Treatment strategy to enhance Nrf2 signaling in older adults: combining acute exercise with the phytochemical sulforaphane - PROJECT SUMMARY:
Redox balance plays a key role in the age-associated increased risk for diseases. One reason for the lower
resistance to oxidative stress with age is a gradual shift in the redox state toward a more oxidized cellular
environment resulting in disruption of cell signaling. Nuclear erythroid factor 2-related factor 2 (Nrf2) is the master
regulator of antioxidant defenses. Nrf2 drives expression of a host of genes involved in cytoprotection and
antioxidant defenses. Our lab was the first to demonstrate Nrf2 activation in response to acute exercise in
humans, and in agreement with animal data, we found an age-related impairment in exercise-induced Nrf2
signaling. This underscores an important problem related to aging, namely that older individuals are less
sensitive to an exercise stimulus compared to younger cohorts. The focus of the proposed study is to try to solve
this problem by amplifying the signal and mitigating the “exercise desensitization” exhibited by older individuals
to restore redox balance. This study will test the hypothesis that combining acute exercise with sulforaphane
will improve Nrf2 activation and downstream signaling in older adults compared to either alone. Sulforaphane is
a phytonutrient found in high concentrations in cruciferous vegetables and a potent Nrf2 activator. The
hypothesis will be tested using two different approaches; the first experiment will use an in vivo–ex vivo approach,
where peripheral blood mononuclear cells (PBMCs) collected from older men and women (≥60y, n=30) pre- and
post-acute exercise (in vivo) will be cultured and stimulated with SFN (ex vivo). This allows for a greater
experimental control of the SFN stimulus. The second experiment will test the clinical translation applying the
sulforaphane stimulus in vivo through an oral supplementation of sulforaphane in the form of whole broccoli
sprout material, prior to acute exercise, in the same individuals. This second experiment will be a randomized
placebo-controlled cross-over design. For all trials Nrf2 signaling will be measured by Nrf2 activation through an
ARE binding assay, nuclear to whole cell ratio of Nrf2 protein, and Nrf2-dependent gene expression (HO-1,
GCLC, NQO1, GR). Potential sex differences will be investigated. The insights gained from this study are
whether combining simple interventions in the category of healthy lifestyle and preventive medicine can improve
the adaptive response to exercise in older individuals. This could have an enormous impact by improving the
health and well-being of older Americans, an important mission of the National Institutes of Aging.
