Barbara Schnitzer, Johannes Borgqvist, Marija Cvijovic
Damaged proteins are inherited asymmetrically during cell division in the yeast Saccharomyces cerevisiae, such that most damage is retained within the mother cell. The consequence is an ageing mother and a rejuvenated daughter cell with full replicative potential. Daughters of old and damaged mothers are however born with increasing levels of damage resulting in lowered replicative lifespans. Remarkably, these prematurely old daughters can give rise to rejuvenated cells with low damage levels and recovered lifespans, called second-degree rejuvenation. We aimed to investigate how damage repair and retention together can promote rejuvenation and at the same time ensure low damage levels in mother cells, reflected in longer health spans. We developed a dynamic model for damage accumulation over successive divisions in individual cells as part of a dynamically growing cell lineage.
Even to this day, a conceptual understanding of ageing as a phenomenon is lacking. Accordingly, the task of explaining the origins of specific symptoms of ageing on an organism level beginning from molecular processes in a single cell is highly complicated, and the first step in achieving this goal is to properly define the term. One of the most feasible theories on the origins of ageing, the disposable soma theory, states that in circumstances with limited resources an organism will prioritise reproduction over maintenance of the body, called the soma, referred to as a division of labour.
Further, its occurrence is motivated by the observation that, in nature, most animals die at a young age due to various factors such as starvation or predation, and therefore natural selection will favour genes resulting in rapid growth followed by reproduction as opposed to traits associated with longevity. Thus, the expected consequence of the removal of such factors leading to death is the degradation of the soma since the germ cells are prioritised. To investigate the precise molecular properties of this degradation, it is advantageous to examine the division of labour in less complex biological systems.
From a single-cell to a whole population model of replicative ageing
To investigate the synergistic role of retention of age-related damage and repair of damage on how ageing of the individual cells contributes to the overall behaviour of the entire population and how this affects cellular rejuvenation and health span, we developed a dynamic model based on ordinary differential equations (ODE) that is capable of simulating and mapping replicative ageing on single-cell and population level.
Starting from a theoretical description of damage accumulation in a single cell, we have developed a holistic model of replicative ageing on the population level. By defining novel features on the population level such as the health span and the rejuvenation index in addition to previously known metrics such as the replicative life span, growth per cell cycle and cumulative growth, we characterised the precise large scale impact of single-cell properties on the lineage.
More precisely, we concluded that investing in an efficient repair machinery early in life followed by a steep decline in the capacity to repair later generates longer health spans compared to having a constant repair capacity throughout the lifespan. Further, we showed that retention of damage, which is detrimental to individual mother cells, reduces the variability in damage levels over generations and increases the average replicative lifespan of the population. Our results emphasise that replicative ageing in a cell population is strongly influenced by how and when damage accumulates during the lives of its individual cells. Thus, using this framework we can concretise vague terms such as healthy ageing and tested evolutionary hypotheses that are otherwise hard to quantify.
We would like to thank all past and present members of the CvijovicLab for valuable input and careful reading of the manuscript.
Citation:Schnitzer B, Borgqvist J, Cvijovic M (2020) The synergy of damage repair and retention promotes rejuvenation and prolongs healthy lifespans in cell lineages. PLoSComputBiol 16(10): e1008314. https://doi.org/10.1371/journal.pcbi.1008314
Editor: Oleg A. Igoshin, Rice University, UNITED STATES
Received: April 15, 2020; Accepted: September 4, 2020; Published: October 12, 2020
Copyright: © 2020 Schnitzer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: This work was supported by Swedish Foundation for Strategic Research (Grant Nr. FFL15-0238 and IB13-0022) to MC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.