IF 8 1区医学

Aging Cell Pub Date : 2024-11-19 DOI: 10.1111/acel.14416

Limeng Liu, Xusheng Hao, Yang Bai, Ye Tian

{"title":"The soil Mycobacterium sp. promotes health and longevity through different bacteria-derived molecules in Caenorhabditis elegans.","authors":"Limeng Liu, Xusheng Hao, Yang Bai, Ye Tian","doi":"10.1111/acel.14416","DOIUrl":"https://doi.org/10.1111/acel.14416","url":null,"abstract":"Commensal bacteria and their derivatives hold significant promise as therapeutic interventions to delay aging. However, with the diverse nature of the soil microbiome and the long lifespan of mammalian models, the exploration of the influence of soil bacteria and bacteria-derived molecules on host aging remains limited. We conducted a lifespan screening in Caenorhabditis elegans using plant root bacterial collection. Our screening identified 8 genera of bacterial isolates capable of extending lifespan, with Mycobacterium sp. Root265 exhibits the most pronounced effect on lifespan extension. Biochemical analysis revealed two specific molecules derived from Root265, polysaccharides (PSs) and arabinogalactan peptidoglycan (AGP), responsible for lifespan extension via daf-16-dependent and -independent pathways, respectively. Notably, AGP exhibited a unique ability to enhance protein homeostasis effectively. Moreover, polar lipids originating from Root265 were found to extend lifespan while mitigating age-related BAS-1 decline in neurons. Intriguingly, even brief exposures to these bioactive compounds were sufficient to achieve the lifespan-promoting effects. We found diverse beneficial bacteria and anti-aging active compounds from soil bacteria. These findings highlight the potential of exploring bacterial derivatives as therapies targeting aging without the constraints associated with direct microbial interventions.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14416"},"PeriodicalIF":8.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A small-molecule screen identifies novel aging modulators by targeting 5-HT/DA signaling pathway. 小分子筛选发现了针对 5-HT/DA 信号通路的新型衰老调节剂。

IF 8 1区医学

Aging Cell Pub Date : 2024-11-18 DOI: 10.1111/acel.14411

Shi-Wei Ye, Shuang-Di Song, Xi-Juan Liu, Yun Luo, Shi-Qing Cai

{"title":"A small-molecule screen identifies novel aging modulators by targeting 5-HT/DA signaling pathway.","authors":"Shi-Wei Ye, Shuang-Di Song, Xi-Juan Liu, Yun Luo, Shi-Qing Cai","doi":"10.1111/acel.14411","DOIUrl":"https://doi.org/10.1111/acel.14411","url":null,"abstract":"The risk of many human diseases including cardiovascular diseases, cancer, neurodegenerative diseases, and musculoskeletal disorders rises significantly in the elderly. With the increase in the aging population, it is becoming increasingly important to understand the biology of healthy aging and develop interventions that slow down the aging process or prevent age-related diseases. In this study, by a high-throughput screen in Caenorhabditis elegans (C. elegans), we identified 11 small molecules that promote healthy aging. Among them, Carbamazepine (a voltage-gated channels inhibitor) and Calmagite (a calcium and magnesium indicator) enhanced serotonin (5-HT) and dopamine (DA) levels, extended lifespan, and preserved several important behaviors in aging C. elegans. These behaviors include slowing responses to food, pharyngeal pumping, locomotion, and male mating. Interestingly, we further found that administration of Carbamazepine or Calmagite alleviated hyperexcitability of aging male diagonal muscles and improved behavioral performance by ameliorating Ca2+ homeostasis. Mechanistically, administration of Carbamazepine or Calmagite induced nuclear translocation of the transcription factor DAF-16 and thus up-regulated its downstream genes numr-1/-2, which are known to promote resistance to metal-induced stresses and longevity. Taken together, our study offers a way for the discovery of drugs that promote healthy aging, and provides potential interventions for preventing behavioral deterioration in the elderly.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14411"},"PeriodicalIF":8.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Muscle fibroblasts and stem cells stimulate motor neurons in an age and exercise-dependent manner. 肌肉成纤维细胞和干细胞刺激运动神经元的方式与年龄和运动有关。

