ZIP-5/Bach1 antagonizes SKN-1/Nrf2 in development and longevity

Many of the genes involved in aging are also involved in embryonic development. These same genes have been linked to cancer development (carcinogenesis). An example of such a gene is daf-2, which is the worm version of the human insulin and insulin-like growth factor receptor. When this gene is mutated in worms (C. elegans), they live twice as long. Victor Jensen studies genes regulated by daf-2 in order to find new genes implicated in longevity. He has identified a gene called zip-5 that, when mutated, allows worms to live 25-35 per cent longer and remain healthier. zip-5’s ability to extend longevity depends on the function of another gene called skn-1. SKN-1 has several functions: it contributes to embryonic gut development, it regulates stress response and is implicated in increased longevity that results from dietary restriction. The human counterpart to SKN-1 is called Nrf2, which regulates stress resistance in human cell lines. Nrf2 also provides a chemoprotective effect against carcinogenesis, injury and inflammation. The action of Nrf2 is opposed by a gene called Bach1 – the human counterpart of the worm zip-5 gene. Inhibiting Bach1 allows for easier activation of Nrf2 target genes, resulting in a stronger chemoprotective effect in cancer. Jensen’s research genetically characterizes this antagonistic relationship and identifies the novel role of zip-5 in longevity and development. He is working to determine whether the Bach1/Nrf2 relationship is parallel to the zip-5/skn-1 relationship in C. elegans, and whether it explains zip-5’s effect on longevity. He hopes his research will reveal a new role for zip- 5/Bach1 in development and longevity, and open the door to new studies looking at how Bach1 inhibition affects carcinogenesis and aging.