Young blood-induced rejuvenation of neurovascular coupling involves endothelial IGF-1/IGF-1R signaling: evidence from heterochronic parabiosis using endothelial IGF-1R deficient and systemic IGF-1 knockdown mice.

Aging is accompanied by progressive impairment of neurovascular coupling (NVC), the mechanism that matches local cerebral blood flow to neuronal activity, contributing to cognitive decline and the development of vascular cognitive impairment and dementia. Exposure to a young systemic milieu through heterochronic parabiosis has been shown to restore NVC in aged mice, suggesting that circulating factors can rejuvenate cerebrovascular function. Yet, the molecular mediators responsible for this effect remain poorly defined. Building on our long-standing research demonstrating that age-related decline in insulin-like growth factor-1 (IGF-1) signaling contributes to cerebrovascular aging and NVC dysfunction, and on recent transcriptomic evidence implicating IGF-1 receptor (IGF-1R) activation in vascular rejuvenation, we hypothesized that the IGF-1/IGF-1R axis plays a role in the young blood-induced restoration of NVC. To test this, we combined heterochronic parabiosis with two complementary transgenic approaches: systemic IGF-1 knockdown (TBG-Cre-AAV8/Igf1^fl/fl) and endothelial-specific IGF-1R deficiency (VE-Cadherin-Cre^ERT2/Igf1r^fl/fl). NVC responses to whisker stimulation were assessed in the somatosensory cortex using laser speckle contrast imaging. Exposure of aged wild-type parabionts to young circulation markedly improved NVC responses, confirming the rejuvenating effect of young blood. This improvement was significantly blunted in aged parabionts paired with IGF-1-deficient young partners and in endothelial IGF-1R-deficient aged parabionts exposed to young blood. These findings demonstrate that both circulating IGF-1 and endothelial IGF-1R signaling contribute to, but do not fully account for, the restoration of NVC in aged mice. Together, our results identify IGF-1/IGF-1R signaling as a critical component of the molecular network through which young blood exerts its neurovascular rejuvenating effects, while indicating that additional circulating and endothelial pathways also participate in the systemic regulation of cerebrovascular aging.