Restriction of sulfur-containing amino acids has long been known to extend lifespan in rodents. However, classic methionine-restriction diets simultaneously deprive animals of cysteine, so the contribution of each amino acid remained unclear. Research on DNA methylation and cellular aging sits alongside this work, but this paper stands out because it is the first to rigorously separate methionine and cysteine using a genetic model.
The authors used mice with a knockout of the Cth gene, which cannot synthesize cysteine from methionine. This allowed them to independently restrict methionine and cysteine in the diet. The animals were fed different regimens: control, methionine-restricted, methionine- and cysteine-restricted, and cysteine-free. For the long-term experiment, they applied 70% cysteine restriction for 10 months. They additionally used Caenorhabditis elegans nematodes with a cth-1 mutation and bacteria that do not synthesize methionine or cysteine. They analyzed weight, body composition, glucose tolerance, gene expression, single-nucleus RNA sequencing of fat tissue and liver, as well as levels of the hormones FGF21, GDF15, leptin, and markers of oxidative stress.
Methionine restriction alone did not cause weight loss or fat tissue browning. In contrast, cysteine deficiency led to rapid weight loss, browning of subcutaneous fat, and increased FGF21. In old mice, 5 days of cysteine deprivation reduced weight by 20% and improved the state of fat tissue and liver. Long-term 70% cysteine restriction in Cth-knockout mice prevented age-related weight gain, improved glucose tolerance, reduced liver steatosis and fibrosis, and shifted immune cell populations toward a less inflammatory profile. In nematodes, cysteine restriction extended lifespan and increased resistance to heat stress, whereas methionine restriction produced no such effect.
The work is the first to prove that cysteine, not methionine, is the key mediator of the beneficial effects of sulfur-containing amino acid restriction. This changes our understanding of the mechanisms behind dietary anti-aging interventions and points to cysteine as an independent target. Unlike neighboring studies focused on methylation, this one shows a direct link between the amino acid composition of food and the thermogenic activity of fat tissue.
It is necessary to determine which molecular pathways, besides UCP1, mediate fat tissue browning under cysteine deficiency. It is also important to test whether cysteine restriction works in mammals with intact cysteine synthesis, for example, through pharmacological inhibition of CTH. Studying the effects of long-term reduction of the intracellular cysteine pool on lysosome-mitochondria communication, as well as on the function of iron-sulfur clusters, is a promising direction.
The results could influence the development of dietary recommendations and pharmacological agents for slowing aging and treating metabolic diseases such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease. In addition, they open the way to new strategies for combating age-related inflammation.
The immediate steps include testing CTH inhibitors in mice with normal cysteine synthesis and studying the causal relationship between increased LAMP2A and IGFBP2 and lifespan extension. Long-term studies in mammals are also needed to confirm the effect of cysteine restriction on lifespan.
The work is directly connected to an unresolved problem in the biology of aging: which specific dietary components trigger longevity mechanisms. Separating the effects of methionine and cysteine clarifies the role of the amino acid composition of food in regulating metabolism and inflammation during aging. It also touches on the question of how dietary interventions can be translated into clinical practice without side effects.
In C. elegans nematodes, cysteine restriction extended lifespan more than methionine restriction, and restoring cysteine in the diet completely abolished this effect.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.