Abstract
BACKGROUND: Protein restriction increases lifespan, however, the specific amino acids affecting lifespan are unclear. Tyrosine and its precursor, phenylalanine, may influence lifespan through their response to low-protein diet, with possible sex disparity. METHODS: We applied cohort study design and Mendelian randomization (MR) analysis. Specifically, we examined the overall and sex-specific relationships between circulating phenylalanine and tyrosine and all-cause mortality in the UK Biobank using Cox regression. To test causality, in two-sample MR analysis, we used genetic variants associated with phenylalanine and tyrosine in UK Biobank with genome-wide significance and uncorrelated (r(2) < 0.001) with each other, and applied them to large genome-wide association studies of lifespan, including parental, paternal, and maternal attained ages in the UK Biobank. We also conducted multivariable MR to examine the independent role of phenylalanine and tyrosine. RESULTS: Tyrosine was associated with shorter lifespan in both observational and MR study, with potential sex disparity. After controlling for phenylalanine using multivariable MR, tyrosine remained related to a shorter lifespan in men (-0.91 years of life, 95% confidence interval (CI) -1.60 to -0.21) but not in women (-0.36 years, 95% CI -0.96 to 0.23). Phenylalanine showed no association with lifespan in either men or women after controlling for tyrosine. CONCLUSIONS: Reducing tyrosine in people with elevated concentrations may contribute to prolonging lifespan, with potential sex-specific differences. It is worthwhile to explore pathways underlying the sex-specific effects.