arNOX: A New Source of Aging

Abstract

An aging-related ENOX protein arNOX (ENOX3) of the cell surface and endosomes shed into body fluids increases in activity linearly with age beginning at about 30 years to a maximum at about age 65. Subjects surviving beyond age 65 frequently have reduced arNOX activity. As is characteristic of other ENOX proteins, arNOX proteins reduce molecular oxygen to water and carry out protein disulfide exchange. A property unique to arNOX proteins is the ability to transfer electrons to oxygen to form superoxide during part of the functional cycle. By generating reactive oxygen species at the cell surface and in body fluids (saliva, serum, perspiration, urine), arNOX provides a mechanism to propagate reactive oxygen species at the cell surface to surrounding cells as occurs in skin aging and to circulating serum lipoproteins of importance to atherogenesis. Five family members identified in yeast and humans have been cloned. The arNOX proteins are synthesized as membrane-anchored proteins with their catalytic N-terminus directed toward the cell’s exterior. A ca. 30-kDa fragment is shed and enters the blood and other body fluids or is internalized into endosomes. With cells and tissue, the source of electrons and cells would be plasma membrane electron transport. With body fluids, the ultimate source of electrons for the reduction of ferricytochrome c appears to be protein thiols and tyrosines. arNOX proteins share many properties with other ENOX proteins including the oscillatory pattern of activity (26-min period), resistance to N-terminal sequencing and chemical degradation, and a propensity of the purified proteins to aggregate. arNOX proteins are widely distributed among aged systems including late passage cultured cells.