Intermittent Methionione Restriction may be an Improvement on Continuous Methionine Restriction

Regulatory systems that detect low levels of the essential amino acid methionine are one of the more important triggers for the metabolic response to fasting and calorie restriction. Methionine is not manufactured in mammalian cells, can only be obtained from the diet, but is nonetheless essential for protein synthesis. Thus reducing only methionine levels in the diet can capture a sizable fraction of the benefits of calorie restriction.

While it is possible for a self-experimenter armed with time, a suitable database of methionine content by food type, and considerable willpower to practice significant levels of methionine restriction, it arguably requires a great deal more effort than simply restricting calories. Medical diets structured to have low methionine levels exist, but are expensive. Methionine restriction is thus not widely practiced as a dietary choice by anyone other than those forced into it by rare medical conditions.

In today's open access paper, researchers demonstrate that intermittent methionine restriction produces similar metabolic changes to continuous methionine restriction, while maintaining greater bone mineral density. This is interesting when considered in analogy to the past decade of work comparing the effects of intermittent fasting with calorie restriction. Some researchers theorize that the periods of refeeding between periods of restriction are beneficial, and that the optimal approach to nutrition is thus some arrangement of periodic fasting.

Intermittent Methionine Restriction Reduces Marrow Fat Accumulation and Preserves More Bone Mass than Continuous Methionine Restriction

Continuous methionine restriction (MR) is one of only a few dietary interventions known to dramatically extend mammalian healthspan. For example, continuously methionine-restricted rodents show less age-related pathology and are up to 45% longer-lived than controls. Intriguingly, MR is feasible for humans, and a number of studies have suggested that methionine-restricted individuals may receive similar healthspan benefits as rodents. However, long-term adherence to a continuously methionine-restricted diet is likely to be challenging (or even undesirable) for many individuals. To address this, we previously developed an intermittent version of MR (IMR) and demonstrated that it confers nearly identical metabolic health benefits to mice as the continuous intervention, despite having a relatively short interventional period (i.e., only three days per week). We also observed that female mice undergoing IMR show a more pronounced amelioration of diet-induced dysglycemia than continuously methionine-restricted counterparts, while male mice undergoing IMR retain more lean body mass as compared with continuously methionine-restricted controls. Prompted by such findings, we sought to determine other ways in which IMR might compare favorably with continuous MR.

While it is known that continuous MR has deleterious effects on bone in mice, including loss of both trabecular and cortical bone, we considered that mice undergoing IMR might retain more bone mass. Here, we report that, as compared with continuous MR, IMR results in a preservation of both trabecular and cortical bone, as well as a dramatic reduction in the accumulation of marrow fat. Consistent with such findings, mechanical testing revealed that the bones of intermittently methionine-restricted mice are significantly stronger than those of mice subjected to the continuous intervention. Finally, static histomorphometric analyses suggest that IMR likely results in more bone mass than that produced by continuous MR, primarily by increasing the number of osteoblasts. Together, our results demonstrate that the more practicable intermittent form of MR not only confers similar metabolic health benefits to the continuous intervention but does so without markedly deleterious effects on either the amount or strength of bone. These data provide further support for the use of IMR in humans.

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