Research Project
10201482
Core B: Animal Core ? Lead PI: Cun Li, MD; Multiple PI: Peter W Nathanielsz, MD, PhD Animal Core Abstract: Significance/Justification of nonhuman primate studies. Extensive separate aging and programming research exists but few studies address programming-aging interactions and none in nonhuman primates (NHP) other than our own recent publications. Baboons are the closest practical experimental species to humans. Knowledge gained will help develop new interventions to increase health span even in early life and permit diagnostic approaches to identify patients at risk of accelerated aging. Premises/hypotheses. 1. Antecedents of aging exist early in hippocampal-hypothalamo-pituitary-adrenal (HHPA) axis, brain structure and function, and behavior; cardiovascular system (CVS); metabolic biomarkers, and associated genetics. 2. Programming-aging interactions are major determinants of life course health span. 2a. Moderate perinatal maternal nutrient reduction alters HHPA axis, brain and behavior, CVS, and metabolic function evident in accelerated changes in aging biomarkers in their IUGR offspring (F1) compared to normal life course (NLC) controls receiving normal perinatal nutrition. 2b. Maternal obesity (MO) in the perinatal period alters function in the HHPA axis, brain and behavior, CVS, and metabolism evident in accelerated changes in aging biomarkers compared to NLC receiving normal perinatal nutrition. 2c. Cortisol replacement intervention to prevent the life course cortisol fall increases the rate of aging in the systems studied evident in accelerated changes in aging biomarkers compared to NLC baboons in which the NLC cortisol falls. 3. Comparing NLC control data with data from three interventions that alter the aging trajectory provides insights into key mechanisms in systems and cellular aging pathways for translation to humans to anticipate age-related mechanisms that decrease health span enabling development of human aging markers and interventions. Our studies will also provide basc information on normal organ function not obtainable in humans. Approach. We study equal male and female baboons in all groups using in vivo techniques ? tether, CVS, endocrine, metabolic approaches, MRI, and in vitro studies on skin fibroblasts. Synergy. All 96 baboons undergo the same procedures allowing data integration across biological systems. Response to IRG observed weaknesses. Specifically, we removed redundancies and addressed colony lifespan variations - our goal is to start from an early age to study aging to obtain a data continuum as animals age. We describe programming models in more detail. Because of lack of enthusiasm and IRG criticisms we removed the maternal glucocorticoid group. We no longer conduct euthanasia on any animals. In the General Overview we justify the title Womb to Tomb with plans to incorporate published fetal data and new data from our fetal and postnatal archives. We present our plans to share unique resources worldwide and clearly state that all animals that have undergone a treatment have age-matched NLC group controls. The human intruder test replaces the isolation stress test. Tether maintenance is described in detail. Animal Welfare. We have experience with all procedures for over 32y.
