Aging Cell最新文献_第2页

Exercise-Induced Cardiac Lymphatic Remodeling Mitigates Inflammation in the Aging Heart.

IF 8 1区医学

Aging Cell Pub Date : 2025-03-13 DOI: 10.1111/acel.70043

Kangsan Roh, Haobo Li, Rebecca Nicole Freeman, Luca Zazzeron, Ahlim Lee, Charles Zhou, Siman Shen, Peng Xia, Justin Ralph Baldovino Guerra, Cedric Sheffield, Timothy P Padera, Yirong Zhou, Sekeun Kim, Aaron Aguirre, Nicolas Houstis, Jason D Roh, Fumito Ichinose, Rajeev Malhotra, Anthony Rosenzweig, James Rhee

{"title":"Exercise-Induced Cardiac Lymphatic Remodeling Mitigates Inflammation in the Aging Heart.","authors":"Kangsan Roh, Haobo Li, Rebecca Nicole Freeman, Luca Zazzeron, Ahlim Lee, Charles Zhou, Siman Shen, Peng Xia, Justin Ralph Baldovino Guerra, Cedric Sheffield, Timothy P Padera, Yirong Zhou, Sekeun Kim, Aaron Aguirre, Nicolas Houstis, Jason D Roh, Fumito Ichinose, Rajeev Malhotra, Anthony Rosenzweig, James Rhee","doi":"10.1111/acel.70043","DOIUrl":"10.1111/acel.70043","url":null,"abstract":"The lymphatic vasculature plays essential roles in fluid balance, immunity, and lipid transport. Chronic, low-grade inflammation in peripheral tissues develops when lymphatic structure or function is impaired, as observed during aging. While aging has been associated with a broad range of heart pathophysiology, its effect on cardiac lymphatic vasculature has not been characterized. Here, we analyzed cardiac lymphatics in aged 20-month-old mice versus young 2-month-old mice. Aged hearts showed reduced lymphatic vascular density, more dilated vessels, and increased inflammation and fibrosis in peri-lymphatic zones. As exercise has shown benefits in several different models of age-related heart disease, we further investigated the effects of aerobic training on cardiac lymphatics. Eight weeks of voluntary wheel running attenuated age-associated adverse remodeling of the cardiac lymphatics, including reversing their dilation, increasing lymph vessel density and branching, and reducing perilymphatic inflammation and fibrosis. Intravital lymphangiography demonstrated improved cardiac lymphatic flow after exercise training. Our findings illustrate that aging leads to cardiac lymphatic dysfunction, and that exercise can improve lymphatic health in aged animals.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70043"},"PeriodicalIF":8.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622857","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

The Mitochondria-Targeted Peptide Therapeutic Elamipretide Improves Cardiac and Skeletal Muscle Function During Aging Without Detectable Changes in Tissue Epigenetic or Transcriptomic Age.

IF 8 1区医学

Aging Cell Pub Date : 2025-03-13 DOI: 10.1111/acel.70026

Wayne Mitchell, Gavin Pharaoh, Alexander Tyshkovskiy, Matthew Campbell, David J Marcinek, Vadim N Gladyshev

{"title":"The Mitochondria-Targeted Peptide Therapeutic Elamipretide Improves Cardiac and Skeletal Muscle Function During Aging Without Detectable Changes in Tissue Epigenetic or Transcriptomic Age.","authors":"Wayne Mitchell, Gavin Pharaoh, Alexander Tyshkovskiy, Matthew Campbell, David J Marcinek, Vadim N Gladyshev","doi":"10.1111/acel.70026","DOIUrl":"10.1111/acel.70026","url":null,"abstract":"Aging-related decreases in cardiac and skeletal muscle function are strongly associated with various comorbidities. Elamipretide (ELAM), a novel mitochondria-targeted peptide, has demonstrated broad therapeutic efficacy in ameliorating disease conditions associated with mitochondrial dysfunction across both clinical and pre-clinical models. Herein, we investigated the impact of 8-week ELAM treatment on pre- and post-measures of C57BL/6J mice frailty, skeletal muscle, and cardiac muscle function, coupled with post-treatment assessments of biological age and affected molecular pathways. We found that health status, as measured by frailty index, cardiac strain, diastolic function, and skeletal muscle force, is significantly diminished with age, with skeletal muscle force changing in a sex-dependent manner. Conversely, ELAM mitigated frailty accumulation and was able to partially reverse these declines, as evidenced by treatment-induced increases in cardiac strain and muscle fatigue resistance. Despite these improvements, we did not detect statistically significant changes in gene expression or DNA methylation profiles indicative of molecular reorganization or reduced biological age in most ELAM-treated groups. However, pathway analyses revealed that ELAM treatment showed pro-longevity shifts in gene expression, such as upregulation of genes involved in fatty acid metabolism, mitochondrial translation, and oxidative phosphorylation, and downregulation of inflammation. Together, these results indicate that ELAM treatment is effective at mitigating signs of sarcopenia and cardiac dysfunction in an aging mouse model, but that these functional improvements occur independently of detectable changes in epigenetic and transcriptomic age. Thus, some age-related changes in function may be uncoupled from changes in molecular biological age.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70026"},"PeriodicalIF":8.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622860","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

