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

Abstract

Inflammaging is the chronic low-grade inflammation that occurs with age that contributes to the pathology of age-related diseases. Monocytes are innate immune cells that become dysregulated with age and which can contribute to inflammaging. Metabolism plays a key role in determining immune cell functions, with anti-inflammatory cells primarily relying on fatty acid oxidation and pro-inflammatory cells primarily relying on glycolysis. It was recently shown that lipopolysaccharide (LPS)stimulated monocytes can compensate for a lack of glucose by utilizing fatty acid oxidation. Given that mitochondrial function decreases with age, we hypothesized that monocytes taken from aged individuals would have an impaired ability to upregulate oxidative metabolism along with impaired effector functions. Aging did not impair LPS-induced oxygen consumption rate during glucose deprivation as measured on a Seahorse XFp system. Additionally, aged monocytes maintained inflammatory gene expression responses and phagocytic capacity during LPS stimulation in the absence of glucose. In conclusion, aged monocytes maintain effector and metabolic functions during glucose deprivation, at least in an ex vivo context.The number of Americans over the age of 65 is expected to increase by approximately 80 million people by 2040 1 . This change will have significant effects on the economy, healthcare, and society in general. Currently, over two-thirds of the healthcare budget is spent on managing chronic diseases of the elderly 2 . Aging is the highest risk factor for the majority of chronic diseases -including cardiovascular disease, diabetes, arthritis, and cancer 3 . While lifespan continues to rise, healthspan (the length of time someone is healthy) has increased more slowly, and Americans are living longer with impaired health and disabilities 4 . Interventions are needed to improve the health and quality of life of the aging population, and studies show that the compression of morbidity is possible with lifestyle changes, pharmaceuticals, and continuous medical advances 3, 5 .Aging is associated with chronic, low-level, systemic inflammation (termed inflammaging) that contributes to most, if not all, age-related diseases 6 . Older adults have higher serum levels of several pro-inflammatory cytokines/proteins such as IL-6, IL-1β , C-reactive protein (CRP), and TNFα 7 . Elevated levels of these molecules in circulation, most notably IL-6, are correlated with an increased risk of morbidity and mortality in elderly populations 8 . Furthermore, they are associated with sarcopenia, malnutrition, arthritis, atherosclerosis, cognitive decline, and other diseases of aging 9 . There is no consensus on the causes of inflammaging, though it is likely due to a host of factors that become dysregulated with age. These "hallmarks of aging" include reduced autophagy and mitophagy, accumulation of DNA and mtDNA damage leading to genomic instability, epigenetic changes, telomere shortening, cellular and immune senescence, dysbiosis, chronic antigenic stress, ...