Proceedings of The Physiological Society

Future Physiology (Leeds, UK) (2017) Proc Physiol Soc 39, C04

Oral Communications

Developmental Programming (DP) and Aging Interactions,: A Future Physiology frontier

P. W. Nathanielsz1, A. H. Kuo2, A. Maloyan3, H. F. Huber1, C. Li1, G. D. Clarke2

1. Animal Science, University of Wyoming, Laramie, Wyoming, United States. 2. Dept Radiology, UT Health Science Center San Antonio, San Antonio, Texas, United States. 3. Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, United States.

Background: DP, defined as responses to challenges in plastic developmental windows alters life course phenotype predisposing to chronic diseases. We hypothesize that DP alters the rate of aging making interactions a Future Life target for physiological studies integrating systems, cellular and molecular physiology. We correlate studies on DP-aging interactions in control (C) and programmed IUGR baboon offspring (F1) to demonstrate DP effects on aging. Hypotheses. 1. Antecedents are present early in cardiovascular system (CVS) aging. 2. Programming-aging interactions are major determinants of life span. Approach/Methods. Procedures were approved by the Texas Biomedical Research Institute Animal Care and Use Committees and conducted in Association for Assessment and Accreditation of Laboratory Animal Care approved facilities. We compare fetal and postnatal data of F1 of well-fed C baboon mothers and IUGR F1 of mothers fed 70% global C diet to evaluate key DP-aging systems and cellular pathways. Term F1 fetuses were removed at CSection and euthanized by exsanguination under isoflurane general anesthesia. All deliveries were spontaneous. We conducted immunohistochemical and mRNA quantification. With MRI in IUGR (N=8 male - M, 8 female - F, 5.7 y) and age matched C (N=8M and 8F 5.6 y) and normal aged baboons (6M, 6 F, mean 15.9 y) we measured left (LV) and right (RV) ventricular parameters wit 2-way ANOVA; p <0.05. Results: Fetal studies. M but not F IUGR fetuses showed LV fibrosis [1]. Cardiac extracellular matrix protein Thrombospondin 1 increased in M IUGR. Autophagy was upregulated in M IUGR. Fetal cardiac tissues exhibited increased diacylglycerol and plasmalogens and decreased triglycerides and phosphatidylcholines. Thus, even in fetal life, IUGR results in sex-dependent dysregulation in cardiac structure and cellular function. Postnatal studies: Ejection fraction, 3D sphericity indices, cardiac index, systolic volume normalized to body surface area, normalized LV wall thickness, and average filling rate differed between IUGR and C. Normalized peak LV filling rate and diastolic sphericity index correlated in OLD and IUGR baboons but not C [2]. RV changes were more marked [3]. Thus, IUGR DP produces myocardial remodeling, reduces systolic and diastolic function with premature aging heart phenotype. IUGR decreased descending aortic cross-section/body surface area and distensibility similar by sexand group. Thus DP changes in vascular development persist in adults with potential effects on coronary perfusion, afterload and blood pressure [4]. Pericardial fat increased in IUGR Mequivalent to a 6y age advance. In conclusion: We propose that IUGR results in cardiac remodeling beginning in fetal life, accelerating CVS aging. This Future Life area of Physiology holds out exciting prospects for a systems-to-molecular physiological phenotype approach - from Womb to Tomb.

Where applicable, experiments conform with Society ethical requirements