Aging Cell最新文献

{"title":"Deciphering Immunosenescence From Child to Frailty: Transcriptional Changes, Inflammation Dynamics, and Adaptive Immune Alterations.","authors":"Wenpu Lai, Qiuyue Feng, Wen Lei, Chanchan Xiao, Juan Wang, Yi Zhu, Lipeng Mao, Yue Zhu, Jiacheng He, Yangqiu Li, Hao Wang, Zhenhua Li, Guobing Chen, Oscar Junhong Luo","doi":"10.1111/acel.70082","DOIUrl":"https://doi.org/10.1111/acel.70082","url":null,"abstract":"<p><p>Aging induces significant alterations in the immune system, with immunosenescence contributing to age-related diseases. Peripheral blood mononuclear cells (PBMCs) offer a convenient and comprehensive snapshot of the body's immune status. In this study, we performed an integrated analysis of PBMCs using both bulk-cell and single-cell RNA-seq data, spanning from children to frail elderlies, to investigate age-related changes. We observed dynamic changes in the PBMC transcriptome during healthy aging, including dramatic shifts in inflammation, myeloid cells, and lymphocyte features during early life, followed by relative stability in later stages. Conversely, frail elderly individuals exhibited notable disruptions in peripheral immune cells, including an increased senescent phenotype in monocytes with elevated inflammatory cytokine expression, heightened effector activation in regulatory T cells, and functional impairment of cytotoxic lymphocytes. Overall, this study provides valuable insights into the complex dynamics of immunosenescence, elucidating the mechanisms driving abnormal inflammation and immunosuppression in frailty.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70082"},"PeriodicalIF":8.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956412","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}

{"title":"3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN-2-Mediated Changes.","authors":"Estevão Scudese, Andrea G Marshall, Zer Vue, Vernat Exil, Benjamin I Rodriguez, Mert Demirci, Larry Vang, Edgar Garza López, Kit Neikirk, Bryanna Shao, Han Le, Dominique Stephens, Duane D Hall, Rahmati Rostami, Taylor Rodman, Kinuthia Kabugi, Jian-Qiang Shao, Margaret Mungai, Salma T AshShareef, Innes Hicsasmaz, Sasha Manus, Celestine N Wanjalla, Aaron Whiteside, Revathi Dasari, Clintoria R Williams, Steven M Damo, Jennifer A Gaddy, Brian Glancy, Estélio Henrique Martin Dantas, André Kinder, Ashlesha Kadam, Dhanendra Tomar, Fabiana Scartoni, Matheus Baffi, Melanie R McReynolds, Mark A Phillips, Anthonya Cooper, Sandra A Murray, Anita M Quintana, Nelson Wandira, Okwute M Ochayi, Magdalene Ameka, Annet Kirabo, Sepiso K Masenga, Chanel Harris, Ashton Oliver, Pamela Martin, Amadou Gaye, Olga Korolkova, Vineeta Sharma, Bret C Mobley, Prasanna Katti, Antentor Hinton","doi":"10.1111/acel.70054","DOIUrl":"https://doi.org/10.1111/acel.70054","url":null,"abstract":"<p><p>Age-related skeletal muscle atrophy, known as sarcopenia, is characterized by loss of muscle mass, strength, endurance, and oxidative capacity. Although exercise has been shown to mitigate sarcopenia, the underlying governing mechanisms are poorly understood. Mitochondrial dysfunction is implicated in aging and sarcopenia; however, few studies explore how mitochondrial structure contributes to this dysfunction. In this study, we sought to understand how aging impacts mitochondrial three-dimensional (3D) structure and its regulators in skeletal muscle. We hypothesized that aging leads to remodeling of mitochondrial 3D architecture permissive to dysfunction and is ameliorated by exercise. Using serial block-face scanning electron microscopy (SBF-SEM) and Amira software, mitochondrial 3D reconstructions from patient biopsies were generated and analyzed. Across five human cohorts, we correlate differences in magnetic resonance imaging, mitochondria 3D structure, exercise parameters, and plasma immune markers between young (under 50 years) and old (over 50 years) individuals. We found that mitochondria are less spherical and more complex, indicating age-related declines in contact site capacity. Additionally, aged samples showed a larger volume phenotype in both female and male humans, indicating potential mitochondrial swelling. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), one such of these mitochondrial dynamic proteins, which we show is required for the integrity of mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved, as Marf, the MFN2 ortholog in Drosophila, knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusin 2.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70054"},"PeriodicalIF":8.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953728","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}

