Brain-wide spatially resolved cell type-dependent age-counteraction and senomorphic effects of GLP-1R agonism and mTOR inhibition

Brain aging is a major contributor to neurodegenerative diseases and is characterized by region- and cell type-specific molecular alterations. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and mammalian target of rapamycin inhibitors (mTORi), particularly rapamycin, have emerged as promising interventions against aging and age-related neurological disorders. GLP-1RAs exert systemic and brain-specific anti-aging effects, partly through hypothalamic GLP-1 receptor signaling, whereas mTOR inhibition promotes longevity and neuroprotection by enhancing autophagy, preserving vascular integrity and neuronal energy metabolism, and reducing pathological protein accumulation. Although these interventions induce convergent transcriptomic, epigenomic, and metabolomic changes, their effects vary across brain regions, suggesting distinct mechanisms and sites of action. Here, we investigate the regional and neuronal subtype-specific responses to GLP-1RA and mTORi treatment in the aging mouse brain. By integrating single-nucleus RNA sequencing with spatial transcriptomics, we map treatment-associated molecular signatures across diverse neuronal populations, circuits, and regions vulnerable to neurodegeneration. This approach identifies shared and distinct pathways through which GLP-1R agonism and mTOR inhibition counteract brain aging and provides mechanistic insight into their neuroprotective effects. These findings may inform the development of targeted anti-aging and therapeutic strategies tailored to the selective regional and cellular vulnerabilities underlying different neurodegenerative disorders.