Project 1: Developmental Programming and Aging Interactions in Primate Brain and Glucocorticoid Function.

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Project 1: Developmental Programming and Aging Interactions in Primate Brain and Glucocorticoid Function Lead PI: Peter Nathanielsz; Multiple PIs: Cun Li, Peter Fox ABSTRACT Controlled translational animal studies are needed to determine how developmental programming-aging interactions by glucocorticoid (GC- cortisol) and other mechanisms, e.g. blood flow and metabolism, influence brain aging and cognitive decline. Evidence supports early blood GC changes and activity and other antecedents of aging. The Barker programming hypothesis states responses to specific challenges in critical developmental time windows alter the developmental trajectory with persistent effects on phenotype. Preliminary data. We 1) confirmed a linear baboon plasma cortisol fall starting at 6y age (human ~15y) and showed a fall in paraventricular nuclear (PVN) vasopressin and increased GC receptor (GR), potential mechanisms for the fall (increased feedback and decreased PVN drive); 2) peripheral cortisol production; and 3) GR and blood flow changes with aging. Premises. 1. Aging antecedents are present early in the hippocampal-hypothalamo-pituitary (HHPA) axis, brain function, and behavior. 2a. Moderate perinatal global nutrient reduction-induced IUGR alters HHPA, brain structure and function, and behavior, evident in changes in IUGR offspring (F1) aging biomarkers compared to controls who received normal perinatal nutrition. 2b. Maternal obesity (MO) in the perinatal period alters HHPA, brain structure and function, and behavior, evident in changes in aging biomarkers in MO F1 vs. controls who received normal perinatal nutrition. 2c. Cortisol replacement from 13y to maintain cortisol at 5y levels increases the HHPA, brain, and behavior rate of aging, evident in changes in HHPA and brain-related aging biomarkers vs. controls. 3. Comparing normative, life course observational control data with data from interventions that alter the aging trajectory provides insights into key mechanisms in systems and cellular aging pathways. Data will provide information for translation to humans to anticipate age-related mechanisms that both increase and decrease health span, enabling development of markers and interventions in human aging Approach. We study 96 baboons over 24-68% of the life course, equal males and females. Groups: 1. Normal life course; 2. IUGR (F1) of 30% globally food reduced mothers; 3. F1 of over-nourished, obese mothers; 4. Cortisol Replacement Intervention beginning at 13y to maintain baboons' cortisol at 5y old levels for 5 years to address cortisol regulated mechanisms. We conduct awake, tether studies, 24h rhythms, HHPA suppression and stimulation, MRI, brain histology, and cognitive tests to relate phenotype to cellular pathways. No baboons are euthanized. We integrate our fetal and adult tissue archives with in vivo studies. Innovation. We propose a new framework to understand aging based on programming-aging interactions. Environment. With our funds, we built our outdoor holding facilities and assembled 96 baboons. We share nonhuman primate (NHP) resources worldwide (see letters). Investigators are experienced in aging and programing NHP studies. New to this Project, Dr. Fox brings brain-imaging and Dr. Salmon powerful cell culture approaches.