Exercise-induced Nrf2-signaling is impaired in aging

Purpose: The transcription factor nuclear erythroid-2 like factor-2 (Nrf2) is the master regulator of antioxidant defense. Data from animal studies suggest exercise elicits significant increases in Nrf2 signaling, and that signaling is impaired with aging resulting in decreased induction of phase II detoxifying enzymes and greater susceptibility to oxidative damage. We have previously shown that older adults have lower resistance to an oxidative challenge as compared to young, and that this response is modified with physical fitness and phytonutrient intervention. We hypothesized that a single bout of submaximal exercise would elicit increased nuclear accumulation of Nrf2, and that this response to exercise would be attenuated with aging.

Methods: Nrf2 signaling in response to 30-min cycling at 70% VO2max was compared in young (23±1y, n=10) and older (63±1, n=10) men. Blood was collected at six time points; pre-exercise, and 10min, 30min, 1h, 4h, and 24h post-exercise. Nrf2 signaling was determined in peripheral blood mononuclear cells by measuring protein expression by western blot of Nrf2 in whole cell and nuclear fractions, and whole cell SOD1, and HMOX, as well as gene expression (RT-PCR) of downstream Nrf2-ARE antioxidants SOD1, HMOX, and NQO1.

Results: Baseline differences in protein expression did not differ between groups. The exercise trial elicited significant increase in whole cell Nrf2 (P=0.003) for both young and older groups. Nuclear Nrf2 levels were increased significantly in the young but not older group (P=0.031). Exercise elicited significant increases in gene expression of HMOX1 and NQO1 in the young (P=0.006, and P=0.055, respectively) whereas gene expression in the older adults was repressed. There were no significant differences in SOD1 or HMOX1 protein expression.

Conclusion: These findings indicate a single session of submaximal aerobic exercise is sufficient to activate Nrf2 at the whole cell level in both young and older adults, but that nuclear import is impaired with aging. Additionally we have shown repressed gene expression of downstream antioxidant targets of Nrf2 in older adults. Together these translational data demonstrate for the first time the attenuation of Nrf2 activity in response to exercise in older adults.