“Restricting food intake has been shown to extend lifespan in several different kinds of animals. In our study, we found transgenic mice that produced more of the hormone fibroblast growth factor-21 (FGF21) got the benefits of dieting without having to limit their food intake. Male mice that overproduced the hormone had about a 30 percent increase in average life span and female mice had about a 40 percent increase in average life span,” said senior author Dr. Steven Kliewer, professor of molecular biology and pharmacology.
The study published online in eLife – a new peer-reviewed, open access journal – defined average life span as the point at which half the members of a given test group remained alive. A study to determine differences in maximum life span is ongoing: While none of the untreated mice lived longer than about 3 years, some of the female mice that overproduced FGF21 were still alive at nearly 4 years, the researchers report.
FGF21 seems to provide its health benefits by increasing insulin sensitivity and blocking the growth hormone/insulin-like growth factor-1 signaling pathway. When too abundant, growth hormone can contribute to insulin resistance, cancer, and other diseases, the researchers said.
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.
In this report, 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. The increase in lifespan extension is comparable to that achieved by caloric restriction (Turturro et al., 1999). While the FGF21-mediated increase in longevity is less than the 50–70% increase seen in pituitary loss-of-function Ames mice and GH receptor/GH binding protein-knockout mice (Brown-Borg et al., 1996; Coschigano et al., 2000), it is similar to that seen in other loss-of-function dwarf models including hypopituitary Snell mice (Flurkey et al., 2002) and mice lacking pregnancy-associated plasma protein-A (PAPP-A), a protease that increases IGF-1 activity (Conover et al., 2010). The FGF21-Tg mice share other phenotypic similarities with long-lived dwarf mice including small size, reduced circulating insulin and IGF-1 concentrations, increased circulating adiponectin levels and female infertility. Like the Ames and Snell dwarf mice, female FGF21-Tg mice live longer than males (Liang et al., 2003; Brown-Borg and Bartke, 2012). These similarities together with our previous finding that FGF21-Tg mice are GH resistant (Inagaki et al., 2008) suggest that FGF21 may increase lifespan by inhibiting the GH/IGF-1 signaling pathway. Because FGF21 also regulates other pathways that impact metabolism, it is not surprising that some of the effects that are seen in dwarf mice, such as increased adiposity in GH receptor-knockout mice (Masternak et al., 2012), are not recapitulated in FGF21-Tg mice.
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