Rodent Models to Study the Roles of the GH–IGF-1 Axis in the Aging and Anti-Aging Effects of Calorie Restriction

Calorie restriction (CR) and inhibition of the growth hormone (GH)–insulin-like growth factor (IGF)-1 axis have been extensively investigated regarding their regulatory effects on aging processes and lifespan. Because CR moderately inhibits GH-IGF-1 signaling, the signal pathway may underlie the effect of CR. Our transgenic (tg/–) rat model, in which the GH–IGF-1 axis is modestly inhibited by overexpression of an antisense GH gene, showed similar characteristics to wild-type (WT)-CR rats in terms of lifespan extension, stress resistance and some neuroendocrine activities. Long-lived GH-receptor (GHR)-knockout (KO) mice, which are deficient in plasma IGF-1, showed no additional increase in lifespan by CR. These findings suggest importance of the GH signaling in the effect of CR. By contrast, the lifespan in Ames dwarf mice, in which the plasma IGF-1 level is also very low, was further increased by CR, suggesting presence of a pathway rather than the GH-IGF-1 axis in the effect of CR. Although the GH-IGF-1 axis may not be a sole pathway, many findings support the role for the GH–IGF-1 axis in the effects of CR. Longevity may be linked to retained cognitive functions in advanced ages. However, longevity models do not necessarily retain cognitive function or neuronal resistance to oxidative or neurotoxic stresses. IGF-1 signaling in the brain is differently regulated among those longevity models, even though systemic IGF-1 signaling is attenuated in most of the models. Knowledge on the regulation of the GH–IGF-1 axis in the brain in these longevity models could help us to devise interventions that retard agingdependent neurodegenerative processes.