Abstract
Age Related Clonal Hematopoiesis (ARCH) arises when a hematopoietic stem cell (HSC) acquires a somatic mutation that confers a competitive growth advantage. ARCH mutations are associated with a tenfold increased risk of myeloid aberrancies, have been implicated in an increased risk for type II diabetes and cardiovascular disease, but are also frequently observed in apparently healthy elderly individuals. We longitudinally tracked the contributions of individual HSCs to peripheral blood and its sorted subsets in a healthy a supercentenarian at ages 103, 110 and 111 years. At age 110, up to ∼75% of the peripheral blood cells were derived from a single HSC, carrying a splice-donor mutation in DNA (cytosine-5)-methyltransferase (DNMT3A). During the course of life, this HSC had undergone at least four additional clonal events, each giving rise to subclonal expansions, including a relatively recently evolved clonal lineage that quickly gained dominance within the timeframe of our sampling. The mutated HSC and its clonal descendants have clear myeloid over lymphoid preference, producing 87.4% of the granulocytes and 77.8% of the monocytes versus 10.6% of the T-cells and 7.4% of the B-cells. Within the lymphoid branch, we observed a 3-fold larger contribution to CD4 T-cells (22%) compared to CD8 T-cells (6.8%), as well as the presence of naïve T-cells that were capable of robust proliferation when tested in vitro. Together with surprisingly high Sj TREC content in sorted T cells this suggested a functional thymic output in this supercentenarian.
Key points Deep sequencing of a longitudinal blood sample drawn from a healthy elderly individual at age 103, 110 and 111 years revealed that a single DNMT3A-mutated HSC and its clonal descendants produce over 75% of the peripheral blood.
A longitudinal analysis spanning a 9-year period reveals an extensive subclonal architecture with ongoing clonal dynamics reminiscent of myeloid dysplasia and malignancies.
While over 22% of the CD4 T-cells were derived from the mutated HSC, in vitro and in vivo evidence revealed an active and functional T-cell thymic output.