High levels of tyrosine, an amino acid tied to protein metabolism, could influence lifespan with sex-specific effects, potentially challenging prevailing ideas about diet and longevity.
That is what a broad genetic analysis based on UK Biobank data suggests, published in Aging.
New Longevity Parameters
Under the eye of English researchers is the role of phenylalanine, an essential amino acid fundamental to protein synthesis and the production of neurotransmitters such as dopamine and norepinephrine, and of tyrosine in a longevity context, i.e., links to greater lifespan. Moreover, lifestyles, especially dietary patterns, have drawn attention: protein restriction in the diet, particularly of amino acids that engage this mechanism, has been linked to longer life.
Experimental studies would have demonstrated tyrosine’s capacity to modulate physiological responses to a low-protein diet, as well as a reduced intake of tyrosine being able to tune amino acid sensing pathways, lower endogenous tyrosine, and extend lifespan in animal models.
By contrast, elevated phenylalanine levels, a precursor to tyrosine, would seem to be associated with telomere shortening, the development of type 2 diabetes, and inflammatory diseases. The evidence would also suggest that phenylalanine is oxidized to meta-tyrosine, a toxic metabolite believed to shorten lifespan in Caenorhabditis elegans. Studies of these amino acids in humans remain limited; guided by this aim, the English researchers launched an exploratory program in this area.
The Study
The investigations into the role of phenylalanine and tyrosine in relation to lifespan extension and/or reduction were conducted using Cox regression, a method well-suited to assess associations between baseline plasma levels of tyrosine and phenylalanine and all-cause mortality in the United Kingdom Biobank (UKB) cohort.
The analysis was stratified by sex, age, smoking status, alcohol use, ethnicity, body mass index, physical activity, education, and the Townsend Deprivation Index—a composite measure of socio-economic disadvantage at the geographic level.
Additionally, the relationship between tyrosine and phenylalanine levels and mortality from cancer and cardiovascular diseases (CVD) was examined. Subsequently, based on these assessments, combined and sex-specific genome-wide association studies (GWAS) of tyrosine and phenylalanine in the UKB were conducted. Heritability was estimated from single-nucleotide polymorphisms (SNPs), and GWAS-derived instruments for circulating tyrosine and phenylalanine were derived, focusing on SNPs achieving genome-wide significance.
The significant SNPs were then applied genome-wide to tyrosine and phenylalanine in the UKB in a two-sample Mendelian randomization (MR) framework and in a GWAS of parental age at death (an indicator of lifespan) in a European-ancestry population to estimate effects on lifespan. Finally, multivariable MR analyses were performed to assess the independent effects of tyrosine and phenylalanine.
The Impact of Phenylalanine and Tyrosine on Longevity
Approximately 272,475 individuals from the UKB cohort had available amino acid data, with information on confounders and vital status. Across the full sample there were 23,964 deaths, including 9,734 in women and 14,230 in men. In particular, plasma phenylalanine was associated with higher all-cause mortality in both sexes, while plasma tyrosine was associated with higher all-cause mortality overall and specifically in men.
Moreover, a higher tyrosine/phenylalanine ratio was linked to a lower risk of all-cause mortality overall and in women. In disease-specific mortality analyses, phenylalanine showed associations with cancer- and cardiovascular-disease–related mortality, whereas tyrosine did not show such specific links.
Analyses using restricted cubic splines (statistical tools used to model nonlinear relationships between variables) suggested potential nonlinearity in the associations, with breakpoints near the population’s average concentrations, indicating stronger associations at higher circulating levels.
Genetic Architecture of Phenylalanine and Tyrosine
In the GWAS, heritability estimates were 0.09 for tyrosine and 0.04 for phenylalanine. In total, 2,422 and 11,379 SNPs reached genome-wide significance for phenylalanine and tyrosine, respectively. Sex-specific analyses identified 1,099 and 946 SNPs in men and women for phenylalanine, and 5,297 and 4,840 variants in men and women for tyrosine, respectively.
After excluding correlated variants, 74 and 21 SNPs were used as instruments for tyrosine and phenylalanine in the joint analyses, compared with 12 and 10 SNPs in sex-specific analyses for phenylalanine and 45 and 29 SNPs for tyrosine.
The SNPs associated with these amino acids mapped to genes important for amino acid regulation, metabolism, and transport, for example, phenylalanine hydroxylase (PAH), SLC17A1, SLC43A1, SLC38A4, CPS1, GSTM1, and GSTA2 for phenylalanine; and PAH, GSTM1, 4-hydroxyphenylpyruvate dioxygenase (HPD), and CPS1 for tyrosine.
The Evidence
From the Mendelian randomization analyses, genetically predicted higher phenylalanine levels were associated with longer lifespan only in men, whereas increases in genetically predicted tyrosine levels were linked to shorter lifespan in the overall population with directionally inverse associations in both sexes, though the strength varied by analytic method in univariable MR analyses.
In multivariate MR analyses, phenylalanine did not remain associated with lifespan in either sex after adjusting for tyrosine.
Conversely, tyrosine was associated with shorter lifespan, particularly in men, after adjusting for phenylalanine, with weaker and less consistent signals in women depending on the method used.
In summary, higher genetically predicted tyrosine levels appear to correlate with shorter lifespan, especially in men and independent of phenylalanine; phenylalanine was not independently associated with lifespan.
These findings underscore the potential role of tyrosine in human longevity and warrant further investigation.
Source
Zhao JV, Sun Y, Zhang J et al. The role of phenylalanine and tyrosine in longevity: a cohort and Mendelian randomization study. Aging, 2026, 17(10), 2500-2533. Doi OI: 10.18632/aging.206326
Abbonati a Karla Miller