Cellular Senescence Is a Central Driver of Cognitive Disparities in Aging.

IF 8 1区医学

Aging Cell Pub Date : 2025-03-12 DOI: 10.1111/acel.70041

Matthew P Baier, Rojina Ranjit, Daniel B Owen, Jenna L Wilson, Megan A Stiles, Anthony M Masingale, Zachary Thomas, Anne Bredegaard, David M Sherry, Sreemathi Logan

{"title":"Cellular Senescence Is a Central Driver of Cognitive Disparities in Aging.","authors":"Matthew P Baier, Rojina Ranjit, Daniel B Owen, Jenna L Wilson, Megan A Stiles, Anthony M Masingale, Zachary Thomas, Anne Bredegaard, David M Sherry, Sreemathi Logan","doi":"10.1111/acel.70041","DOIUrl":"10.1111/acel.70041","url":null,"abstract":"Cognitive function in aging is heterogeneous: while some older individuals develop significant impairments and dementia, others remain resilient and retain cognitive function throughout their lifespan. The molecular mechanisms that underlie these divergent cognitive trajectories, however, remain largely unresolved. Here, we utilized a high-resolution home-cage-based cognitive testing paradigm to delineate mechanisms that contribute to age-related cognitive heterogeneity. We cognitively stratified aged C57Bl/6N male mice by cognitive performance into intact (resilient) or impaired subgroups based on young performance benchmarks. Cognitively impaired males exhibited marked reactive gliosis in the hippocampus, characterized by microglial activation, increased astrocyte arborization, and elevated transcriptional expression of reactivity markers. These changes were accompanied by increased markers of cellular senescence and the associated senescence-associated secretory phenotype (SASP) in impaired animals, including p16INK4a, SASP factors (e.g., Il-6, Il-1b, Mmp3), and SA-β-gal staining in the hippocampus. Notably, clearance of senescent cells using senolytic agents dasatinib and quercetin ameliorated the heterogeneity in cognitive performance observed with age and attenuated impairment-associated gliosis, senescence markers, and mitochondrial dysfunction. Aged female mice could not be stratified into subgroups yet showed increased neuroinflammation with age that was not resolved with senolytics. Collectively, our findings implicate cellular senescence as a central driver of sex-specific neuroinflammation that drives divergent cognitive trajectories in aging. Thus, we demonstrate that senolytic treatment is an effective therapeutic strategy to mitigate cognitive impairment by reducing neuroinflammation and associated metabolic disturbances.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70041"},"PeriodicalIF":8.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612862","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

Phosphorylation of an RNA-Binding Protein Rck/Me31b by Hippo Is Essential for Adipose Tissue Aging.

IF 8 1区医学

Aging Cell Pub Date : 2025-03-11 DOI: 10.1111/acel.70022

Eunbyul Yeom, Hyejin Mun, Jinhwan Lim, Yoo Lim Chun, Kyung-Won Min, Johana Lambert, L Ashley Cowart, Jason S Pierce, Besim Ogretmen, Jung-Hyun Cho, Jeong Ho Chang, J Ross Buchan, Jason Pitt, Matt Kaeberlein, Sung-Ung Kang, Eun-Soo Kwon, Seungbeom Ko, Kyoung-Min Choi, Yong Sun Lee, Yoon-Su Ha, Seung-Jin Kim, Kwang-Pyo Lee, Hyo-Sung Kim, Seo Young Yang, Chang Hoon Shin, Je-Hyun Yoon, Kyu-Sun Lee

