Developmental Programming of Mammalian Aging

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Abstract It is well known that the risk of adult disease can be altered by factors acting during development, both pre- and postnatally. Recent studies in our laboratory have shown that hormonal intervention limited to six weeks during early postnatal life can alter adult metabolic characteristics and determine how long an animal will live. However, the potential of early life interventions to slow the rate of aging and reduce the risk of age- related chronic diseases has not been adequately explored. The proposed HYPOTHESIS is that interventions during rapid pre- and peri-pubertal growth can produce permanent beneficial changes in carbohydrate, lipid, and energy metabolism, thus promoting healthy aging. This hypothesis will be tested using two pharmacological and one environmental intervention which have already been shown to improve glucose homeostasis in adults and to be well tolerated by juveniles. In three SPECIFIC AIMS, juvenile mice will be treated with metformin, a drug with multiple beneficial effects in adults with type 2 diabetes or with MSI-1436, a novel experimental anti-obesity and anti-diabetic drug, or exposed to a modest reduction of environmental temperature, a safe, cost free and readily translatable intervention. The effects of these three interventions will be tested on glucose homeostasis, energy metabolism, body composition, physical endurance, responses to nutritional stress (high fat diet), and gene expression. Using RT-PCR, multiple tissues will be analyzed for expression of genes mechanistically related to healthspan and longevity, including those related to insulin, GH, IGF-1, mTORC1 and mTORC2 signaling, glucose and lipid metabolism, and inflammation. Unbiased RNA-Seq studies of adipose tissue will also be conducted to search for novel mechanisms linking early life interventions and adult phenotype and aging. Separate cohort of animals from each treatment group will be used for studies of glucose homeostasis, energy metabolism, body composition, and physical endurance at the ages of 24 and 30 months and for determination of longevity. The results will determine whether simple and safe lifestyle interventions during childhood and adolescence can promote extension of healthspan and lifespan and begin to identify mechanisms of developmental programing of mammalian aging and potential targets for pharmacological interventions. Three Specific Aims are proposed: Specific Aim 1: To determine the impact of early life treatment with metformin on adult metabolic characteristics causally related to aging. Specific Aim 2: To determine the impact of early life treatment with MSI-1436 (an experimental anti- obesity drug) on adult metabolic characteristics causally related to aging. Specific Aim 3: To determine the impact of a mild reduction of environmental temperature during early life on adult metabolic characteristics causally related to aging.