolism, plays a central role in maintaining mitochondrial function. Loss of Sirt3 can lead to reduced energy levels and an impaired ability to repair cellular damage, a hallmark of the aging process. In this study we investigated the impact of Sirt3 loss on mitochondrial function, metabolic responses and cellular aging processes in male and female mouse embryonic fibroblasts (MEF) exposed to etoposide-induced DNA damage, which is commonly associated with cellular dysfunction and senescence. We found that Sirt3 contributes to the sex-specific metabolic response to etoposide treatment. While male MEF exhibited minimal damage suggesting potential prior adaptation to stress due to Sirt3 loss, female MEF lacking Sirt3 experienced higher vulnerability to genotoxic stress, implying a pivotal role of Sirt3 in their resistance to such challenges. These findings offer potential insights into therapeutic strategies targeting Sirt3- and sex-specific signalling pathways in diseases associated with DNA damage that play a critical role in the aging process.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"222 ","pages":"Article 111996"},"PeriodicalIF":5.3,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441524","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":"Fisetin as a senotherapeutic agent: Evidence and perspectives for age-related diseases","authors":"Juliette Tavenier ,&nbsp;Jan O. Nehlin ,&nbsp;Morten Baltzer Houlind ,&nbsp;Lene Juel Rasmussen ,&nbsp;Tamara Tchkonia ,&nbsp;James L. Kirkland ,&nbsp;Ove Andersen ,&nbsp;Line Jee Hartmann Rasmussen","doi":"10.1016/j.mad.2024.111995","DOIUrl":"10.1016/j.mad.2024.111995","url":null,"abstract":"<div><div>Fisetin, a flavonoid naturally occurring in plants, fruits, and vegetables, has recently gained attention for its potential role as a senotherapeutic agent for the treatment of age-related chronic diseases. Senotherapeutics target senescent cells, which accumulate with age and disease, in both circulating immune cell populations and solid organs and tissues. Senescent cells contribute to development of many chronic diseases, primarily by eliciting systemic chronic inflammation through their senescence-associated secretory phenotype. Here, we explore whether fisetin as a senotherapeutic can eliminate senescent cells, and thereby alleviate chronic diseases, by examining current evidence from <em>in vitro</em> studies and animal models that investigate fisetin’s impact on age-related diseases, as well as from phase I/II trials in various patient populations. We discuss the application of fisetin in humans, including challenges and future directions. Our review of available data suggests that targeting senescent cells with fisetin offers a promising strategy for managing multiple chronic diseases, potentially transforming future healthcare for older and multimorbid patients. However, further studies are needed to establish the safety, pharmacokinetics, and efficacy of fisetin as a senotherapeutic, identify relevant and reliable outcome measures in human trials, optimize dosing, and better understand the possible limitations of fisetin as a senotherapeutic agent.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"222 ","pages":"Article 111995"},"PeriodicalIF":5.3,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of opioids on the hallmarks of ageing","authors":"Ana Rita Tavares Henriques ,&nbsp;João Pedro Silva ,&nbsp;Félix Carvalho","doi":"10.1016/j.mad.2024.111994","DOIUrl":"10.1016/j.mad.2024.111994","url":null,"abstract":"<div><div>Opioids rank among the most hazardous substances of abuse, leading to opioid use disorders (which greatly diminish life quality) and contributing to the highest drug-related mortality rates. Nonetheless, both the therapeutic and recreational use of opioids is escalating globally. Interestingly, chronic opioid users often exhibit signs consistent with accelerated ageing, suggesting that they likely interfere with well-characterized ageing mechanisms (e.g., telomere shortening, epigenetic changes, mitochondrial dysfunction, cellular senescence). Here, we review the most recent advances regarding the impact of opioids on well-characterized hallmarks of ageing, to ascertain a potential association between opioid use and accelerated ageing. Our findings indicate that there is accumulating evidence supporting a close association between the use of opioids and the early onset of some ageing hallmarks, namely mitochondrial dysfunction, genomic instability, or telomere shortening. However, there is still limited data available regarding how opioids specifically impact other ageing hallmarks, like nutrient sensing, cellular senescence, or loss of proteostasis. Taking into consideration the high prevalence of opioid use, strengthening the understanding of the mechanisms underlying opioids’ impact on ageing assumes utmost relevance, both in terms of improving risk assessment, as well as to help researchers and clinicians prevent or mitigate these effects in clinical settings.