Biological aspects of ageing

Abstract

This contribution discusses the possible causes of ageing and the processes that may control it. It is argued that ageing is multifactorial, resulting from cellular and molecular homeostatic dysfunction. It is suggested that the intrinsic instability of DNA and proteins, as well as the effects of endogenous and exogenous agents upon them, provide the ultimate source of homeostatic decline, resulting in age-related increases in DNA damage and aberrant protein molecules. Particularly important are oxygen free radicals, often originating in mitochondria, which, if not eliminated by antioxidant defence systems (enzymic and non-enzymic), can damage lipids, proteins and DNA, especially within mitochondria. Glucose and other molecules possessing reactive carbonyl groups can also damage proteins and DNA. If not rapidly eliminated by the proteasome-mediated proteolysis, some oxidized proteins can form crosslinked species which inhibit proteasomal activity, thereby compromising cellular homeostasis, including removal of damaged mitochondria. Normal ageing is characterized by a decline in an organism's ability to repair damaged DNA and eliminate the altered protein forms, especially in non-mitotic tissues. Age-related compromise in the removal of altered proteins contributes to neurodegenerative conditions (Alzheimer's, Parkinson's and Huntington's diseases) whose pathologies are associated with aggregated aberrant proteins molecules. Caloric restriction can delay ageing and its associated homeostatic decline (at least in animal models), possibly due to the up-regulatory effects of substantially lowered insulin levels on proteolysis. It is also suggested that absolute perfection in DNA repair and removal of altered protein forms could theoretically inhibit ageing, but this is incompatible with evolution.