Womb to Tomb: Developmental Programming and Aging Interactions in Primates

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ABSTRACT Specific aims/significance. In our well-characterized baboon nonhuman primate (NHP) models of developmental programming and aging we use both categorical group and longitudinal, life course approaches to evaluate interactive programming-aging mechanisms. Developmental programming can be defined as responses to challenges in critical developmental time windows that alter life course phenotype. Premises/hypotheses. 1. Aging antecedents are present early in the hippocampal-hypothalamo-pituitary- adrenal (HHPA) axis (HHPAA), brain, and behavior; cardiovascular system (CVS); and metabolism. 2. Programming-aging interactions are major determinants of life course HHPA, brain, behavior, CVS, and metabolic health span. 3. Comparing normative, life course observational control data with data from three interventions that alter aging trajectory provides insights into key aging mechanisms and cellular pathways and information needed for translation to humans to anticipate age-related mechanisms that either increase or decrease health span. Findings enable development of markers and beneficial interventions in human aging. Projects - 1. HHPAA, Brain, and Behavior. 2: CVS Function. 3: Metabolism. Cores - A: Administrative; B: Animal; C: Genomics; D: MRI; E: Samples and Data Management. Synergy: All components study all 96 animals with in vivo MRI and tether studies and in vitro histological, cell culture, and molecular approaches. We study 96 baboons in 4 groups, equal males and females at 6–17 years (y) (human equivalent ~18–68y; 24– 68% of the life course). Groups: 1. 48 normal life course controls (NLC); 2. 16 IUGR offspring (F1) of moderately undernourished mothers; 3. 16 F1 of obese, over-nourished mothers; 4. In 16 at 12–17y we clamp plasma cortisol to normal 5y levels. Comparison of aging mechanisms in NLC and interventions provides information on life course whole animal and cellular mechanisms modified by programming-aging interactions. New preliminary data. We present new evidence of increased cortisol and accelerated brain, CVS, and metabolic aging in IUGR. Responsiveness to PAR-16-143 Complex Integrated Multi-Component Projects in Aging Research (U19). We address requested “Large-scale longitudinal observational studies… integration of multiple outcomes with molecular, genetic, mechanistic data and interventions… animal models for aging- related conditions… multiple endpoints to elucidate mechanisms.” Investigators are from multiple institutions and have worked and published together in aging research and programming and in completing large NIH P01s, R24s, P51s. We share resources worldwide. Innovation. Life course NHP studies are rare. We assembled unique cohorts and built our own custom facility for these studies. We now 1. perform biopsies not euthanasia, enabling further applications on these cohorts; 2. combine U19 in vivo and in vitro data with histological and molecular data from our extensive fetal (130 fetuses) and postnatal archives (120 adults birth to 25y) to produce a new mechanistic programming and aging framework from womb to tomb.