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Published on: May 9, 2015
Keap1/Nrf2 signaling regulates oxidative stress tolerance and lifespan in Drosophila
Gerasimos P Sykiotis1, Dirk Bohmann
1Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.
Abstract:
Keap1/Nrf2 signaling defends organisms against the detrimental effects of oxidative stress and has been suggested to abate its consequences, including aging-associated diseases like neurodegeneration, chronic inflammation, and cancer. Nrf2 is a prominent target for drug discovery, and Nrf2-activating agents are in clinical trials for cancer chemoprevention. However, aberrant activation of Nrf2 by keap1 somatic mutations may contribute to carcinogenesis and promote resistance to chemotherapy. To evaluate potential functions of Keap1 and Nrf2 for organismal homeostasis, we characterized the pathway in Drosophila. We demonstrate that Keap1/Nrf2 signaling in the fruit fly is activated by oxidants, induces antioxidant and detoxification responses, and confers increased tolerance to oxidative stress. Importantly, keap1 loss-of-function mutations extend the lifespan of Drosophila males, supporting a role for Nrf2 signaling in the regulation of longevity. Interestingly, cancer chemopreventive drugs potently stimulate Drosophila Nrf2 activity, suggesting the fruit fly as an experimental system to identify and characterize such agents.
Insights
The Keap1/Nrf2 pathway protects against oxidative stress. Loss of keap1 in fruit flies extended lifespan, suggesting Nrf2 signaling regulates longevity and offers a model for studying cancer chemopreventive drugs.
Area of Science:
- Molecular biology
- Genetics
- Aging research
Background:
- Keap1/Nrf2 signaling protects against oxidative stress and aging-related diseases.
- Nrf2 is a drug target for cancer chemoprevention, but its aberrant activation can promote cancer.
- The role of Keap1/Nrf2 in organismal homeostasis requires further investigation.
Purpose of the Study:
- To characterize Keap1/Nrf2 pathway function in Drosophila.
- To investigate the role of Keap1/Nrf2 signaling in longevity and stress tolerance.
- To assess the utility of Drosophila as a model for identifying cancer chemopreventive agents.
Main Methods:
- Drosophila melanogaster as a model organism.
- Analysis of Keap1/Nrf2 pathway activation by oxidants.
- Assessment of oxidative stress tolerance.
- Lifespan analysis of keap1 loss-of-function mutants.
- Testing of cancer chemopreventive drugs for Nrf2 activation.
Main Results:
- Keap1/Nrf2 signaling in Drosophila is activated by oxidants.
- This pathway induces antioxidant and detoxification responses, increasing oxidative stress tolerance.
- keap1 loss-of-function mutations significantly extended lifespan in male flies.
- Cancer chemopreventive drugs effectively stimulated Drosophila Nrf2 activity.
Conclusions:
- Keap1/Nrf2 signaling plays a conserved role in oxidative stress response and longevity regulation.
- Drosophila serves as a valuable model for studying Nrf2-mediated longevity and for discovering chemopreventive drugs.
- Targeting Keap1/Nrf2 may offer therapeutic strategies for aging-associated diseases and cancer.
