A new review examines how mutations turn tissues into cellular mosaics and how their contribution to aging can be tested
A new review examines how mutations turn tissues into cellular mosaics and how their contribution to aging can be tested
On August 7, Elizabeth Pan, Alexander Maslov, and Jan Vijg published a review of somatic mutations, which are DNA changes that arise in the body's cells after conception. The authors discuss how new measurement methods could help determine whether these errors alter tissue function with age.
When a cell copies its DNA or repairs DNA damage, an error sometimes remains in the sequence. When the cell divides, it passes the error to its descendants, allowing clones, which are groups of cells carrying the same mutation, to grow within the tissue. Neighboring cells therefore acquire different sets of DNA changes, creating a genomic mosaic.
For many years, these errors were easiest to detect in tumors, where an altered clone expands into a large mass of cells. Single-cell sequencing reads the DNA of an individual cell. Other methods compare the two strands of the same DNA molecule, because a genuine mutation should appear in both strands. Researchers can now measure mutations in normal tissues and examine how their frequency changes with age.
In a 2022 study, researchers sequenced the genomes of 208 intestinal crypts, which are mucosal invaginations where cells are continuously renewed, from 56 animals representing 16 species. Species with longer lifespans had lower annual rates of somatic mutation. This observation provides a quantitative relationship that researchers can test across different tissues and species.
This causal sequence is already established in cancer: a DNA change gives a cell a reproductive advantage, the clone expands, and a tumor forms. In the blood, clonal hematopoiesis follows similar logic outside tumors: an expanded cell lineage carrying a shared mutation is associated with vascular inflammation and the risk of myocardial infarction. The authors propose testing a similar sequence in aging tissues. Mutations in DNA regions that regulate gene activity may alter the function of the affected cell, and an expanded clone may then alter tissue function.
“The main open question is whether accumulated somatic mutations can collectively cause tissues and organs to lose function,” the review authors write.
Future experiments will need to link a specific clone carrying a mutation to a measurable loss of function in a particular tissue.