Cell Tree Rings: the shape of somatic evolution as a human aging timer

Abstract

Biological age is typically estimated using biomarkers whose states have been observed to correlate with chronological age. A persistent limitation of such aging clocks is that it is difficult to establish how the biomarker states are related to the mechanisms of aging. Somatic mutations could potentially form the basis for a more fundamental aging clock since the mutations are both markers and drivers of aging and have a natural timescale. Cell lineage trees inferred from these mutations reflect the somatic evolutionary process and thus, it has been conjectured, the aging status of the body. Such a timer has been impractical thus far, however, because detection of somatic variants in single cells presents a significant technological challenge.

Here we show that somatic mutations detected using single-cell RNA sequencing (scRNAseq) from hundreds of cells can be used to construct a cell lineage tree whose shape correlates with chronological age. De novo single-nucleotide variants (SNVs) are detected in human peripheral blood mononuclear cells using a modified protocol. Penalized multiple regression is used to select from over 30 possible metrics characterizing the shape of the phylogenetic tree resulting in a Pearson correlation of 0.8 between predicted and chronological age and a median absolute error less than 6 years. The geometry of the cell lineage tree records the structure of somatic evolution in the individual and represents a new modality of aging timer. In addition to providing a single number for biological age, it unveils a temporal history of the aging process, revealing how clonal structure evolves over life span. Cell Tree Rings complements existing aging clocks and may help reduce the current uncertainty in the assessment of geroprotective trials.