The antiaging protein Klotho is a key factor in susceptibility to cerebral ischemia.

Abstract

Ischemic cerebrovascular events are among the leading causes of death and disability worldwide, disproportionately affecting the elderly due to vascular aging, oxidative stress, and chronic inflammation. During cerebral ischemia, oxygen and glucose deprivation trigger a cascade of pathological events, including excitotoxicity, mitochondrial dysfunction, blood-brain barrier disruption, and neuroinflammation. Emerging evidence identifies Klotho as a multifunctional protein with anti-aging, antioxidant, and anti-inflammatory properties that may confer neuroprotection against ischemic injury. Aging is associated with a progressive decline in Klotho expression, correlating with increased stroke susceptibility and poorer recovery outcomes. Experimental studies demonstrate that Klotho attenuates glutamatergic excitotoxicity by regulating the GluN2B subunit and excitatory amino acid transporters. It reduces oxidative stress through inhibition of NADPH oxidase and activation of SOD2 and FOXO3 pathways, while preserving blood-brain barrier integrity by downregulating aquaporin-4 and matrix metalloproteinase-9. Moreover, Klotho suppresses pro-inflammatory signaling by inhibiting NF-κB, RelA, and NLRP3 inflammasome activation, and enhances anti-inflammatory responses via PPAR-γ modulation. Beyond limiting neuronal death, Klotho promotes neurogenesis and synaptic plasticity by regulating neurotrophic factors and Wnt signaling, thereby supporting neural stem cell survival and functional recovery after ischemia. Collectively, these findings position Klotho as a central regulator of neuronal homeostasis and post-ischemic repair. This review provides the first comprehensive mechanistic integration of Klotho's neuroprotective role in ischemic cerebrovascular injury, proposing it as a unifying molecular axis linking brain aging to ischemic vulnerability and regenerative capacity.