IF 8 1区医学

Aging Cell Pub Date : 2024-11-18 DOI: 10.1111/acel.14413

Casper Soendenbroe, Peter Schjerling, Cecilie J L Bechshøft, Rene B Svensson, Laurent Schaeffer, Michael Kjaer, Bénédicte Chazaud, Arnaud Jacquier, Abigail L Mackey

{"title":"Muscle fibroblasts and stem cells stimulate motor neurons in an age and exercise-dependent manner.","authors":"Casper Soendenbroe, Peter Schjerling, Cecilie J L Bechshøft, Rene B Svensson, Laurent Schaeffer, Michael Kjaer, Bénédicte Chazaud, Arnaud Jacquier, Abigail L Mackey","doi":"10.1111/acel.14413","DOIUrl":"https://doi.org/10.1111/acel.14413","url":null,"abstract":"Exercise preserves neuromuscular function in aging through unknown mechanisms. Skeletal muscle fibroblasts (FIB) and stem cells (MuSC) are abundant in skeletal muscle and reside close to neuromuscular junctions, but their relative roles in motor neuron maintenance remain undescribed. Using direct cocultures of embryonic rat motor neurons with either human MuSC or FIB, RNA sequencing revealed profound differential regulation of the motor neuron transcriptome, with FIB generally favoring neuron growth and cell migration and MuSC favoring production of ribosomes and translational machinery. Conditioned medium from FIB was superior to MuSC in preserving motor neurons and increasing their maturity. Lastly, we established the importance of donor age and exercise status and found an age-related distortion of motor neuron and muscle cell interaction that was fully mitigated by lifelong physical activity. In conclusion, we show that human muscle FIB and MuSC synergistically stimulate the growth and viability of motor neurons, which is further amplified by regular exercise.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14413"},"PeriodicalIF":8.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Compromised CD8+ T cell immunity in the aged brain increases severity of neurotropic coronavirus infection and postinfectious cognitive impairment. 老年脑部 CD8+ T 细胞免疫功能受损会增加神经性冠状病毒感染和感染后认知障碍的严重程度。

IF 8 1区医学

Aging Cell Pub Date : 2024-11-17 DOI: 10.1111/acel.14409

Katie L Reagin, Rae-Ling Lee, Luke A Williams, Loren Cocciolone, Kristen E Funk

{"title":"Compromised CD8+ T cell immunity in the aged brain increases severity of neurotropic coronavirus infection and postinfectious cognitive impairment.","authors":"Katie L Reagin, Rae-Ling Lee, Luke A Williams, Loren Cocciolone, Kristen E Funk","doi":"10.1111/acel.14409","DOIUrl":"10.1111/acel.14409","url":null,"abstract":"Advanced age increases the risk of severe disease from SARS-CoV-2 infection, as well as incidence of long COVID and SARS-CoV-2 reinfection. We hypothesized that perturbations in the aged antiviral CD8+ T cell response predisposes elderly individuals to severe coronavirus infection, re-infection, and postinfectious cognitive sequelae. Using MHV-A59 as a murine model of respiratory coronavirus, we found that aging increased CNS infection and lethality to MHV infection. This was coupled with increased CD8+ T cells within the aged CNS but reduced antigen specificity. Aged animals also displayed a decreased proportion of CD103+ resident memory cells (TRM), which correlated with increased severity of secondary viral challenge. Using a reciprocal adoptive transfer paradigm, data show that not only were fewer aged CD8+ T cells retained within the adult brain post-infection, but also that adult CD8+ cells expressed lower levels of TRM marker CD103 when in the aged microenvironment. Furthermore, aged animals demonstrated spatial learning impairment following MHV infection, which worsened in both aged and adult animals following secondary viral challenge. Spatial learning impairment was accompanied by increased TUNEL positivity in hippocampal neurons, suggestive of neuronal apoptosis. Additionally, primary cell coculture showed that activated CD8+ T cells induced TUNEL positivity in neurons, independent of antigen-specificity. Altogether, these results show that non-antigen specific CD8+ T cells are recruited to the aged brain and cause broad neuronal death without establishing a TRM phenotype that confers lasting protection against a secondary infection.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14409"},"PeriodicalIF":8.0,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Metabolomic characterization of unintentional weight loss among community-dwelling older Black and White men and women. 居住在社区的黑人和白人老年男性和女性无意中体重减轻的代谢组学特征。

