Age-correlated stress resistance improves fitness of yeast: support from agent-based simulations

BACKGROUND: Resistance to stress is often heterogeneous among individuals within a population, which helps protect against intermittent stress (bet hedging). This is also the case for heat shock resistance in the budding yeast Saccharomyces cerevisiae. Interestingly, the resistance appears to be continuously distributed (vs. binary, switch-like) and correlated with replicative age (vs. random). Older, slower-growing cells are more resistant than younger, faster-growing ones. Is there a fitness benefit to age-correlated stress resistance? RESULTS: Here this hypothesis is explored using a simple agent-based model, which simulates a population of individual cells that grow and replicate. Cells age by accumulating damage, which lowers their growth rate. They synthesize trehalose at a metabolic cost, which helps protect against heat shock. Proteins Tsl1 and Tps3 (trehalose synthase complex regulatory subunit TSL1 and TPS3) represent the trehalose synthesis complex and they are expressed using constant, age-dependent and stochastic terms. The model was constrained by calibration and comparison to data from the literature, including individual-based observations obtained using high-throughput microscopy and flow cytometry. A heterogeneity network was developed, which highlights the predominant sources and pathways of resistance heterogeneity. To determine the best trehalose synthesis strategy, model strains with different Tsl1/Tps3 expression parameters were placed in competition in an environment with intermittent heat shocks. CONCLUSIONS: For high severities and low frequencies of heat shock, the winning strain used an age-dependent bet hedging strategy, which shows that there can be a benefit to age-correlated stress resistance. The study also illustrates the utility of combining individual-based observations and modeling to understand mechanisms underlying population heterogeneity, and the effect on fitness.