NAD+ and metabolic regulation of age-related proteoxicity: A possible role for methylglyoxal?

A common biochemical characteristic of aging is proteotoxicity i.e. the accumulation of altered proteins. While many studies have shown that NAD+ is important when lifespan is modulated by dietary means, it is uncertain whether or how NAD+ affects either formation or elimination of altered proteins. It is suggested here that changes in NAD+ availability can affect generation of methylglyoxal (MG) from glycolytic intermediates, which in turn can damage proteins, promote generation of reactive oxygen species and induce mitochondrial dysfunction. The proposal can also help to explain how, by altering NAD+ regeneration from NADH, dietary supplementation with glycerol or glucose, which decreases lifespan in the nematode Caenorhabditis elegans, could cause MG generation to increase, whereas oxaloacetate supplementation, which increases lifespan, could lower the potential for MG formation. The proposal also suggests how upregulation of mitogenesis and mitochondrial activity, and increased aerobic activity, help to decrease the potential for MG formation and resultant proteotoxicity, with consequential beneficial effects with respect to aging.