{"title":"Dietary Restriction Mitigates Vascular Aging, Modulates the cGAS-STING Pathway and Reverses Macrophage-Like VSMC Phenotypes in Progeroid DNA-Repair-Deficient Ercc1^Δ ^/- Mice.","authors":"S J M Stefens, J van der Linden, J M Heredia-Genestar, R M C Brandt, S Barnhoorn, I Nieuwenhuizen-Bakker, N van Vliet, J H M Odijk, Y Ridwan, D Stuijts, M Batenburg, J H J Hoeijmakers, R Kanaar, J Essers, I van der Pluijm","doi":"10.1111/acel.70062","DOIUrl":"https://doi.org/10.1111/acel.70062","url":null,"abstract":"<p><p>Aging is a major risk factor for cardiovascular diseases, and the accumulation of DNA damage significantly contributes to the aging process. This study aimed to identify the underlying molecular mechanisms of vascular aging in DNA-repair-deficient progeroid Ercc1^Δ/- mice and to explore the therapeutic effect of dietary restriction (DR). RNA sequencing analysis revealed that DR reversed gene expression of vascular aging processes, including extracellular matrix remodeling, in the Ercc1^Δ/- aorta. Notably, this analysis indicated the presence of macrophage-like vascular smooth muscle cells (VSMCs) and suggested cGAS-STING pathway activation. The presence of macrophage-like VSMCs and increased STING1 expression were confirmed in Ercc1^Δ/- aortic tissue and were both reduced by DR. In vitro, cisplatin-induced DNA damage activated the cGAS-STING pathway in Ercc1^Δ/- VSMCs but not in wildtype VSMCs. These findings identify the involvement of the cGAS-STING pathway in DNA damage-driven vascular aging and underscore the therapeutic benefits of DR for vascular aging. Furthermore, upstream regulator analysis revealed compounds that may replicate the beneficial effects of DR, providing promising leads for further investigation.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70062"},"PeriodicalIF":8.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955762","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}

{"title":"Identification of Senomorphic miRNAs in Embryonic Progenitor and Adult Stem Cell-Derived Extracellular Vesicles.","authors":"Tianpeng Zhang, Allancer D C Nunes, Jieun Lee, Dana Larocca, Giovanni Camussi, Sai Kiang Lim, Vicky U Bascones, Luise Angelini, Ryan D O'Kelly, Xiao Dong, Laura J Niedernhofer, Paul D Robbins","doi":"10.1111/acel.70071","DOIUrl":"https://doi.org/10.1111/acel.70071","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) are secreted by most cell types, transmitting crucial signaling molecules like proteins, small RNAs, and DNA. We previously demonstrated that EVs from murine and human mesenchymal stem cells (MSCs) functioned as senomorphics to suppress markers of senescence and the inflammatory senescence-associated secretory phenotype (SASP) in cell culture and in aged mice. Here we demonstrate that EVs from additional types of human adult stem cells and embryonic progenitor cells have a senomorphic activity. Based on their miRNA profiles showing prevalence in stem cell EVs versus nonstem cell EVs and the number of age-related genes targeted, we identified eight miRNAs as potential senomorphic miRNAs. Analysis of these miRNAs by transfection into etoposide-induced senescent IMR90 human fibroblasts revealed that each of the miRNAs alone regulated specific senescence and SASP markers, but none had complete senomorphic activity. Evaluation of ~300 combinations of miRNAs for senotherapeutic activity identified a senomorphic cocktail of miR-181a-5p, miR-92a-3p, miR-21-5p, and miR-186-5p that markedly reduced the expression of p16^INK4a, p21^Cip1, IL-1β, and IL-6 and the percentage of SA-ß-gal-positive cells. Transcriptome analysis identified multiple pathways affected by the miRNA cocktail, including cellular senescence and inhibition of PCAF and HIPK2 in the p53 signaling pathway. Finally, treatment of aged mice with liposomes containing the four miRNA cocktail suppressed markers of senescence and inflammation in multiple tissues. These studies suggest that EVs derived from stem cells suppress senescence and inflammation, at least in part, through miRNAs and that a senomorphic miRNA cocktail could be used to target senescence and inflammation to extend health span.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70071"},"PeriodicalIF":8.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954302","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}

