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Multi-scale model suggests the trade-off between protein and ATP demand as a driver of metabolic changes during yeast replicative ageing

Barbara Schnitzer, Linnea Österberg, Iro Skopa, View ORCID ProfileMarija Cvijovic
doi: https://doi.org/10.1101/2022.03.07.483339
Barbara Schnitzer
1Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden
2Department of Mathematical Sciences, University of Gothenburg, Gothenburg, Sweden
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Linnea Österberg
1Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden
2Department of Mathematical Sciences, University of Gothenburg, Gothenburg, Sweden
3Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
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Iro Skopa
1Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden
2Department of Mathematical Sciences, University of Gothenburg, Gothenburg, Sweden
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Marija Cvijovic
1Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden
2Department of Mathematical Sciences, University of Gothenburg, Gothenburg, Sweden
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  • ORCID record for Marija Cvijovic
  • For correspondence: marija.cvijovic@chalmers.se
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Abstract

The accumulation of protein damage is one of the major drivers of replicative ageing, describing a cell’s reduced ability to reproduce over time even under optimal conditions. Reactive oxygen and nitrogen species are precursors of protein damage and therefore tightly linked to ageing. At the same time, they are an inevitable by-product of the cell’s metabolism. Cells are able to sense high levels of reactive oxygen and nitrogen species and can subsequently adapt their metabolism through gene regulation to slow down damage accumulation. However, the older or damaged a cell is the less flexibility it has to allocate enzymes across the metabolic network, forcing further adaptions in the metabolism. To investigate changes in the metabolism during replicative ageing, we developed an multi-scale mathematical model using budding yeast as a model organism. The model consists of three interconnected modules: a Boolean model of the signalling network, an enzyme-constrained flux balance model of the central carbon metabolism and a dynamic model of growth and protein damage accumulation with discrete cell divisions. The model can explain known features of replicative ageing, like average lifespan and increase in generation time during successive division, in yeast wildtype cells by a decreasing pool of functional enzymes and an increasing energy demand for maintenance. We further used the model to identify three consecutive metabolic phases, that a cell can undergo during its life, and their influence on the replicative potential, and proposed an intervention span for lifespan control.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 08, 2022.
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Multi-scale model suggests the trade-off between protein and ATP demand as a driver of metabolic changes during yeast replicative ageing
Barbara Schnitzer, Linnea Österberg, Iro Skopa, Marija Cvijovic
bioRxiv 2022.03.07.483339; doi: https://doi.org/10.1101/2022.03.07.483339
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Multi-scale model suggests the trade-off between protein and ATP demand as a driver of metabolic changes during yeast replicative ageing
Barbara Schnitzer, Linnea Österberg, Iro Skopa, Marija Cvijovic
bioRxiv 2022.03.07.483339; doi: https://doi.org/10.1101/2022.03.07.483339

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