IF 8 1区医学

Aging Cell Pub Date : 2024-11-15 DOI: 10.1111/acel.14410

Shanshan Yao, Megan M Marron, Samaneh Farsijani, Iva Miljkovic, George C Tseng, Ravi V Shah, Venkatesh L Murthy, Anne B Newman

{"title":"Metabolomic characterization of unintentional weight loss among community-dwelling older Black and White men and women.","authors":"Shanshan Yao, Megan M Marron, Samaneh Farsijani, Iva Miljkovic, George C Tseng, Ravi V Shah, Venkatesh L Murthy, Anne B Newman","doi":"10.1111/acel.14410","DOIUrl":"10.1111/acel.14410","url":null,"abstract":"This study aims to understand the metabolic mechanisms of unintentional weight loss in older adults. We investigated plasma metabolite associations of subsequent weight change over 2 years in 1536 previously weight stable participants (mean age 74.6 years, 50% women, 35% Black) from the Health, Aging and Body Composition (Health ABC) Study. Multinomial logistic regressions were used to examine associations of the 442 metabolites with weight loss with/without an intention and weight gain >3% annually relative to weight stability. The metabolite associations of unintentional weight loss differed from those of intentional weight loss and weight gain. Lower levels of aromatic amino acids, phospholipids, long-chain poly-unsaturated triglycerides, and higher levels of amino acid derivatives, poly-unsaturated fatty acids, and carbohydrates were associated with higher odds of unintentional weight loss after adjusting for age, sex, race, and BMI categories. Prevalent diseases attenuated four and lower mid-thigh muscle mass and poorer appetite each attenuated 2 of 77 identified metabolite associations by >20%, respectively. Other factors (e.g., energy expenditure, diet, and medication) attenuated all associations by <20%. While 16 metabolite associations were attenuated by 20%-48% when adjusting for all these risk factors, 47 metabolite associations remained significant. Altered amino acid metabolism, impaired mitochondrial fatty acid oxidation, and inflammaging implicated by identified metabolites appear to precede unintentional weight loss in Health ABC older adults. Furthermore, these pathways seem to be associated with prevalent diseases especially diabetes, lower muscle mass, and poorer appetite.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14410"},"PeriodicalIF":8.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IF 8 1区医学

Aging Cell Pub Date : 2024-11-15 DOI: 10.1111/acel.14401

Jessica Conway, Erica N De Jong, Andrea J White, Ben Dugan, Nia Paddison Rees, Sonia M Parnell, Lisa E Lamberte, Archana Sharma-Oates, Jack Sullivan, Claudio Mauro, Willem van Schaik, Graham Anderson, Dawn M E Bowdish, Niharika A Duggal

