Developmental Origins of Phenotypic Characteristics that Predict Longevity

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DESCRIPTION (provided by applicant): It is well established that developmental events can act as determinants of adult disease. For example, maternal undernutrition, as well as overnutrition, represent risk factors for development of various components of metabolic syndrome in the offspring. Yet it is unknown whether (or to what extent) early growth and development influence mammalian aging. On the basis of preliminary data derived from hormonal replacement therapy in long-lived mutants, we propose that the period of rapid pre- and post-weaning growth may represent a critical "time window" for the effects of early hormonal milieu on healthspan and lifespan. To test the validity of this novel concept and to begin identifying the underlying mechanisms, we will determine whether a defined (six week) period of hormonal therapy, started at different stages of postnatal development, can influence phenotypic characteristics associated with longevity and whether the hormone-induced alterations in these characteristics will persist after the treatment is stopped. To test the hypothesis that the period of rapid postnatal growth represents a critical time window for development of metabolic characteristics that influence (and likely predict) aging, the following specific aims are proposed: 1. To determine the effects of treating long-lived hypopituitary Prop1df (Ames dwarf) mice with growth hormone (GH) or with a combination of hormones starting at one week, two weeks or two months of age on oxygen consumption (VO2), respiratory quotient (RQ), body temperature and expression of genes related to insulin action, fat and carbohydrate metabolism. 2. To determine whether hormone-induced changes in VO2, RQ, body temperature, insulin signaling and gene expression persist after the treatment is stopped. 3. To determine the effects of early treatment with a combination of GH, prolactin and thyroxine as compared to treatment with GH alone on adipokine levels, insulin and glucose tolerance and other characteristics associated with extended longevity of Ames dwarf mice. The results will begin to fill the gap in the present understanding of the developmental influences on aging and set the stage for addressing broader questions of major public health significance, e.g.: How does nutrition and nutrition-related endocrine signaling during different stages of development affect growth and ultimately healthspan and lifespan? What is the relationship of key metabolic parameters in young adults to aging and longevity? And what early lifestyle and/or pharmacological interventions could effectively increase healthspan and life expectancy? PUBLIC HEALTH RELEVANCE: There is considerable evidence that growth hormone (GH) and other hormones that stimulate growth are also importantly involved in the control of aging and longevity. Our recent findings indicate that the actions of GH early in life (starting before weaning and continuing to the age of puberty) influence life expectancy. In the proposed studies we will use normal as well as long- lived mutant mice, and therapy with GH or with a combination of hormones to elucidate this novel and somewhat unexpected effect. We will determine at which stages of early postnatal life hormone levels influence metabolic characteristics that differ in normal and long-lived mice and thus may predict longevity. We will also determine which of these hormone-induced changes persist after hormone treatment is stopped. Because nutrition has major effects on the level of various hormones, understanding the relationships between early hormone action and aging is important for discovering how aging can be postponed and life expectancy improved by judicious modifications of the diet during rapid pre-pubertal growth.