Carnosine: can understanding its actions on energy metabolism and protein homeostasis inform its therapeutic potential?

Abstract

The dipeptide carnosine (β-alanyl-L-histidine) has contrasting but beneficial effects on cellular activity. It delays cellular senescence and rejuvenates cultured senescent mammalian cells. However, it also inhibits the growth of cultured tumour cells. Based on studies in several organisms, we speculate that carnosine exerts these apparently opposing actions by affecting energy metabolism and/or protein homeostasis (proteostasis). Specific effects on energy metabolism include the dipeptide's influence on cellular ATP concentrations. Carnosine's ability to reduce the formation of altered proteins (typically adducts of methylglyoxal) and enhance proteolysis of aberrant polypeptides is indicative of its influence on proteostasis. Furthermore these dual actions might provide a rationale for the use of carnosine in the treatment or prevention of diverse age-related conditions where energy metabolism or proteostasis are compromised. These include cancer, Alzheimer's disease, Parkinson's disease and the complications of type-2 diabetes (nephropathy, cataracts, stroke and pain), which might all benefit from knowledge of carnosine's mode of action on human cells.

Figure 1

(A) Structure of L-carnosine, the dipeptide β-alanyl-L-histidine; (B) structure of methylgloxal (2-oxopropanal).

Figure 2

An overview of glycolysis by which the conversion of glucose to pyruvate is coupled to the production of ATP for energy and NADH for biosynthesis. The entry of glycerol into the glycolytic pathway is also shown. The scheme indicates the hypothetical action of carnosine in the activation of fructose 1,6-bisphosphatase to create a futile, ATP-consuming, cycle which also inhibits glycolytic ATP generation.

Figure 3

Metabolic sources of methylglyoxal (MG) and the possible role of carnosine in scavenging MG and suppressing the formation of protein-AGEs. Protein-AGEs cause inflammation and ageing. MG-carnosine is excreted in urine.

Figure 4

The possible effects of carnosine on the formation and catabolism of abnormal proteins. MG, methyglyoxal; AGE, advanced glycation end-product; Hsp70, heat shock protein 70 (shown as an example).