{"title":"The 15-Year Survival Advantage: Immune Resilience as a Salutogenic Force in Healthy Aging.","authors":"Muthu Saravanan Manoharan, Grace C Lee, Nathan Harper, Justin A Meunier, Marcos I Restrepo, Fabio Jimenez, Sreenath Karekatt, Anne P Branum, Alvaro A Gaitan, Kian Andampour, Alisha M Smith, Michael Mader, Michelle Noronha, Devjit Tripathy, Nu Zhang, Alvaro G Moreira, Lavanya Pandranki, Sandra Sanchez-Reilly, Hanh D Trinh, Clea Barnett, Luis Angel, Leopoldo N Segal, Susannah Nicholson, Robert A Clark, Weijing He, Jason F Okulicz, Sunil K Ahuja","doi":"10.1111/acel.70063","DOIUrl":"https://doi.org/10.1111/acel.70063","url":null,"abstract":"<p><p>Human aging presents an evolutionary paradox: while aging rates remain constant, healthspan and lifespan vary widely. We address this conundrum via salutogenesis-the active production of health-through immune resilience (IR), the capacity to resist disease despite aging and inflammation. Analyzing ~17,500 individuals across lifespan stages and inflammatory challenges, we identified a core salutogenic mechanism: IR centered on TCF7, a conserved transcription factor maintaining T-cell stemness and regenerative potential. IR integrates innate and adaptive immunity to counter three aging and mortality drivers: chronic inflammation (inflammaging), immune aging, and cellular senescence. By mitigating these aging mechanisms, IR confers survival advantages: At age 40, individuals with poor IR face a 9.7-fold higher mortality rate-a risk equivalent to that of 55.5-year-olds with optimal IR-resulting in a 15.5-year gap in survival. Optimal IR preserves youthful immune profiles at any age, enhances vaccine responses, and reduces burdens of cardiovascular disease, Alzheimer's, and serious infections. Two key salutogenic evolutionary themes emerge: first, female-predominant IR, including TCF7, likely reflects evolutionary pressures favoring reproductive success and caregiving; second, midlife (40-70 years) is a critical window where optimal IR reduces mortality by 69%. After age 70, mortality rates converge between resilient and non-resilient groups, reflecting biological limits on longevity extension. TNFα-blockers restore salutogenesis pathways, indicating IR delays aging-related processes rather than altering aging rates. By reframing aging as a salutogenic-pathogenic balance, we establish TCF7-centered IR as central to healthy longevity. Targeted midlife interventions to enhance IR offer actionable strategies to maximize healthspan before biological constraints limit benefits.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70063"},"PeriodicalIF":8.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955763","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}

{"title":"AI-Driven Identification of Exceptionally Efficacious Polypharmacological Compounds That Extend the Lifespan of Caenorhabditis elegans.","authors":"Konstantin Avchaciov, Khalyd J Clay, Kirill A Denisov, Olga Burmistrova, Michael Petrascheck, Peter O Fedichev","doi":"10.1111/acel.70060","DOIUrl":"https://doi.org/10.1111/acel.70060","url":null,"abstract":"<p><p>Analysis of existing lifespan-extending geroprotective compounds suggested that polypharmacological compounds are the most effective geroprotectors, specifically those that bind multiple biogenic amine receptors. To test this hypothesis, we used graph neural networks to predict polypharmacological geroprotectors and evaluated them in Caenorhabditis elegans. Over 70% of the selected compounds extended lifespan, with effect sizes in the top 5% compared to all geroprotectors recorded in the DrugAge database. Thus, our study reveals that rationally designing polypharmacological compounds enables the design of geroprotectors with exceptional efficacy.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70060"},"PeriodicalIF":8.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957704","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}

