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

Nicholas A Carlini·Brady E Hanson·Bradley A Ruple·Jesse C Craig·Caitlin C Fermoyle·Alec I McKenzie·Angela V Bisconti·Edward Z Pelka·Mark A Supiano·Eric Tuday·Russell S Richardson·Micah J Drummond·Namakkal S Rajasekaran·Ryan M Broxterman·Joel D Trinity
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Abstract

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&#x202f;&#xb1;&#x202f;7&#x202f;y) and 24 older adults (12M/12F, age 67&#x202f;&#xb1;&#x202f;8&#x202f;y) were randomized to receive either placebo or PB125 (200&#x202f;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&#x202f;&#xb1;&#x202f;1.5 to 3.8&#x202f;&#xb1;&#x202f;1.3%, p&#x202f;<&#x202f;0.0001) and popliteal FMD (PB125: 1.5&#x202f;&#xb1;&#x202f;1.5 to 2.3&#x202f;&#xb1;&#x202f;1.4%, p&#x202f;=&#x202f;0.033) in older, but not younger adults (both, p&#x202f;>&#x202f;0.27). During bed rest, PB125 preserved brachial (3.8&#x202f;&#xb1;&#x202f;1.3 to 3.6&#x202f;&#xb1;&#x202f;1.4%, p&#x202f;=&#x202f;0.543) and popliteal FMD (2.3&#x202f;&#xb1;&#x202f;1.4 to 2.7&#x202f;&#xb1;&#x202f;1.4%, p&#x202f;=&#x202f;0.269), LVC (1.1&#x202f;&#xb1;&#x202f;0.8 to 1.1&#x202f;&#xb1;&#x202f;1.5 AUC, p&#x202f;=&#x202f;0.530) and circulating SOD concentrations (28.3&#x202f;&#xb1;&#x202f;7.2 to 28.6&#x202f;&#xb1;&#x202f;8.6 U/mL, p&#x202f;=&#x202f;0.888) in older adults compared to placebo (all, p&#x202f;<&#x202f;0.05). Following limb immobilization, PB125 preserved popliteal FMD (4.4&#x202f;&#xb1;&#x202f;2.8 to 3.4&#x202f;&#xb1;&#x202f;1.8%, p&#x202f;=&#x202f;0.302) in younger adults compared to placebo (p&#x202f;<&#x202f;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.

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HumansNF-E2-Related Factor 2FemaleEndothelium, VascularAgingMaleAgedAdultMiddle AgedVasodilationDouble-Blind MethodBed RestSuperoxide DismutaseYoung AdultPhysical inactivityRedox balanceVascular functionJournal ArticleRandomized Controlled Trial

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Nicholas A Carlini, Brady E Hanson, Bradley A Ruple, Jesse C Craig, Caitlin C Fermoyle, Alec I McKenzie, Angela V Bisconti, Edward Z Pelka, Mark A Supiano, Eric Tuday, Russell S Richardson, Micah J Drummond, Namakkal S Rajasekaran, Ryan M Broxterman, Joel D Trinity. 2026-05-07. Targeted Nrf2 activation improves vascular endothelial function with aging and prevents vascular dysfunction following disuse in younger and older adults.. https://doi.org/10.1016/j.freeradbiomed.2026.05.282

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Journal Article; Randomized Controlled Trial resourceAdult subjectAged subjectAging subjectDouble-Blind Method subjectFemale subjectHumans subjectJournal Article subjectMale subjectMiddle Aged subjectRandomized controlled trials study

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