The evolutionary trade-off between stem cell niche size, aging, and tumorigenesis.

Many epithelial tissues within multicellular organisms are continually replenished by small independent populations of stem cells largely responsible for maintaining tissue homeostasis. These continually dividing populations are subject to mutations that can lead to tumorigenesis but also contribute to aging. Mutations accumulate in stem cell niches and change the rate of cell division and differentiation; the pace of this process and the fate of specific mutations depend strongly on niche population size. Here, we create a mathematical model of the intestinal stem cell niche, crypt system, and epithelium. We calculate the expected effect of fixed mutations in stem cell niches and their effect on tissue homeostasis throughout the intestinal epithelium over organismal lifetime. We find that, due to the small population size of stem cell niches, mutations predominantly fix via genetic drift and decrease stem cell fitness, leading to niche and tissue attrition, and contributing to organismal aging. We also explore mutation accumulation at various stem cell niche sizes and demonstrate that an evolutionary trade-off exists between niche size, tissue aging, and the risk of tumorigenesis. Further, mouse and human niches exist at a size that minimizes the probability of tumorigenesis, at the expense of accumulating deleterious mutations due to genetic drift. Finally, we show that the trade-off between the probability of tumorigenesis and the extent of aging depends on whether or not mutational effects confer a selective advantage in the stem cell niche.