Mitochondrial Dysfunction in Monocytes of the Innate Immune System Contributes to Inflammaging

Inflammaging is the name given to the constant activation of the immune system that occurs in older individuals. Inflammation is useful and necessary in the short term, for the destruction of pathogens and damaged cells, or to recruit immune cells to aid in regeneration and clearance of metabolic waste. When inflammation continues without resolution, however, it becomes very harmful to tissue function. The chronic inflammation of aging has many contributing causes: the accumulation of senescent cells and their pro-inflammatory signaling; changes in the gut microbiome that favor inflammatory microbial species; persistent infections by viral pathogens such as cytomegalovirus; and so forth. Here, researchers look at how monocytes of the innate immune system change with age, becoming more inflammatory in response to the aging tissue environment.

Monocytes are circulating cells of the innate immune system which participate in a breadth of host defense and inflammatory processes, including antigen presentation, phagocytosis, inflammatory cytokine and chemokine production, and extravasation into tissue followed by differentiation to macrophages or dendritic cells. As a principal circulating inflammatory cell, monocytes have long been speculated to be major contributors to the age-associated chronic inflammatory state often termed "inflammaging". Because inflammaging is thought to underlie the bulk of age-related chronic diseases, monocytes are potential therapeutic targets for strategies meant to ameliorate aging-related disease.

Within the context of aging, multiple previous studies have found profound monocyte and macrophage dysfunction, including increased basal inflammation, impaired inflammatory activation, altered phagocytosis, and impaired migration/chemotaxis. In recent years, a variety of cellular metabolic programs have been shown to be linked to immune cell functions. However, immunometabolic studies have not been extensively undertaken in the aging field, and whether aging triggers shifts in immune cell metabolic programs is not well-understood.

We were the first to demonstrate that aging impaired mitochondrial function in monocytes when we showed that isolated human classical monocytes displayed reduced mitochondrial respiratory capacity. Now researchers have demonstrated a gene transcription pattern in isolated CD14+ classical monocytes from older individuals suggestive of a decrease in mitochondrial function and oxidative phosphorylation and, concomitantly, an increase in glycolytic energy production. Subsequent experiments found increased reactive oxygen species (ROS) production and enhanced glucose uptake in unstimulated monocytes from older adults.

In addition to increased ROS and decreased mitochondrial spare capacity, the researchers noted trends toward increased mitochondrial mass and reduced mitochondrial membrane potential in monocytes from older adults, and using these assays in tandem demonstrated that mitochondrial membrane potential was substantially decreased on a per mitochondrion basis. Overall, classical monocytes from older adults appeared to have a degree of mitochondrial dysfunction which may increase reliance on glycolytic metabolism during a quiescent state, and this may cause the increase in basal inflammatory activity in monocytes demonstrated here and in previous studies.

Link: https://doi.org/10.20900/immunometab20200025