Exercise as a multiscale recalibration of stress-related homeostatic balance

Abstract

Chronic stress disrupts homeostasis in the brain and body, leading to anxiety, depression, and cardiovascular and metabolic dysfunction. Although exercise can counter these effects, the mechanisms are scattered across fields and not yet integrated. This review proposes a multi-scale framework. Exercise is not only stress-relieving; it is also a controllable challenge that can recalibrate the system when repeated bouts are matched by sufficient recovery and bioenergetic support. We propose that repeated exercise engages a stress response–adaptation–recovery cycle, in which peripheral signals from skeletal muscles, liver, adipose tissue and gut convey body metabolic state to the brain and are consolidated into durable plasticity only when mitochondrial capacity, substrate availability, and redox balance permit recovery. These signals pass through the blood-brain barrier and engage plasticity switches, including neurotrophic signals, epigenetic modification and metabolic coupling, thus stabilizing the neural circuits of threat appraisal, reward processing and contextual memory. By integrating these dimensions, we clarify how exercise can transform short-term physical stress into lasting resilience and provide direction for future research.