Transcriptional and epigenetic decoding of the microglial aging process

Xiaoyu Li; Yuxin Li; Yuxiao Jin; Yuheng Zhang; Jingchuan Wu; Zhen Xu; Yubin Huang; Lin Cai; Shuai Gao; Taohui Liu; Fanzhuo Zeng; Yafei Wang; Wenxu Wang; Ti-Fei Yuan; Hengli Tian; Yousheng Shu; Feifan Guo; Wei Lu; Ying Mao; Xifan Mei; Yanxia Rao; Bo Peng

doi:10.1038/s43587-023-00479-x

Transcriptional and epigenetic decoding of the microglial aging process

Nat Aging. 2023 Oct;3(10):1288-1311. doi: 10.1038/s43587-023-00479-x. Epub 2023 Sep 11.

Authors

Xiaoyu Li¹, Yuxin Li¹, Yuxiao Jin², Yuheng Zhang¹, Jingchuan Wu³, Zhen Xu⁴, Yubin Huang⁴, Lin Cai^{1

5}, Shuai Gao¹, Taohui Liu¹, Fanzhuo Zeng^{1

6}, Yafei Wang¹, Wenxu Wang¹, Ti-Fei Yuan⁷, Hengli Tian⁵, Yousheng Shu¹, Feifan Guo¹, Wei Lu¹, Ying Mao³, Xifan Mei⁶, Yanxia Rao⁸, Bo Peng^{9

10

11}

Affiliations

¹ Department of Neurosurgery, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Innovative Center for New Drug Development of Immune Inflammatory Diseases, Ministry of Education, Fudan University, Shanghai, China.
² Department of Neurology, Zhongshan Hospital, Department of Laboratory Animal Science, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.
³ Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
⁴ Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
⁵ Department of Neurology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁶ Department of Orthopedics, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China.
⁷ Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁸ Department of Neurology, Zhongshan Hospital, Department of Laboratory Animal Science, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China. yanxiarao@fudan.edu.cn.
⁹ Department of Neurosurgery, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Innovative Center for New Drug Development of Immune Inflammatory Diseases, Ministry of Education, Fudan University, Shanghai, China. peng@fudan.edu.cn.
¹⁰ Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China. peng@fudan.edu.cn.
¹¹ Co-Innovation Center of Neurodegeneration, Nantong University, Nantong, China. peng@fudan.edu.cn.

Abstract

As important immune cells, microglia undergo a series of alterations during aging that increase the susceptibility to brain dysfunctions. However, the longitudinal characteristics of microglia remain poorly understood. In this study, we mapped the transcriptional and epigenetic profiles of microglia from 3- to 24-month-old mice. We first discovered unexpected sex differences and identified age-dependent microglia (ADEM) genes during the aging process. We then compared the features of aging and reactivity in female microglia at single-cell resolution and epigenetic level. To dissect functions of aged microglia excluding the influence from other aged brain cells, we established an accelerated microglial turnover model without directly affecting other brain cells. By this model, we achieved aged-like microglia in non-aged brains and confirmed that aged-like microglia per se contribute to cognitive decline. Collectively, our work provides a comprehensive resource for decoding the aging process of microglia, shedding light on how microglia maintain brain functions.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aging / genetics
Animals
Brain
Cognitive Dysfunction* / genetics
Epigenesis, Genetic
Female
Male
Mice
Microglia*