PT  - JOURNAL ARTICLE
AU  - Johannes Borgqvist
AU  - Niek Welkenhuysen
AU  - Marija Cvijovic
TI  - Repair, resilience and asymmetric segregation of damage in the context of replicative ageing: it is a balancing act
AID  - 10.1101/446302
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 446302
4099  - http://biorxiv.org/content/early/2019/05/24/446302.short
4100  - http://biorxiv.org/content/early/2019/05/24/446302.full
AB  - Accumulation of damaged proteins is a hallmark of ageing, occurring in organisms ranging from bacteria and yeast to mammalian cells. During cell division in Saccharomyces cerevisiae, damaged proteins are retained within the mother cell, resulting in a new daughter cell with full replicative potential and an ageing mother with a reduced replicative lifespan (RLS). The cell-specific features determining the lifespan remain elusive. It has been suggested that the RLS is dependent on the ability of the cell to repair and retain pre-existing damage. To deepen the understanding of how these factors influence the life span of individual cells, we developed and experimentally validated a dynamic model of damage accumulation accounting for replicative ageing. The model includes five essential properties: cell growth, damage formation, damage repair, cell division and cell death, represented in a theoretical framework describing the conditions allowing for replicative ageing, starvation, immortality or clonal senescence. We introduce the resilience to damage, which can be interpreted as the difference in volume between an old and a young cell. We show that the capacity to retain damage deteriorates with high age, that asymmetric division allows for retention of damage, and that there is a trade-off between retention and the resilience property. Finally, we derive the maximal degree of asymmetry as a function of resilience, proposing that asymmetric cell division is beneficial with respect to replicative ageing as it increases the RLS of a given organism. The proposed model contributes to a deeper understanding of the ageing process in eukaryotic organisms.