Abstract
Fibroblast growth factor-21 (FGF21) is a hormone secreted by the liver during fasting that elicits diverse aspects of the adaptive starvation response. Among its effects, FGF21 induces hepatic fatty acid oxidation and ketogenesis, increases insulin sensitivity, blocks somatic growth and causes bone loss. Here we show that transgenic overexpression of FGF21 markedly extends lifespan in mice without reducing food intake or affecting markers of NAD+ metabolism or AMP kinase and mTOR signaling. Transcriptomic analysis suggests that FGF21 acts primarily by blunting the growth hormone/insulin-like growth factor-1 signaling pathway in liver. These findings raise the possibility that FGF21 can be used to extend lifespan in other species.DOI: http://dx.doi.org/10.7554/eLife.00065.001
Highlights
Caloric restriction without malnutrition is a proven means of inhibiting aging in species ranging from worms to nonhuman primates (Masoro, 2005; Bishop and Guarente, 2007; Kenyon, 2010)
We examined whether these and additional metabolic parameters were altered in groups of older (26–27-month-old) wild-type and Fibroblast growth factor-21 (FGF21)-Tg mice
We demonstrate that chronic exposure of mice to the starvation hormone, FGF21, increases median survival time by ~30% and ~40% in males and females, respectively, without decreasing food intake
Summary
Caloric restriction without malnutrition is a proven means of inhibiting aging in species ranging from worms to nonhuman primates (Masoro, 2005; Bishop and Guarente, 2007; Kenyon, 2010). The effect of caloric restriction on longevity appears to be mediated by multiple nutrient-sensing pathways including those involving insulin and insulin-like growth factor (IGF-1), target of rapamycin (TOR), AMP kinase and sirtuins. Pharmacologic and/or genetic manipulation of these pathways increases longevity to varying degrees, suggesting the feasibility of drugs that increase lifespan in the absence of caloric restriction (Bishop and Guarente, 2007; Kenyon, 2010; Barzilai et al, 2012). FGF21 increases insulin sensitivity and causes a corresponding decrease in basal insulin concentrations; FGF21 increases hepatic fatty acid oxidation, ketogenesis and gluconeogenesis; and, FGF21 sensitizes mice to torpor, a hibernationlike state of reduced body temperature and physical activity (Potthoff et al, 2012). Transgenic (Tg) mice overexpressing FGF21 are markedly smaller than wild-type mice and have a corresponding decrease in circulating IGF-1 concentrations despite having elevated growth hormone (GH) levels
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