Age-related arterial stiffness and cerebrovascular dysfunction in mice correlate with cognitive impairment but are not reduced with long-term ALT-711 treatment.

Age-related increases in large artery stiffness contribute to cerebrovascular dysfunction and cognitive impairment. Alagebrium Chloride (ALT-711) is a collagen crosslink breaker that reduces vascular stiffness. We hypothesized that long-term treatment with ALT-711 would reverse age-related large artery stiffness, thereby preserving cerebral artery function and cognitive function. We treated old male and female C57BL/6 mice (20 months) with ALT-711 (1 mg/kg/day) or vehicle via oral gavage for 4 months and measured arterial stiffness, cerebral artery endothelial function, cognitive function, and collagen crosslinking. Treatment with ALT-711 did not significantly reduce stiffness in large arteries or cerebral arteries. There was no effect of ALT-711 on cerebral artery endothelial function, cognitive function, or collagen crosslinking. However, we found that collagen crosslinking was greater in old mice than in young, untreated C57BL/6 mice. In old mice, aortic collagen crosslinking was correlated with carotid artery passive stiffness. Additionally, among old mice, the passive stiffness of the cerebral artery negatively correlated with cerebral artery endothelial function and cognitive function. Cerebral artery endothelial function was negatively correlated with Frailty Index. In sum, age-related cerebral artery stiffness is negatively correlated with cognitive function and may be a promising therapeutic target to combat cerebrovascular dysfunction and cognitive decline with age.