Aging and the role of reactive nitrogen species.

The role of reactive oxygen species and its effects on aging has received considerable attention in the past 47 years since Dr. Denham Harman first proposed the "free radical theory of aging." Though not completely understood due to the incalculable number of pathways involved, the number of manuscripts that facilitate the understanding of the underlying effects of reactive radical species on the oxidative stress on lipids, proteins, and DNA and its contribution to the aging process increases nearly exponentially each year. More recently, the role of reactive nitrogen species, such as nitric oxide and its by-products--nitrate (NO3-), nitrite (NO2-), peroxynitrite (ONOO-), and 3-nitrotyrosine--have been shown to have a direct role in cellular signaling, vasodilation, and immune response. Nitric oxide is produced within cells by the actions of a group of enzymes called nitric oxide synthases. Presently, there are three distinct isoforms of nitric oxide synthase: neuronal (nNOS or NOS-1), inducible (iNOS or NOS-2), and endothelial (eNOS or NOS-3), and several subtypes. While nitric oxide (NO*) is a relative unreactive radical, it is able to form other reactive intermediates, which could have an effect on protein function and on the function of the entire organism. These reactive intermediates can trigger nitrosative damage on biomolecules, which in turn may lead to age-related diseases due to structural alteration of proteins, inhibition of enzymatic activity, and interferences of the regulatory function. This paper will critically review the evidence of nitration and the important role it plays with aging. Furthermore, it will summarize the physiological role of nitration as well as the mechanisms leading to proteolytic degradation of nitrated proteins within biological tissues.