The repository is part of the publication: B. Schnitzer, L. Österbeg, M. Cvijovic, The choice of the objective function in flux balance analysis is crucial for predicting replicative lifespans in yeast. (2022) PLoS ONE 17(10): e0276112 https://doi.org/10.1371/journal.pone.0276112
The model is adapted from our publication: Multi-scale model suggests the trade-off between protein and ATP demand as a driver of metabolic changes during yeast replicative ageing, Schnitzer and Österberg et al., 2022 (https://www.biorxiv.org/content/10.1101/2022.03.07.483339v1) (https://github.com/cvijoviclab/IntegratedModelMetabolismAgeing)
Abstract
Flux balance analysis (FBA) models are a powerful tool to study genome-scale models of the cellular metabolism, based on finding the optimal flux distributions over the network. While the objective function is crucial for the outcome, its choice, even though motivated by evolutionary arguments, has not been directly connected to related measures. Here, we used an available multi-scale mathematical model of the cellular metabolism, damage accumulation and ageing, to systematically test the effect of commonly used objective functions on features of replicative ageing in budding yeast, such as the number of cell divisions and the corresponding time between divisions. The simulations confirmed that assuming maximal growth is essential for reaching realistic lifespans. The usage of the parsimonious solution or the additional maximisation of a growth-independent energy cost can improve lifespan predictions, explained by enhancing respiratory and antioxidative activity, using resources otherwise allocated to cellular growth, specifically in early life. Our work provides a new perspective on choosing the objective function in FBA models by connecting it to replicative ageing.
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Functions contains all functions needed to run the model, as well as a schematic picture of the code structure. To run a lifespan simluation, only the file "IntegratedModel.jl" is needed to be imported.
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ModelFiles contains relevant model files for the modules of the integrated model: Boolean model for the signalling, FBA model for the central carbon metabolism.
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Simulations contains all simulations relevant in the publication. FlexibilityGrid contains simulations to generate Figure 1,4 and S1. ParsimoniousCheck_enzymes contains simulations to generate Figure 3C. ParsimoniousCheck_fluxes contains simulations to generate Figure 3B and D and S2. Lastly, ParsimoniousCheck_normalisedFluxes contains simulations to generate 2A and B, 3A, S3 and S4. In each folder, the file type defines the purpose of the file (executable or parameter definitions: .jl, result: .txt, plotting function .R, plots .svg).
The simulations were tested with the Julia programming language, version 1.6.1, including important packages MAT (reading in FBA model), JuMP (optimisation toolbox) and Gurobi (solver for linear programs).