Aged bone marrow macrophages drive systemic aging and age-related dysfunction via extracellular vesicle-mediated induction of paracrine senescence.

Jing Hou, Kai-Xuan Chen, Chen He, Xiao-Xiao Li, Mei Huang, Yang-Zi Jiang, Yu-Rui Jiao, Qiao-Ni Xiao, Wen-Zhen He, Ling Liu, Nan-Yu Zou, Min Huang, Jie Wei, Ye Xiao, Mi Yang, Xiang-Hang Luo, Chao Zeng, Guang-Hua Lei, Chang-Jun Li

Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China.Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China. · pubmed

Paper

Abstract

The accumulation and systemic propagation of senescent cells contributes to physiological aging and age-related pathology. However, which cell types are most susceptible to the aged milieu and could be responsible for the propagation of senescence has remained unclear. Here we found that physiologically aged bone marrow monocytes/macrophages (BMMs) propagate senescence to multiple tissues, through extracellular vesicles (EVs), and drive age-associated dysfunction in mice. We identified peroxisome proliferator-activated receptor α (PPARα) as a target of microRNAs within aged BMM-EVs that regulates downstream effects on senescence and age-related dysfunction. Demonstrating therapeutic potential, we report that treatment with the PPARα agonist fenofibrate effectively restores tissue homeostasis in aged mice. Suggesting conservation to humans, in a cohort study of 7,986 participants, we found that fenofibrate use is associated with a reduced risk of age-related chronic disease and higher life expectancy. Together, our findings establish that BMMs can propagate senescence to distant tissues and cause age-related dysfunction, and they provide supportive evidence for fenofibrate to extend healthy lifespan.

The following analysis is generated by AI and may contain errors. It is separate from the authors’ abstract and is not peer review.

Research summary

The paper addresses the role of aged bone marrow macrophages in propagating senescence and age-related dysfunction, which is directly related to the mechanisms of aging and potential interventions to extend healthy lifespan. The identification of PPARα as a target and the therapeutic implications of fenofibrate provide important insights into potential strategies for combating age-related decline. However, while the findings are significant, they do not represent a major breakthrough that could transform the field, hence the score of 5.

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