Generalized reversal of glial and neurovascular cell transcriptomic aging signatures by glucagon-like peptide-1 receptor agonist

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. Recently, we demonstrated that brain endothelial cell (EC) aging is transcriptomically and functionally reversible by treatment with exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist (GLP-1RA)(1). Here, we report that the reversal of transcriptomic aging signatures by GLP-1RA treatment is a generalized phenomenon in multiple major brain cell types, including glial (including astrocyte (AC), oligodendrocyte precursor cell (OPC), microglia (MG) and oligodendrocyte (OLG)) and mural (i.e. pericyte (PC) and smooth muscle cell (SMC)) cells. The age-related expression changes ameliorated by GLP-1RA encompass cell type-shared and specific functional pathways implicated in aging and neurodegeneration. These results show the feasibility of brain ageing reversal by pharmacological means, provide mechanistic insights into the neurological benefits of GLP-1RAs in diabetic patients(2, 3), and imply that GLP-1RA may be a generally applicable pharmacological intervention for non-diabetic patients at risk of age-related neurodegeneration.