Mice live longer and lose weight while eating more when FGF21 is present

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A single hormone seems to coordinate the lengthening of life produced by a low-protein diet.

A new study from the Pennington Biomedical Research Center, published in the journal Nature Communicationfound that reducing the amount of protein in the diet produced a range of favorable health outcomes, including increased lifespan, and that these effects were dependent on a liver-derived metabolic hormone called Fibroblast Growth Factor 21 (FGF21).

It has long been known that reducing the amount of food one eats improves health and prolongs lifespan, and there is growing interest in the possibility that reducing protein or amino acid intake contributes to this beneficial effect. Several recent studies suggest that diets low in protein, but not so low in protein as to cause malnutrition, can improve health. Conversely, overconsumption of high-protein diets has been associated with increased mortality in certain age groups.

A few years ago, the Neurosignaling Lab at Pennington Biomedical discovered that the metabolic hormone FGF21 was a key signal linking the body to the brain during protein restriction. Without this signal, young mice failed to change their eating behavior or metabolism when fed 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 alter its metabolism or his eating behavior,” said Christopher Morrison, Ph.D., professor and director of the Neurosignaling Lab.

The group’s most recent work, led by postdoctoral researcher Cristal M. Hill, Ph.D., demonstrates that low-protein diets produce beneficial metabolic effects in aged mice, improving metabolic health, reducing frailty and prolonging lifetime. These beneficial effects were also apparent when protein intake was reduced in middle-aged mice, even protecting against the harms of obesity. Importantly, these beneficial effects were lost in mice lacking FGF21, suggesting that its action in the brain is essential for improving health and longevity.

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

However, Dr Hill said several questions remain. It’s unclear exactly how these observations will translate to aging humans, but the hope is that this work will uncover new molecular and neural pathways that can be harnessed to improve people’s health.

“This groundbreaking research has important implications for extending people’s health and lifespan. If scientists can better understand how diets and nutritional hormones like FGF21 work to extend lifespan, these findings could offset many health issues that arise in middle age and later,” said 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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