Speaker
Description
Hormesis, a biphasic phenomenon of low-dose stimulation and high-dose inhibition, poses a modelling challenge due to nonlinear, history-dependent dynamics. Static curves cannot capture temporal evolution, hysteresis, or recovery. Existing approaches are empirical, high-dimensional, or lack explicit dose-memory, limiting their ability to capture hysteresis and recovery. Here we propose a minimal, interpretable ODE model with explicit dose-memory to address this gap.
The model comprises a biological response and a dose-memory variable, governed by six fitted parameters covering stimulation, stimulation attenuation, adaptation, homeostasis, toxicity, and memory decay; the dose-memory variable enables hysteresis and phase-lagged recovery. Parameter estimation combined Differential Evolution (global) with L-BFGS-B refinement. Validated against weekly intrinsic mitochondrial respiration data from an excessive exercise training study \cite{Flockhart2021}, weeks 1-4 for calibration and week 5 as validation, yielding R2=0.998, RMSE=0.105.
Sensitivity analysis showed toxicity and stimulation parameters dominated model output; memory-related parameters showed negligible sensitivity, an identifiability limitation of weekly resolution, not a structural deficiency. Daily sampling or perturbation protocols are recommended to resolve memory dynamics. The framework generalises conceptually to other repeated-exposure systems exhibiting stimulation, adaptation, and recovery.
Bibliography
@article{Flockhart2021,
title = {Excessive exercise training causes mitochondrial functional impairment and decreases glucose tolerance in healthy volunteers},
volume = {33},
issn = {15504131},
url = {https://linkinghub.elsevier.com/retrieve/pii/S1550413121001029},
doi = {10.1016/j.cmet.2021.02.017},
language = {en},
number = {5},
urldate = {2026-03-13},
journal = {Cell Metabolism},
author = {Flockhart, Mikael and Nilsson, Lina C. and Tais, Senna and Ekblom, Björn and Apró, William and Larsen, Filip J.},
month = may,
year = {2021},
pages = {957--970.e6},
}
