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

Abstract

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 (R² = 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.

Keywords

Somatic mutations / species-specific lifespan / mutation burden / N-ethyl-N-nitrosourea / DNA repair

Supplementary materials

The supplementary material for this article is available at: Supplementary materials.

Acknowledgements

A list of longevity quotients was kindly provided by Dr. Steven Austad (University of Alabama at Birmingham).

Authors contribution

Ablaeva J: Resources, investigation.

Seluanov A: Resources.

Heid J: Investigation, writing-original draft.

Lee M: Investigation.

Sun S: Writing-original draft, formal analysis.

Vijg J: Writing-original draft, conceptualization.

Zhang Z, Maslov AY: Formal analysis.

Gorbunova V: Conceptualization.

Conflicts of interest

Jan Vijg is an Editorial Board Member of Geromedicine. Alexander Y. Maslov and Jan Vijg are co-founders and shareholders of MutaGenTech, Inc. The other authors declare no conflicts of interest.

Ethical approval

All animal procedures were performed in accordance with institutional guidelines and were approved by the Institutional Animal Care and Use Committee (IACUC) under protocols UCAR-2009-054R (reference #101526) and UCAR-2008-030R (reference #101127).

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

All raw sequencing data has been deposited into NCBI SRA under accession number PRJNA1452926.

Funding

This work was supported by the National Institutes of Health grants P01 AG047200, P01 AG017242, and U01 ES029519, a Hevolution grant to Andrei Seluanov and an Impetus grant to Vera Gorbunova.

Copyright

© The Author(s) 2026.

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