Aging is associated with a general loss of ability to modulate responses to a physiological stress. The mechanisms underlying the loss of capacity of the aging organism is unclear. One area of focus is at the cellular level, where the accumulation of the highly heat-inducible 79 kDa heat shock proteins (HSP70) is associated with increased heat tolerance. These HSPs are produced in response to stressors and appear to be important in the cell's tolerance to these stressors. We have demonstrated that production of HSP70 increases in response to hyperthermia, suggesting that HSP70 may serve as a biomarker for tissues at risk from multiple physiological stressors. We have also noted that older rats are less thermotolerant to heat challenge than young rats and are less capable of generating protective HSPs. While passive hyperthermia attenuated HSP70 accumulation in older vs. young rats, exertional hyperthermia resulted in similar levels of HSPs in these groups, suggesting that the aged organism retains the ability to accumulate HSPs under certain stress conditions. thus, our guiding hypotheses are that: (a) the aged organism retains the ability to respond to stress through the accumulation of HSPS, and (b) differences in accumulation of HSP70 between young and aged organisms are the result of changes in HSP70 gene regulation. We will examine these hypotheses by: (1) determining if HSP70 accumulation is associated with cell damage following passive and exertional heat stress in senescent vs. mature and young conscious rats; (2) evaluating the effects of hyperthermia and metabolic acidosis on HSP70 synthesis in older rats using primary cell cultures derived from tissue explants; (3) examining if the patterns of translocation of HSPs to the outer cell membrane during heat and metabolic stress are altered in aged rats using flow cytometry techniques; and (4) determining if the loss of post-transcriptional regulation of the HSP gene occurs in older rats. We will use a unique integrated approach that includes whole animal, cellular, and molecular techniques to pursue basic mechanisms in the stress response. By using a variety of state-of-the-art techniques, we will be able to address important mechanistic questions involving stress protein function and regulation, cellular injury, and aging that will have widespread application to numerous clinical problems (heat, stroke, septic shock, cardiovascular disease, etc.) in the aged population. The results of this research will help us to design new therapies to protect the elderly against situations involving physiological stress, and potentially, a variety of diseases associated with aging.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Respiratory and Applied Physiology Study Section (RAP)
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Sierra, Felipe
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University of Iowa
Other Health Professions
Schools of Arts and Sciences
Iowa City
United States
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