Genome Stability and Ageing

Abstract

Ageing is defined as the progressive attrition of tissue/organ function resulting in an increased susceptibility to disease and death. The DNA mutation and damage theory of ageing posits that the accrual of genetic damage over time is the underlying cause of ageing. Evidence for this theory stems from the fact that numerous human progeroid syndromes are caused by inherited defects in genome maintenance mechanisms, linking excess genetic damage with accelerated ageing. These diseases have been modelled in mice and other organisms. However, the molecular mechanism by which genomic instability drives ageing is currently not known. The nematode, C. elegans, is a genetically tractable, well-studied model organism for investigating mechanisms of ageing and DNA repair pathways identified in mammalian systems are well conserved in the worm. Furthermore, proliferating and post-mitotic cells, which have distinct responses to genomic instability, are clearly delineated in the worm. Thus worms provide an opportunity to study the importance of genomic stability in each of these compartments in the context of a whole organism. Genomic instability can interfere with transcription, trigger apoptosis, attenuate proliferative capacity, and cause metabolic changes. Here, we first examine the DNA repair pathways that are conserved between worms and mammals, with an overview of the spatial and temporal activity of each of these repair pathways. This chapter then explores evidence from studies in the nematode that genomic instability, healthspan and organismal ageing are linked.