A single hormone directs body’s responses to low-protein diet: Mice live longer and lose weight while eating more when FGF21 is present

A single hormone seems to coordinate the lifespan produced by a low protein diet.

A new study from the Pennington Biomedical Research Center, published in the journal Nature communicationfound that a reduction in the amount of protein in the diet resulted in a number of beneficial health outcomes, including a prolongation of life, and that these effects are due to a liver-derived metabolic hormone called Fibroblast Growth Factor 21 (FGF21).

It has long been known that reducing the amount you eat improves health and prolongs life, and there has been a growing interest in the possibility that reduced protein or amino acid intake contributes to this beneficial effect. Several recent studies suggest that diets that are low in protein, but not so low as to produce malnutrition, can improve health. Conversely, overconsumption of high-protein diets has been linked to increased mortality in certain age groups.

A few years ago, Pennington Biomedicals Neurosignaling Laboratory discovered that the metabolic hormone FGF21 was a key signal that linked the body to the brain during protein restriction. Without this signal, young mice failed to change their eating behavior or metabolism when put on a low-protein diet.

“Our data suggest that FGF21 talks to the brain, and that without this signal the mouse does not” know “that it is eating a low-protein diet. As a result, the mouse fails to adaptively change its metabolism or feeding behavior,” said Christopher Morrison, Ph.D. , Professor and Head of the Neurosignaling Lab.

The group’s recent work, led by postdoctoral fellow Cristal M. Hill, Ph.D., shows that low-protein diets provide beneficial metabolic effects in aged mice, improve metabolic health, reduce weakness, and prolong life. These beneficial effects were also evident when protein intake decreased in middle-aged mice, which even protected against the disadvantages of obesity. Importantly, these beneficial effects were lost in mice lacking FGF21, suggesting that its effect on the brain is crucial for increasing health and longevity.

“We have previously shown that FGF21 acts in the brain to improve the metabolic health of young mice fed a low-protein diet. These new data extend this work by showing that FGF21 also improves metabolic health and prolongs life. Overall, these data provide clear evidence because FGF21 is the first known hormone that coordinates eating behavior and metabolic health to improve longevity during protein restriction, says Dr. Hill.

However, Dr. Hill said several questions remain. It is unclear exactly how these observations will be translated into aging people, but the hope is that this work will reveal new molecular and neural pathways that can be used to improve human health.

“This groundbreaking research has important implications for prolonging human health and longevity. If researchers can better understand how diets and nutritional hormones such as FGF21 work to prolong life, these findings could compensate for many of the health problems that occur in middle age and later,” says Pennington. Biomedical Executive Director John Kirwan, Ph.D.

This work was supported by National Institutes of Health grants R01DK105032, R01DK121370, R01DK123083 and F32DK115137. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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