The effects of growth hormone and IGF-1 deficiency on cerebrovascular and brain ageing

Research studies clearly indicate that age-related changes in cellular and tissue function are linked to decreases in the anabolic hormones, growth ho rmone and insulin-like growth factor (IGF)-1. Although there has been exten sive research on the effects of these hormones on bone and muscle mass, the ir effect on cerebrovascular and brain ageing has received little attention . We have also observed that in response to moderate calorie restriction (a treatment that increases mean and maximal lifespan by 30-40%), age-related decreases in growth hormone secretion are ameliorated (despite a decline i n plasma levels of IGF-1) suggesting that some of the effects of calorie re striction are mediated by modifying the regulation of the growth hormone/IG F-1 axis. Recently, we have observed that microvascular density on the surf ace of the brain decreases with age and that these vascular changes are ame liorated by moderate calorie restriction. Analysis of cerebral blood flow p aralleled the changes in vasculature in both groups. Administration of grow th hormone for 28 d was also found to increase microvascular density in age d animals and further analysis indicated that the cerebral vasculature is a n important paracrine source of IGF-1 for the brain. In subsequent studies, administration of GHRH (to increase endogenous release of growth hormone) or direct administration of IGF-1 was shown to reverse the age-related decl ine in spatial working and reference memory. Similarly, antagonism of IGF-1 action in the brains of young animals impaired both learning and reference memory. Investigation of the mechanisms of action of IGF-1 suggested that this hormone regulates age-related alterations in NMDA receptor subtypes (e .g. NMDAR2A and R2B). The beneficial role of growth hormone and IGF-1 in am eliorating vascular and brain ageing are counterbalanced by their well-reco gnised roles in age-related pathogenesis. Although research in this area is still evolving, our results suggest that decreases in growth hormone and I GF-1 with age have both beneficial and deleterious effects. Furthermore, pa rt of the actions of moderate calorie restriction on tissue function and li fespan may be mediated through alterations in the growth hormone/IGF-1 axis .