A cloning assay for 6‐thioguanine resistance provides evidence against certain somatic mutational theories of aging

The frequencies of 6‐thioguanine‐resistant primary clones from the kidneys and skeletal muscles of aging male cohorts of two F1 hybrid strains of Mus musculus varied from 0.59 to 10.96 × 10⁻⁵ and did not increase as a function of donor age (up to 40 months). Resistant clones were shown to be severely deficient in the activity of hypoxanthine‐guanine phosphoribosyltransferase (EC 2.4.2.8). These deficiencies presumably resulted from molecular alterations at this X‐linked locus, including point mutations. No alterations of the X‐chromosome were observed at the level of the light microscope. These results are inconsistent with predictions of the intrinsic mutagenesis and protein synthesis error catastrophe theories of aging. They do not rule out, however, somatic mutational theories that invoke comparatively large‐scale chromosomal lesions, many of which would be likely to be lethal at the cellular level.