Since 2007, we have annually tracked the dynamics of immune system changes with the Stanford Ellison Longitudinal Aging (SELA) cohort, which consists of ~150 young (20-40) and old (60+) individuals of various ages for which we determined cell subset phenotypes and cytokine responses at high resolution, whole blood gene expression, serum cytokines, HAI response to annual flu vaccination, and a standardized clinical evaluation. Given the length of time and the depth of profiling, the SELA cohort is a unique resource. Using a novel systems approach which leverages the high-dimensional and longitudinal nature of the data allowed us to gain increased insight into immune-aging and describe an individual’s immune baseline homeostatic state as shifting slowly along a continuum and a trajectory, well beyond what can normally be obtained from cross-sectional analyses. We utilized this to build a reliable metric of immune-age (IMM-AGE), which captures a life-long process of change in immune cell subset composition and cell responses in a single value. IMM-AGE only partially correlates with chronological age and yet has prognostic clinical value with respect to all-cause-mortality in healthy older adults beyond well-established risk factors. In addition, using SELA we have identified several strong links between cardiovascular disease and immune-based predictive markers, correlative to IMM-AGE, that offer better and earlier detection than existing standard clinical tests. Understanding human immune variation and aging through the lens of a quantitative patterned process led us to testable hypotheses which we will explore here. Specifically, our two research projects address two questions – (1) what drives immune-aging; and (2) how does it relate to immune response, disease severity, and treatment? To answer these questions we will continue the longitudinal profiling of SELA, now with more epigenetic and environmental data, and recruit additional cohorts: a healthy twin cohort (ages 40-60), a current gap in SELA and one informative of early immune aging; a cohort of older adults vigorously exercising and living well which can be leveraged to distinguish features of biological aging and those modifiable by lifestyle and for which we have measured immune parameters in 2011; and two additional cohorts, first of heart transplant subjects and second of subjects in the Women’s Health Initiative with retrospective information on cardiovascular state. These latter cohorts will allow us to test hypotheses raised from our published studies on the relation of immune-aging to cardiovascular disease and its connection to flu history, an observed epidemiological association whose mechanism has been unclear to date. Last, we will use post-vaccination samples from SELA collected over 12+ years to map flu-specific B and T cell response history and test whether this information, coupled with immune- age, can help predict flu vaccine responses in older adults, a currently unsol...