Research Paper Advance Articles
The role of phenylalanine and tyrosine in longevity: a cohort and Mendelian randomization study
- 1 School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- 2 State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, China
- 3 Department of Genetics, University of Georgia, Athens, Georgia, GA 30602, USA
- 4 Institute of Bioinformatics, University of Georgia, Athens, Georgia, GA 30602, USA
Received: September 12, 2024 Accepted: July 18, 2025 Published: October 3, 2025
https://doi.org/10.18632/aging.206326How to Cite
Copyright: © 2025 Zhao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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 (r2 < 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.