Longevity Briefs: Higher Tyrosine Levels May Reduce Lifespan

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

For years, scientists have observed that restricting protein intake can extend lifespan in various organisms. As a result, scientists have become interested in the effects of restricting or increasing the intake of different amino acids – the molecular building blocks of protein chains. One amino acid of particular interest is tyrosine. Tyrosine is used to synthesise important neurotransmitters like dopamine, with a few studies suggesting that supplemental tyrosine improves cognitive function. It is also used in protein synthesis and may help preserve muscle function in old age. However, animal studies also suggest that reducing tyrosine levels can extend lifespan.

Tyrosine can by synthesised within the body, meaning it is not technically an essential amino acid (an amino acid that can only be obtained from the diet). However, phenylalanine is required to synthesise tyrosine, and phenylalanine is an essential amino acid, so tyrosine levels are still effectively limited by dietary intake. In this study, researchers look at a large biomedical database to see if there was any relationship to be found between levels of these two amino acids and mortality.

The discovery:

The study looked at data from the UK Biobank, a vast database containing health information from hundreds of thousands of participants in the UK, and found that higher circulating tyrosine levels were correlated with higher all-cause mortality in men, with the relationship in women being less clear.

First, they examined the relationship between circulating levels of phenylalanine and tyrosine and all-cause mortality (death from any cause). This initial analysis revealed that higher tyrosine levels were associated with a shorter average lifespan. However, this does not prove that higher tyrosine levels cause higher mortality rates because both observations could have been caused by something else – for example, people might have elevated tyrosine because they eat a lot of red meat, which is known to increase mortality.

In an attempt to control for this, researchers used a technique called Mendelian randomisation (MR). Instead of comparing participants with high vs low phenylalanine or tyrosine levels, researchers compared participants who had different gene variants known to affect these amino acids. Because the distribution of these gene variants within the population is random and not influenced by the environment, an association between a gene variant linked to increased tyrosine levels and mortality is more likely to be causative. You can think of this as a kind of like a ‘natural experiment’ – instead of randomly assigning amino acid supplements to participants and seeing if they live longer, nature has randomly assigned gene variants that influence amino acid levels.

The analysis included over 400 000 participants and revealed that genetic predisposition for higher tyrosine levels was associated with a statistically significant reduction in lifespan in men of nearly one year (0.91 years of life lost on average). In women the reduction was 0.36 years, which was not statistically significant. Genetic variants related to higher phenylalanine levels showed no significant association with mortality after controlling for tyrosine genetic variants.

The implications:

While previous studies suggest that tyrosine supplementation may be beneficial to cognition, this study suggests that elevated tyrosine levels are associated with increased mortality, at least in men. This is consistent with animal studies that have found that tyrosine restriction extends lifespan. These findings aren’t necessarily mutually exclusive – they may simply mean that tyrosine levels above a certain value are harmful, but that short-term supplementation can still be beneficial below those levels, while chronic supplementation could be harmful. Research in animals has shown that restricting tyrosine intake causes metabolic changes aimed at conserving tyrosine and redirects that tyrosine towards certain processes such as the production of neurotransmitters. It is therefore possible that tyrosine supplementation and tyrosine restriction are actually producing some of the same benefits, just in different ways.

It should be noted that while Mendelian randomisation studies may imply that gene variants that increase tyrosine levels also increase mortality, they cannot prove that tyrosine levels themselves were responsible. MR studies assume that the gene variants in question don’t influence the activity of other genes or pathways that could influence mortality, don’t influence behaviour, and are completely randomly distributed throughout the population.