An intermittent variation of the dietary intervention methionine restriction protects against obesity and provides additional metabolic health benefits to mice, according to a study from the Johnson Laboratory, recently published in Aging Cell.

The results of this work are important in that they suggest that a limited period of dietary intervention (i.e., only three days per week) may be sufficient to produce the anti-aging effects associated with continuous methionine restriction. Such an approach could allow people to eat as normal for the majority of the week, but still receive the health benefits described for continuous methionine restriction.

Methionine restriction has been shown to protect rodents against diet-induced obesity and can extend their healthy lifespan by up to 45%. Promisingly, recent studies have suggested that the effects of methionine restriction on health and lifespan are likely to be conserved in humans. Given that the vegan diet is low in total protein and amino acids, methionine restriction is possible for people. However, such a diet might not be practicable or desirable for everyone.

As a result, the Johnson Laboratory sought to develop a version of methionine restriction that produces the same benefits as the continuous intervention, while also being more convenient and easier to perform. They were inspired by published reports that intermittent forms of other health-promoting interventions (i.e., the ketogenic diet and calorie restriction) are similarly effective to their continuous counterparts.

The team first tested whether two increasingly stringent versions of intermittent methionine restriction offered the same protection against obesity as the continuous intervention. They fed male mice one of four high-fat diets: 1) a control diet containing typical amounts of methionine, 2) a continuously methionine-restricted diet, 3) a diet containing typical amounts of methionine for four days, followed by a methionine-restricted diet for three days, and 4) a diet containing typical amounts of methionine for four days, followed by a diet completely lacking methionine for three days. The authors found that the more stringent of the two forms of intermittent methionine restriction was just as effective as the continuous intervention in protecting against the dramatic weight gain and fat accumulation seen in mice fed the high-fat control diet. Similarly, the authors observed that intermittent methionine restriction also completely protected female mice against diet-induced obesity.

Next, they explored the effects of intermittent methionine restriction on physiological changes that normally result from continuous methionine restriction. For this purpose, they measured the levels of four metabolic markers (the hormones IGF-1, adiponectin, leptin, and FGF-21) in blood samples from previously treated mice. As expected, they found that intermittent methionine restriction resulted in changes similar to those of continuous methionine restriction. This finding is particularly interesting given that a body of evidence suggests that low IGF-1 levels are associated with an extension of healthy lifespan. So, it is likely that intermittent methionine restriction will produce an extension of lifespan similar to what has previously been observed for continuous methionine restriction.

An image showing the comparative effects of continuous methionine restriction and intermittent methionine restriction in rodents on outcomes for obesity, hepatosteatosis, and dysglycemia.

Continuous methionine restriction (MR) extends the healthy lifespan of a number of model organisms, including rodents. A novel intervention featuring only three days of stringent MR per week (aka, intermittent MR; IMR) protects mice against diet-induced obesity, fatty liver (aka, hepatosteatosis), and dysregulation of blood sugar (aka, dysglycemia). It also produces beneficial changes in the levels of multiple energy-sensing and longevity-regulating hormones. As a result, IMR is likely a preferable health-promoting strategy to continuous MR.

“This is a very exciting result and actually one of the more significant findings to come from the Orentreich Foundation in recent years” notes senior author Dr. Jay Johnson, an Associate Research Scientist at OFAS. “In addition to protecting mice against diet-induced weight gain, intermittent MR also guards against the development of both fatty liver and dysglycemia. In fact, intermittent MR is actually more effective at maintaining normal blood sugar than classical MR … and this despite four fewer days of dietary intervention per week. Interestingly, mice undergoing intermittent MR also retain more of their lean body mass as compared with their continuously methionine-restricted counterparts. As a result, we consider intermittent MR to be a superior alternative to the classical intervention, and we hope that many of the benefits that it confers to mice will also hold true for humans.”

To view the article, published in Aging Cell, visit https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13629.