Dietary Methionine Restriction and Beyond

Nine essential amino acids, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine, are elementally required from food intake. Dietary protein has never been doubted in its nutritional value since the macromolecules chained by the amino acid blocks have been designed to fulfill cell structure and function. Until 1993 an article published by Orentreich et al. with the data that a fivefold precipitating reduction of dietary L-methionine from 0.86% to 0.17% (weight of methionine/ weight of all amino acids),  resulted in a 30% longer lifespan of male rats. This finding was replicated by other researchers after the debut study that methionine restriction (MR) increases mean lifespan in other species like yeast, C-elegans, drosophila and mice and many others.

It was about the third chronicle account of dietary restriction which was the nearly missed blindspot in our understanding. The first time in the 1950s,  when fat deposition in blood vessels was found as a major feature of the cardiac coronary disease and cholesterol was the main factor in heart disease developing,  a mediterranean-style diet in lower animal fat was widely spreaded. Second, carbohydrates were restricted in weight-loss and diabetes by use of ketogenic diet in 1980 till today. The single amino acid methionine was identified as a detrimental molecule if in excessive intake, a new program of methionine restriction (MR) was proposed since then.

To the knowledge of the amino acid, methionine is an essential one which only can be obtained from the food then to be introduced into protein chains. tRNA-Met, or methionyl-tRNA, carrying methionine into translation machinery by recognizing the start codon AUG on mRNA. It forms a ternary complex with eukaryotic initiation factor 2 (eIF2) and GTP, to start protein synthesis. The availability and functionality of tRNA-Met can  affect global protein synthesis rates. Also, Methionine, as a source for one-carbon metabolism, is important for maintaining genomic stability and epigenetic control of DNA and histones. Methionine is mediated to S-adenosylmethionine (SAM), which is the universal methyl donor for RNA, DNA, and chromatin methylation. SAM is then converted to S-adenosylhomocysteine (SAH) through various transmethylation reactions. SAH is hydrolyzed to homocysteine by SAH hydrolase, then be re-methylated to methionine by methionine synthase to complete the methionine cycle. Alternatively, homocysteine can be diverted into the transsulfuration pathway for use in glutathione production and maintenance of redox homeostasis. SAM is also utilized for polyamine synthesis, which produces S-methyl-5’-thioadenosine (MTA) as a byproduct that can then be recycled back to methionine in the methionine salvage pathway.

Numerous reports in recent decades have shown that dietary methionine restriction results in an enhancement of stress resistance, improving metabolic function and cellular reproduction, leading to a prolonged lifespan. Lower dietary methionine levels has potentially been linked to improved insulin sensitivity and lower cholesterol levels, thereby contributing to benefit overall aging related diseases. Certain cancer cells are believed to rely on methionine for growth, the consequent limiting its utilization may starve these cells in methionine-dependent manner.

The underlying mechanisms of the beneficial effects of methionine restriction on aging are very complex and not yet fully understood. One possibility could be through influencing insulin/IGF-1 and mTORC1 (mammalian target of rapamycin complex 1) signaling, which regulated longevity in animal models. Methionine activating mTORC1 is suppressing autophagy which plays an important role in the removal of damaged organelles. The reduction of methionine protects cells from oxidative stress and promotes autophagy. An elevated concentration of circulating fibroblast growth factor 21 (FGF21) by reducing methionine has been implicated as a potential mechanism. FGF21 and its receptors (FGFRs) are widely distributed in liver, adipose tissue, and pancreas. As a novel target involved in metabolic regulation FGF21 has significant effects on enhancing insulin sensitivity induced by dietary methionine reduction. By increasing the expression of hepatic FGF21 and activating GCN2/ATF4/PPARα signaling in liver cells, methionine reduction accelerates energy expenditure and promotes fat oxidation and glucose metabolism.

Unfortunately, animal protein and dairy food we take daily are in methionine overloading. For the aim of methionine restriction, certain grains, seeds and nuts can serve as alternative protein sources that offer a reduced methionine content. Some plant foods like legumes, are also the source of protein that can provide a lower methionine profile. But most plant proteins are lower with lysine, an additional supplement of the essential amino acid required.

Yeast extract substituting the traditional food protein has rapidly been used.  As an industrial-agricultural renovation, the yeast whole protein is composed of rich group B vitamins, minerals and high protein yield with all essential amino acids but lower levels of methionine, especially. Furthermore, we have applied new techniques to reduce nucleic acid ( focusing the foibles of the extract ) to satisfy the food nutrient standards readily for amino acid substitutions. It is the ideal source of alternative protein in methionine reduction and restriction. Methionine in pure yeast protein products contains a concentration about 1.4% (weight/weight ratio),  well below 5% of average percentage of amino acid composition in protein construction and codon usage. To obtain a much more reduced methionine in yeast extract to the level of 0.8-1.0%, as a food protein source feasible, additional strategies have been planned recently.  Even though methionine restriction therapy is still in the research stage and clinical trial phase,  it could be a new promising method applied in the disease treatment.

There was a notion that "a calorie is a calorie" which suggested that calories intake decided calories output and weight wavering. However, it seems to contradict the recent study. The specific composition of our diet, particularly the amino acid intake, may be more important than total diet calorie count. The limiting amino acids, including methionine, have the privilege to the destiny of the metabolic pathway and the checkpoint of cell function, for shortage of methionine supply will increase the catabolism of other amino acids. Recent research has shed light on some nuanced aspects of this apparent paradox: food quality rather than quantity matters so that the relationship between calorie intake and body weight is not always straightforward. The body appears to have finely tuned control mechanisms that monitor and respond to energy intake and expenditure. The overall diet quality, not just quantity, appears to be crucial for health and longevity. The key seems to lie more in the dietary composition and individual metabolic responses, rather than in simply eating more or less. Mechanism and the application of methionine restriction are perfect examples providing for the investigation.

As the excess of methionine could induce chronically inflammation, tumorigenesis and cell aging, the deficiency of methionine will cause several harmful effects such as growth pause in youths and osteoporosis in elderly and vegetarians. A gradient methionine restriction would be necessary to get an optimal dose/concentration, to fit the individual requirements and their metabolism rate. In sum,  methionine restriction offering potential therapeutic avenues for various diseases and aging-related conditions are agreed,  yeast protein extract would hopefully be the stepstone to trace unknown fields.

Written by Dr. Haining Jin， and  Dr. Bin Xu