Inflammation and depression: an evolutionary framework for the role of physical activity and exercise

Abstract

Major Depressive Disorder (MDD) is a leading global health challenge, affecting nearly 5% of the population. Mounting evidence suggests that systemic low-grade chronic inflammation (SLGCI) plays a central role in the development and progression of MDD. This persistent inflammatory state results from unresolved immune activation and sustained exposure to modern lifestyle factors, such as sedentary behavior, poor diet, inadequate sleep, and psychological stress. Regular physical activity (PA), particularly exercise, has been shown to modulate inflammatory processes and improve depressive symptoms. This narrative review examines the complex interactions between inflammation and MDD, focusing on the role of PA and exercise in mitigating SLGCI and neuroinflammation. This is approached through an evolutionary lens, exploring how the mismatch between ancestral and modern activity levels may contribute to the rise of MDD. In addition, it highlights the potential risks of excessive exercise, including overtraining and its association with depressive symptoms. Finally, this work proposes a practical framework for optimizing PA and exercise as preventive and therapeutic tools for MDD by aligning modern PA patterns with ancestral behavioral norms.

Keywords: Major Depressive Disorder; exercise; lifestyle; mismatch; neuroinflammation; systemic low-grade chronic inflammation.

Figure 1

Conceptual framework illustrating how chronic inflammation contributes to Major Depressive Disorder (MDD), and how exercise and lifestyle factors may counteract it. On the left side, chronic low-grade inflammation (↑ SLGCI) is fueled by modern lifestyle factors such as poor diet, sedentary behavior, smoking, alcohol consumption, inadequate sleep, and psychosocial stress. This leads to increased systemic levels of proinflammatory molecules (e.g., IL-1β, IL-6, TNF-α), which can cross the blood–brain barrier and activate microglia. Activated microglia release additional cytokines and neurotoxic metabolites (e.g., quinolinic acid) via the kynurenine pathway, contributing to neuroinflammation, impaired serotonin signaling, glutamatergic excitotoxicity, reduced BDNF levels, and ultimately, the development of MDD or depressive symptoms. On the right side, regular exercise and healthy lifestyle habits—such as physical activity in natural environments, social interaction, adequate sunlight exposure, stress management, and a nutrient-rich diet—are associated with reduced systemic inflammation (↓ SLGCI). Exercise promotes anti-inflammatory effects through various pathways, including shear stress-induced production of exerkines (e.g., IL-6 with anti-inflammatory action, BDNF), improved mitochondrial function, and modulation of immune responses. These adaptations help decrease peripheral and central inflammation, enhance neuroplasticity, and alleviate depressive symptoms. BDNF, Brain-derived neurotrophic factor; IDO, indoleamine 2,3-dioxygenase; KYN, Kynurenine; MDD, Major Depressive Disorder. NF-κB, Nuclear Factor kappa-light-chain-enhancer of activated B cell; PGC1-α, Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; QUIN, Quinolinic acid; SLGCI, Systemic low-grade chronic inflammation. Created with BioRender.com.