Graduation Year
2026
Document Type
Master's Thesis
Degree
Master of Science
Program
Biological Science
Partner Organization
Buck Institute for Research on Aging
Program Director
Patti Culross, MD, MPH
First Reader
Pankaj Kapahi, PhD
Second Reader
Yifan Xiang, MD, PhD
Abstract
Menopause— characterized by the cessation of ovarian function and, subsequently, menstruation — is a significant risk factor for osteoporosis, type II diabetes, cardiovascular disease, and Alzheimer’s disease in women. Despite extensive characterization of menopausal phenotypes, the metabolic basis contributing to menopause has not been systematically investigated. To investigate this, we utilized the Mendelian randomization (MR) approach to identify metabolites causally associated with age at menopause by leveraging five large-scale metabolomics genome-wide association studies (GWAS) against two independent GWAS built on menopausal timing. Our research identified 66 significant metabolite-menopause causal associations, with uridine identified as the strongest regulator of delaying menopause (Beta = 3.83, p-value = 2.29×10-4). To investigate SNP-level interactions, we extracted MR-derived significant SNPs and related genes, performed Qiagen Ingenuity Pathway Analysis (IPA), revealing enrichment in phospholipid biosynthesis and cancer-related signaling networks linked to uridine-associated variants. To validate this finding, dietary uridine supplementation in Drosophila revealed improved fecundity trajectory and extended lifespan without affecting healthspan. Together, our study identifies novel metabolic drivers of menopause timing and provides convergent genetic and experimental evidence supporting uridine as a regulator of delayed reproductive aging.