{"title":"Phosphorylation of an RNA-Binding Protein Rck/Me31b by Hippo Is Essential for Adipose Tissue Aging.","authors":"Eunbyul Yeom, Hyejin Mun, Jinhwan Lim, Yoo Lim Chun, Kyung-Won Min, Johana Lambert, L Ashley Cowart, Jason S Pierce, Besim Ogretmen, Jung-Hyun Cho, Jeong Ho Chang, J Ross Buchan, Jason Pitt, Matt Kaeberlein, Sung-Ung Kang, Eun-Soo Kwon, Seungbeom Ko, Kyoung-Min Choi, Yong Sun Lee, Yoon-Su Ha, Seung-Jin Kim, Kwang-Pyo Lee, Hyo-Sung Kim, Seo Young Yang, Chang Hoon Shin, Je-Hyun Yoon, Kyu-Sun Lee","doi":"10.1111/acel.70022","DOIUrl":"https://doi.org/10.1111/acel.70022","url":null,"abstract":"The metazoan lifespan is determined in part by a complex signaling network that regulates energy metabolism and stress responses. Key signaling hubs in this network include insulin/IGF-1, AMPK, mTOR, and sirtuins. The Hippo/Mammalian Ste20-like Kinase1 (MST1) pathway has been reported to maintain lifespan in Caenorhabditis elegans, but its role has not been studied in higher metazoans. In this study, we report that overexpression of Hpo, the MST1 homolog in Drosophila melanogaster, decreased lifespan with concomitant changes in lipid metabolism and aging-associated gene expression, while RNAi Hpo depletion increased lifespan. These effects were mediated primarily by Hpo-induced transcriptional activation of the RNA-binding protein maternal expression at 31B (Me31b)/RCK, resulting in stabilization of mRNA-encoding a lipolytic hormone, Akh. In mouse adipocytes, Hpo/Mst1 mediated adipocyte differentiation, phosphorylation of RNA-binding proteins such as Rck, decapping MRNA 2 (Dcp2), enhancer Of MRNA decapping 3 (Edc3), nucleolin (NCL), and glucagon mRNA stability by interacting with Rck. Decreased lifespan in Hpo-overexpressing Drosophila lines required expression of Me31b, but not DCP2, which was potentially mediated by recovering expression of lipid metabolic genes and formation of lipid droplets. Taken together, our findings suggest that Hpo/Mst1 plays a conserved role in longevity by regulating adipogenesis and fatty acid metabolism.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70022"},"PeriodicalIF":8.0,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603043","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

Telomere Position Effect-Over Long Distances Acts as a Genome-Wide Epigenetic Regulator Through a Common Alu Element.

IF 8 1区医学

Aging Cell Pub Date : 2025-03-10 DOI: 10.1111/acel.70027

Raphaël Chevalier, Victor Murcia Pienkowski, Nicolas Jullien, Leslie Caron, Pascal Verdier Pinard, Frédérique Magdinier, Jérôme D Robin

{"title":"Telomere Position Effect-Over Long Distances Acts as a Genome-Wide Epigenetic Regulator Through a Common Alu Element.","authors":"Raphaël Chevalier, Victor Murcia Pienkowski, Nicolas Jullien, Leslie Caron, Pascal Verdier Pinard, Frédérique Magdinier, Jérôme D Robin","doi":"10.1111/acel.70027","DOIUrl":"https://doi.org/10.1111/acel.70027","url":null,"abstract":"Among epigenetic modifiers, telomeres represent attractive modulators of the genome in part through position effects. Telomere Position Effect-Over Long Distances (TPE-OLD) modulates gene expression by changes in telomere-dependent long-distance loops. To gain insights into the molecular mechanisms of TPE-OLD, we performed a genome-wide transcriptome and methylome analysis in proliferative fibroblasts and myoblasts or differentiated myotubes with controlled telomere lengths. By integrating omics data, we identified a common TPE-OLD dependent cis-acting motif that behaves as an insulator or enhancer. Next, we uncovered trans partners that regulate these activities and observed the consistent depletion of one candidate factor, RBPJ, at TPE-OLD associated loci upon telomere shortening. Importantly, we confirmed our findings by unbiased comparisons to recent Human transcriptomic studies, including those from the Genotype-Tissue Expression (GTEx) project. We concluded that TPE-OLD acts at the genome-wide level and can be relayed by RBPJ bridging Alu-like elements to telomeres. In response to physiological (i.e., aging) or pathological cues, TPE-OLD might coordinate the genome-wide impact of telomeres through recently evolved Alu elements acting as enhancers in association with RBPJ.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70027"},"PeriodicalIF":8.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595928","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

Associations Between Leisure-Time Physical Activity and Metabolomics-Based Markers of Biological Aging in Late Midlife: Short-Term and Long-Term Follow-Up.

