Could one amino acid help explain why men tend to live shorter lives?

Researchers combined blood amino acid measurements with genetic evidence to investigate whether two closely linked nutrients could help explain differences in longevity between men and women.

Study: The role of phenylalanine and tyrosine in longevity: a cohort and Mendelian randomization study. Image Credit: SergeiShimanovich / Shutterstock

Higher circulating levels of tyrosine may be associated with shorter lifespan, with evidence suggesting a clearer relationship in men than in women, according to a new cohort and Mendelian randomization study published in the journal Aging.

Background

Dietary interventions, including calorie restriction and protein restriction, have shown promise in increasing longevity across various animal species. Since proteins are composed of amino acids, researchers hypothesize that protein restriction-mediated changes in circulating amino acid levels may influence lifespan.

Tyrosine, an amino acid synthesized from its precursor phenylalanine, is a precursor to several neurotransmitters, including dopamine, epinephrine, and norepinephrine. These vital brain chemicals help regulate mood, cognition, and stress response, which are closely associated with metabolic health status and may influence longevity.

In animals, tyrosine has been shown to be involved in regulating physiological responses to a low-protein diet and influencing lifespan. Furthermore, elevated circulating phenylalanine has been associated with telomere loss, inflammatory disease, and type 2 diabetes. Mechanistic studies have shown that oxidation of phenylalanine can lead to the formation of meta-tyrosine, a toxic metabolite associated with reduced lifespan in C. elegans.

Sex is strongly associated with lifespan, with men consistently having shorter life expectancy than women. Interestingly, tyrosine levels are also influenced by sex, with young women having lower levels than young men. However, it largely remains unknown whether tyrosine levels can explain this sex difference in lifespan in humans.

To gain insight into this potential relationship, researchers at the University of Hong Kong, China, and the University of Georgia, USA, examined the overall and sex-specific associations between circulating phenylalanine and tyrosine and all-cause mortality among UK Biobank participants. They conducted Mendelian randomization analysis to strengthen causal inference, using parental attained age as a genetic proxy for lifespan.

Key findings

The study analysis included 272,475 UK Biobank participants with available information on mortality, circulating amino acid levels, and confounding factors, including age, sex, socioeconomic deprivation, smoking, alcohol consumption, physical activity, ethnicity, education, and body mass index.

The analysis controlling for potential confounding factors revealed that circulating phenylalanine is associated with increased all-cause mortality risk in both men and women. Similarly, circulating tyrosine was positively associated with all-cause mortality risk in men but not in women, though the difference between the sexes was not statistically significant.

The analysis of disease-specific mortality indicated that phenylalanine, but not tyrosine, was positively associated overall with cardiovascular disease- and cancer-related mortality.

The univariable Mendelian randomization analysis revealed that genetically predicted higher circulating phenylalanine levels were associated with longer lifespan in men but not in women. In contrast, genetically predicted higher tyrosine levels were associated with shorter lifespan in both men and women in the primary Mendelian randomization analysis, although some additional analyses produced less certain results.

The analysis controlling for tyrosine showed no clear association between phenylalanine and lifespan. However, when controlling for phenylalanine, tyrosine was associated with shorter lifespan in men, whereas findings in women were less consistent across Mendelian randomization methods.

Study significance

The study suggests that higher circulating tyrosine levels may be independently associated with a shorter lifespan, with the clearest evidence in men. However, further research is needed to establish the biological mechanisms underlying this relationship.

Although it is not fully known how tyrosine influences lifespan, one potential mechanism may be tyrosine-mediated insulin resistance, which is associated with an increased risk of several chronic diseases and a reduced lifespan. Insulin resistance is also known to have sex-specific effects.

Experimental evidence suggests that calorie restriction can reduce insulin resistance and produce sex-specific effects on longevity and metabolic health. Insulin resistance may also interact with testosterone, a sex hormone that has been associated with survival, with a clearer effect in men.

Furthermore, tyrosine serves as a precursor to important neurotransmitters regulated by sex hormones such as testosterone, which the authors suggest could help explain the observed sex-specific associations.

Taken together, the study highlights the involvement of tyrosine in longevity. Circulating tyrosine levels are modifiable, including through dietary changes such as protein restriction. However, the study did not test these interventions in humans, and circulating amino acid levels may not directly reflect dietary intake. Such approaches, therefore, require further study before they can be considered strategies for extending lifespan.

The authors also discuss, rather than directly evaluate, the long-term use of tyrosine supplements that are commonly recommended for mood enhancement and mental alertness. Because supplementation was not tested, the findings cannot establish that tyrosine supplements shorten lifespan. Instead, the authors note that their results do not support a long-term longevity benefit from tyrosine supplementation.

The study selected genetic variants of tyrosine and phenylalanine from the UK Biobank and applied them to large genome-wide association studies of lifespan involving the same UK Biobank population. Such sample overlap may introduce bias into the Mendelian randomization estimates. However, a sensitivity analysis using genetic variants linked to amino acid levels from a separate genome-wide association study that did not include UK Biobank participants showed associations in broadly consistent directions.

Given the non-linear nature of the observed associations between phenylalanine and tyrosine and mortality, the researchers suggest that the positive associations are more applicable to people with higher levels of phenylalanine or tyrosine. Future studies should validate these findings in populations with varying amino acid levels.