An Evolutionary Metric for Estimating PhyloAges from Bulk Sequencing of Hematopoietic Stem Cells Reveals the Tempo of Blood Aging in Cancer and Longevity

The phylogeny of a person's hematopoietic stem cells (HSCs) can be used to quantify physiological aging of blood using a phyloAge model based on diversity decay metrics. However, this procedure currently requires accurate HSC genome sequences, which are expensive and time-consuming to obtain. We show that metrics of diversity decay can be derived from the somatic variant frequency spectrum (VFS) using more affordable, routine bulk sequencing, because HSCs evolve without recombination at a clock-like rate. We found that VFS-based models produce phyloAge estimates similar to those derived from HSC genome phylogenies. Customized for protein-coding variation and sequencing read depth, VFS-based HSC phyloAge estimates were, on average, 168 years more than chronological ages in 157 patients with acute myeloid leukemia, consistent with excess HSC aging observed in cancer patients using single cell genome phylogenies. We also tested the hypothesis that variants in cancer driver genes may confer longevity, as they occur in a significant fraction of long-lived individuals. Indeed, HSC phyloAge estimates were significantly lower, consistent with reduced hematologic cancer risk among extremely old individuals. Thus, the new metrics and models broaden the utility of the phyloAge approach, making it feasible and efficient for clinical and research applications.