Division of Neurology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
Commun Biol. 2021 Jun 2;4(1):656. doi: 10.1038/s42003-021-02208-9.
Pharmacological reversal of brain aging is a long-sought yet challenging strategy for the prevention and treatment of age-related neurodegeneration, due to the diverse cell types and complex cellular pathways impacted by the aging process. Here, we report the genome-wide reversal of transcriptomic aging signatures in multiple major brain cell types, including glial and mural cells, by systemic glucagon-like peptide-1 receptor (GLP-1R) agonist (GLP-1RA) treatment. The age-related expression changes reversed by GLP-1RA encompass both shared and cell type-specific functional pathways that are implicated in aging and neurodegeneration. Concomitantly, Alzheimer's disease (AD)-associated transcriptomic signature in microglia that arises from aging is reduced. These results show the feasibility of reversing brain aging by pharmacological means, provide mechanistic insights into the neurological benefits of GLP-1RAs, and imply that GLP-1R agonism may be a generally applicable pharmacological intervention for patients at risk of age-related neurodegeneration.
通过系统给予胰高血糖素样肽-1 受体（GLP-1R）激动剂（GLP-1RA）治疗，我们报告了在多种主要脑细胞类型（包括神经胶质细胞和壁细胞）中，全基因组逆转转录组衰老特征。GLP-1RA 逆转的与年龄相关的表达变化既包括与衰老和神经退行性变相关的共享功能途径，也包括细胞类型特异性功能途径。同时，衰老引起的小胶质细胞中与阿尔茨海默病（AD）相关的转录组特征减少。这些结果表明通过药理学手段逆转大脑衰老的可行性，为 GLP-1RAs 的神经益处提供了机制见解，并暗示 GLP-1R 激动可能是一种适用于有年龄相关性神经退行性病变风险的患者的普遍适用的药物干预措施。
