Somatic mutations in human ageing: New insights from DNA sequencing and inherited mutations

Abstract

The accumulation of somatic mutations is a driver of cancer and has long been associated with ageing. Due to limitations in quantifying mutation burden with age in non-cancerous tissues, the impact of somatic mutations in other ageing phenotypes is unclear. Recent advances in DNA sequencing technologies have allowed the large-scale quantification of somatic mutations in ageing tissues. These studies have revealed a gradual accumulation of mutations in normal tissues with age as well as a substantial clonal expansion driven mostly by cancer-related mutations. Nevertheless, it is difficult to envision how the burden and stochastic nature of age-related somatic mutations identified so far can explain most ageing phenotypes that develop gradually. Studies across species have also found that longer-lived species have lower somatic mutation rates, though these could be due to selective pressures acting on other phenotypes such as perhaps cancer. Recent studies in patients with higher somatic mutation burden and no signs of accelerated ageing further question the role of somatic mutations in ageing. Overall, with a few exceptions like cancer, recent DNA sequencing studies and inherited mutations do not support the idea that somatic mutations accumulating with age drive ageing phenotypes, and the phenotypic role, if any, of somatic mutations in ageing remains unclear.

Keywords: DNA damage; Genome; Longevity; Tumorigenesis.