Altered Mitochondrial Calcium Metabolism is a Major Factor in Inflammaging

In this study, we report a surprising discovery that mitochondrial Ca2+ (mCa2+) uptake capacity in macrophages drops significantly with age. This amplifies cytosolic Ca2+ (cCa2+) signaling and promotes NF-κB activation, rendering the macrophages prone to chronic low-grade inflammatory output at baseline and hyper-inflammatory when stimulated. Although mitochondrial dysfunction has long been a suspected driver of aging, our study pinpoints the mitochondrial calcium uniporter (MCU) complex as a keystone molecular apparatus that links age-related changes in mitochondrial physiology to macrophage-mediated inflammation. Both chronic low-grade inflammation and mitochondrial dysfunction are known hallmarks of aging, but mechanistic links between these two processes have not been defined with clear links to human biology. For example, defective mitophagy in Prkn-/- mice may contribute to inflammaging by shedding mitochondrial DNA as an inflammatory stimulus in senescent cells. Although a progressive age-associated decline in mitophagy is not evident in human myeloid cells, if one supposes that there is a steady age-associated shedding of inflammatory mediators from other senescent cells, our findings predict that the decreased mCa2+-uptake capacity will render the macrophages hyper-responsive to such inflammatory stimuli from senescent cells and thereby drive inflammaging. A recent study performed a comprehensive analysis of mitochondrial phenotypes in purified human c...
Source: Fight Aging! - Category: Research Authors: Tags: Daily News Source Type: blogs