Endothelial IGF-1/IGF-1R signaling supports young-blood-induced restoration of blood–brain barrier integrity and microvascular architecture in aged mice: evidence from the heterochronic parabiosis model

Aging is associated with blood-brain barrier (BBB) breakdown and microvascular rarefaction, key contributors to cerebral neuroinflammation, hypoperfusion, and vascular cognitive impairment and dementia (VCID). Exposure to a young systemic milieu through heterochronic parabiosis has been shown to restore BBB integrity and enhance cerebrovascular function in aged mice, suggesting that circulating factors can rejuvenate the aging brain. However, the molecular mediators responsible for these effects remain poorly defined. Circulating insulin-like growth factor-1 (IGF-1) declines markedly with age and has been implicated in endothelial dysfunction and BBB disruption, raising the possibility that IGF-1/IGF-1 receptor (IGF-1R) signaling contributes to the vascular rejuvenation induced by young blood. To test this hypothesis, we combined heterochronic parabiosis with complementary transgenic approaches targeting either endothelial IGF-1R deletion (VE-Cadherin-CreERT2/Igf1rfl/fl) or systemic IGF-1 knockdown (TBG-Cre-AAV8/Igf1fl/fl). BBB permeability to fluorescent tracers and cortical microvascular density were quantified by intravital two-photon microscopy through chronic cranial windows. We found that exposure of aged mice to young circulation markedly reduced BBB leakage and increased cortical capillary density. These beneficial effects were significantly attenuated in aged parabionts lacking endothelial IGF-1R or paired with young partners deficient in systemic IGF-1, demonstrating that both endothelial receptor activation and circulating IGF-1 availability are required for full cerebrovascular rejuvenation. Despite this attenuation, partial improvement persisted, indicating that IGF-1/IGF-1R signaling contributes to, but does not fully account for, the vascular benefits of young blood. These findings identify the IGF-1/IGF-1R axis as an important mediator of young blood-induced restoration of BBB integrity and microvascular density. Targeting downstream effectors of IGF-1R signaling, together with lifestyle interventions that enhance somatotropic axis responsiveness, may offer geroscience-guided strategies to preserve BBB function and cognitive resilience in aging.