Declining signal dependence of N rf2‐ M af S ‐regulated gene expression correlates with aging phenotypes

Summary Aging is a degenerative process characterized by declining molecular, cell and organ functions, and accompanied by the progressive accumulation of oxidatively damaged macromolecules. This increased oxidative damage may be causally related to an age‐associated dysfunction of defense mechanisms, which effectively protect young individuals from oxidative insults. Consistently, older organisms are more sensitive to acute oxidative stress exposures than young ones. In studies on the Drosophila N rf2 transcription factor C nc C , we have investigated possible causes for this loss of stress resistance and its connection to the aging process. Nrf2 is a master regulator of antioxidant and stress defense gene expression with established functions in the control of longevity. Here, we show that the expression of protective N rf2/ C nc C target genes in unstressed conditions does not generally decrease in older flies. However, aging flies progressively lose the ability to activate N rf2 targets in response to acute stress exposure. We propose that the resulting inability to dynamically adjust the expression of N rf2 target genes to the organism's internal and external conditions contributes to age‐related loss of homeostasis and fitness. In support of this hypothesis, we find the D rosophila small M af protein, M afS, an N rf2 dimerization partner, to be critical to maintain responsiveness of the N rf2 system: overexpression of M afS in older flies preserves N rf2/ C nc C signaling competence and antagonizes age‐associated functional decline. The maintenance of acute stress resistance, motor function, and heart performance in aging flies overexpressing M af S supports a critical role for signal responsiveness of N rf2 function in promoting youthful phenotypes.