Fight Aging!

A reduced intake of calories triggers protective responses to low nutrient availability, dramatically altering the operation of cellular metabolism. For so long as adequate levels micronutrients are still ingested, this response to calorie restriction is beneficial. The cell maintenance processes of autophagy operate more efficiently, for example, and this improved autophagy is thought to be the primary mechanism by which calorie restriction improves health and slows aging. This response to calorie restriction is triggered by a variety of independent sensors that assess the availability of various components of the diet, where essential amino acids are one of the more important components in this respect. Researchers have assessed the metabolic response to diets low in the essential amino acid methionine, and found it to produce broadly similar effects to overall calorie restriction in laboratory animals.

The authors of today's open access paper argue that methionine restriction is likely misnamed, as: (a) low methionine diets are also low in the non-essential amino acid cysteine; (b) in a low cysteine environment, methionine is consumed to produce cysteine, meaning one can't really distinguish between the effects of low methionine and low cysteine easily; (c) given a suitably engineered animal, with the methionine to cysteine pathway disabled, one can show that in fact the important metabolic response occurs as a result of low cysteine levels and not as a result of low methionine levels.

Cysteine reduction rather than methionine restriction promotes immunometabolic fitness to confer survival benefit in aging

Cysteine is a dietary non-essential yet biochemically irreplaceable amino acid. Methionine, the other sole proteinogenic sulfur amino acid (SAA), lacks a thiol group and hence cannot form complexes with metals, including disulfide bond formation, nucleophilic catalysis, and redox signaling. Typically, cysteine and methionine contents are high in animal-based diets, while plant-based vegetarian foods are lower in SAA. It is now recognized that cysteine is essential for organismal metabolism through pleiotropic effects, including regulation of coenzyme A (CoA) and glutathione (GSH)-mediated redox balance. Creation of forced cysteine depletion by deletion of cystathionine γ-lyase (CTH) and feeding a cysteine-free diet causes rapid, progressive 30% weight loss. In addition, cysteine depletion induces activation of central nervous system nuclei that control sympathetic nervous system (SNS)-derived norepinephrine, which causes rapid adipose tissue browning and thermogenesis through β3-adrenergic receptors.

However, an important underappreciated issue is that methionine restriction (MR) is erroneously called MR because this diet also lacks cystine. Interestingly, it has been well established that an 80% reduction of methionine content (in a diet with 0% cystine) in adult rats resulted in robust 40% increases in median and maximum lifespan. Additional independent studies confirmed that MR, which in fact lacks both methionine and cysteine, robustly enhances lifespan in mice despite an increase in food intake, without restriction of calories. Moreover, using methionine-and cysteine-titrated diets in wild-type mice, the anti-adiposity effects of SAA restriction have been linked to cysteine restriction.

When dietary cystine is eliminated, host redirects substrates from methionine cycle and generates cysteine via CTH in transsulfuration pathway, leaving it unclear which SAA controls aging. Here, we show that selective cysteine restriction in Caenorhabditis elegans enhanced lifespan and stress survival independently of methionine. Notably, cysteine-free diets (methionine-replete or restricted) in Cth-deficient mice induced pro-metabolic effects, whereas MR with normal cysteine was ineffective. Sustained 70% cysteine reduction in aged CTH knockout mice reprogrammed the immunometabolic axis, conferring healthspan benefits. Thus, lowering cysteine while keeping the methionine pool intact enhances healthy lifespan.