FGF21 is Required for Protein Restriction to Extend Life in Mice

In today's open access research, scientists demonstrate that mice lacking FGF21 do not benefit from protein restriction, a dietary intervention that usually produces slowed aging and extended life span in that species. FGF21 has been the subject of a fair amount of attention from the research community in the context of aging in recent years, attention drawn to this gene because it is upregulated by the practice of calorie restriction, as well as by protein restriction. Artificially increasing FGF21 expression via genetic engineering has been shown to extend life in mice.

Like many aspects of cellular biochemistry altered by calorie restriction, FGF21 influences many very fundamental cellular behaviors, such as regulation of growth. Further, it is involved in higher level systems such as insulin metabolism, mitochondrial function, and immune activity. This makes it a little challenging to determine the degree to which it is important, or which of its activities are important. This is a common issue in the response to calorie restriction. Showing that FGF21 knockout prevents extended life resulting from protein restriction, and then tracing some of the downstream differences, is a step towards a better understanding of the very complex, sweeping changes that take place in response to a reduced intake of protein or calories.

FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice

A variety of dietary interventions (i.e., calorie restriction, intermittent fasting, fasting mimetics, and dietary restriction) improve health and lifespan. Epidemiological data suggest that lowering dietary protein content supports metabolic improvements and resilience, while high protein intake correlates with increased mortality. Protein restriction (PR) is a form of dietary restriction in the absence of energy restriction that extends lifespan and improves general health measures in various organisms, including rodents, fruit flies, and yeast.

The PR-induced improvements on health naturally create an interest in the underlying cellular mechanisms. Most work has accentuated the ability of protein or amino acid restriction to engage a host intracellular nutrient-sensing pathways, including mTOR, GCN2, AMPK, autophagy, etc. However, several years ago our lab hypothesized that an endocrine effector signal of protein restriction might exist. This focus led to the discovery that the liver-derived hormone FGF21 is robustly induced by PR and that the deletion of FGF21 blocks adaptive metabolic responses to PR in young mice.

FGF21 increases energy expenditure, enhances glucose metabolism, and upregulates the thermoregulatory marker UCP1. FGF21 also crosses the blood-brain barrier, and several studies suggest that the physiological effects of FGF21 are mediated by the brain. Recent data from our lab indicate that FGF21/Klb signaling in the brain is essential for PR to increase energy expenditure, improve glucose homeostasis, and protect against diet-induced obesity in young mice.

Factoring in FGF21's key role in facilitating the metabolic response to PR in young mice, and that transgenic overexpression of FGF21 extends lifespan and improves insulin sensitivity, we hypothesized that increases in FGF21 might mediate the beneficial effects of long-term PR in aging animals. Here we demonstrate that, in male mice, FGF21 is required for the effects of PR on lifespan and metabolism. Indeed, mice that are FGF21 deficient are not only resistant to the health benefits effects of PR, but they also exhibit early-onset weight loss, increased frailty, and reduced lifespan when fed a low protein diet. Collectively, these data represent a suggest that FGF21 is essential for the pro-longevity effects of PR and highlight the power of a single endocrine hormone to coordinate metabolic and behavioral responses that improve metabolism and longevity.

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