Factors mediating age-associated systemic inflammation

National Institute On Aging

Investigators

Linked publications & trials

Abstract

Inflammation is an acknowledged component of age-associated conditions including frailty, hypertension, cardiovascular disorders, metabolic and neurodegenerative disorders such as Parkinsons and Alzheimers diseases. However, a key feature of age-associated inflammation is lack of significant overt manifestation of symptoms with increase in cytokines such as IL-1, IL-6 and TNF in the human blood that correlate with poor outcomes of several chronic age-related ailments. Other immunological features associated with chronic systemic inflammation include paucity and poor functional capability of lymphocytes. These changes are collectively referred to as inflammaging. Aging humans also experience gut-dysbiosis due to shortened telomeres, which create gut wall disintegration as well as a consequence of dietary insults to the gut lining. The goal of this project is to mimic age-associated low-grade inflammation in humans in young mice. We postulated that age-dependent impairment of gut integrity may permit low-level transfer of commensal bacteria or bacterial products to escape into the body, which would trigger variety of cell types to produce inflammatory agents that constitute low-grade systemic inflammation. Currently, two different models have been described that generate chronic inflammation in young mice. In one model mice are treated with high dose of 3-5% (w/v) dextran sodium sulfate (DSS) provided in drinking water followed by recovery for 7-10 days. This regimen is repeated to generate chronic inflammation. This model mirrors situations in which antigen-activated immune cells fail to turn down inflammatory response after repeated acute infections. In a second model lipopolysaccharide (LPS) is injected intravenously daily to simulate chronic infections such as noted in oral diseases. In our model we would like to mimic inflammation that represents age-associated deterioration of the gut barrier followed by transmission of commensal fecal bacteria and or bacterial products to the blood and tissues to elicit inflammatory responses. We expect that this mouse model will be useful in studying the cellular and molecular basis for the cause and effect of systemic inflammation in the aging of various tissues, age-associated chronic diseases such as Parkinson's Disease and obesity.