Neuroinflammation and Cellular Senescence in Brain Aging and Neurodegeneration

Against the backdrop of a rapidly aging global population, the incidence of neurodegenerative diseases such as Alzheimer's and Parkinson's continues to rise, imposing a severe socioeconomic burden. Neuroinflammation is recognized as the core mechanism linking physiological brain aging to pathological cognitive decline. This paper aims to systematically elucidate the multi-level activation mechanisms of neuroinflammation during aging and comprehensively evaluate drug intervention strategies targeting this process. Research reveals that the chronicity of neuroinflammation is driven by multiple cellular and molecular events. At the cellular level, aging and dysfunction in microglia and astrocytes lead to their respective transitions toward pro-inflammatory M1 and neurotoxic A1 phenotypes. These changes interact synergistically with blood-brain barrier dysfunction, peripheral immune cell infiltration, and abnormal aggregation of pathological proteins like Aβ and α-synuclein, forming a vicious cycle. At the molecular level, signaling pathways including NLRP3 inflammasome, NF-κB, and JAK/STAT are persistently activated, while epigenetic modifications play crucial regulatory roles. Addressing these mechanisms, this review systematically examines six major intervention strategies: modulating neuroimmune cell function, inhibiting core inflammatory pathways, targeting inflammatory mediators like cytokines, employing senolytics to clear senescent cells, enhancing endogenous anti-inflammatory defenses, and exploring multi-target natural products and drug repurposing. Research indicates that targeting neuroinflammation offers a highly promising new avenue for delaying brain aging and related diseases. However, this field still faces numerous challenges, including target specificity, blood-brain barrier delivery, individual heterogeneity, and difficulties in clinical translation. Future breakthroughs will depend on more precise drug design, innovative delivery technologies, biomarker development, and interdisciplinary collaborative research.