{"title":"Age-related loss of intestinal barrier integrity plays an integral role in thymic involution and T cell ageing.","authors":"Jessica Conway, Erica N De Jong, Andrea J White, Ben Dugan, Nia Paddison Rees, Sonia M Parnell, Lisa E Lamberte, Archana Sharma-Oates, Jack Sullivan, Claudio Mauro, Willem van Schaik, Graham Anderson, Dawn M E Bowdish, Niharika A Duggal","doi":"10.1111/acel.14401","DOIUrl":"https://doi.org/10.1111/acel.14401","url":null,"abstract":"The intestinal epithelium serves as a physical and functional barrier against harmful substances, preventing their entry into the circulation and subsequent induction of a systemic immune response. Gut barrier dysfunction has recently emerged as a feature of ageing linked to declining health, and increased intestinal membrane permeability has been shown to promote heightened systemic inflammation in aged hosts. Concurrent with age-related changes in the gut microbiome, the thymic microenvironment undergoes a series of morphological, phenotypical and architectural alterations with age, including disorganisation of the corticomedullary junction, increased fibrosis, increased thymic adiposity and the accumulation of senescent cells. However, a direct link between gut barrier dysbiosis and thymic involution leading to features of immune ageing has not been explored thus far. Herein, we reveal strong associations between enhanced microbial translocation and the peripheral accumulation of terminally differentiated, senescent and exhausted T cells and the compensatory expansion of regulatory T cells in older adults. Crucially, we demonstrate that aged germ-free mice are protected from age-related increases in intestinal permeability, highlighting the direct impact of mucosal permeability on thymic ageing. Together, these findings establish a novel mechanism by which gut barrier dysfunction drives systemic activation of the immune system during ageing through thymic involution. This enhances our understanding of drivers of T cell ageing and opens up the possibility for the use of microbiome-based interventions to restore immune homeostasis and promote healthy ageing in older adults.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14401"},"PeriodicalIF":8.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Trends of genetic contributions on epigenetic clocks and related methylation sites with aging: A population-based adult twin study. 表观遗传时钟和相关甲基化位点的遗传贡献随年龄增长的趋势：基于人群的成人双胞胎研究。

IF 8 1区医学

Aging Cell Pub Date : 2024-11-14 DOI: 10.1111/acel.14403

Xuanming Hong, Hui Cao, Weihua Cao, Jun Lv, Canqing Yu, Tao Huang, Dianjianyi Sun, Chunxiao Liao, Yuanjie Pang, Runhua Hu, Ruqin Gao, Min Yu, Jinyi Zhou, Xianping Wu, Yu Liu, Shengli Yin, Wenjing Gao, Liming Li

{"title":"Trends of genetic contributions on epigenetic clocks and related methylation sites with aging: A population-based adult twin study.","authors":"Xuanming Hong, Hui Cao, Weihua Cao, Jun Lv, Canqing Yu, Tao Huang, Dianjianyi Sun, Chunxiao Liao, Yuanjie Pang, Runhua Hu, Ruqin Gao, Min Yu, Jinyi Zhou, Xianping Wu, Yu Liu, Shengli Yin, Wenjing Gao, Liming Li","doi":"10.1111/acel.14403","DOIUrl":"10.1111/acel.14403","url":null,"abstract":"Several crucial acceleration periods exist during aging process. Epigenetic clocks, serving as indicators of aging, are influenced by genetic factors. Investigating how the genetic contributions on these clocks change with age may provide novel insights into the aging process. In this study, based on 1084 adult twins from the Chinese National Twin Registry (CNTR), we established structural equation models (SEMs) to evaluate the trends in genetic influence with aging for epigenetic clocks, which include PC-Horvath, PC-Hannum, PC-PhenoAge, PC-GrimAge, and DunedinPACE. A decline in overall heritability was observed for all five clocks from ages 31 to 70, with a relatively stable trend at first. Subsequently, apart from PC-GrimAge, the other four clocks displayed a more evident drop in heritability: DunedinPACE and PC-PhenoAge experienced a clear decline between 55 and 65 years, while PC-Horvath and PC-Hannum showed a similar decrease between 60 and 70 years. In contrast, the heritability of PC-GrimAge remained stable throughout. An analysis of methylation sites (CpGs) from these clocks identified 41, 26, 4, and 36 CpG sites potentially underlying heritability changes in DunedinPACE, PC-Horvath, PC-Hannum, and PC-PhenoAge, respectively. Data from the CNTR were collected through two surveys in 2013 and 2018. Based on 308 twins with longitudinal data, declines in genetic components were observed at follow-up compared to baseline, with significant decreases in the four PC-clocks. DunedinPACE peaked in 5-year longitudinal genetic contribution changes at age 55-60, while PC-clocks consistently peaked at age 50-55. These findings may offer novel insights into the role of genetic variations in aging.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14403"},"PeriodicalIF":8.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting NAMPT-OPA1 for treatment of senile osteoporosis. 靶向 NAMPT-OPA1 治疗老年性骨质疏松症。

