Aging impairs mitochondrial respiratory capacity in classical monocytes

Abstract

Aging is a critical healthcare concern, with age-related inflammation disposing individuals to a variety of diseases. Monocytes are affected by the aging process, with increased inflammation and impaired cellular functions such as phagocytosis. Mechanisms by which aging alters monocyte function are unknown, but recent research suggests that the balance of metabolic processes determine immune cell phenotype and function. Given the known association between aging and mitochondrial dysfunction in other tissues, we hypothesized that aging would impair mitochondrial function in monocytes. To test this, we isolated classical monocytes from young and older adults and tested mitochondrial function by a Seahorse assay. Aging reduced mitochondrial respiratory capacity and spare capacity in monocytes. Mitochondrial dysfunction is a potential mechanism by which aging alters monocyte phenotype and may impair inflammatory functions, especially in low-glucose environments where oxidative metabolism is necessary to meet energy demands.

Monocytes from Older Adults Maintain Capacity for Metabolic Compensation during Glucose Deprivation and Lipopolysaccharide Stimulation

“…AMPK is the critical regulator orchestrating this metabolic switch, which provides fatty acids to the mitochondria through downstream effects 19 . Decreased mitochondrial function is known to occur in many cell types with age 21 , and we have previously provided evidence for reduced mitochondrial function in classical monocytes with aging-namely that aging impairs mitochondrial maximal respiration and spare capacity 13 .…”

“…Their heterogenous and highly adaptable nature, ability to respond to pathogens and cellular garbage, communication with the adaptive immune system, and numerous defects with age make them a key contributor to inflammaging. Monocytes from older individuals have impaired migration and phagocytosis, diminished ability to activate the adaptive immune system, altered receptor expression, cytokine production, and subset proportions 12,13 .In response to activation, immune cells regularly change their functions dramatically. For example, monocytes activated by lipopolysaccharide (LPS) undergo vigorous cellular growth and an increased demand for the production of proteins, lipids, cytokines, and reactive oxygen species (ROS) 14,15 .…”

“…Their heterogenous and highly adaptable nature, ability to respond to pathogens and cellular garbage, communication with the adaptive immune system, and numerous defects with age make them a key contributor to inflammaging. Monocytes from older individuals have impaired migration and phagocytosis, diminished ability to activate the adaptive immune system, altered receptor expression, cytokine production, and subset proportions 12,13 .…”

“…Aged mice have been shown to have increased lactate and reduced glycolytic intermediates in muscle and liver tissue which suggest an increased reliance on anaerobic glycolysis 22 . Whether or not mitochondrial dysregulation is a primary cause of age-related monocyte dysfunction has yet to be determined, though we've recently provided evidence that aging impairs maximal and spare mitochondrial respiratory capacity in classical monocytes isolated from humans 13 .…”

“…This switch is regulated by AMP-activated protein kinase (AMPK) which stimulates catabolic pathways including fatty acid oxidation, autophagy, and mitochondrial biogenesis 14 . Since we have previously demonstrated mitochondrial dysfunction in monocytes 13 , we hypothesized that aging would result in a reduced ability to upregulate oxidative metabolism when glucose is unavailable following LPS-stimulation and that this would be associated with reduced inflammation and phagocytic capacity.…”