Reduced mitochondrial calcium uptake in macrophages is a major driver of inflammaging.

Mitochondrial dysfunction is linked to age-associated inflammation or inflammaging, but underlying mechanisms are not understood. Analyses of 700 human blood transcriptomes revealed clear signs of age-associated low-grade inflammation. Among changes in mitochondrial components, we found that the expression of mitochondrial calcium uniporter (MCU) and its regulatory subunit MICU1, genes central to mitochondrial Ca 2+ (mCa 2+ ) signaling, correlated inversely with age. Indeed, mCa 2+ uptake capacity of mouse macrophages decreased significantly with age. We show that in both human and mouse macrophages, reduced mCa 2+ uptake amplifies cytosolic Ca 2+ oscillations and potentiates downstream nuclear factor kappa B activation, which is central to inflammation. Our findings pinpoint the mitochondrial calcium uniporter complex as a keystone molecular apparatus that links age-related changes in mitochondrial physiology to systemic macrophage-mediated age-associated inflammation. The findings raise the exciting possibility that restoring mCa 2+ uptake capacity in tissue-resident macrophages may decrease inflammaging of specific organs and alleviate age-associated conditions such as neurodegenerative and cardiometabolic diseases.