PT  - JOURNAL ARTICLE
AU  - Johannes Borgqvist
AU  - Niek Welkenhuysen
AU  - Marija Cvijovic
TI  - The triangle of ageing: a model of how repair, resilience to damage and asymmetric segregation are responses to replicative ageing
AID  - 10.1101/446302
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 446302
4099  - http://biorxiv.org/content/early/2018/10/17/446302.short
4100  - http://biorxiv.org/content/early/2018/10/17/446302.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. This results 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 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. Based on these, we derive the triangle of ageing: a complete theoretical framework describing the conditions allowing for replicative ageing, starvation, immortality or clonal senescence. Exploiting this framework, we propose that the retention mechanism is fundamental for ageing. Furthermore, we suggest that resilience to damage is a central trait influencing replicative ageing which can be used as a basis for life prolonging strategies. In addition, the model is in agreement with experimental data consisting of RLS distributions and mean generation times from three yeast strains: the short lived sir2 Δ, the wild type wt and the long lived fob1 Δ. This validates the underlying assumptions and we conclude that strains with an efficient repair machinery require retention. Finally, the triangle of ageing suggests that asymmetric cell division is beneficial with respect to replicative ageing as it increases the RLS of a given organism. Thus, the proposed model indicates that in order to obtain a mechanistic understanding of the ageing process in eukaryotic organisms it is critical to investigate the constituents of the retention machinery.Author summary Cells age by accumulating damage over time. In budding yeast, damage is inherited asymmetrically such that most is retained within the mother cell. Nevertheless the nature and the interplay behind the driving forces of this process remain unknown. In this study, we develop a single cell model of accumulation of damage accounting for replicative ageing that includes five key properties: cell growth, formation of damage, repair of damage, cell division and cell death. Using mathematical analysis of the model, we derive the triangle of ageing, a theoretical framework identifying damage retention as a key factor underlying ageing in yeast. This model represents an important step in elucidating the mechanisms behind damage segregation and can be valuable for understanding similar phenomena in other organisms.