. A reversible early oxidized redox state that precedes macromolecular ROS damage in aging nontransgenic and 3xTg-AD mouse neurons. J Neurosci. 2012 Apr 25;32(17):5821-32. PubMed.

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  1. Just to be clear, in our paper, we show that nicotinamide acts as a precursor to more NAD(P) and NAD(P)H, not as an antioxidant. More importantly, we begin to advance the concept that redox is not synonymous with reactive oxygen species (ROS). Redox is the relative strength of accepting or donating electrons. ROS are only produced as byproducts of redox reactions. Redox reactions are essential for metabolism. Some ROS are essential for numerous cellular signaling reactions (Finkel, 2003), and most ROS are detoxified by endogenous antioxidants. Hence, ROS levels are the net result of rates of production and detoxification. Our results show that neuron ROS levels did not change with age before six months when others have found cognitive deficits in the mice we studied, while redox agents NADH and glutathione did change at early ages. Therefore, antioxidants do not directly affect the redox reaction; they only consume the byproducts. We show that nicotinamide is most directly a precursor for NAD+ and, hence, NADH and NADPH, not an antioxidant. Given the failure of antioxidant treatments for AD, cancer, heart disease, and aging, antioxidants that lower ROS may only be targeting a secondary byproduct for which redox state is more proximal to the metabolic deficits of these age-related diseases. Therefore, treating AD with antioxidants may be no better than treating gray hair with hair dye.

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