Mitigating age-related somatic mutation burden.

De novo somatic mutations are difficult to analyze because of their random nature. Apart from the few clonally amplified mutations, the far majority differs from cell to cell. Recent advances in single-cell, single-molecule and high-depth sequencing have shown that somatic mutations accumulate with age in virtually all tissues. Mutations arise through errors during replication or repair of damaged DNA. Age-related somatic mutation accumulation is inevitable due to the lack of an evolutionary advantage in protecting genome sequence integrity far beyond the period of first reproduction. Somatic mutation rate might be mitigated by adopting genome maintenance strategies of (i) extremely long-lived animals; (ii) species living under high genotoxic conditions; or (iii) stem or germ cells. Genomes are inherently unstable and require constant DNA repair to maintain their genetic information. However, selective pressure has optimized repair mechanisms in somatic cells only to allow transmitting genetic information to the next generation, not to maximize sequence integrity long beyond the reproductive age. Recent studies have confirmed that somatic mutations, due to errors during genome repair and replication, accumulate in tissues and organs of humans and model organisms. Here, we describe recent advances in the quantitative analysis of somatic mutations in vivo. We also review evidence for or against a possible causal role of somatic mutations in aging. Finally, we discuss options to prevent, delay or eliminate de novo , random somatic mutations as a cause of aging. [ABSTRACT FROM AUTHOR]