Mutagen-induced somatic mutation rate in primary mammalian cells in relation to maximum life span

AIMS: Testing the hypothesis that excess mutations induced in primary fibroblasts by a low dose of N-ethyl-N-nitrosourea (ENU) are inversely correlated with species-specific maximum life span. METHODS: To measure excess mutations induced by ENU we treated primary cells of 10 mammalian species, greatly differing in life span. We treated all cells with a low dose, non-toxic dose of ENU (20 ug/ml). We then extracted DNA from all treated and untreated cells and quantified somatic mutation burden by single-molecule sequencing. We measured excessive mutations by calculating the ΔSNVs and we analyzed this across species with linear regression. RESULTS: The average values for ΔSNV were found to range from 0.773 in mice to 0.367 in whale, resulting in a modest inverse correlation with species-specific maximum life span (R ² = 0.2067, P < 0.001). CONCLUSION: We conclude that DNA repair accuracy, the main determinant of genome sequence integrity, modestly correlates with life span suggesting that longer lived species have better repair capacities compared to shorter-lived species, which is in keeping with genome instability being a primary hallmark of aging and highlights its important role for longevity.