IF 8 1区医学

Aging Cell Pub Date : 2025-03-10 DOI: 10.1111/acel.70033

Katri Ruutu, Niko S Wasenius, Kothandaraman Narasimhan, Tuija M Mikkola, Merja K Laine, Johan G Eriksson

{"title":"Associations Between Leisure-Time Physical Activity and Metabolomics-Based Markers of Biological Aging in Late Midlife: Short-Term and Long-Term Follow-Up.","authors":"Katri Ruutu, Niko S Wasenius, Kothandaraman Narasimhan, Tuija M Mikkola, Merja K Laine, Johan G Eriksson","doi":"10.1111/acel.70033","DOIUrl":"https://doi.org/10.1111/acel.70033","url":null,"abstract":"Physical activity (PA) may delay the onset of age-related diseases by decelerating biological aging. We investigated the association between leisure-time physical activity (LTPA) and metabolomics-based aging markers (MetaboAge and MetaboHealth) in late midlife and during 16 years of follow-up. At the 16-year follow-up, we also investigated the association between device-based PA and MetaboAge and MetaboHealth. We included 1816 individuals (mean age 61.6 years) from the Helsinki Birth Cohort Study at baseline and followed them up for 5 (n = 982) and 16 years (n = 744), respectively. LTPA was assessed via questionnaire at baseline and 16 years later and device-based PA with ActiGraph accelerometer at the 16-year follow-up. Fasting blood samples were applied to calculate MetaboAge acceleration (ΔmetaboAge) and MetaboHealth at baseline and at both follow-ups. Covariate-adjusted multiple regression analyses and linear mixed models were applied to study the associations. A higher volume of LTPA at baseline was associated with a lower MetaboHealth score at the 5-year follow-up (p < 0.0001 for time × LTPA interaction). No associations were detected at the 16-year follow-up. An increase in LTPA over 16 years was associated with a decrease in MetaboHealth score (p < 0.001) and a decrease in LTPA with an increase in MetaboHealth score. Higher device-based PA was associated with a lower MetaboHealth score, but not with ΔmetaboAge. In conclusion, higher LTPA in late midlife and device-based PA in old age were associated with improved MetaboHealth. Increasing LTPA with age may protect against MetaboHealth-based aging. The results support the importance of PA for biological aging in later life.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70033"},"PeriodicalIF":8.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595926","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

Serum Proteomic and Metabolomic Signatures of High Versus Low Physical Function in Octogenarians.

IF 8 1区医学

Aging Cell Pub Date : 2025-03-10 DOI: 10.1111/acel.70002

Ceereena Ubaida-Mohien, Ruin Moaddel, Sally Spendiff, Norah J MacMillan, Marie-Eve Filion, Jose A Morais, Julián Candia, Liam F Fitzgerald, Tanja Taivassalo, Paul M Coen, Luigi Ferrucci, Russell T Hepple

{"title":"Serum Proteomic and Metabolomic Signatures of High Versus Low Physical Function in Octogenarians.","authors":"Ceereena Ubaida-Mohien, Ruin Moaddel, Sally Spendiff, Norah J MacMillan, Marie-Eve Filion, Jose A Morais, Julián Candia, Liam F Fitzgerald, Tanja Taivassalo, Paul M Coen, Luigi Ferrucci, Russell T Hepple","doi":"10.1111/acel.70002","DOIUrl":"https://doi.org/10.1111/acel.70002","url":null,"abstract":"Physical function declines with aging, yet there is considerable heterogeneity, with some individuals declining very slowly while others experience accelerated functional decline. To gain insight into mechanisms promoting high physical function with aging, we performed proteomics, targeted metabolomics, and targeted kynurenine-focused metabolomic analyses on serum specimens from three groups of octogenarians: High-functioning master athletes (HF, n = 16), healthy normal-functioning non-athletes (NF, n = 12), and lower functioning non-athletes (LF, n = 11). Higher performance status was associated with evidence consistent with: Lower levels of circulating proinflammatory markers, as well as unperturbed tryptophan metabolism, with the normal function of the kynurenic pathway; higher circulating levels of lysophosphatidylcholines that have been previously associated with better mitochondrial oxidative capacity; lower activity of the integrated stress response; lower levels of circulating SASP protein members; and lower levels of proteins that reflect neurodegeneration/denervation. Extending the observations of previous studies focused on the biomarkers of aging that predict poor function, our findings show that many of the same biomarkers associated with poor function exhibit attenuated changes in those who maintain a high function. Because of the cross-sectional nature of this study, results should be interpreted with caution, and bidirectional causality, where physical activity behavior is both a cause and outcome of differences in the biomarker changes, remains a possible interpretation.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70002"},"PeriodicalIF":8.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583991","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

