CodeAge · The role of Chronic DNA damage in Ageing and Age-related pathology

Ageing is an inexorable homeostatic failure of largely unknown aetiology that leads to increased vulnerability to disease limiting the quality of life in the elderly and creating high costs to the society. Until recently, the daunting complexity of the ageing process, the conspicuous lack of tools to study it, and a dearth of experimentally tractable model systems have greatly hindered any hypothesis-driven reductionist approaches to understand the molecular basis of ageing. Whereas molecular and cellular damage is thought to be a cause of ageing and age-related pathologies, little is known about the molecular events that underlie ageing or determine longevity. A large number of progeroid syndromes that are characterized by an early onset of age-related pathology are linked to inborn defects in genome maintenance thus pointing towards damage in (nuclear) DNA as a major culprit of ageing and age-related pathology. DNA damage fuelled by intrinsic andenvironmental sources of genotoxic insult and by errors of genome maintenance mechanisms invariably accumulates with advancing age. The outcome of DNA damage is diverse and generally adverse: DNA lesions may physically obstruct essential processes including DNA replication and transcription. In addition, DNA damage activates checkpoint responses that lead to a reduction in cell proliferation potential (cellular senescence) or to an increase in cell death. As a result, depending on the type and severity of DNA injuries and the cellular response to DNA damage, these cellular mechanisms impair organ maintenance and function during ageing. The CodAge ITN proposes an integrated approach in studying the role of Chronic DNA damage in Ageing and age-related pathology.