A miR-10a-5p-γCaMKII axis links periphery-to-brain signaling to cognitive vulnerability during female midlife.

Jing Qu, Jing Yang, Wenwen Li, Xiaoyan Zeng, Xingzhi He, Hongfeng Guo, Jun Lu, Xi Jiang, Xiaofan Zhuang, Chunyan Qian, Zuyun Liu, Jinyan Huang, Hao Wang, Han Xu, Haohong Li, Zhihua Gao, Lijun Kang, Hailan Hu, Huan Ma

Department of Neurology of Second Affiliated Hospital and Liangzhu Laboratory, School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China. · pubmed

Paper

Abstract

Although women live longer, they paradoxically face heightened susceptibility to cognitive and systemic decline emerging in midlife-an underexplored transition from resilience to vulnerability. Here, we investigate biological processes associated with this female-biased vulnerability and their molecular regulation. Senescence-associated features were preferentially elevated in middle-aged females in human brain and spleen tissues, with similar changes in mice. In female mice, epigenetic upregulation of the X-linked RNA-binding protein RBMX promoted midlife increases in splenic miR-10a-5p, while complementary in vivo approaches supported a peripheral contribution to cerebral miR-10a-5p abundance. miR-10a-5p repressed calcium/calmodulin-responsive kinase γCaMKII, and modulation of this axis influenced mitochondrial function, cellular senescence, and memory in mice. In neurons derived from Alzheimer's disease patients and in model mice, miR-10a-5p inhibition attenuated disease-associated phenotypes, supporting relevance to pathological aging. Together, these findings link periphery-to-brain communication to emerging brain vulnerability during female midlife and indicate that this transition may remain amenable to intervention.

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 claims that a peripheral-to-brain signaling axis involving miR-10a-5p and γCaMKII drives age-related cognitive vulnerability in females. This is relevant to longevity research because it identifies a specific molecular mechanism underlying the transition from resilience to vulnerability in midlife, suggesting that targeting this peripheral signal could prevent age-associated cognitive decline rather than merely treating downstream symptoms.

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