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"222 ","pages":"Article 111994"},"PeriodicalIF":5.3,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142349662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of mitochondria in cytokine and chemokine signalling during ageing","authors":"Maria Kalykaki ,&nbsp;Teresa Rubio-Tomás ,&nbsp;Nektarios Tavernarakis","doi":"10.1016/j.mad.2024.111993","DOIUrl":"10.1016/j.mad.2024.111993","url":null,"abstract":"<div><div>Ageing is accompanied by a persistent, low-level inflammation, termed “inflammageing”, which contributes to the pathogenesis of age-related diseases. Mitochondria fulfil multiple roles in host immune responses, while mitochondrial dysfunction, a hallmark of ageing, has been shown to promote chronic inflammatory states by regulating the production of cytokines and chemokines. In this review, we aim to disentangle the molecular mechanisms underlying this process. We describe the role of mitochondrial signalling components such as mitochondrial DNA, mitochondrial RNA, N-formylated peptides, ROS, cardiolipin, cytochrome c, mitochondrial metabolites, potassium efflux and mitochondrial calcium in the age-related immune system activation. Furthermore, we discuss the effect of age-related decline in mitochondrial quality control mechanisms, including mitochondrial biogenesis, dynamics, mitophagy and UPR^mt, in inflammatory states upon ageing. In addition, we focus on the dynamic relationship between mitochondrial dysfunction and cellular senescence and its role in regulating the secretion of pro-inflammatory molecules by senescent cells. Finally, we review the existing literature regarding mitochondrial dysfunction and inflammation in specific age-related pathological conditions, including neurodegenerative diseases (Alzheimer’s and Parkinson’s disease, and amyotrophic lateral sclerosis), osteoarthritis and sarcopenia.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"222 ","pages":"Article 111993"},"PeriodicalIF":5.3,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142290770","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":"Mosaic loss of Y chromosome and the association to mortality in Danish men aged 56–100 years","authors":"Dominika Marzena Hozakowska-Roszkowska ,&nbsp;Jonas Mengel-From ,&nbsp;Teodora K. Hristozova ,&nbsp;Jacob Krabbe Pedersen ,&nbsp;Bernard Jeune ,&nbsp;Karen Andersen-Ranberg ,&nbsp;Jacob V.B. Hjelmborg ,&nbsp;Kaare Christensen ,&nbsp;Richard Röttger ,&nbsp;Marianne Nygaard","doi":"10.1016/j.mad.2024.111979","DOIUrl":"10.1016/j.mad.2024.111979","url":null,"abstract":"<div><p>Mosaic loss of the Y chromosome (mLOY) is a common somatic mutation in the blood of elderly men and several studies have found mLOY in blood cells to be associated with an increased risk of various diseases and mortality. However, most of these studies have focused on middle-aged and older adults, meaning that mLOY in extremely old individuals like centenarians is understudied.</p><p>To explore mLOY across a wider age range compared to earlier studies and to specifically focus on centenarians, mLOY was estimated in 917 Danish men aged 56–100 years. We found that the percentage of men with LOY increased with age until age 85, after which it plateaued at around 40 %. Consistently, a longitudinal comparison of mLOY revealed that mLOY predominantly increased with age, although inter-individual variation was seen. Using a twin sub-sample, the broad-sense heritability of mLOY was estimated at 72 %, indicating a substantial genetic influence.</p><p>Supporting previous findings, mLOY was found to associate with increased mortality across all study participants and in men younger than 80 years. In centenarians, however, a higher level of mLOY associated with better survival, most likely due to selection, although confirmation of our findings in larger studies is needed.