The Aging Brain Immune Interface: Mechanisms of Neuroinflammation, Immune Dysregulation, and Neurodegeneration

The aging brain sits at a crossroads where immune vigilance gradually gives way to chronic, low grade inflammation and impaired repair capacity. Microglia which is the brain’s resident immune cells shift from agile homeostatic responders into primed inflammatory states that amplify even minor insults. Astrocytes adopt maladaptive reactive phenotypes, and the blood brain barrier becomes increasingly porous, allowing peripheral cytokines and immune cells to shape CNS function. Together, these changes create an immune environment that is persistently activated yet inefficient, blurring the line between protective neuroimmune signaling and pathological neuroinflammation. This dysregulated immune landscape is now recognized as a central driver of neurodegenerative vulnerability. Systemic aging marked by immunosenescence, inflammaging, metabolic dysfunction, and gut microbiome shifts feeds continuous inflammatory cues into the CNS, overwhelming its capacity for resolution. The consequences of systemic immune aging are particularly important for the brain. The central nervous system is not immunologically isolated but continuously communicates with peripheral immune tissues through circulating cytokines, chemokines, metabolites, extracellular vesicles, immune cells, neural pathways, and barrier interfaces. During aging, alterations in vascular endothelial cells, pericytes, astrocytes and other components of the blood brain barrier can modify the interaction between the peripheral immune system and the CNS. These changes may facilitate abnormal immune signaling and, in some contexts, peripheral immune-cell trafficking into the aging brain. As a result, neuroinflammation becomes self perpetuating, accelerating synaptic loss, protein aggregation, and neuronal decline. A research topic focused on the aging brain immune interface offers a timely platform to dissect these mechanisms and highlight emerging therapeutic strategies aimed at restoring immune balance and protecting the aging brain.By integrating systemic immunology, neuroimmunology, aging biology and neuroscience, this Research Topic aims to establish the aging brain-immune interface as a central mechanistic framework for understanding neurological resilience and neurodegenerative disease.Aging fundamentally reshapes the brain’s immune landscape. Microglia shift into chronically primed states, astrocytes adopt reactive phenotypes, and blood-brain barrier integrity declines, allowing peripheral immune signals to exert greater influence on CNS function. These changes convert neuroinflammation from a transient protective response into a persistent driver of synaptic dysfunction and neuronal vulnerability. Systemic aging processes including immunosenescence, inflammaging, metabolic decline, and gut microbiome alterations further amplify this imbalance, accelerating cognitive decline and neurodegenerative disease.This Research Topic invites contributions that deepen mechanistic and translational understanding of the aging brain immune interface. We welcome studies on microglial and astrocytic aging, neuroimmune signaling, blood-brain barrier dysfunction, peripheral-CNS immune crosstalk, metabolic and microbial regulation of neuroinflammation, and immune contributions to neurodegeneration. Submissions using single cell multi omics, advanced imaging, computational modeling, gut-brain axis approaches, and emerging therapeutic strategies such as senolytic, microglial modulators, metabolic interventions, and microbiome targeted treatments are strongly encouraged. This Topic aims to highlight convergent mechanisms and accelerate development of interventions that restore immune homeostasis and protect the aging brain.We welcome the submission of Original Research, Review, Mini Review, and Perspective articles on themes including, but not limited to:- Microglial priming and dysfunction in the aging brain- Reactive astrocyte phenotypes and their role in neuroinflammation- Blood-brain barrier breakdown and peripheral-CNS immune crosstalk- Immunosenescence and inflammaging as drivers of neurodegeneration- Gut microbiome regulation of neuroinflammatory processes- Metabolic dysfunction and its links to CNS immune dysregulation- Single-cell multi-omics and advanced imaging approaches to neuroimmune aging- Therapeutic strategies: senolytics, microglial modulators, and microbiome-targeted interventions Topic editors: Sagar Vyavahare, Sandeep Kumar, Ashish Kothari Source: https://www.frontiersin.org/research-topics/85587/the-aging-brain-immune-interface-mechanisms-of-neuroinflammation-immune-dysregulation-and-neurodegeneration