Abstract
Calorie restriction (CR) delays aging and extends lifespan in numerous organisms, including mice. Down-regulation of the somatotropic axis, including a reduction in insulin-like growth factor-1 (IGF-1), likely plays an important role in CR-induced lifespan extension, possibly by reducing cell proliferation rates, thereby delaying replicative senescence and inhibiting tumor promotion. Accordingly, elucidating the mechanism(s) by which IGF-1 is reduced in response to CR holds therapeutic potential in the fight against age-related diseases. Up-regulation of fibroblast growth factor 21 (FGF21) is one possible mechanism given that FGF21 expression is induced in response to nutritional deprivation and has been implicated as a negative regulator of IGF-1 expression. Here we investigated alterations in hepatic growth hormone (GH)-mediated IGF-1 production and signaling as well as the role of FGF21 in the regulation of IGF-1 levels and cell proliferation rates in response to moderate CR in adult mice. We found that in response to moderate CR, circulating GH and hepatic janus kinase 2 (JAK2) phosphorylation levels are unchanged but that hepatic signal transducer and activator of transcription 5 (STAT5) phosphorylation levels are reduced, identifying STAT5 phosphorylation as a potential key site of CR action within the somatotropic axis. Circadian measurements revealed that the relative level of FGF21 expression is both higher and lower in CR vs. ad libitum (AL)-fed mice, depending on the time of measurement. Employing FGF21-knockout mice, we determined that FGF21 is not required for the reduction in IGF-1 levels or cell proliferation rates in response to moderate CR. However, compared to AL-fed WT mice, AL-fed FGF21-knockout mice exhibited higher basal rates of cell proliferation, suggesting anti-mitotic effects of FGF21. This work provides insights into both GH-mediated IGF-1 production in the context of CR and the complex network that regulates FGF21 and IGF-1 expression and cell proliferation rates in response to nutritional status.
Highlights
Calorie restriction (CR), reduced caloric intake without malnutrition, increases maximum lifespan and delays the onset of many age-related diseases in organisms ranging from worms to rodents, and possibly non-human primates [1,2]
We found that there was no significant difference in hepatic janus kinase 2 (JAK2) phosphorylation in CR compared to ad libitum (AL) mice, with a non-significant trend towards higher levels in CR mice, while interestingly, hepatic signal transducer and activator of transcription 5 (STAT5) phosphorylation was significantly reduced in CR compared to AL mice (Figure 1C, D and Figure S3 in File S1)
In the context of moderate CR in adult mice, the studies presented here demonstrate the following: 1) Circulating growth hormone (GH) and hepatic JAK2 phosphorylation levels are unchanged in CR compared to AL-fed week-old male control C57BL/6NTac (WT) mice, changes in factors within the hepatic GH-mediated insulin-like growth factor-1 (IGF-1) production pathway upstream of JAK2 cannot account for the reduction in IGF-1 observed in response to moderate CR. 2) Hepatic STAT5 phosphorylation levels are reduced in CR compared to AL-fed WT mice and may in part mediate the reduction in IGF-1 in these mice
Summary
Calorie restriction (CR), reduced caloric intake without malnutrition, increases maximum lifespan and delays the onset of many age-related diseases in organisms ranging from worms to rodents, and possibly non-human primates [1,2]. Decreased signaling through the somatotropic axis is one mechanism that has been suggested to mediate these effects of CR [3], perhaps through a reduction in cell proliferation, which is predicted to contribute to lifespan extension by delaying cellular replicative senescence and inhibiting the promotional phase of carcinogenesis [4]. CR in mice leads to a reduction in circulating levels of insulin-like growth factor-1 (IGF-1) in association with reduced rates of proliferation in a number of cell types [5,6,7,8,9]. Disruption of IGF-1 signaling in several mouse models mimics many of the effects of CR including, increased maximum lifespan, reduced tumor progression, delayed cellular replicative senescence and reduced rates of cell proliferation [4,13,14,15,16,17,18]. Identifying mechanisms that regulate IGF-1 signaling and cell proliferation in response to CR in mice could provide insight into the biology of aging and offer therapeutic targets for treating agerelated diseases
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