title: Fragile DNA repair mechanism reduces ageing in multicellular model.
abstract: DNA damages, as well as mutations, increase with age. It is believed that these result from increased genotoxic stress and decreased capacity for DNA repair. The two causes are not independent, DNA damage can, for example, through mutations, compromise the capacity for DNA repair, which in turn increases the amount of unrepaired DNA damage. Despite this vicious circle, we ask, can cells maintain a high DNA repair capacity for some time or is repair capacity bound to continuously decline with age? We here present a simple mathematical model for ageing in multicellular systems where cells subjected to DNA damage can undergo full repair, go apoptotic, or accumulate mutations thus reducing DNA repair capacity. Our model predicts that at the tissue level repair rate does not continuously decline with age, but instead has a characteristic extended period of high and non-declining DNA repair capacity, followed by a rapid decline. Furthermore, the time of high functionality increases, and consequently slows down the ageing process, if the DNA repair mechanism itself is vulnerable to DNA damages. Although counterintuitive at first glance, a fragile repair mechanism allows for a faster removal of compromised cells, thus freeing the space for healthy peers. This finding might be a first step toward understanding why a mutation in single DNA repair protein (e.g. Wrn or Blm) is not buffered by other repair proteins and therefore, leads to severe ageing disorders.
authors.affiliation: Niels Bohr Institute/CMOL, University of Copenhagen, Copenhagen, Denmark. kmoss@nbi.dk
authors.forename: Kristian Moss
authors.initials: KM
authors.lastname: Bendtsen
authors.forename: Jeppe
authors.initials: J
authors.lastname: Juul
authors.forename: Ala
authors.initials: A
authors.lastname: Trusina
mesh_terms: D000375:Aging / Q000235:genetics*; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D008954:Models, Biological; D008962:Models, Theoretical