Assessment of Somatic Mosaicism as a Biomarker of Aging

Random mutations in stem cells lead to a pattern of mutations throughout the tissue supported by those stem cells, as daughter cells are imprinted with a particular combination of mutations based on the ancestor stem cell and the timing of cell division versus timing of mutations. In principle, one can take a sample of somatic cells and reverse engineer the progression of mutations in the underlying stem cell and progenitor cell populations from the variety and combination of mutations observed in the sample. That progression can then be used as the basis for a measure of chronological or biological age, a novel form of aging clock to join the many others derived from age-related changes in biological data.

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. This complements existing aging clocks and may help reduce the current uncertainty in the assessment of geroprotective trials.