Liu Ruonan, Zhu Zheng, Zhu Yuanyue, Lin Xin, Li Hongjie, Wang Tiange, Zheng Jie, Li Mian, Zhao Zhiyun, Xu Yu, Lu Jieli, Wang Weiqing, Ning Guang, Bi Yufang, Hu Weiguo, Xu Min
Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Geriatric Medical Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Geroscience. 2025 Jul 23. doi: 10.1007/s11357-025-01794-4.
Gut microbiota (GM) is implicated in aging biology, yet its dual regulatory role in the distinct yet interconnected processes of lifespan extension and aging remains poorly understood. This study employed genetic approaches to identify GM taxa exerting causal effects on longevity and aging and assess the mediation role of cerebrospinal fluid (CSF) proteins. We leveraged summary statistics of the GM taxa (207 taxa, 7738 participants from the Dutch Microbiome Project), the CSF proteins (7008 aptamers, 3506 participants), and the longevity and aging phenotypes (UK Biobank, Longevity Genomics, and Edinburgh DataShare) from the largest genome-wide association studies so far. We performed bidirectional Mendelian randomization (MR) to explore causal relationships between GM and longevity and aging and two mediation analyses, the two-step MR and the multivariable MR (MVMR), to discover potential mediating proteins. Nine taxa exhibited causal associations with longevity-related phenotypes, such as the Bacteroides vulgatus and Blautia. Three taxa demonstrated causal associations with aging-related phenotypes, such as Streptococcus. Among them, Streptococcus was causally associated with aging (β = 0.3310, P = 0.0019) and lifespan-shortening (β = - 0.0247, P = 0.0184), while Bacteroides vulgatus associated with aging (β = 0.3884, P = 0.0204) and lifespan-promoting (β = 0.0354, P = 0.0198). Mediation MR analysis found that CSF protein CD28 mediated the causal effects of Streptococcus on longevity (mediation proportion 11.7%, P = 0.0394). These findings establish genetic links between GM, CSF proteins, and longevity and aging-related outcomes, advancing gut-brain axis understanding while offering insights for future mechanistic exploration and clinical investigation.
肠道微生物群（GM）与衰老生物学有关，但其在寿命延长和衰老这两个不同但相互关联的过程中的双重调节作用仍知之甚少。本研究采用遗传学方法来识别对寿命和衰老有因果影响的GM分类群，并评估脑脊液（CSF）蛋白的中介作用。我们利用了GM分类群（207个分类群，来自荷兰微生物组计划的7738名参与者）、CSF蛋白（7008个适配体，3506名参与者）以及寿命和衰老表型（英国生物银行、长寿基因组学和爱丁堡数据共享）的汇总统计数据，这些数据来自迄今为止最大规模的全基因组关联研究。我们进行了双向孟德尔随机化（MR）以探索GM与寿命和衰老之间的因果关系，并进行了两项中介分析，即两步MR和多变量MR（MVMR），以发现潜在的中介蛋白。九个分类群与寿命相关表型存在因果关联，如普通拟杆菌和布劳特氏菌。三个分类群与衰老相关表型存在因果关联，如链球菌。其中，链球菌与衰老（β = 0.3310，P = 0.0019）和寿命缩短（β = -0.0247，P = 0.0184）存在因果关联，而普通拟杆菌与衰老（β = 0.3884，P = 0.0204）和寿命延长（β = 0.0354，P = 0.0198）存在关联。中介MR分析发现，CSF蛋白CD28介导了链球菌对寿命的因果影响（中介比例11.7%，P = 0.0394）。这些发现建立了GM、CSF蛋白与寿命和衰老相关结果之间的遗传联系，推进了对肠-脑轴的理解，同时为未来的机制探索和临床研究提供了见解。
