Abstract 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 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 in diabetic patients, and imply that GLP-1R agonism may be a generally applicable pharmacological intervention for patients at risk of age-related neurodegeneration. Competing Interest Statement CUHK filed a patent application based partly on the discovery reported in the study. Exenatide used in the study was provided by AstraZeneca Hong Kong Limited. AstraZeneca Hong Kong Limited had otherwise no role in the funding, design, execution or data interpretation of the study. Footnotes * Conflict of Interest CUHK filed a patent application based partly on the discovery reported in the study. Exenatide used in the study was provided by AstraZeneca Hong Kong Limited. AstraZeneca Hong Kong Limited had otherwise no role in the funding, design, execution or data interpretation of the study. * https://singlecell.broadinstitute.org/single_cell/study/SCP1182/...

Genome-wide reversal of glial and neurovascular cell transcriptomic aging signatures by GLP-1R agonism

10.1101/2020.12.21.423879