The hormetic landscape: from evolutionary origination to mechanistic pathways in therapeutics

Abstract

Hormesis is a biphasic dose-response, where mild stress triggers adaptive defense responses that increase cellular resilience. The hormesis is now recognized as a core concept with applications in toxicology, metabolism, aging, and evolutionary biology. A historical review, evolutionary explanations, and recent molecular insights led to the concept of hormesis as an anticipatory, "predict-and-prepare" strategy that allows organisms to adapt to changing conditions are addressed. The mitohormesis, autophagy, xenohormesis, epigenetic remodeling, and their interdependence with signaling pathways (Nrf2-KEAP1, AMPK-SIRT1, NF-κB, and heat-shock response). The stress-induced reversal of differentiation in basal metazoans also defy the irreversible aging concept demonstrate conservative plasticity programs. The relevance of translational research using toxin-derived therapeutics and lifestyle-based hormetic interventions are discussed, including challenges of the hormetic zone, inter-individual variability, and bioactivity cliffs. The future scope of integrating AI and ML into nonlinear modeling of precise hormetic dosing, with considerable applications in aging, regenerative medicine, and precision therapeutics.