IF 8 1区医学

Aging Cell Pub Date : 2024-11-14 DOI: 10.1111/acel.14400

Chao-Wen Bai, Bo Tian, Ming-Chao Zhang, Qin Qin, Xin Shi, Xi Yang, Xiang Gao, Xiao-Zhong Zhou, Hua-Jian Shan, Jin-Yu Bai

{"title":"Targeting NAMPT-OPA1 for treatment of senile osteoporosis.","authors":"Chao-Wen Bai, Bo Tian, Ming-Chao Zhang, Qin Qin, Xin Shi, Xi Yang, Xiang Gao, Xiao-Zhong Zhou, Hua-Jian Shan, Jin-Yu Bai","doi":"10.1111/acel.14400","DOIUrl":"https://doi.org/10.1111/acel.14400","url":null,"abstract":"Senescence of bone marrow mesenchymal stem cells (BMSCs) impairs their stemness and osteogenic differentiation, which is the principal cause of senile osteoporosis (SOP). Imbalances in nicotinamide phosphoribosyltransferase (NAMPT) homeostasis have been linked to aging and various diseases. Herein, reduction of NAMPT and impaired osteogenesis were observed in BMSCs from aged human and mouse. Knockdown of Nampt in BMSCs promotes lipogenic differentiation and increases age-related bone loss. Overexpression of Nampt ameliorates the senescence-associated (SA) phenotypes in BMSCs derived from aged mice, as well as promoting osteogenic potential. Mechanistically, NAMPT inhibits BMSCs senescence by facilitating OPA1 expression, which is essential for mitochondrial dynamics. The defect of NAMPT reduced mitochondrial membrane potential, interfered with mitochondrial fusion，and increased SA protein and phenotypes. More importantly, we have confirmed that P7C3, the NAMPT activator, is a novel strategy for reducing SOP bone loss. P7C3 treatment significantly prevents BMSCs senescence by improving mitochondrial function through the NAMPT-OPA1 signaling axis. Taken together, these results reveal that NAMPT is a regulator of BMSCs senescence and osteogenic differentiation. P7C3 is a novel molecule drug to prevent the pathological progression of SOP.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14400"},"PeriodicalIF":8.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Aged hippocampal single-cell atlas screening unveils disrupted neuroglial system in postoperative cognitive impairment. 老年海马单细胞图谱筛选揭示了术后认知障碍的神经胶质细胞系统紊乱。

IF 8 1区医学

Aging Cell Pub Date : 2024-11-14 DOI: 10.1111/acel.14406

Zizheng Suo, Ting Xiao, Yinyin Qu, Yuxiang Zheng, Wenjie Xu, Bowen Zhou, Jing Yang, Jie Yu, Hui Zheng, Cheng Ni

