Abstract 6282: Age-related shifts in the immune system revealed from single-cell RNA-seq using non-negative matrix factorization

Abstract Unraveling the molecular mechanisms driving aging and identifying potential therapeutic targets for age-related diseases are essential to increase healthspan. The aging immune system undergoes significant alterations, contributing to immune dysfunction and increased susceptibility to diseases. Identifying gene programs associated with immune aging is key to understanding these changes and developing strategies to counteract their effects. In this study, we leverage non-negative matrix factorization (NMF), an interpretable and powerful dimensionality reduction technique, to identify gene expression programs in the immune system that shift with age. We analyze single-cell RNA sequencing (scRNA-seq) data from the large OneK1K cohort, which includes 981 participants aged 19 to 97 years and encompasses 1.27 million peripheral blood mononuclear cells. We reveal two distinct age-related transitions in the immune system composition and function occurring with an average peak around 39.3 and 71.8 years of age. These transitions are characterized by the activation or suppression of particular gene programs, reflecting changes in immune cell types, their interactions, and signaling pathways. Our findings provide a clearer understanding of the molecular underpinnings of immune aging by uncovering gene programs associated with it. These potential biomarkers of immune aging could enhance therapeutic strategies aimed at rejuvenating immune function in aging populations. Citation Format: Ragnhild Laursen, David Martin-Pestana, Nicolai J. Birkbak. Age-related shifts in the immune system revealed from single-cell RNA-seq using non-negative matrix factorization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6282.