Longevity Briefs: Could Limiting Dietary Methionine Improve Health In Old Age?

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:

Changes in the metabolism are thought to be a core component of ageing and a key driver of age-related diseases. In essence, the way our bodies absorb, process and allocate nutrients and energy is disrupted with increasing age. Among the nutrients mishandled during ageing are the amino acids methionine and tyrosine. Methionine is an essential amino acid – a protein building block that can only be obtained from the diet. Previous research has shown that limiting methionine in the diet extends lifespan in various organisms, from yeast to rodents. Tyrosine, on the other hand, has been studied for its potential to improve cognitive health. However, the relationship between tyrosine and ageing is complex and not well understood.

When it comes to the treatment of ageing, it is important to know whether an intervention started in later life has a significant effect on the ageing process, or whether that intervention needs to be started in youth, before significant age-related deterioration has occurred. Interventions that work in late life are more desirable for obvious reasons. However, it wasn’t clear if methionine restriction constituted such a treatment. In this study, researchers investigate whether methionine restriction in late life is sufficient to improve health and slow biological ageing in mice, and also investigate the effects of inhibiting the degradation of tyrosine.

The discovery:

Researchers divided 18-month-old mice (roughly equivalent to middle-aged humans) into three groups containing 8-10 mice each, plus one additional group of 4-month-old young mice. The young mice and an older control group were fed a normal diet, while the methionine restriction group was fed a diet containing significantly lower levels of methionine. The third group was fed a normal diet but given nitisinone, a drug that inhibits the tyrosine degradation pathway. The study lasted 6 months.

The researchers found that despite starting later in life, methionine restriction improved several health markers in mice, including body weight (mostly through reduced fat mass), muscle function and lung function. These effects were more pronounced among male mice when compared to female mice, possibly because methionine levels increased significantly during normal ageing in male but not female mice. Overall frailty (scored based on 26 characteristics like gait and vision) was also reduced in the methionine restriction group compared to old mice fed a normal diet. However, when using epigenetic clocks (algorithms that estimate the biological rate of ageing based on changes to the DNA molecule), there was no significant difference between normally fed mice and methionine restricted mice. A separate experiment using a mouse model of Alzheimer’s disease also found improved muscle and kidney health with methionine restriction, but no changes to the burden of amyloid plaque, the key hallmark of Alzheimer’s disease.

Researchers also investigated the effects of a low sulphur amino acid diet (which primarily restricts the intake of methionine and cysteine) in a small subset of human participants from a separate clinical trial. As in the mice, there was no significant effect on biological age as estimated by epigenetic clocks.

The implications:

This research suggests that late-life methionine restriction can improve several aspects of health in mice but doesn’t have any significant effect on biological ageing, nor was biological ageing affected in humans. Yet while measurements of biological age are useful for assessing whether an intervention might be slowing ageing in the short term, what we really care about is whether health in older age can be improved. In that sense, methionine restriction was a success in mice, and is worthy of further exploration in humans. Inhibiting tyrosine degradation, on the other hand, showed no significant benefit. This finding contradicts previous animal studies and will need further investigation.

Methionine is a fundamental building block of proteins, and the mechanisms through which methionine restriction could impact health are complex and numerous. Methionine levels impact oxidative stress (damage to cells caused by metabolic byproducts), growth signalling pathways and the regulation of fatty acids. Some humans studies already suggest that methionine restriction might help to ameliorate conditions like obesity and cancer. However, methionine cannot be synthesised in the body and so failing to obtain sufficient methionine from the diet can have significant health consequences. Cutting out methionine-rich foods could also inadvertently lead to other nutrient deficiencies. For these reasons, it isn’t advisable to embark on a methionine-restricted diet without some form of medical supervision.