</p></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"222 ","pages":"Article 111979"},"PeriodicalIF":5.3,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0047637424000794/pdfft?md5=d66bfb064b99df1c2395b6acff28c045&pid=1-s2.0-S0047637424000794-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142239884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and validation of cardiometabolic risk predictive models based on LDL oxidation and candidate geromarkers from the MARK-AGE data","authors":"Andrei Valeanu ,&nbsp;Denisa Margina ,&nbsp;Daniela Weber ,&nbsp;Wolfgang Stuetz ,&nbsp;María Moreno-Villanueva ,&nbsp;Martijn E.T. Dollé ,&nbsp;Eugène HJM Jansen ,&nbsp;Efstathios S. Gonos ,&nbsp;Jürgen Bernhardt ,&nbsp;Beatrix Grubeck-Loebenstein ,&nbsp;Birgit Weinberger ,&nbsp;Simone Fiegl ,&nbsp;Ewa Sikora ,&nbsp;Grazyna Mosieniak ,&nbsp;Olivier Toussaint ,&nbsp;Florence Debacq-Chainiaux ,&nbsp;Miriam Capri ,&nbsp;Paolo Garagnani ,&nbsp;Chiara Pirazzini ,&nbsp;Maria Giulia Bacalini ,&nbsp;Daniela Gradinaru","doi":"10.1016/j.mad.2024.111987","DOIUrl":"10.1016/j.mad.2024.111987","url":null,"abstract":"<div><p>The predictive value of the susceptibility to oxidation of LDL particles (LDLox) in cardiometabolic risk assessment is incompletely understood. The main objective of the current study was to assess its relationship with other relevant biomarkers and cardiometabolic risk factors from MARK-AGE data. A cross-sectional observational study was carried out on 1089 subjects (528 men and 561 women), aged 40–75 years old, randomly recruited age- and sex-stratified individuals from the general population. A correlation analysis exploring the relationships between LDLox and relevant biomarkers was undertaken, as well as the development and validation of several machine learning algorithms, for estimating the risk of the combined status of high blood pressure and obesity for the MARK-AGE subjects. The machine learning models yielded Area Under the Receiver Operating Characteristic Curve Score ranging 0.783–0.839 for the internal validation, while the external validation resulted in an Under the Receiver Operating Characteristic Curve Score between 0.648 and 0.787, with the variables based on LDLox reaching significant importance within the obtained predictions. The current study offers novel insights regarding the combined effects of LDL oxidation and other ageing markers on cardiometabolic risk. Future studies might be extended on larger patient cohorts, in order to obtain reproducible clinical assessment models.</p></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"222 ","pages":"Article 111987"},"PeriodicalIF":5.3,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0047637424000873/pdfft?md5=1386a90e65cd9d45e836df338224fc15&pid=1-s2.0-S0047637424000873-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142274207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of a natural model of adult mice with different rate of aging","authors":"Judith Félix ,&nbsp;Estefanía Díaz-Del Cerro ,&nbsp;Antonio Garrido ,&nbsp;Mónica De La Fuente","doi":"10.1016/j.mad.2024.111991","DOIUrl":"10.1016/j.mad.2024.111991","url":null,"abstract":"<div><p>Aging is a heterogeneous process, so individuals of the same age may be aging at a different rate. A natural model of premature aging in mice have been proposed based on the poor response to the T-maze. Those that take longer to cross the intersection are known as Prematurely Aging Mice (PAM), while those that show an exceptional response are known as Exceptional non-PAM (E-NPAM), being the rest non-PAM (NPAM). Although many aspects of PAM and E-NPAM have been described, some aspects of their brain aging have not been studied. Similarly, it is known that PAM, NPAM and E-NPAM show a different rate of aging and longevity, but the differences between these three groups in behavior, immune function and oxidative-inflammatory state are unknown. The present study aims to deepen the study of brain aging in PAM and E-NPAM, and to study the differences in behavior, immunity, and oxidative-inflammatory state of peritoneal leukocytes between PAM, NPAM and E-NPAM. Results show deteriorated brains in PAM. Moreover, NPAM show an oxidative state similar to E-NPAM, an anxiety similar to PAM, and an intermediate immunity and lifespan between PAM and E-NPAM. In conclusion, immune function seems to be more associated with the longevity achieved.</p></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"222 ","pages":"Article 111991"},"PeriodicalIF":5.3,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0047637424000915/pdfft?md5=0f665552aebe743365069cd5591a4e16&pid=1-s2.0-S0047637424000915-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142239885","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}