Restoring the FOXO1 geroprotective pathway via seno-resistant mesenchymal progenitor cells alleviates primate epididymal aging.

Huifen Lu, Linguo Cai, DongLiang Lv, Guoqiang Sun, Jinghui Lei, Taixin Ning, Zijuan Xin, Haoyan Huang, Ying Jing, Daoyuan Huang, Shuhui Sun, Shuai Ma, Weiqi Zhang, Fei Gao, Rui Chen, Yingying Qin, Weihong Song, Andy Peng Xiang, Juan Carlos Izpisua Belmonte, Guang-Hui Liu, Jing Qu, Si Wang

Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Aging Translational Medicine Center, Beijing Municipal Geriatric Medical Research Center, Beijing Key Laboratory of Environment and Aging, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Aging Translational Medicine Center, Beijing Municipal Geriatric Medical Research Center, Beijing Key Laboratory of Environment and Aging, Xuanwu Hospital Capital Medical University, Beijing, 100053, China. · pubmed

Paper

Abstract

Aging of the male reproductive system is characterized by declining fertility, with epididymal dysfunction being a critical yet poorly understood contributor. Through a multimodal analysis in non-human primates that integrated histology and transcriptomics, we delineated a coherent epididymal aging phenotype encompassing epithelial senescence, chronic inflammation, fibrosis, and functional decline. Single-nucleus transcriptomics revealed principal cells (PCs) as the predominant and most transcriptionally perturbed epithelial cell type. Within PCs, the longevity-associated transcription factor FOXO1 was markedly downregulated with age. Functional studies in human epididymal epithelial cells demonstrated that FOXO1 deficiency drives cellular senescence. Mechanistically, FOXO1 transcriptionally activates LHX1, and this axis is essential for counteracting senescence. Furthermore, intervention with senescence-resistant mesenchymal progenitor cells or their exosomes mitigated epididymal aging phenotypes and restored FOXO1 expression in vivo and in vitro. Our study establishes the FOXO1-LHX1 axis as a key protective pathway against primate epididymal aging, providing mechanistic insights and potential therapeutic targets for preserving male reproductive health.

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Research summary

The study identifies the FOXO1-LHX1 axis as a protective pathway against epididymal aging and demonstrates that restoring this pathway can alleviate aging phenotypes. This research is relevant as it addresses the underlying mechanisms of aging in the male reproductive system, potentially contributing to longevity and age-related health improvements.

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