Targeted Nrf2 activation improves vascular endothelial function with aging and prevents vascular dysfunction following disuse in younger and older adults

Aging and physical inactivity/disuse contribute to cardiovascular disease, which is attributable, in part, to vascular endothelial dysfunction associated with impaired nuclear-factor erythroid 2-related factor 2 (Nrf2) signaling. However, the ability to augment Nrf2 activation and its effects on age- and disuse-related vascular dysfunction in humans remains limited. In a double-blind, randomized, placebo-controlled study design 20 younger adults (8M/12F, age 27±7 y) and 24 older adults (12M/12F, age 67±8 y) were randomized to receive either placebo or PB125 (200 mg/day, Nrf2 activator) across three visits: baseline, 2 weeks of supplementation, and following either 5 days of bed rest (old) or 2 weeks of limb immobilization (young). Brachial and popliteal artery flow-mediated dilation (FMD), passive leg movement-induced (PLM) leg blood flow (LBF) and vascular conductance (LVC) and serum antioxidant status (superoxide dismutase, SOD) were assessed at each timepoint. Compared to placebo, 2 weeks of PB125 increased brachial (PB125: 2.8±1.5 to 3.8±1.3%, p<0.0001) and popliteal FMD (PB125: 1.5±1.5 to 2.3±1.4%, p=0.033) in older, but not younger adults (both, p>0.27). During bed rest, PB125 preserved brachial (3.8±1.3 to 3.6±1.4%, p=0.543) and popliteal FMD (2.3±1.4 to 2.7±1.4%, p=0.269), LVC (1.1±0.8 to 1.1±1.5 AUC, p=0.530) and circulating SOD concentrations (28.3±7.2 to 28.6±8.6 U/mL, p=0.888) in older adults compared to placebo (all, p<0.05). Following limb immobilization, PB125 preserved popliteal FMD (4.4±2.8 to 3.4±1.8%, p=0.302) in younger adults compared to placebo (p<0.05). These findings demonstrate targeted Nrf2 activation with PB125 improves age-related vascular endothelial dysfunction while preserving vascular function and antioxidant capacity following periods of disuse.