Characterizing Immune Aging in the Context of Cellular Circuits and Functionalities

Aging of the immune system leads to a degradation in immune response, increasing vulnerability to infectious, cardiovascular, and autoimmune diseases. At the cellular level, innate and adaptive immune cell compositions shift over time. We previously harnessed these dynamics to define a trajectory of immune aging by longitudinally tracking immune cell subsets in the peripheral blood of ~140 healthy individuals from the Stanford-Ellison Aging Study as they age. The position of each individual on this trajectory, at any given time, defines their IMM-AGE– an integrative score of immune age and health that predicts all-cause mortality with higher accuracy than existing methods.

We hypothesized that an individual`s IMM-AGE score correlates with their ability to mount an effective immune response. To investigate this, we utilized CyTOF to simultaneously measure 85 immune-related markers encompassing functionality, exhaustion, senescence, and metabolic states, in 40 young and older adults. A semi-supervised clustering approach identified 144 distinct immune cell subsets and states, and in-conjunction with linear and non-linear modelling, and network motif analysis, we characterized the shift in cellular dynamics and cell-cell relationships across the IMM-AGE spectrum.

In total, we identified 44 immune cell subsets whose frequencies dynamically shift with IMM-AGE, revealing new insights into additional populations that shift in abundance during immune aging. Importantly, our approach disentangled the interplay between T-cell exhaustion and memory subsets, uncovering changes in cell states previously obscured by memory functionality. Furthermore, we examined cell-cell interactions by defining immune cell modules within low- and high-IMM-AGE individuals. Our results revealed distinct and non-random alterations in intercellular correlations over the course of immune aging, highlighting a restructuring of immune cell circuits and the ways in which cells may coordinate.

Our detailed, high-resolution understanding of how immune system components shift with age provides a crucial foundation for exploring how these changes coalesce into functional loss or gain. Understanding the mechanisms that govern the decline in immune response in the elderly, may offer potential avenues for developing novel therapeutic strategies to enhance immune function and extend healthspan in the elderly.