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 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.
Highlights
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
We demonstrated that a generalized reversal of functionally relevant transcriptomic changes at the genome-wide level in multiple glial and vascular cell types in the aged brain is pharmacologically achievable with glucagon-like peptide-1 receptor (GLP-1R) agonism
While disease-associated microglia (DAM) is associated with neuropathology development in an Alzheimer’s disease (AD) mouse model[20], it remains incompletely understood what the functional significance of DAM-like MGs are in the aged brain
Summary
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. 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. Most cellular processes are implicated in or impacted by aging, ranging from metabolism, stress response, immune responses, cellular senescence, to gene expression, and genomic stability[1] These complex molecular changes presumably lead to an alteration of cellular states and compositions in body organs[1,2], manifesting as age-related functional decline. Given the complexity of biological changes involved and a lack of targetable sets of driving pathways, anti-aging pharmacotherapy is considered highly challenging It remains an attractive pursuit for tackling age-related disorders, such as neurodegeneration for which aging is the strongest risk factor. How GLP-1RA treatment impacts glial and other neurovascular cell types, whose agerelated expression changes play crucial roles in brain aging and degeneration, remained unclear
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