Temporal Changes in Alzheimer's Disease-Related Biomarkers in the CSF of Cognitively Normal Subjects at Different Ages: The Chongqing Ageing and Dementia Study.

IF 8 1区医学

Aging Cell Pub Date : 2025-03-09 DOI: 10.1111/acel.70036

Wei-Wei Li, Dong-Yu Fan, Qi Sun, Lei-Kai Wang, Bing-Qiang Huang, Zhong-Yuan Yu, Ding-Yuan Tian, Ying-Ying Shen, Cheng-Rong Tan, Gui-Hua Zeng, Fan Zeng, Jin Fan, Zhen Wang, Yan-Jiang Wang, Jun Wang

{"title":"Temporal Changes in Alzheimer's Disease-Related Biomarkers in the CSF of Cognitively Normal Subjects at Different Ages: The Chongqing Ageing and Dementia Study.","authors":"Wei-Wei Li, Dong-Yu Fan, Qi Sun, Lei-Kai Wang, Bing-Qiang Huang, Zhong-Yuan Yu, Ding-Yuan Tian, Ying-Ying Shen, Cheng-Rong Tan, Gui-Hua Zeng, Fan Zeng, Jin Fan, Zhen Wang, Yan-Jiang Wang, Jun Wang","doi":"10.1111/acel.70036","DOIUrl":"https://doi.org/10.1111/acel.70036","url":null,"abstract":"Revealing the temporal evolution of cerebrospinal fluid (CSF) biomarkers during aging is critical to understanding disease pathogenesis and developing early diagnoses and interventions for Alzheimer's disease (AD). CSF was obtained from 549 cognitively normal subjects between 18 and 93 years of age. 12 AD-related biomarkers were evaluated, including amyloid β (Aβ42, Aβ40, Aβ42/Aβ40 ratio), hyperphosphorylated tau (P-tau), neuronal injury/degeneration (T-tau, NFL, NSE, H-FABP, VILIP-1), neuroinflammation biomarkers (YKL-40, TREM2), and α-synuclein (α-synuclein). Associations between these biomarkers and age as well as apolipoprotein E (APOE) ε4 status were evaluated, and the associations among biomarkers were assessed. CSF Aβ42, P-tau, and T-tau levels exhibited nonlinear associations with age, among which Aβ42 was significantly modulated by APOE ε4 status. Specifically, an accelerated decline in Aβ42 levels occurred at 45.69 years of age in the APOE ε4+ group, which was almost 23 years earlier than that in the APOE ε4- group (68.02 years). The age-related change pattern of CSF P-tau is similar to that of T-tau, with both increasing slightly with age but showing an accelerated change at ≈60 years of age in the APOE ε4+ group. All the other biomarkers except for α-synuclein were linearly associated with age, and APOE ε4 status had no effect on these associations. Most biomarkers were positively correlated with each other except for Aβ42/Aβ40 ratio. The evolution of AD-related biomarkers in CSF varies throughout the adult lifespan, with the APOE ε4 allele modifying the temporal changes in CSF Aβ42 levels, as well as potentially influencing P-tau and T-tau levels.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70036"},"PeriodicalIF":8.0,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583992","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 Single-Cell Transcriptome Atlas Characterizes the Immune Landscape of Human Testes During Aging.

