Reframing brain aging: neuroinflammation as an interconnected network process

Abstract

Neuroinflammation has emerged as a central component of brain aging, shaping the balance between neural resilience and vulnerability to cognitive decline. Rather than representing a simple consequence of neuronal damage, neuroinflammatory processes are increasingly recognized as active regulators of synaptic integrity, neuronal survival, and circuit function. Under physiological conditions, neuroimmune signaling may contribute to tissue homeostasis, synaptic maintenance, and adaptive responses to cellular stress; however, persistent or dysregulated inflammatory activity may disrupt these functions, promoting network instability and increasing vulnerability to age-related pathology. These processes arise from complex interactions among neurons, glial cells, vascular elements, and peripheral immune signals that together form dynamic neuroimmune networks. Within the aging brain, microglia and astrocytes play key roles in coordinating immune surveillance, synaptic remodeling, and inflammatory signaling. Age-related alterations in glial function can disrupt homeostatic communication within neuron–glia networks, promoting persistent low-grade inflammation and altered synaptic regulation. Importantly, neuroinflammatory activity in the brain is strongly influenced by systemic factors, including peripheral immune aging, changes in blood–brain barrier integrity, and signals originating from the gut–brain axis. In this mini-review, we discuss brain aging from a network perspective, emphasizing how multiscale interactions between cellular and systemic processes shape neuroinflammatory trajectories across the lifespan. We further highlight emerging approaches—including multi-omics technologies, advanced neuroimaging, and systems-level analyses—that are enabling a more integrated understanding of neuroinflammatory dynamics. Viewing neuroinflammation as a network phenomenon may provide new insights into mechanisms of cognitive aging and identify potential targets for strategies aimed at preserving brain health.