The gradual acquisition of mutations in the genome of somatic cells is a hallmark of aging and leads to the evolution of a range of age-associated diseases, such as cancer. The accrual of such mutations within adult stem cells is thought to be of particular biological relevance, because these cells are long lived and can therefore accumulate a significant mutation burden during the lifetime of an organism, which is then propagated in all daughter cells. Somatic stem cells, or their immediate progeny, are also a likely cell of origin for malignant transformation. Although the DNA damage response of various tissue-specific stem cell types has been extensively explored using agonists such as ionizing radiation or chemotherapeutic agents, it is unclear what the major source of DNA damage is under physiologic conditions and how this is resolved into mutations within stem cells. A recent manuscript published in Nature sheds new light on this issue using the hematopoietic system as a model tissue to explore how by-products of the metabolism of alcohol can act as a mutagen within hematopoietic stem cells (HSCs), leading to their functional attrition and impaired hematopoiesis.
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