A number of studies have suggested that people who survive to extreme old age exhibit better immune function throughout later life in comparison to peers who died at earlier ages. This analysis is an example of the type, and the data shows a natural killer cell population that exhibits signs of greater efficiency and more youthful activity. How and why long-lived individuals exhibit better immune function is a separate question. Studies of genetic variation in very large human data sets suggest that genetics plays a much smaller role in late life survival than the consequences of lifestyle choices (such as physical fitness) and environmental exposures (such the burden of infectious disease).
Centenarians are an established model of successful and healthy ageing. Previous research on centenarians' immune systems has been limited to small-scale studies using a single methodology, such as flow cytometry or targeted gene expression analyses. However, these studies lacked comprehensive multi-omics integration and validation across diverse cohorts.
This study integrated single cell RNA sequencing (scRNA-seq), mass cytometry, and flow cytometry to analyse peripheral blood mononuclear cells (PBMCs) from 31 centenarians, 17 centenarian offspring, and 26 offsprings' spouses or neighbours as controls across three cohorts to generate a multi-omics atlas of centenarian immune status. Through comprehensive analysis, we showed that centenarians possess natural killer (NK) cells with "young" signatures and enhanced cytotoxicity linked to RUNX3 upregulation. Reinforced NK cell-T cell interactions via the MHC-I and MIF pathways promoted T cell function in centenarians. The study overcomes the limitations of prior studies by combining high-resolution single-cell data with functional assays, offering a unified model of immune health in extreme ageing.
Our findings, combined with existing evidence, redefine healthy immune ageing by demonstrating that centenarians maintain cytotoxic and regulatory balance through unique NK and T cell adaptations. For researchers, our study establishes a framework for exploring immune resilience, emphasising multi-omics approaches. For clinicians, targeting the identified pathways (RUNX3, MHC-I, or MIF) could help delay age-related immune decline, potentially reducing susceptibility to infections, cancer, and chronic inflammation.
Link: https://doi.org/10.1016/j.ebiom.2025.105922
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