Cerebral Microvascular Senescence and Inflammation in Diabetes.

Abstract

Stress-induced premature senescence can contribute to the accelerated metabolic aging process in diabetes. Progressive accumulation of senescent cells in the brain, especially those displaying the harmful inflammatory senescence-associated secretory phenotype (SASP), may lead to cognitive impairment linked with metabolic disturbances. In this context, the senescence within the neurovascular unit (NVU) should be studied as much as in the neurons as emerging evidence shows that neurogliovascular communication is critical for brain health. It is also known that cerebrovascular dysfunction and decreased cerebral blood flow (CBF) precede the occurrence of neuronal pathologies and overt cognitive impairment. Various studies have shown that endothelial cells, the major component of the NVU, acquire a senescent phenotype via various molecular mediators and pathways upon exposure to high glucose and other conditions mimicking metabolic disturbances. In addition, senescence in the other cells that are part of the NVU, like pericytes and vascular smooth cells, was also triggered upon exposure to diabetic conditions. The senescence within the NVU may compromise functional and trophic coupling among glial, vascular, and neuronal cells and the resulting SASP may contribute to the chronic neurovascular inflammation observed in Alzheimer’s Disease and Related Dementias (ADRD). The link between diabetes-mediated cerebral microvascular dysfunction, NVU senescence, inflammation, and cognitive impairment must be widely studied to design therapeutic strategies.