A NINE-YEAR LONGITUDINAL STUDY IN THE BLOOD OF A SUPERCENTENARIAN REVEALS AN EXTENSIVE SUBCLONAL ARCHITECTURE AND ONGOING SUBCLONAL DYNAMICS

van den Akker, E. B.; Makrodimitris, S.; Hulsman, M.; Brugman, M. H.; Nikolic, T.; Bradley, T.; Waisfisz, Q.; Baas, F.; Jakobs, M. E.; de Jong, D.; Slagboom, P. E.; Staal, F. J.; Reinders, M. J.; Holstege, H.

doi:10.1101/788752

bioRxiv · 10.1101/788752

A NINE-YEAR LONGITUDINAL STUDY IN THE BLOOD OF A SUPERCENTENARIAN REVEALS AN EXTENSIVE SUBCLONAL ARCHITECTURE AND ONGOING SUBCLONAL DYNAMICS

van den Akker, E. B.·Makrodimitris, S.·Hulsman, M.·Brugman, M. H.·Nikolic, T.·Bradley, T.·Waisfisz, Q.·Baas, F.·Jakobs, M. E.·de Jong, D.·Slagboom, P. E.·Staal, F. J.·Reinders, M. J.·Holstege, H.

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Abstract

The aged hematopoietic system is characterized by decreased immuno-competence and by a reduced number of hematopoietic stem cells (HSCs) that actively generates new blood cell (age-related clonal hematopoiesis, ARCH). While both aspects are commonly associated with an increased risk of aging-related diseases, it is currently unknown to what extent these aspects co-occur during exceptional longevity. Here, we investigated these aspects in blood cells of an immuno-hematopoietically normal female who reached 111 years. Blood samples were collected across a 9-year period at ages 103, 110 and 111 years. We applied several genetic sequencing approaches to investigate clonality in peripheral blood samples and sorted cell subsets. Immuno-competence was characterized using flow cytometry, T-cell receptor excision circle (TREC) assays, and in vitro proliferation assays. We identified a single DNMT3A-mutated HSC clone with a complex subclonal architecture and observed ongoing subclonal dynamics within the 9-year timeframe of our sampling. The mutated HSC generated 78-87% myeloid cells, 6-7% of the B-cells, 6% of CD8+ T-cells, and notably 22% of the CD4+ T-cells. Intriguingly, we found that T-cells were capable of robust proliferation when challenged in vitro. Moreover, we observed a surprisingly high TREC content, indicative of recent generation of naive T-cells. Concluding, we observed long-term stability of extreme ARCH with ongoing clonal dynamics combined with functional T-cell immunity. Our results indicate that extreme ARCH does not compromise immuno-competence and that a clonally expanded CD4+ T-cell subset may serve as a potential hallmark of the supercentenarian immune system. Key pointsO_LILongitudinal blood sampling from a female aged 103-111 revealed a dynamic clonal hematopoiesis contributing to myeloid and lymphoid subsets C_LIO_LIDespite the highly advanced age and extreme clonal hematopoiesis we observed functional T-cell immunity C_LI

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van den Akker, E. B., Makrodimitris, S., Hulsman, M., Brugman, M. H., Nikolic, T., Bradley, T., Waisfisz, Q., Baas, F., Jakobs, M. E., de Jong, D., Slagboom, P. E., Staal, F. J., Reinders, M. J., Holstege, H.. 2019-10-01. A NINE-YEAR LONGITUDINAL STUDY IN THE BLOOD OF A SUPERCENTENARIAN REVEALS AN EXTENSIVE SUBCLONAL ARCHITECTURE AND ONGOING SUBCLONAL DYNAMICS. https://doi.org/10.1101/788752

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