A NETWORK THEORY OF AGING - THE INTERACTIONS OF DEFECTIVE MITOCHONDRIA, ABERRANT PROTEINS, FREE-RADICALS AND SCAVENGERS IN THE AGING PROCESS

Evolution theory indicates that ageing is caused by progressive accumu lation of defects, since the evolutionary optimal level of maintenance is always below the minimum required for indefinite survival. Evoluti onary theories also suggest that multiple processes are operating in p arallel, but unfortunately they make no predictions about specific mec hanisms. To understand and evaluate the many different mechanistic the ories of ageing which have been proposed, it is therefore important to understand and study the network of maintenance processes which contr ol cellular homeostasis. In this paper we describe a Network Theory of Ageing which integrates the contributions of defective mitochondria, aberrant proteins, and free radicals to the ageing process, and which includes the protective effects of antioxidant enzymes and proteolytic scavengers. The model simulations not only confirm and explain many e xperimental, age related findings like an increase in the fraction of inactive proteins, a significant rise in protein half-life, an increas e in the amount of damaged mitochondria, and a drop in the energy gene ration per mitochondrion, but they also show interactions between the different theories which could not have been observed without the netw ork approach. In some simulations, for example, the mechanism of the f inal breakdown seems to be a consequence of the cooperation of mitocho ndrial and cytoplasmic reactions, the mitochondria being responsible f or a long term, gradual change which eventually triggers a short lived cytoplasmic error loop.