{"title":"At the Nexus Between Epigenetics and Senescence: The Effects of Senolytic (BI01) Administration on DNA Methylation Clock Age and the Methylome in Aged and Regenerated Skeletal Muscle.","authors":"Toby L Chambers, Jaden Wells, Pieter Jan Koopmans, Francielly Morena, Zain B Malik, Nicholas P Greene, Antonio Filareto, Michael Franti, Patrizia Sini, Harald Weinstabl, Robert T Brooke, Milda Milčiūtė, Juozas Gordevičius, Steve Horvath, Yuan Wen, Cory M Dungan, Kevin A Murach","doi":"10.1111/acel.70068","DOIUrl":"https://doi.org/10.1111/acel.70068","url":null,"abstract":"<p><p>Senescent cells emerge with aging and injury. The contribution of senescent cells to DNA methylation age (DNAmAGE) in vivo is uncertain. Furthermore, stem cell therapy can mediate \"rejuvenation\", but how tissue regeneration controlled by resident stem cells affects whole tissue DNAmAGE is unclear. We assessed DNAmAGE with or without senolytics (BI01) in aged male mice (24-25 months) 35 days following muscle healing (BaCl₂-induced regeneration versus non-injured). Young injured mice (5-6 months) without senolytics were comparators. DNAmAGE was decelerated by up to 68% after injury in aged muscle. DNAmAGE was modestly but further significantly decelerated by injury recovery with senolytics. ~1/4 of measured CpGs were altered by injury then recovery regardless of senolytics in aged muscle. Specific methylation changes caused by senolytics included differential regulation of Col, Hdac, Hox, and Wnt genes, which likely contributed to improved regeneration. Altered extracellular matrix remodeling using histological analysis aligned with the methylomic findings with senolytics. Without senolytics, regeneration had a contrasting effect in young mice and tended not to influence or modestly accelerate DNAmAGE. Comparing young to old injury recovery without senolytics using methylome-transcriptome integration, we found a more coordinated molecular profile in young and differential regulation of genes implicated in muscle stem cell performance: Axin2, Egr1, Fzd4, Meg3, and Spry1. Muscle injury and senescent cells affect DNAmAGE and aging influences the transcriptomic-methylomic landscape after resident stem cell-driven tissue reformation. Our data have implications for understanding muscle plasticity with aging and developing therapies aimed at collagen remodeling and senescence.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70068"},"PeriodicalIF":8.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953250","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}

{"title":"Senescent Macrophages Promote Age-Related Revascularization Impairment by Increasing Antiangiogenic VEGF-A165B Expression.","authors":"Minghong Chen, Junyu Chen, Yu Liu, Xuerui Wang, Meilian Yao, Jing Chen, Jian Zhang, Qun Huang","doi":"10.1111/acel.70059","DOIUrl":"https://doi.org/10.1111/acel.70059","url":null,"abstract":"<p><p>Peripheral arterial disease is a common vascular disease in the elderly. Therapeutic revascularization, including angiogenic and arteriogenic therapy, is a promising treatment approach for peripheral arterial disease. However, the progress of clinical trials is not ideal, possibly due to insufficiency of preclinical models, such as not taking into account the effect of aging on vascular regeneration. Macrophages are crucial in angiogenesis and arteriogenesis. The aging microenvironment typically makes recruited monocytes and macrophages more susceptible to senescence. However, the feature of macrophages in ischemic hindlimb muscle of old individuals and their underlying role remains unclear. In this study, we reveal that macrophages of ischemic skeletal muscle in old mice are more senescent and proinflammatory. By transplanting macrophages into mice following hindlimb ischemia, we find senescent macrophages inhibit revascularization. Mechanistically, these senescent macrophages induce endothelial dysfunction via increasing vascular endothelial growth factor A-165B (VEGF-A165B) expression and secretion, and eventually impair revascularization. Notably, plasma VEGF-A165B levels are elevated in old patients with PAD and positively associated with a lower ankle brachial index (ABI). Our study suggests that targeting the senescent macrophages presents an avenue to improve age-related revascularization damage.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70059"},"PeriodicalIF":8.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957707","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}

