Longevity genes and calorie restriction: early post-natal effects

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DESCRIPTION (provided by applicant): Prenatal developmental events can influence adult phenotype and the risk of adult disease. However, it is unknown whether (or to what extent) the actions of hormones and nutrients on early postnatal growth can influence mammalian aging, adult health and longevity. We have recently shown that: (i) the remarkable extension of longevity in hypopituitary Ames dwarf mice can be completely reversed by a six-week course of growth hormone (GH) injections started at the age of 2 weeks; and (ii) limiting nutrient availability during the first three weeks of postnatal life by increasing the numbers of pups in a litter increases both median and maximal lifespan in genetically normal mice. Based on these novel and largely unexpected findings, we hypothesize that the period of rapid postnatal growth represents a critical time window for development of lifelong metabolic and other phenotypic characteristics that influence-and likely predict-longevity and functionality during old age. To test the validity of this hypothesis, we will examine the impact of modestly reducing the amount of available nutrients during suckling (or suckling and the immediate post-weaning period) in normal mice, and the effects of early (starting at one or two weeks) as compared to late (starting at eight weeks) GH replacement therapy in Ames dwarfs and in GHRH-/- mice with isolated GH deficiency. Endpoints will include both longevity and a series of age-sensitive traits related to health span, including indices of immune function, locomotion, stress resistance, and cataract development. We will pay special attention to endpoints related to fuel metabolism, with tests of somatotropic and insulin signaling, pancreatic beta cell function, metabolic rate and respiratory quotient, and expression of GH and insulin-related genes in the liver, skeletal muscle, and both subcutaneous and intra-abdominal (visceral) fat. Lastly, we will in parallel studies see whether early life nutrient limitation, before or before and after weaning, will benefit GHRKO (Laron dwarf) mice, which unlike Ames dwarf mice fail to benefit from calorie restriction (CR) when CR is started at the age of 2 months. Results of the proposed studies will be used to accept or reject specific hypotheses concerning mechanisms by which early hormonal or nutritional interventions can influence aging and longevity. In sum, we will take our studies of the interactions of longevity genes and CR in a novel direction to address the impact of transient changes in nutritional and hormonal signals during early postnatal life on mammalian aging, health span and longevity. Results of these studies will address critical gaps in the present understanding of developmental influences on aging and set a stage for addressing the relationships between early nutrition, growth and adult health which are of major public health significance.