BLUNTED RESPONSE TO STRESS IN YOUNG IL-10TM/TM MICE: IMPLICATION FOR THE VULNERABILITY IN FRAILTY

Abstract

AbstractThe hypothalamic pituitary adrenal axis (HPA axis) is a major neuroendocrine system for stress response and for regulating the immune system. Aged rats as well as older humans demonstrate progressive loss of control of the HPA axis, resulting in impaired diurnal rhythm and hypersecretion of glucocorticoids during times of stress. Higher levels and a blunted diurnal rhythm of cortisol have been observed in frail compared to more robust older adults. Understanding the factors underlying disturbed glucocorticoid secretion that precede age-related diseases and frailty are of considerable importance to prevent vulnerability and disability in late life. In order to study this system in vivo, we utilized a mouse model of chronic inflammation and as frailty and measured changes in plasma corticosterone and pro-inflammatory levels after acute cold stress. The plasma corticosterone level was determined 2 weeks before cold stimulation in 10 young (3 months), 10 old (21 months) C57BL/6J mice, and 10 young IL-10 tm/tm (3 months). 5 mice from each group were exposed to cold stress, the remainder served as controls and were not exposed to cold. The treatment groups were exposed to four degrees Celsius for 5 hours and the controls were kept in room temperature conditions at twenty five degrees Celsius. The results showed higher basal plasma corticosterone (P<0.01) and normal IL-6 and TNFR-1 levels in young IL-10tm/tm, compared to young and old C57BL/6J mice. However, there were unchanged corticosterone level and higher IL-6 and TNFR-1 levels (P=0.04, 0.02, respectively) in young IL-10tm/tm mice after acute cold stress compared to young wild type mice. Lower GRa mRNA expression in hippocampus was also observed in control and treated young IL-10tm/tm (P<0.01), compared the age-matched wild type mice. These findings provide initial evidence for the hypothesis that HPA axis dysfunction is through whole life of frail subjects and even earlier than changes in immune system.