{"title":"Aged hippocampal single-cell atlas screening unveils disrupted neuroglial system in postoperative cognitive impairment.","authors":"Zizheng Suo, Ting Xiao, Yinyin Qu, Yuxiang Zheng, Wenjie Xu, Bowen Zhou, Jing Yang, Jie Yu, Hui Zheng, Cheng Ni","doi":"10.1111/acel.14406","DOIUrl":"https://doi.org/10.1111/acel.14406","url":null,"abstract":"Glia-neuron interaction is a crucial feature in aged hippocampus during the occurrence of postoperative cognitive impairment. However, the regulatory effects of microglia, astrocytes, and oligodendrocytes in this glia-neuron interaction, the potential mechanisms and gene targets are still to be elucidated. Here, single-cell RNA sequencing was performed to detect the perioperative genomic expression characteristics of neuroglial system in the hippocampus of aged mice, and to investigate the potential cross-cellular mechanisms and valuable treatment options for glia-neuron interaction-related cognitive impairment. We found that postoperative neurons and glia cells exhibited protein dysmetabolism and mitochondrial electron misrouting. Impaired autophagy and circadian rhythm worsened microglia activation/neuroinflammation, and exacerbated these metabolic alterations. Reactive microglia also aggravated astrocyte and oligodendrocyte cytotoxicity through the PGD2/DP and complement pathways, altering glutamate level and synaptic function via the \"tripartite synapses\" model, and affecting neuronal myelination. Ligand-receptor communication also indicated these synaptic and axonal dysfunctions via enhanced MDK and PTN pathways. Additionally, we found that anesthetic dexmedetomidine hold therapeutic potential within the disrupted neuroglial system. It enhanced neuronal metabolic rebalance (Atf3-related) and reduced neuroinflammation from a multicellular perspective, therefore improving postoperative cognitive impairment. Together, our study proposes an aged hippocampal cell atlas and provides insights into the role of disrupted glia-neuron cycle in postoperative cognitive impairment. Our findings also elucidate the therapeutic potential and mechanism of dexmedetomidine intervention.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14406"},"PeriodicalIF":8.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Age-associated metabolic and epigenetic barriers during direct reprogramming of mouse fibroblasts into induced cardiomyocytes. 在将小鼠成纤维细胞直接重编程为诱导心肌细胞的过程中，与年龄相关的代谢和表观遗传学障碍。

IF 8 1区医学

Aging Cell Pub Date : 2024-11-14 DOI: 10.1111/acel.14371

Francisco Santos, Magda Correia, Rafaela Dias, Bárbara Bola, Roberta Noberini, Rita S Ferreira, Diogo Trigo, Pedro Domingues, José Teixeira, Tiziana Bonaldi, Paulo J Oliveira, Christian Bär, Bruno Bernardes de Jesus, Sandrina Nóbrega-Pereira

{"title":"Age-associated metabolic and epigenetic barriers during direct reprogramming of mouse fibroblasts into induced cardiomyocytes.","authors":"Francisco Santos, Magda Correia, Rafaela Dias, Bárbara Bola, Roberta Noberini, Rita S Ferreira, Diogo Trigo, Pedro Domingues, José Teixeira, Tiziana Bonaldi, Paulo J Oliveira, Christian Bär, Bruno Bernardes de Jesus, Sandrina Nóbrega-Pereira","doi":"10.1111/acel.14371","DOIUrl":"https://doi.org/10.1111/acel.14371","url":null,"abstract":"Heart disease is the leading cause of mortality in developed countries, and novel regenerative procedures are warranted. Direct cardiac conversion (DCC) of adult fibroblasts can create induced cardiomyocytes (iCMs) for gene and cell-based heart therapy, and in addition to holding great promise, still lacks effectiveness as metabolic and age-associated barriers remain elusive. Here, by employing MGT (Mef2c, Gata4, Tbx5) transduction of mouse embryonic fibroblasts (MEFs) and adult (dermal and cardiac) fibroblasts from animals of different ages, we provide evidence that the direct reprogramming of fibroblasts into iCMs decreases with age. Analyses of histone posttranslational modifications and ChIP-qPCR revealed age-dependent alterations in the epigenetic landscape of DCC. Moreover, DCC is accompanied by profound mitochondrial metabolic adaptations, including a lower abundance of anabolic metabolites, network remodeling, and reliance on mitochondrial respiration. In vitro metabolic modulation and dietary manipulation in vivo improve DCC efficiency and are accompanied by significant alterations in histone marks and mitochondrial homeostasis. Importantly, adult-derived iCMs exhibit increased accumulation of oxidative stress in the mitochondria and activation of mitophagy or dietary lipids; they improve DCC and revert mitochondrial oxidative damage. Our study provides evidence that metaboloepigenetics plays a direct role in cell fate transitions driving DCC, highlighting the potential use of metabolic modulation to improve cardiac regenerative strategies.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14371"},"PeriodicalIF":8.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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