DNA damage and ageing: new-age ideas for an age-old problem

Abstract

Loss of genome maintenance may causally contribute to ageing, as exemplified by the premature appearance of multiple symptoms of ageing in a growing family of human syndromes and in mice with genetic defects in genome maintenance pathways. Recent evidence revealed a similarity between such prematurely ageing mutants and long-lived mice harbouring mutations in growth signalling pathways. At first sight this seems paradoxical as they represent both extremes of ageing yet show a similar 'survival' response that is capable of delaying age-related pathology and extending lifespan. Understanding the mechanistic basis of this response and its connection with genome maintenance would open exciting possibilities for counteracting cancer or age-related diseases, and for promoting longevity.

Figure 1

Schematic representation of ‘stochastic damage’ and the connection with ageing and longevity assurance mechanisms. DNA is continually damaged by chemical alterations (such as spontaneous hydrolysis, deamination), by environmental agents as well as endogenous products (that is, ROS). Cells respond through a battery of DNA repair and genome surveillance systems that counteract DNA damage, thereby ensuring that their vital genetic information is preserved and faithfully transmitted to progeny. Nevertheless, a fraction of the damage escapes repair and accumulates, resulting in mutations, senescence or cell death and cellular dysfunction. Too much persisting DNA damage interferes with normal DNA metabolism, such as transcription, and triggers suppression of the growth hormone/IGF1 somatotropic axis, which is known to decline with age. Dampening of the insulin/IGF1 pathway and oxidative metabolism is thought to reduce the induction and effects of DNA damage by shifting the energy equilibrium from growth and proliferation to pathways that preserve somatic maintenance and thus attempt to extend lifespan (survival response). NER progeroid mice accumulate DNA damage much more rapidly than naturally ageing mice as a consequence of their repair defect, and onset of the life-extending ‘survival’ response is accelerated. Thus, studies in mice with inherited defects in genome maintenance seem to reconcile two apparently contrasting theories on ageing: the genetic basis of ageing and the stochastic damage accumulation. As random damage drives the age-related functional decline, longevity assurance mechanisms determine the rate of damage accumulation and the functional decline with age.