Molecular interception and immunological characterization of age-associated disease

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PROJECT SUMMARY In developed countries, noncommunicable diseases such as cancer, cardiovascular disease, chronic respiratory illness, and diabetes account for the majority of deaths among people aged 70 and older. The global economic burden to care for patients with noncommunicable diseases is astronomical. In 2010, it cost an estimated 47 trillion dollars in 2010-2030, which is equivalent to 75% of global gross domestic product in 2010, to provide care for patients with chronic disease. Clearly, we need a better strategy to identify patients at greatest risk so that we can prevent disease development or provide earlier intervention. Our recent work has suggested that a decline in immune function is a major, potentially modifiable, risk factor for the development of cardiovascular disease. It remains unclear, however, at what point in the patient’s lifespan does the immune system age and contribute to disease, how genetic and environmental factors affect immune age, and whether decline in immune function is also associated with the development of other noncommunicable diseases associated with chronological aging. Project 2 is designed to understand the relationship between immune-aging (whose deepened understanding and relationship to flu response we assess in Project 1) and the development of diseases associated with chronological aging - an association that we hypothesize begins in middle-age but extends throughout the individual’s life span. In Project 2, first, we add a middle age cohort of twins (MAT-SELA) demographically similar to the SELA cohort, to not only expand the age range of patients to be profiled, but also to disentangle the effects of genetics and the environment to immune aging. To further isolate the environmental effects on immune age, we will also compare the immune age of a super fit older cohort (AL-SELA) with that of the SELA cohort, who are normal, older patients leading sedentary lifestyles. Second, we perform an in-depth analysis of how immune age affects the development of cardiovascular disease, building from our previous work, by serially profiling the immune age of patients who are at greatest risk for developing atherosclerosis (e.g., plaque build-up, heart attack or stroke), monitoring these patients by non-invasive imaging for the development and/or progression of cardiovascular disease, and documenting any major adverse clinical events. Furthermore, we apply advanced immune-based assays developed by our lab to interrogate the molecular and cellular components of the atherosclerotic plaque, extending our recent finding that flu specific T cells are found in the atherosclerotic plaque, in order to better understand the underlying mechanisms behind recent clinical observations that having the flu increases the risk of heart attack and stroke. Lastly, we will determine if immune age contributes to other non-communicable diseases by comparing the immune gene signatures associated with advanced aging in our cohorts with publicly available databases to associate the immune state with disease likelihood, severity, and prognosis.