For the past 40 years or so, oxidative stress has been increasingly recognized as a contributing factor in aging and in various forms of pathophysiology generally associated with aging. Our view of oxidative stress has been largely "
superoxide-centric", as we focused on the pathological sources of this
oxygen-derived
free radical and the types of molecular havoc it can wreak, as well as on the protection provided by the
antioxidant enzymes, especially the
superoxide dismutases, catalases, and
glutathione peroxidases. In the last decade our view of oxidative stress has broadened considerably, and it is now often seen as an imbalance that has its origins in our genes, and the ways in which gene expression is regulated. At the center of this new focus is the
transcription factor called nuclear factor (erythroid-derived 2)-like 2, or Nrf2. Nrf2 is referred to as the "master regulator" of the
antioxidant response, modulating the expression of hundreds of genes, including not only the familiar
antioxidant enzymes, but large numbers of genes that control seemingly disparate processes such as immune and inflammatory responses, tissue remodeling and
fibrosis,
carcinogenesis and
metastasis, and even
cognitive dysfunction and addictive behavior. Thus, the dysregulation of Nrf2-regulated genes provides a logical explanation for the connections, both direct and indirect, between observable oxidative stress and perhaps 200 human diseases involving these various physiological processes, each reflecting a network involving many gene products. The evolutionary self-association of these many genes under the common control of Nrf2 suggests that the immune and inflammatory systems may present the largest demand for increased
antioxidant protection, apart from constitutive oxidative stress resulting from mitochondrial oxygen consumption for metabolic purposes. Gene expression microarray data on human primary vascular endothelial cells and on the SK-N-MC human
neuroblastoma-derived cell line have been obtained in response to the dietary supplement
Protandim, a potent composition of highly synergistic
phytochemical Nrf2 activators. Pathway analysis of results shows significant modulation by
Protandim of pathways involving not only
antioxidant enzymes, but of those related to
colon cancer,
cardiovascular disease, and
Alzheimer disease.