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.
Highlights
IntroductionAt the cellular level, ageing is thought to be caused, at least in part, by the accumulation of unrepaired damage to mitochondrial or nuclear DNA [1,2,3]
In humans, ageing is associated with the gradual deterioration of physiological functions, – blood vessels become less flexible, bones turn brittle, muscle mass is lost, and the immune system becomes more vulnerable to infections.At the cellular level, ageing is thought to be caused, at least in part, by the accumulation of unrepaired damage to mitochondrial or nuclear DNA [1,2,3]
A temporary steady state exists where the repair rate of the system fluctuates around an average value of RÃ: In this state, the average repair rate is maintained because cells with a low repair rate are more likely to go apoptotic and be replaced by cells with a higher repair rate
Summary
At the cellular level, ageing is thought to be caused, at least in part, by the accumulation of unrepaired damage to mitochondrial or nuclear DNA [1,2,3]. In slowly proliferating cells, such as neurons or bone cells with lifespans well over 30 years, ageing can be contributed to the accumulation of damage in individual cells. For highly proliferating cells with typical lifespans of a few days [5], unrepaired DNA damage causes cell cycle arrest and apoptosis. Repaired DNA damage can result in a mutation and in highly proliferating cells the mutation is passed down through the lineage until the cell line reaches the Hayflick limit.
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