Aging-proteotoxicity-mitochondria-glycation-NAD

Aging, proteotoxicity, mitochondria, glycation, NAD and

It is suggested that NAD+ availability strongly affects cellular aging and organism lifespan: low
NAD+ availability increases intracellular levels of glycolytic triose phosphates (glyceraldehyde-
3-phosphate and dihydroxyacetone-phosphate) which, if not further metabolized, decompose
spontaneously into methylglyoxal (MG), a glycating agent and source of protein and mitochondrial
dysfunction and reactive oxygen species (ROS). MG-damaged proteins and other aberrant
polypeptides can induce ROS generation, promote mitochondrial dysfunction and inhibit
proteasomal activity. Upregulation of mitogenesis and mitochondrial activity by increased aerobic
exercise, or dietary manipulation, helps to maintain NAD+ availability and thereby decreases
MG-induced proteotoxicity. These proposals can explain the apparent paradox whereby aging is
seemingly caused by increased ROS-mediated macromolecular damage but is ameliorated by
increased aerobic activity. It is also suggested that increasing mitochondrial activity decreases
ROS generation, while excess numbers of inactive mitochondria are deleterious due to increased
ROS generation. The muscle- and brain-associated dipeptide, carnosine, is an intracellular buffer
which can delay senescence in cultured human fi broblasts and delay aging in senescenceaccelerated
mice. Carnosine’s ability to react with MG and possibly other deleterious carbonyl
compounds, and scavenge various ROS, may account for its protective ability towards ischemia
and ageing.

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