Disuse following injury, illness, or surgery is linked to functional deficiencies, hospital readmission, impaired recovery, and increased mortality. Older Veterans are particularly vulnerable to disuse as functional (vascular and skeletal muscle mitochondrial dysfunction) and structural (loss in muscle mass and strength) deficits are present as a consequence of the aging process. The accelerated declines that occur during disuse further deplete an already diminished physiological and functional reserve capacity. Current skeletal muscle-focused strategies to mitigate atrophy and losses in strength are ineffective and the mechanism(s) contributing to accelerated losses are unknown. Therefore, identifying the mechanism(s) and developing effective strategies to minimize losses in vascular and skeletal muscle function, systems that are inextricably linked to mobility, disease progression, and health, is critical to delay the onset of disability and preserve the health of older adults. Supported by preliminary and previous data, it is our central hypothesis that oxidative stress triggers the accelerated declines in vascular and skeletal muscle function during disuse. To mechanistically and comprehensively identify the obligatory role of oxidative stress in disuse-induced dysfunction two novel and fundamentally unique approaches to diminish oxidative stress are proposed including; 1) a mitochondrial targeted antioxidant (MitoQ; Aim 1) and 2) the nuclear factor erythroid-2-like 2 (Nrf2) activator, PB125 (Aim 2). A total of 72 healthy older men and women (> 65 yrs.) will be block randomized to 3 groups; CONTROL, MitoQ, and PB125. Five days of bed rest, a model of disuse mimicking acute hospitalization, will be used to evoke oxidative stress and losses in vascular and skeletal muscle function. In Specific Aim 1, participants will receive MitoQ (consisting of mitoquinone) during 5 days of bed rest. It is expected that MitoQ will blunt the increase in oxidative stress by limiting mitochondrial-derived reactive oxygen species (ROS) production leading to preserved vascular and skeletal muscle function, thereby revealing a critical role of mitochondrial-derived ROS. In Specific Aim 2, the novel Nrf2 activator, PB125, will be administered during 5 days of bed rest. It is expected that activation of Nrf2 with PB125 will restore the age-related dysfunction of the Nrf2 signaling pathway resulting in the induction of endogenous antioxidant enzymes that will, in turn, maintain redox balance induced by disuse. The primary outcome measure for both aims is the assessment of vascular function as measured by passive leg movement (PLM). Secondary outcome measures will assess the contributions of oxidative stress to the observed changes in vascular and skeletal muscle function before and after bed rest and will include direct measurements of free radicals, mitochondrial function and hydrogen peroxide production, markers of oxidative stress at the cellular, tissue, and syste...