Immune Aging Clock Quantifies Immunosenescence and Identifies Therapeutic Target

Clinical laboratories increasingly seek objective metrics that capture cell type–specific immune decline and its systemic correlates. Precision tools could also help identify molecular levers of senescence in key lymphocyte subsets. New findings now describe a high-resolution Human Immune Aging Clock that quantifies immune age. The results also implicate the transcription factor RUNX1 as a decelerator of T-cell senescence.

China National Center for Bioinformation, a research center affiliated with the Chinese Academy of Sciences (CAS), with collaborators at the CAS Institute of Zoology and Quzhou Affiliated Hospital of Wenzhou Medical University, has developed the Human Immune Aging Clock (HIAC). The platform uses single-cell multi-omics to measure immunosenescence at subtype resolution. The work identifies RUNX1 as a functional “brake” on T cell aging and systematically characterizes multiscale dynamics of immune decline.

Investigators profiled peripheral blood from 230 healthy individuals spanning 60 years, generating an atlas of nearly 1.2 million peripheral blood mononuclear cells (PBMCs) and defining 24 immune cell subtypes. They built a multilayered framework comprising pAge (cell proportions), tAge (cell type–specific transcriptomes), TCRAge [T cell receptor (TCR) repertoire], and an integrated multimodal clock termed immAge. Aging was marked by reduced naïve T cells with expansion of exhausted T cells and monocytes, indicating coincident immune exhaustion and chronic inflammation.

The immAge model achieved a mean absolute error of 5.66 years in predicting chronological age, with T cell–based models performing best. An “immune aging pace” metric stratified individuals into accelerators and decelerators. Decelerators showed higher naïve T cell proportions, fewer senescence and inflammation signatures, plasma metabolomes enriched for immunomodulatory and antioxidant molecules, and favorable physiology including improved glycemic control, better liver function, and enhanced cardiopulmonary capacity. Notably, a critical inflection point in immune remodeling was observed around age 40.

Gene regulatory analyses pinpointed RUNX1 as a central regulator whose protein levels decline with age in CD4+ and CD8+ T cells and inversely track the senescence marker γ-H2A.X in CD4+ cells. Functional studies showed RUNX1 deletion in young-donor T cells triggered cell-cycle arrest, senescence-associated secretory phenotype (SASP) activation, telomere shortening in CD8− T cells, and impaired cytotoxicity, whereas overexpression in aged T cells restored CD27 and lengthened telomeres. Adoptive transfer of aged CD8+ T cells overexpressing RUNX1 into immunodeficient mice sustained lower senescence markers and higher CD27. The study, published in Immunity on April 14, concludes that RUNX1 is both a biomarker and functional regulator—and the first validated intrinsic target—for modulating human T cell senescence.

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