The life span of organisms differs widely among species: C. elegans live 14-25 days, mice for a couple of years, humans into their eighties on average, and organisms such as the giant clam can live upwards of 500 years. There are likely conserved mechanisms that regulate the efficiency of cell function in youth that declines with age, ultimately resulting in systemic and organismal failure and death. In spite of the large number of ideas that have been proposed to account for the loss in efficiency and function as an organism ages, no common integrative theory for aging that is evolutionarily conserved has been advanced and thus, represents a major gap in knowledge. The oxygen paradox highlights the mystery that O2 is so critical a fuel for the metabolic machinery of life, yet so toxic to all forms of life inhabiting this planet. The key to this paradox are the two simple, yet biologically fundamental redox reactions: the first reaction, which is essentially the reverse of photosynthetic water splitting, marks the dawn of eucarya in which mitochondria `respire' oxygen to enzymatically generate proton gradient fueling oxidative phosphorylation and the second reaction where O2 in excess is consumed to generate reactive species that induce damage. To maximize the first reaction and minimize the second, life needed to maintain oxygen levels under tight control. It has been proposed that the evolutionary response to this paradox was to create cholesterol within membranes as a way to ?tame? oxygen and allow for its biologic use as an energy source and as a primary feature that links membranes and metabolism. We hypothesize that caveolin, a scaffolding protein that organizes cholesterol into membrane microdomains, exists as a ?capacitor? to create the efficiency of metabolism in youth through regulation of membrane oxygen and that with aging, caveolin expression is decreased in certain organs, thereby leading to increased oxygen toxicity. We further propose that this toxicity can be limited by re-expression of caveolin in the setting of advanced age. The following specific aims will be studies:
Specific Aim 1 : Determine what aspects of caveolin serve as membrane oxygen capacitors.
Specific Aim 2 : Determine the impact of age and caveolin expression on organ oxygen storage capacity and toxicity.
Oxygen is a toxic molecule in living systems when it is available in excess due to uncontrolled generation of reactive species that induce molecular damage resulting in accelerated aging. However, it is also critical to life as it provides for the generation of energy that fuels biological processes. The goal of this study is to determine the role of caveolin proteins in the molecular regulation of oxygen and the potential to provide for healthy aging.
|Schilling, Jan M; Head, Brian P; Patel, Hemal H (2018) Caveolins as Regulators of Stress Adaptation. Mol Pharmacol 93:277-285|
|Kong, Cherrie H T; Bryant, Simon M; Watson, Judy J et al. (2018) The Effects of Aging on the Regulation of T-Tubular ICa by Caveolin in Mouse Ventricular Myocytes. J Gerontol A Biol Sci Med Sci 73:711-719|