Aging Impairs Mitochondrial Function and Mitophagy and Elevates Interleukin 6 Within the Cerebral Vasculature

Abstract

Background: The blood‐brain barrier (BBB) is critical for cerebrovascular health. Although aging impairs the integrity of the BBB, the mechanisms behind this phenomenon are not clear. As mitochondrial components activate inflammation as mitochondria become dysfunctional, we examined how aging impacts cerebrovascular mitochondrial function, mitophagy, and inflammatory signaling; and whether any alterations correlate with BBB function. Methods and Results: We isolated cerebral vessels from young (2–3 months of age) and aged (18–19 months of age) mice and found that aging led to increases in the cyclin‐dependent kinase inhibitor 1 senescence marker with impaired mitochondrial function, which correlated with aged mice exhibiting increased BBB leak compared with young mice. Cerebral vessels also exhibited increased expression of mitophagy proteins Parkin and Nix with aging. Using mitophagy reporter (mtKeima) mice, we found that the capacity to increase mitophagy from baseline within the cerebral vessels on rotenone treatment was reduced with aging. Aging within the cerebral vessels also led to the upregulation of the stimulator of interferon genes and increased interleukin 6 (IL‐6), a cytokine that alters mitochondrial function. Importantly, exogenous IL‐6 treatment of young cerebral vessels upregulated mitophagy and Parkin and impaired mitochondrial function; whereas inhibiting IL‐6 in aged cerebral vessels reduced Parkin expression and increased mitochondrial function. Furthermore, treating cerebral vessels of young mice with mitochondrial N‐formyl peptides upregulated IL‐6, increased Parkin, and reduced Claudin‐5, a tight junction protein integral to BBB integrity. Conclusions: Aging alters the cerebral vasculature to impair mitochondrial function and mitophagy and increase IL‐6 levels. These alterations may impair BBB integrity and potentially reduce cerebrovascular health with aging.