A cocktail of rapamycin, acarbose and phenylbutyrate prevents age-related cognitive decline in mice by altering aging pathways

Thesis (Master's)--University of Washington, 2022Aging is a primary risk factor for cognitive dysfunction and exacerbates multiple biological processes in the brain, including but not limited to nutrient sensing dysregulation, insulin sensing dysfunction and histone deacetylation. Therefore, pharmaceutical intervention of aging that targets several distinct but overlapping pathways provides a basis for testing combinations of drugs in a cocktail. A recent study showed that middle-aged mice treated with a drug cocktail of anti-aging drugs rapamycin, acarbose, and phenylbutyrate for three months had increased resilience to age related cognitive decline. This finding provided the rationale to investigate the comprehensive transcriptomic and molecular changes within the brain of mice that received this cocktail treatment or control substance. Transcriptome profiles were generated through RNA sequencing and pathway analysis was performed by gene set enrichment analysis to evaluate the overall TNA message effect of the drug cocktail. Molecular endpoints representing aging pathways were measured through immunohistochemistry to further validate the attenuation of brain aging in the hippocampus of mice that received the cocktail treatment, each individual drug or controls. Results indicated that biological processes that aggravate with increasing age were suppressed and autophagy, which decreases with aging, was enhanced in the brains of mice given the drug cocktail. The molecular endpoint assessments indicated that the treatment with the drug cocktail was overall more effective than any of the individual drugs for relieving cognitive impairment by targeting multiple aging pathways