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

摘要

Calorie restriction (CR) and inhibition of the growth hormone (GH)–insulin-like growth factor (IGF)-1 axishave been extensively investigated regarding their regulatory effects on aging processes and lifespan. Because CRmoderately inhibits GH-IGF-1 signaling, the signal pathway may underlie the effect of CR. Our transgenic (tg/–) ratmodel, in which the GH–IGF-1 axis is modestly inhibited by overexpression of an antisense GH gene, showed similarcharacteristics to wild-type (WT)-CR rats in terms of lifespan extension, stress resistance and some neuroendocrineactivities. Long-lived GH-receptor (GHR)-knockout (KO) mice, which are deficient in plasma IGF-1, showed noadditional increase in lifespan by CR. These findings suggest importance of the GH signaling in the effect of CR. Bycontrast, 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 notbe a sole pathway, many findings support the role for the GH–IGF-1 axis in the effects of CR. Longevity may be linked toretained cognitive functions in advanced ages. However, longevity models do not necessarily retain cognitive function orneuronal resistance to oxidative or neurotoxic stresses. IGF-1 signaling in the brain is differently regulated among thoselongevity models, even though systemic IGF-1 signaling is attenuated in most of the models. Knowledge on the regulationof the GH–IGF-1 axis in the brain in these longevity models could help us to devise interventions that retard agingdependentneurodegenerative processes.