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Somatic mosiacism is the tendency for aged tissues to display a mix of mutations, spread through cell lineages from an original mutation in a stem cell or progenitor cell. The consensus in the research community is that this degrades tissue function, contributing to the aging process, but there is a lack of evidence for whether or not this is significant across the present human life span. Clearly eventually it has to become a problem, given ways to deal with all of the other aspects of aging, but without a grasp of the size of the effect, it is hard to say whether or not this issue should be targeted now or later.
How does one go about repairing somatic mosiacism in any case? This is a tough question. Repairing diverse mutations in living tissue is possible in the grand scheme of things, given sufficiently advanced molecular nanotechnology, but it is possible with the tools of the next twenty years or so? That would likely mean programmable, highly efficient gene therapies, but in the open access paper here researchers demonstrate that, in the case of at least one gene, there may be other, simpler possibilities.
Normal tissues progressively accumulate cells carrying somatic mutations, some of which are linked to neoplasia and other diseases. This process is exemplified by human esophageal epithelium (EE), in which mutations generated by cell-intrinsic processes colonize the majority of normal epithelium by middle age. The most common mutations are under strong positive selection, meaning that there is an excess of protein altering over silent mutations within each gene. This indicates that these mutations confer a competitive advantage over wild-type cells and drive clonal expansions in normal tissue.
We speculated that, as in other systems of competitive selection, altering the tissue environment may change the relative fitness of particular mutations and their prevalence in the tissue. In this study, we focused on p53 mutations because these are the most enriched during malignant transformation. p53 is mutated in 5%-10% of normal EE but in almost all esophageal squamous cell carcinomas (ESCCs). This argues that ESCC emerges from the p53 mutant cell population in normal epithelium and that mutation of p53 is required for cancer development.
We speculated that altering the selective pressure on mutant cell populations may cause them to expand or contract. We tested this hypothesis by examining the effect of oxidative stress from low-dose ionizing radiation (LDIR) on wild-type and p53 mutant cells in the mouse esophagus. We found that LDIR drives wild-type cells to stop proliferating and differentiate. p53 mutant cells are insensitive to LDIR and outcompete wild-type cells following exposure. Remarkably, combining antioxidant treatment and LDIR reverses this effect, promoting wild-type cell proliferation and p53 mutant differentiation, reducing the p53 mutant population. Thus, p53-mutant cells can be depleted from the normal esophagus by redox manipulation, showing that external interventions may be used to alter the mutational landscape of an aging tissue.