A network theory of ageing: the interactions of defective mitochondria, aberrant proteins, free radicals and scavengers in the ageing process.

Evolution theory indicates that ageing is caused by progressive accumulation of defects, since the evolutionary optimal level of maintenance is always below the minimum required for indefinite survival. Evolutionary theories also suggest that multiple processes are operating in parallel, but unfortunately they make no predictions about specific mechanisms. To understand and evaluate the many different mechanistic theories of ageing which have been proposed, it is therefore important to understand and study the network of maintenance processes which control 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 experimental, age related findings like an increase in the fraction of inactive proteins, a significant rise in protein half-life, an increase in the amount of damaged mitochondria, and a drop in the energy generation per mitochondrion, but they also show interactions between the different theories which could not have been observed without the network approach. In some simulations, for example, the mechanism of the final breakdown seems to be a consequence of the cooperation of mitochondrial and cytoplasmic reactions, the mitochondria being responsible for a long term, gradual change which eventually triggers a short lived cytoplasmic error loop.