Mutation in aging mice occurs in diverse cell types that proliferate postmutation.

ABSTRACT

To determine the relationship between aging, cell proliferation and mutation in different cell types, hearts, brains and kidneys from G11 PLAP mice between 1 week and 24 months of age were examined. Mutant cells were detected in tissue sections by staining for Placental Alkaline Phosphatase (PLAP) activity, an activity that marks cells that have sustained a frameshift mutation in a mononucleotide tract inserted into the coding region of the human gene encoding PLAP. The number of PLAP(+) cells increased with age in all three tissues. The types of cells exhibiting a mutant phenotype included cells that are proliferative, such as kidney epithelial cells, and cells that do not frequently replicate, such as cardiac muscle cells and neurons. In the brain, PLAP(+) cells appeared in various locations and occurred at similar frequencies in different regions. Within the cerebellum, PLAP(+) Purkinje cell neurons appeared at a rate similar to that seen in the brain as a whole. PLAP(+) cells were observed in kidney-specific cell types such as those in glomeruli and collecting tubules, as well as in connective tissue and blood vessels. In the heart, PLAP(+) cells appeared to be cardiac muscle cells. Regardless of tissue and cell type, PLAP(+) cells occurred as singletons and in clusters, both of which increased in frequency with age. These data show that age-associated accumulation of mutant cells occurs in diverse cell types and is due to both new mutation and proliferation of mutant cells, even in cell types that tend to not proliferate.