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Age-and Brain Region-Specific Differences in Mitochondrial Bioenergetics in Brown Norway Rats
Pandya, J., J. Royland, R. McPhail, P. Sullivan, AND P. Kodavanti. Age-and Brain Region-Specific Differences in Mitochondrial Bioenergetics in Brown Norway Rats. NEUROBIOLOGY OF AGING. Elsevier Science Ltd, New York, NY, 42:25-34, (2016).
There are currently an estimated 6 million Americans at age 85 and older and the number is constantly growing. The World Health Organization (WHO) estimates that the worldwide aged population (65+ years) will increase more than threefold by 2050 (World Health Organization. 2011). Factors that affect susceptibility to environmental chemical exposures at different life stages are an area of growing concern in the risk assessment of human health. Animal models used to investigate the role of aging on physiological endpoints have demonstrated age-specific responses to environmental stressors (Elder et al., 2000. Kodavanti et al., 2011, MacPhail et al., 2012) Thus. environmental chemicals may contribute to susceptibility by affecting the aged differently from the young adults (Park et al., 2005.Royland et al., 2012). Research to better understand the biological processes of aging, as well as to learn about chemically-induced susceptibility, is needed to optimize risk assessment and to minimize health risks in senior populations.
Mitochondria are central regulators of energy homeostasis and play a pivotal role in mechanisms of cellular senescence. The objective of the present study was to evaluate mitochondrial bio-energetic parameters in five brain regions [brainstem (BS), frontal cortex (FC), cerebellum (CER), striatum (STR), hippocampus (HIP)] of four diverse age groups [1 Month (young), 4 Month (adult), 12 Month (middle-aged), 24 Month (old age)] to understand age-related differences in selected brain regions and their contribution to age-related chemical sensitivity. Mitochondrial bioenergetics parameters and enzyme activity were measured under identical conditions across multiple age groups and brain regions in Brown Norway rats (n = 5). The results indicate age- and brain region-specific patterns in mitochondrial functional endpoints. For example, an age-specific decline in ATP synthesis (State 111 respiration) was observed in BS and HIP. Similarly, the maximal respiratory capacities (State V1 and V2) showed age-specific declines in all brain regions examined (young > adult > middle-aged > old age). Amongst all regions, HIP had the greatest change in mitochondrial bioenergetics, showing declines in the 4, 12 and 24 Month age groups. Activities of mitochondrial pyruvate dehydrogenase complex (PDHC) and electron transport chain (ETC) complexes I, II, and IV enzymes were also age- and brain-region specific. In general changes associated with age were more pronounced, with enzyme activities declining as the animals aged (young > adult > middle-aged > old age). These age and brain-region specific observations may aid in evaluating brain bioenergetics impact on the age-related susceptibility to environmental chemical stressors.