{"title":"VDAC1-Targeted NHK1 Peptide Recovers Mitochondrial Dysfunction Counteracting Amyloid-β Oligomers Toxicity in Alzheimer's Disease.","authors":"Fabrizio Cavallaro, Stefano Conti Nibali, Salvatore Antonio Maria Cubisino, Pietro Caruso, Stefania Zimbone, Iolanda Rita Infantino, Simona Reina, Vito De Pinto, Angela Messina, Maria Laura Giuffrida, Andrea Magrì","doi":"10.1111/acel.70069","DOIUrl":"https://doi.org/10.1111/acel.70069","url":null,"abstract":"<p><p>Mitochondrial dysfunction has been implicated in a broad range of age-related pathologies and has been proposed as a causative factor in Alzheimer's disease (AD). Analysis of post-mortem brains from AD patients showed increased levels of Voltage-dependent anion-selective channel 1 (VDAC1) in the dystrophic neurites surrounding amyloid-β (Aβ) deposits, suggesting a direct association between VDAC1 and mitochondrial toxicity. VDAC1 is the most abundant pore-forming protein of the outer mitochondrial membrane and, as a channel, it plays a pivotal role in regulating cellular bioenergetics, allowing the continuous exchange of ions and metabolites (ATP/ADP, Krebs cycle intermediates) between cytosol and mitochondria. In light of this evidence, we looked into the effects of Aβ oligomers on VDAC1 functions through electrophysiological and respirometric techniques. Our findings indicate that Aβ oligomers significantly modify the conductance, voltage dependency, and kinetic features of VDAC1, as well as its slight selectivity for anions, leading to a marked preference for cations. Given that VDAC1 is mainly involved in the trafficking of charged molecules in and out of mitochondria, a general reduction of cell viability and mitochondrial respiration was detected in neuroblastoma cells and primary cortical neurons exposed to Aβ oligomers. Interestingly, the toxic effect mediated by Aβ oligomers was counteracted by the use of NHK1, a small synthetic, cell-penetrating peptide that binds and modulates VDAC1. On these results, VDAC1 emerges as a crucial molecule in mitochondrial dysfunction in AD and as a promising pharmacological target for the development of new therapeutic avenues for this devastating neurodegenerative disease still without a cure.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70069"},"PeriodicalIF":8.0,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144053228","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}

{"title":"Aged Gut Microbiota Contributes to Cognitive Impairment and Hippocampal Synapse Loss in Mice.","authors":"Mingxiao Li, Yiyang Bao, Jiaoqi Ren, Wenjing Wei, Xuefei Yu, Xiaofang He, Mutalifu Gulisima, Lili Sheng, Ningning Zheng, Jianbo Wan, Houguang Zhou, Ling Zhao, Houkai Li","doi":"10.1111/acel.70064","DOIUrl":"https://doi.org/10.1111/acel.70064","url":null,"abstract":"<p><p>Gut microbiota alteration during the aging process serves as a causative factor for aging-related cognitive decline, which is characterized by the early hallmark, hippocampal synaptic loss. However, the impact and mechanistic role of gut microbiota in hippocampal synapse loss during aging remains unclear. Here, we observed that the fecal microbiota of naturally aged mice successfully transferred cognitive impairment and hippocampal synapse loss to young recipients. Multi-omics analysis revealed that aged gut microbiota was characterized with obvious change in Bifidobacterium pseudolongum (B.p) and metabolite of tryptophan, indoleacetic acid (IAA) in the periphery and brain. These features were also reproduced in young recipients that were transplanted with aged gut microbiota. Fecal B.p abundance was reduced in patients with cognitive impairment compared to healthy subjects and showed a positive correlation with cognitive scores. Microbiota transplantation from patients who had fewer B.p abundances yielded worse cognitive behavior in mice than those with higher B.p abundances. Meanwhile, supplementation of B.p was capable of producing IAA and enhancing peripheral and brain IAA bioavailability, as well as improving cognitive behaviors and microglia-mediated synapse loss in 5 × FAD transgenic mice. IAA produced from B.p was shown to prevent microglia engulfment of synapses in an aryl hydrocarbon receptor-dependent manner. This study reveals that aged gut microbiota -induced cognitive decline and microglia-mediated synapse loss that is, at least partially, due to the deficiency in B.p and its metabolite, IAA. It provides a proof-of-concept strategy for preventing neurodegenerative diseases by modulating gut probionts and their tryptophan metabolites.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70064"},"PeriodicalIF":8.0,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956285","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}