This comprehensive review identifies neuroinflammation as the central mechanism connecting normal brain aging to pathological cognitive decline, mapping six distinct therapeutic intervention strategies. The analysis highlights how aging microglia shift toward pro-inflammatory M1 phenotypes while astrocytes become neurotoxic A1 variants, creating destructive feedback loops with blood-brain barrier breakdown and pathological protein aggregation like Aβ and α-synuclein.
The therapeutic landscape appears increasingly sophisticated, moving beyond single-target approaches toward multi-pronged strategies including senolytics for clearing senescent cells, NLRP3 inflammasome inhibitors, and natural products with multiple anti-inflammatory targets. This represents a maturation in neuroinflammation research, acknowledging the complexity of aging brain pathology rather than seeking silver bullets.
However, the field remains hampered by fundamental delivery challenges—getting therapeutics across the blood-brain barrier—and the inherent difficulty of modulating inflammation without compromising beneficial immune functions. The emphasis on drug repurposing suggests researchers are pragmatically leveraging existing compounds rather than developing novel therapeutics, potentially accelerating clinical translation but possibly limiting breakthrough potential.
