Cytomegalovirus (CMV) infection is linked to increased risk of frailty and death in older populations. Despite being correlated to age-related disease, a mechanism linking CMV infection and unhealthy aging is unknown. We have recently reported that CMV infection alters mitochondrial structure and function promoting oxidative stress. CMV infection increases electron transport chain (ETC) activity resulting in elevate reactive oxygen species (ROS). Excess ROSis known to damage proteins and lipids and can induce mutations in mitochondrial DNA. Mitochondrial dysfunction is recognized as a hallmark of aging. This COBRE proposal is designed to identify mechanisms by which CMV exacerbates ROS leak, contributing to age-associated mitochondrial dysfunction. To test our hypothesis, we will integrate multiple model systems to delineate the role of CMV induced ROSon lipid peroxide levels (Specific Aim 1), the contribution of CMV-associated ROSproduction on endogenous mtDNA mutations (Specific Aim 2) and the contribution of lipid peroxides generated during CMV infection to exacerbate aged associated mitochondrial dysfunction (Specific Aim 3). CMV infection occurs for the lifetime of the host and reactivation is frequent throughout the hosts life. This suggests that oxidative stress may promote mitochondrial dysfunction that can accumulate over time. Our aims are designed to generate strong preliminary data to support NIH R01 grant applications. The manipulation of host mitochondria by CMV may clarify the role of CMV as a modulator that promotes unhealthy aging. Thus, fully understanding how a chronic viral infection can exacerbate aging represents a significant public health issue and novel therapeutic approach to both healthy aging and antiviral therapy.