A growing body of research suggests that a variety of dietary interventions (i.e., calorie restriction, intermittent fasting, fasting simulations, and dietary restrictions) can improve health and prolong life. Epidemiological data suggest that reducing dietary protein content contributes to improved metabolism and resilience, while excessive protein intake is associated with increased mortality.
Protein restriction (PR) is a form of dietary restriction without energy restriction that extends the lifespan of various organisms and improves general health measures, including rodents, drosophila, and yeast. Restricting proteins instead of fats or carbohydrates can prolong the lifespan of fruit flies. In rodents, PR also extends lifespan, and there is evidence that lowering protein intake has had beneficial outcomes for health, which is not related to energy intake.
As an alternative to total PR, limiting certain amino acids, including methionine restrictions, threonine and/or tryptophan restrictions, and branched-chain amino acid (BCAA) restrictions, can also extend the lifespan of various organisms.
The health improvements caused by PR have sparked interest in potential cellular mechanisms. Most studies have highlighted the ability of protein or amino acid restriction to participate in intracellular nutrient sensing pathways, including mTOR, GCN2, AMPK, autophagy, and more. However, a few years ago our lab hypothesized that there might be protein-restricted endocrine effect signals.
Recently, researchers at the Pennington Biomedical Research Center published an article in the journal Nature Communication titled "FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice", which shows that Limiting protein in aging male mice has significant beneficial effects on longevity and metabolic health, and a single metabolic hormone, FGF21, is critical to the anti-aging effects of this dietary intervention.
Restricting dietary proteins is increasingly recognized as a unique way to improve metabolic health, and there is growing interest in the mechanisms behind this beneficial effect. FGF21 was discovered in 2000, and in the 20 years since, more and more studies have revealed a variety of key roles and mechanisms in regulating body metabolism as an important signaling factor.
FGF21 is essential for increasing longevity during dietary protein restriction
To test the role of FGF21 in mediating the longevity effects of long-term dietary PR, the researchers placed 60 male C57BL/6 J (control wild-type) mice and 60 male Fgf21 KO mice in a control (CON) or low-protein (LP) diet, divided into four groups of 30 each (see figure below). Mice began eating these foods at will from 3 months of age until natural death.
Schematic diagram of a metabolic aging study
The researchers observed that the LP diet extended the lifespan of wild-type (WT) mice. However, exposing FGF21 KO mice to the LP diet reduced their lifespan.
The above research data show that the life extension caused by PR requires FGF21. To test whether FGF21 contributes to the effect of long-term PR on the health span of elderly mice, from 3 months to 22 months of age, the researchers fed WT and Fgf21 KO mice a control group or an LP diet ,4 groups per diet/genotype, n = 12 mice).
The results showed that the LP diet reduced weight gain in the WT mice, while the Fgf21 KO mice did not have this effect. Energy expenditure (EE), which was adjusted for body weight by analysis of variance, increased by LP diet at both WT mice at 12 and 20 months of age; conversely, Fgf21 KO mice did not increase EE in LP. These data suggest that protein restriction in the diet consistently reduces body weight, but increases food intake and energy expenditure in aging mice, and these effects depend on the increase in circulating FGF21.
FGF21 mediated low protein-induced changes in weight gain, food intake, and body composition in older mice
Protein restriction protects age-related functional decline through FGF21
Inadequate protein intake, especially when malnourished in older adults, can lead to poor functional and structural events such as muscle atrophy and an increased risk of fractures. The researchers found that significant genotype* dietary interactions were observed. The LP diet increased the fall latency in WT mice, but this effect was largely canceled in Fgf21 KO mice. The original grip strength of WT mice was not affected by the LP diet, but when normalized to body weight, grip strength increased significantly. Similarly, both the original grip force and the normalized grip force of Fgf21 KO mice decreased significantly due to LP. Finally, movement and movement activity in the metabolic chamber at 20 months of age indicates that genotype or diet has no effect. These data suggest that protein restriction increases functional performance, and these beneficial effects depend on FGF21.
Taken together, the study work together proves several important conclusions. First, in male C57BL/6J mice, dietary protein intake restriction had beneficial effects on weight gain, obesity, glucose homeostasis, physical fitness, and metabolic health, which ultimately reduced weakness and prolonged lifespan.
Second, these beneficial effects can be reproduced if the diet is started in middle age, and in middle age, PR can also prevent the harmful effects of diet-induced obesity in old age. Finally, almost all of these PR-induced beneficial effects rely on the liver-derived hormone FGF21. Undetectable protein restriction in FGF21-KO mice was initially benign, but eventually led to negative outcomes later in life, such as FGF21-KO mice in the LP group dying earlier than their control group.
Taken together, these data suggest that in the process of restricting dietary protein, the increase in circulating FGF21 mediates the increase in lifespan and the improvement of healthy lifespan, thus identifying a new mechanism that pushes mammals to extend their lifespan in the case of restricting dietary protein.
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