Aging impairs induction of redox factor-1 after heat stress: a potential mechanism for heat-induced liver injury

Aging is associated with reduced tolerance to physiological stressors such as hyperthermia. In animal models, heat stress is associated with increased oxidative damage in the livers of old rats. In this study, we evaluated the expression of redox factor-1 (Ref-1), a DNA repair enzyme, and thioredoxin-1 (Trx-1), an antioxidant protein. We hypothesized that these proteins would be induced by heat stress in young animals, and that aging would attenuate this response. Young (6 mo) and old (24 mo) male Fischer 344 rats were exposed to a two-heat stress protocol, and livers were harvested at several time points after the second heat stress. Ref-1 and Trx-1 were evaluated by immunoblot and immunohistochemistry. In young rats, Ref-1 was induced by ~50% immediately (0 h) after heat stress, and returned to control levels at 2 h. We observed no change in Ref-1 after hyperthermia in old rats; however, aging was associated with a 2-fold increase in Ref-1 expression. At 2 h after heat stress, Trx-1 was increased in old rats, but there was no change in young rats. In tissue sections, we observed frequent ductular reactions in the old rats that were positive for both Ref-1 and Trx-1. The impairment in the induction of Ref-1 suggests a mechanism for the increased oxidative injury observed in old rats after heat stress. Furthermore, the observation of ductular reactions positive for both Ref-1 and Trx-1 demonstrates a proliferative cellular niche that develops with aging.