Our understanding of somatic mutations and their connection to the aging process has seen significant advancements over the years, substantially influencing our perspective on human life span, aging, and disease. Tracing back to the seminal work of Gioacchino Failla and Leo Szilard from the 1950s, in which they posited an exponential increase in mammalian mortality rates owing to the accumulation of spontaneous mutations in organs and tissues 1, 2, research in this field has progressively underscored the crucial role of somatic mutations in cancer and their potential involvement in other age-related diseases. Indeed, it is now realized that somatic mutations are both inevitable and irreversible. Mutations are a consequence of errors in the repair of DNA damage. Error rate can vary across cell types and species but will not reduce to zero. Indeed, zero mutations would leave no substrate for evolution to act on and would also be energetically too costly [3]. Hence, mutations are inevitable. They are also irreversible because once the original template is gone, lost sequence information cannot be restored.

Our current vision is schematically depicted in Figure 1, showing how somatic mutation accumulation, in conjunction with cellular responses to DNA damage, for example, apoptosis and cellular senescence, can causally contribute to aging and cancer. However, the exploration of somatic mutation accumulation in aging remains relatively uncharted, primarily due to the challenges associated with the quantitative analysis of these mutations in normal human tissues.

The advent of next-generation sequencing and single-cell whole genome sequencing has provided the scientific community with tools to directly discern the somatic mutation burden in human somatic cells and tissues and study the effects of age, and environmental and lifestyle factors. These advances have now brought us close to addressing the question of whether the accumulation of random mutations in somatic cells can adversely affect cell function to the extent that aging ensues.

Here, we will first briefly review the technical difficulties in studying somatic mutations in normal human tissues and the recently emerged approaches to tackle these challenges. Next, we will discuss the possibility that somatic mutation burden scales with functional life span of cells, that is, is higher in short-lived than in long-lived species and higher in disposable, differentiated cells than in stem cells or germ cells.