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Considerable evidence points to macular oxidative stress as a key driver of age-related macular degeneration (AMD).  In particular, retinal pigmented epithelial (RPE) cells subjected to oxidative stress are prone to apoptosis or senescence; lose their tight junctions; decrease their production of factors which provide trophic support for retinal photoreceptors, suppress choroidal neovascularization, and control complement activation; and boost their production of vascular endothelial growth factor (VEGF), a major stimulant to neovascularization – all effects which are consistent with the pathogenesis of AMD.  There is good reason to suspect that NADPH oxidase activity in RPE cells is the key source of the oxidative stress that compromises RPE function in AMD.   Studies with other cell lines indicate that a number of risk factors for AMD – including cigarette smoke, homocysteine, hyperglycemia, cadmium, and up-regulated activation of the alternative complement cascade – have the ability to stimulate NADPH oxidase activity, as does all-trans-retinal, a suspected pathogenic factor in AMD.  Hence, measures which can down-regulate NADPH oxidase activity may have potential for preventing or controlling AMD.  These may include high-dose statins – found to reverse features of early AMD in about half of patients in a recent pilot study – and spirulina, a rich source of the chromophore phycocyanobilin (PhyCB ).  PhyCB is a biliverdin derivative that can mimic the intracellular physiological role of bilirubin as an NADPH oxidase inhibitor.  Patients with Gilbert syndrome or relatively high plasma unconjugated bilirubin may be at lower risk for AMD owing to bilirubin’s inhibitory impact on NADPH oxidase; this prediction could be readily tested in epidemiological studies.