P01AI153559

High Resolution Longitudinal Immune Monitoring for Elucidating Immune Aging Dynamics

Since 2007, we have annually tracked the dynamics of immune system changes with the Stanford Ellison Longitudinal Aging (SELA) cohort. This cohort consists of approximately 150 young (20-40) and old (60+) individuals of various ages. We have 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. The SELA cohort is a unique resource due to the length of time and depth of profiling.

Using a novel systems approach that leverages the high-dimensional and longitudinal nature of the data, we have gained increased insight into immune aging. We have described an individual's immune baseline homeostatic state as shifting slowly along a continuum and trajectory, well beyond what can normally be obtained from cross-sectional analyses. This has allowed us 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, correlating to Imm-Age. These markers offer better and earlier detection than existing standard clinical tests. Understanding human immune variation and aging through the lens of a quantitative patterned process has 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. We will also recruit additional cohorts, including a healthy twin cohort (ages 40-60) to fill a current gap in SELA and provide information on early immune aging. Additionally, we will recruit 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. We have already measured immune parameters in this cohort in 2011. Furthermore, we will establish two additional cohorts: one consisting of heart transplant subjects and another consisting 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.

Lastly, we will use post-vaccination samples from SELA collected over 12+ years to map flu-specific B and T cell response history. We will test whether this information, coupled with Imm-Age, can help predict flu vaccine responses in older adults. This is currently an unsolved problem with major clinical implications.

Insights from this work will lead to the refinement of the metric, its connection to human physiology, and provide a means to assess how immune aging plays a role in chronic and acute age-associated conditions.

The Leland Stanford Junior University

NOT APPLICABLE

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Palo Alto, California 943041049 United States

Single Zip Code

NIAID Investigator Initiated Program Project Applications (P01 Clinical Trial Not Allowed) (PAR-20-072)

Amendment Since initial award the total obligations have increased 358% from $3,100,000 to $14,200,000.