On the struggle between chemistry and biology during aging - implications for DNA repair, apoptosis and proteolysis, and a novel route of intervention

The possible effects of specific spontaneous changes in protein chemistry on age-related homeostatic dysfunction are discussed. Spontaneous racemization and isomerization of aspartic acid and deamidation of asparagine to four possible forms of aspartic acid in caspases and their substrates could profoundly alter apoptotic activity. Deamidation of asparagine residues at critically important sites of DNA glycosylases could compromise base excision repair activity. Furthermore, as oxidative damage may enhance asparagine/aspartate instability in proteins, and erroneously-synthesized proteins show increased susceptibility to oxidative attack, it is beginning to appear that the aberrant protein forms that accumulate during ageing are possibly interrelated. The role of cell growth rates in controlling constitutive proteolytic elimination of various forms of aberrant polypeptides is then discussed. Finally, it is pointed out that three recently described agents that delay senescence in cultured cells (aminoguanidine, N-t-butylhydroxylamine and kinetin) resemble carnosine in that they are also likely to react with glycoxidised proteins, as well as possess anti-oxidant activity. These observations suggest that pluripotency may be a necessary pre-requisite for effective anti-ageing activity.