Effect of Oxidative Stress on Lifespan and Cellular Survival

When cells experience oxidative stress, the integrated stress response (ISR) signaling pathway is activated. One of the first outcomes of such ISR-activated response is to temporarily halt protein synthesis, which aids in cellular recovery. However, if cells cannot recover from the stress, they activate the cell death pathways which kills the affected cells, usually by apoptosis, which can then lead to either acquisition or prevention of diseases depending on the situation. In physiological aging, a compromised stress response is observed as an organism ages, which leads to disrupted homeostasis and elevated risk of disease. Thus, longevity of an organism is directly related to its ability to effectively cope with cellular stressors such as oxidative stress. Intracellular reactive oxygen species (ROS) resulting from normal metabolism cause most damage to cellular macromolecules and the mitochondria play a central role in this process as they are the principal source of ROS. Under the oxidative stress umbrella, this thesis is divided into two parts; 1) evaluating if oxidative stress contributes to aging and lifespan using a Daphnia as model for aging research and 2) exploring the regulatory role of PKR in determining cellular survival in response to oxidative stress in mammalian cells. The relationship between naturally occurring variations in the mitochondrial (MT) genomes leading to differences in the rate of aging associated organismal decline remains relatively unexplored. MT complex I, a vii component of electron transport chain (ETC), is a key source of ROS and the NADH dehydrogenase subunit 5 (ND5) is a highly conserved core protein of the essential subunits that constitute the backbone of complex I. We explored if there are naturally occurring, inherited sequence variations in ND5 that may correlate with a short or long lifespan. Our results indicate that the short-lived clones have ND5 variants that correlate with reduced complex I activity, increased oxidative damage to proteins, and heightened expression of ROS scavenger enzymes