Nrf2‐regulated antioxidant defenses in rodent models of longevity

Abstract

Lifespan is extended by rapamycin treatment, caloric restriction (CR), crowded litter (CL), and in genetic models such as the Snell Dwarf mouse. Various mechanisms have been proposed by which lifespan is extended in these rodent models, including improved antioxidant defenses. The transcription factor nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) has been suggested to be the “master regulator” of cellular antioxidant defenses. However, whether these rodent longevity models show enhanced Nrf2 activation and antioxidant enzyme expression is unknown. The purpose of this study was to determine the expression of Nrf2 and ARE‐regulated antioxidant enzymes in four rodent models of longevity. Endogenous antioxidant enzyme and Nrf2 expression were not consistently increased in long‐lived animals, with considerable variation existing between models. While Nrf2 and its targets were greater than controls in Snell liver and heart, antioxidant defenses were significantly lower than controls across all tissues in CL animals. CR resulted in increased antioxidant defenses in some, but not all, tissues. Rapamycin did not affect Nrf2‐regulated enzymes, but expression differed between sexes. Not all models of longevity displayed similar Nrf2‐regulated antioxidant enzymes and these data suggest that sex, age, and tissue specific differences must be considered with regard to antioxidant capacity and longevity.