O-Glcnacylation: Nutrient Sensor in Chronic Diseases of Aging

O-linked N-acetylglucosamine (O-GlcNAc) is a dynamic nutrient sensor that regulates nearly all aspects of cellular physiology (see ►“O-GlcNAcylation: Nutrient Sensor that Regulates Cell Physiology”). Recent studies have shown that abnormal O-GlcNAcylation underlies the etiology of major diseases of aging, such as cancer, Alzheimer’s disease (AD), and diabetes (see ►“Diabetes and O-GlcNAcylation”). Increased O-GlcNAcylation is a hallmark of all cancer types examined to date, and the glycan regulates metabolism, growth signaling cascades, oncogene proteins, tumor-suppressor proteins, and cell division. O-GlcNAcylation is particularly abundant in normal brain, where it regulates synaptic functions, learning and memory, and modulates functions of cytoskeletal proteins. In aging brains and in AD neurons, in particular, glucose utilization is dramatically reduced, leading directly to reduced O-GlcNAcylation. Reduced O-GlcNAcylation promotes hyperphosphorylation of brain proteins, such as tau, neurofilaments, and other proteins, leading to neurofibrillary tangle formation and neuronal death. In contrast to the protective roles of O-GlcNAc in brain, prolonged high levels of O-GlcNAcylation, as occurred in obesity and diabetes, contribute directly to nutrient toxicity and cardiovascular disease. Homeostatic balance between O-GlcNAcylation and phosphorylation appears to be critical for maintenance of cellular health, particularly as we age.