IF 8 1区医学

Aging Cell Pub Date : 2025-03-06 DOI: 10.1111/acel.70032

Qiaoling Jiang, Lina Cui, Xichen Nie, Hui Cai, Wenxiu Zhang, Xiaojian Lu, Yifei Guo, James M Hotaling, Bradley R Cairns, Xiaoyan Wang, Jingtao Guo

{"title":"A Single-Cell Transcriptome Atlas Characterizes the Immune Landscape of Human Testes During Aging.","authors":"Qiaoling Jiang, Lina Cui, Xichen Nie, Hui Cai, Wenxiu Zhang, Xiaojian Lu, Yifei Guo, James M Hotaling, Bradley R Cairns, Xiaoyan Wang, Jingtao Guo","doi":"10.1111/acel.70032","DOIUrl":"https://doi.org/10.1111/acel.70032","url":null,"abstract":"Aging disrupts immune regulation, affecting tissue function and increasing vulnerability to various diseases. However, the effects of aging on immune cells within human testes are not well understood. In this study, we utilized single-cell RNA sequencing to profile immune cells from 33 human testis samples from individuals aged 21 to 69. Our analysis revealed key immune cell types, including CD8+ T cells, monocytes, cDC2 cells, and various macrophage subtypes within the testes. We observed an age-related change in monocytes and MRC1hi tissue-resident macrophage (TRM), a pattern consistent in both human and mouse testes. Individuals aged 40 and older showed notable shifts in pathways related to phagocytosis, cytokine signaling, and antigen presentation. Monocytes also exhibited pro-inflammatory characteristics, potentially contributing to the low-grade inflammation commonly associated with aging. Together, these findings provide insights into age-related immune cell alterations in human testes and uncover molecular mechanisms underlying these shifts, offering a valuable resource for understanding immune aging in the reproductive system.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70032"},"PeriodicalIF":8.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143571770","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

Downregulation of NAD Kinase Expression in β-Cells Contributes to the Aging-Associated Decline in Glucose-Stimulated Insulin Secretion.

IF 8 1区医学

Aging Cell Pub Date : 2025-03-05 DOI: 10.1111/acel.70037

Guan-Jie Li, Mei-Ling Cheng, Yu-Ting Lin, Yu-Hsuan Ho, Gigin Lin, Chih-Yung Chiu, Hung-Yao Ho

{"title":"Downregulation of NAD Kinase Expression in β-Cells Contributes to the Aging-Associated Decline in Glucose-Stimulated Insulin Secretion.","authors":"Guan-Jie Li, Mei-Ling Cheng, Yu-Ting Lin, Yu-Hsuan Ho, Gigin Lin, Chih-Yung Chiu, Hung-Yao Ho","doi":"10.1111/acel.70037","DOIUrl":"https://doi.org/10.1111/acel.70037","url":null,"abstract":"Nicotinamide adenine dinucleotide kinase (NADK) is essential to the generation of nicotinamide adenine dinucleotide phosphate (NADP(H)), an important metabolic coupling factor involved in glucose-stimulated insulin secretion. In the present study, we showed that the expression of Nadk and Nadk2 transcripts and NADP(H) content were lower in islets of 80-week-old (aged) mice than those of 8-week-old (young) mice. This was associated with diminished oral glucose tolerance of old mice and the glucose-stimulated insulin secretion (GSIS) response of islets. Knockdown (KD) of Nadk or Nadk2 gene expression in NIT-1 cells impaired glucose-stimulated insulin secretion. Metabolomic analysis revealed that Nadk KD specifically affected purine metabolism in glucose-stimulated cells. The levels of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) were higher in KD cells than in the non-targeting control (NTC) cells. Phosphorylation of AMP-activated protein kinase (AMPK) was elevated in glucose-treated KD cells compared to that of NTC cells. Increased AICAR level and AMPKα phosphorylation were observed in the glucose-stimulated islets of the aged mice. Genetic and pharmacological inhibition of AMPK promoted glucose-stimulated insulin release by KD cells and the aged mouse islets. It is likely that NADK is modulatory to AMPK activation in pancreatic β-cells and to their GSIS response. Enhanced AICAR formation in KD cells was accompanied by significantly increased conversion from inosine monophosphate (IMP) in a tetrahydrofolate (THF)-dependent manner. Folate supplementation augmented the GSIS response of KD cells and aged mouse islets. Taken together, these findings suggest that the aging-associated decline in NADK expression may underlie the reduced insulin secretory capacity of pancreatic β-cells.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70037"},"PeriodicalIF":8.0,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565518","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