Dynamic model assuming mutually inhibitory biomarkers of frailty suggests bistability with contrasting mobility phenotypes.

Abstract

Bistability is a fundamental biological phenomenon associated with "switch-like" behavior reflecting the capacity of a system to exist in either of two stable states. It plays a role in gene regulation, cell fate switch, signal transduction and cell oscillation, with relevance for cognition, hearing, vision, sleep, gait and voiding. Here we consider a potential role for bistability in the existence of specific frailty states or phenotypes as part of disablement pathways. We use mathematical modeling with two frailty biomarkers (insulin growth factor-1, IGF-1 and interleukin-6, IL-6), which mutually inhibit each other. In our model, we demonstrate that small variations around critical IGF-1 or IL-6 blood levels lead to strikingly different mobility outcomes. We employ deterministic modeling of mobility outcomes, calculating the average trends in population health. Our model predicts the bistability of clinical outcomes: the deterministically-computed likelihood of an individual remaining mobile, becoming less mobile, or dying over time either increases to almost 100% or decreases to almost zero. Contrary to statistical models that attempt to estimate the likelihood of final outcomes based on probabilities and correlations, our model predicts functional outcomes over time based on specific hypothesized molecular mechanisms. Instead of estimating probabilities based on stochastic distributions and arbitrary priors, we deterministically simulate model outcomes over a wide range of physiological parameter values within experimentally derived boundaries. Our study is "a proof of principle" as it is based on a major assumption about mutual inhibition of pathways that is oversimplified. However, by making such an assumption, interesting effects can be described qualitatively. As our understanding of molecular mechanisms involved in aging deepens, we believe that such modeling will not only lead to more accurate predictions, but also help move the field from using mostly studies of associations to mechanistically guided approaches.