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

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.

The choice of the objective function in flux balance analysis is crucial for predicting replicative lifespans in yeast

“…To study how and why an efficient usage of the resources can increase the replicative lifespan, we analysed the respective changes of the mean fluxes over time, focusing on parameters in the regime where we observed the biggest deviations between the solutions: ϵ 1 ≥ 30% for maximal growth as a first objective and not NGAM as a second, as well as maximal ATP production followed by maximal growth. Since the metabolism changes significantly during ageing, we separated the lifespan of each cell in two phases according to [ 13 , 29 ]. Phase I is considered the maximal growth phase dominated by a fermenting metabolism.…”

“…However, the generation time is also an important feature during competitive growth. Here, we presented a systematic analysis of objective functions in the context of replicative ageing, utilising an enzyme-constrained FBA model of the central carbon metabolism of budding yeast cells, embedded in a published integrated model of nutrient signalling, metabolism and protein damage accumulation [ 29 ]. We found that maximal growth is the most important objective with regard to the replicative lifespan, in line with previous studies [ 20 , 21 , 23 ].…”

“…We exploited our previously published multi-scale model (yMSA), incorporating modules for the metabolism, regulation and damage accumulation in S. cerevisiae yeast cells [ 29 ]. In the model, the metabolism is represented by an enzyme-constrained FBA model of the central carbon metabolism.…”

“…In that way, the model allows to simulate replicative ageing as the accumulation of damage, which is steered by the metabolism and the regulatory network. All mathematical and computational details of the model as well as model parameters can be found in [ 29 ]. In particular, we used parameters of a cell with a non-metabolic damage formation f 0 = 0.0001 and damage repair r 0 = 0.0005, as well as a regulation factor 0.04.…”

“…While rationalising experimental data in order to decide which objective function fits the best under certain conditions is feasible, it is more challenging to experimentally measure the objective function and study its consequences on long-term dynamic effects like ageing. For that reason, we exploit our recently published multi-scale mathematical model of yeast metabolism and ageing [ 29 ]. The central carbon metabolism including the creation of reactive oxygen species (ROS) is represented by an enzyme-constrained flux balance model, that is further constrained by the regulation upon oxidative stress and nutrient availability, and connected to a dynamical model of damage accumulation and growth, including discrete cell division event.…”