Differential effects of environmental enrichment and physical exercise on glial biology in aging and aging-related conditions: a systematic review.

Background: Aging is associated with progressive changes in glial cell dynamics, including altered morphology, activation states, and neuroimmune interactions of microglia, astrocytes, and other glial populations. These changes contribute to chronic neuroinflammation, impaired brain homeostasis, and increased vulnerability to cognitive decline and neurodegenerative disorders. Non-pharmacological lifestyle interventions such as environmental enrichment (EE) and physical exercise (PE) have shown promise in modulating brain aging, but their comparative and combined effects on glial cells remain incompletely understood. Objectives: This systematic review aimed to synthesize and compare the effects of EE, PE, and their combination on glial cell dynamics during aging. Specific aims included evaluating their individual and combined impacts on microglial and astrocytic morphology and function, identifying molecular mechanisms and neuroimmune crosstalk, benchmarking experimental paradigms, and examining regional, temporal, and lifespan variations in outcomes. Methods: A systematic search was conducted in PubMed, Scopus, and Google Scholar up to November 2025, following PRISMA 2020 guidelines. Preclinical (primarily rodent) studies were included if they examined well defined EE (cognitive, sensory, and social stimulation), isolated PE, or combined interventions in physiological aging models or in disease, injury, or stress paradigms considered relevant to aging because they shared glial mechanisms such as chronic neuroinflammation or impaired cellular homeostasis. These model classes were interpreted separately during synthesis, and studies were required to report glial relevant outcomes. A structured risk-of-bias assessment using the SYRCLE tool was conducted. Data were narratively synthesized due to anticipated heterogeneity. Results: Included studies showed that EE is consistently associated with increase in microglial number and morphological complexity and modulates peripheral T cell subsets, with stronger effects observed after long-term exposure. In contrast, PE more consistently reverses age-related microglial gene expression changes and induces region-specific remodeling of astrocytic morphology. Combined EE+PE interventions produced additive benefits on neurogenesis but yielded variable and non-superior effects on glial modulation. Molecular pathways such as BDNF-TrkB signaling and inflammatory cascades mediated these effects, with neuroimmune crosstalk (particularly involving peripheral T cells) influencing central glial states. Methodological heterogeneity and limited sex-specific analyses constrained generalizability. Conclusion: Environmental enrichment and PE exert distinct yet partially overlapping effects on glial plasticity and neuroinflammation across physiological aging and aging relevant pathological contexts, with EE showing greater strength in modulating glial-immune interfaces and PE in metabolic/anti-inflammatory glial remodeling. Combined interventions do not consistently outperform single modalities for glial outcomes.