Dietary methionine restriction affects cancer outcome in a mouse model

A recent study by Guo et al. (2019) published in Nature has demonstrated that dietary restriction of the amino acid methionine can reduce tumour growth and improve the outcome of chemotherapy and radiation treatments in mice. The authors also conducted a proof-of-principle study in humans, which showed that a reduction in dietary methionine had a similar metabolic effect as that seen in mice - this may suggest a conserved response between humans and mice to dietary restriction of this amino acid.

Methionine is an essential amino acid involved in protein synthesis, regulation of protein function and methylation reactions. It is metabolised as part of a group of reactions called one-carbon metabolism, which are also targeted by a number of cancer treatments involving chemotherapy and radiation. Dietary methionine restriction has previously been shown to extend the life span of various animal species and delay the onset of ageing-associated diseases and cancers. In the brain, methionine restriction also delays the onset of neurodegenerative diseases. In rodents, methionine restriction consistently reduces body weight and adiposity levels and prevents high-fat diet-induced obesity, despite increasing food consumption.

These graphs illustrate the increased survival time and decreased body weight (despite greater food intake) of mice fed a methionine-restricted diet. Credit: Perrone et al. (2019), "Metabolic adaptations to methionine restriction that benefit health and lifespan in rodents".

A recent study by Cooke et al. (2018) revealed that methionine restriction attenuates kidney injury and slows the progression of kidney disease in nephrectomised mice, by down-regulating renal inflammation and fibrosis. Wang et al. (2019) also demonstrated that methionine restriction slows kidney senescence through hydrogen sulfide production and AMPK pathway activation. The is likely to be one of the reasons why low proteins and very low protein diets are consistently associated with slower progression to end-stage renal disease in many different species.

In this study, Jason Locasale and colleagues investigated whether dietary restriction of methionine could have anti-cancer properties, through interaction with other therapies that target one-carbon metabolism. In a series of cancer models in mice, the authors observed that restricting levels of methionine in the diets of the mice resulted in inhibition of tumour growth. When used in combination with the chemotherapy drug 5-fluorouracil, or radiation therapy, tumour growth was further reduced.

Additionally, in a preliminary study, six healthy middle-aged individuals received a low methionine diet (equivalent to an 83% reduction in daily methionine intake) for three weeks. The authors noted that metabolite levels in the study participants correlated with those seen in mice on the same dietary restriction. They therefore proposed that the findings provide evidence that a specific dietary manipulation may potentially influence cancer outcomes.

The study authors hypothesised that the degree of methionine restriction employed in their study would be possible to achieve with many vegan, vegetarian or Mediterranean diets. Beef, poultry, lamb and other meats are some of the richest sources of methionine; this study therefore adds to the evidence supporting the benefits of a predominantly plant-based diet for humans. It would be interesting to know how this research may apply to carnivorous species such as the cat, that have evolved to consume a diet much richer in methionine, when compared with humans or rodents.

Learn more about methionine restriction here:

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