Methionine Restriction as the Cause of Calorie Restriction Benefits

Diet is the key to a great many evolution-driven adaptations in the machinery of our bodies; changes in dietary intake cause the controlling mechanisms of metabolism to sit up and take notice. In particular, lowering the intake of calories by 30-40% or so, and while maintaining an optimal level of micronutrients, causes metabolic processes to operate in a mode that extends life and provides numerous other health benefits. Practiced as a lifestyle, this is known as a calorie restriction diet, and the laboratory version for animals is often called dietary restriction. Calorie (or dietary) restriction provides similar health and longevity benefits in almost every species tested to date.

Diet, of course, is more than a simple count of calories. Composition of food varies enormously, here thinking in terms of the proportions of different proteins, carbohydrates, fats, and so forth. This matters. Take methionine for example: this is one of the essential amino acids that we humans, and other mammals, cannot create and so must obtain through our diet. Through experimentation, researchers are starting to see that restricting the content of methionine in the diet of mammals - while leaving the calorie count unchanged - has many of the same results as restricting overall calories. Is the biological switch for the better state of human metabolism, that brought on by calorie restriction, essentially no more than a methionine sensor?

This is an interesting question, and one still up for debate. The experimentation in rats continues, as illustrated by recently published research. Here the focus is largely on mitochondrial function and damage. To see why this is important you might want to head back into the archives to read about the link between mitochondria, the free radicals they produce, and aging. But on with the paper:

Eighty percent dietary methionine restriction (MetR) in rodents (without calorie restriction), like dietary restriction (DR), increases maximum longevity and strongly decreases mitochondrial reactive oxygen species (ROS) production and oxidative stress. Eighty percent MetR also lowers the degree of membrane fatty acid unsaturation in rat liver.

Mitochondrial ROS generation and the degree of fatty acid unsaturation are the only two known factors linking oxidative stress with longevity in vertebrates. However, it is unknown whether 40% MetR, the relevant methionine restriction degree to clarify the mechanisms of action of standard (40%) DR, can reproduce these effects in mitochondria from vital tissues of strong relevance for aging. Here we study the effect of 40% MetR on ROS production and oxidative stress in rat brain and kidney mitochondria.

Male Wistar rats were fed during 7 weeks semipurified diets differing only in their methionine content: control or 40% MetR diets. It was found that 40% MetR decreases mitochondrial ROS production [and] lowers oxidative damage to kidney mitochondrial DNA


Forty percent MetR, differing from 80% MetR, did not inhibit the increase in rat body weight. These changes are very similar to the ones previously found during dietary and protein restriction in rats. We conclude that methionine is the only dietary factor responsible for the decrease in mitochondrial ROS production and oxidative stress, and likely for part of the longevity extension effect, occurring in DR.

So there is one research group who think that the important parts of calorie restriction are based upon a methionine sensing mechanism. Given the research to date, I'll wager that there is a great deal of money to be made in establishing a competitively priced and reasonable range of very low methionine foods for humans - if humans can tolerate methionine levels low enough to inhibit weight gain in addition to other benefits, and if very low methionine in humans works as we would expect given all the data on human calorie restriction.

If I had to take an educated guess at what is going on under the hood, I'd say that reduction in visceral fat is at the root of some of the benefits of calorie restriction - though perhaps not to the same degree as mitochondrial changes and enhanced autophagy. Removing visceral fat via surgery in mice has been shown to extend life, for example, and we know that excess fat causes harm in the long term through chronic inflammation. We shall see how it all pans out, as the researchers continue their work. But there's more than enough evidence to date for you and I to give serious thought to practicing calorie restriction as a lifestyle.

ResearchBlogging.orgCaro P, Gomez J, Sanchez I, Naudi A, Ayala V, López-Torres M, Pamplona R, & Barja G (2009). Forty percent methionine restriction decreases mitochondrial oxygen radical production and leak at complex I during forward electron flow and lowers oxidative damage to proteins and mitochondrial DNA in rat kidney and brain mitochondria. Rejuvenation research, 12 (6), 421-34 PMID: 20041736