Synergistic effects of repair, resilience and retention of damage determine the conditions for replicative ageing

Abstract

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 an ageing mother while a new daughter cell exhibits full replicative potential. The cell-specific features determining the ageing remain elusive. It has been suggested that the replicative ageing 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 of individual cells, we developed and experimentally validated a dynamic model of damage accumulation accounting for replicative ageing on the single cell level. 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 lifespan of a given organism. The proposed model contributes to a deeper understanding of the ageing process in eukaryotic organisms. Cell division, growth and death are fundamental features of any living organism. During its life cycle, a cell produces a set of functional components such as proteins or other metabolites, which will ultimately allow the cell to divide, giving rise to a newly born daughter cell. However, due to inherent imperfections in the cellular machinery over time, cells are slowly deteriorating causing essential intracellular functions to perish. At the very end of a cell's lifespan, age-associated damage builds up consistently impairing the ability of the cell to divide and survive, which eventually culminates in cell death. In environments with a sufficient amount of food, damage will be formed as a consequence of cell growth. This causes the partitioning of damage between the progenitor and progeny during cell division to be an important function. An asymmetric distribution of cell mass after division constitutes a vital part of ageing in the yeast Saccharomyces cerevisiae (S.cerevisiae). The number of divisions before cell death is a measure of the age of a single yeast cell, which has been studied substantially by means of experiments 1,2 , and it is called the replicative life span (RLS). The asymmetric division of the budding yeast results in a large ageing mother cell with a finite RLS and a new small daughter cell with full replicative potential 3. Replicative ageing in...

The Synergy of Damage Repair and Retention Promotes Rejuvenation and Prolongs Healthy Lifespans in Cell Lineages

“…The single cell model of damage accumulation builds on our replicative ageing model [42], describing the dynamics of functional (P (t)) and damaged (malfunctioning) D(t) proteins over time. In the model presented here, the protein content evolves non-linearly depending on cell growth (g), the resilience to damage (Q), the damage formation rate (k 1 ), the damage repair rate (k 2 ) and a repair capacity (R) ( Fig 1A).…”

“…Cells divide if the amount of functional proteins has reached a critical threshold P (t) = 1. At cell division the protein content is distributed between the mother and the new-born daughter cell according to their size proportion (s) and damage retention (re) ( Fig 1A) and is based on the principle of mass conservation over generations [39,42]. For simplicity, we assume s and re to be constant over the lifespan of a cell.…”

“…In previous studies repair or degradation of damage is typically modelled as linear [39,40,42] or saturating functions of the present damage, inspired by Michaelis-Menten kinetics [43,44]. In the study presented here, linear, saturated and declining profiles can be generated by changing the repair capacity R. Two distinct cases of the repair capacity are considered: unlimited repair capacity, corresponding to a constant rate of repair independent of the damage levels in the cell, and decline in repair capacity, corresponding to a continuous effect of damaged components on the repair machinery, especially evident towards the end of the cell's life where the effective rate of repair drops to zero.…”

“…It should not be connected to any oscillatory behaviour since only maximally half a period is captured by the model due to the bounds on P (t) ∈ [0, 1], D(t) ∈ [0, 1] and R ∈ [π −1 , ∞]. R changes the period length of the sine and so tunes how much the repair declines with increasing D. As R approaches infinity sin D(t) R ≈ D(t) R and the repair velocity becomes a linear function as in [42]. It is equivalent to a very large period length of the sine function.…”

“…stress, and this increases the population fitness [39][40][41]. Also, an age-dependent maximal degree of retention has been suggested [42]. More recent modelling studies highlight the importance of the repair machinery in replicative ageing, since asymmetric damage distribution at cell division alone cannot eliminate damage from the system [43,44].…”