Fight Aging!

This open access paper is an interesting companion piece to yesterday's discussion of the potential for expansion of mutations in stem cell populations to contribute to degenerative aging. What evolutionary constraints have led to the present state of stem cell populations in mammals: why are they not larger, with more capacity for tissue maintenance and regeneration in later life, for example?

Multicellular organisms continually accumulate mutations within their somatic tissues, constituting a significant, but poorly quantified, burden on tissue maintenance. To investigate this burden in a specific, well-parameterized context, we model the mammalian intestine and quantify the expected impact of mutation accumulation in stem cell populations. Furthermore, we explore how the population size of the stem cell niche influences mutation accumulation and demonstrate the expected trade-off between the risk of accumulating deleterious mutations, population size, and the risk of tumorigenesis. However, we further characterize how this trade-off can be expected to manifest over the lifetime of two well-studied mammalian systems, mice and humans, by estimating the expected effect of mutation accumulation on cellular homeostasis.

The intestinal epithelium is in constant flux, with populations of stem cells distributed throughout the intestine differentiating into other, transient, cell populations. These stem cells exist within small discrete populations in intestinal crypts, a compartmentalization thought to have evolved as a mechanism to deter tumorigenesis, as cells accumulating mutations that are beneficial to cellular fitness have a physical hindrance to spreading throughout the tissue. However, small populations are subject to significant genetic drift, that is, random changes in allele frequency that eventually lead to fixation or loss, and less effective selection.

The accumulation of damage causing the loss of cellular fitness is a hallmark of aging and is especially relevant when DNA damage occurs in stem cells, compromising their role in tissue renewal. Indeed, several mouse models with the diminished ability to maintain cellular genome integrity succumb to accelerated age-related phenotypes through the loss of tissue homeostasis caused by stem and progenitor cell attrition. Just as stem cell mutations conferring a beneficial fitness effect will increase cell production, mutations conferring a deleterious fitness effect will lead to decreased cell production and the diminished maintenance of healthy tissue.

When mutations confer a selective advantage or disadvantage within the niche, there exists an intermediate crypt size that minimizes the probability that any crypt accumulates the large beneficial mutations necessary to initiate a tumor. By modeling the fixation of mutations drawn from a full distribution of mutational effects and accumulating throughout the populations of the entire intestinal epithelium, we show that a secondary trade-off exists - populations maintained at a size that results in the lowest rate of tumorigenesis are expected to accumulate deleterious mutations that manifest in tissue attrition and contribute to organismal aging.

At small stem cell niche sizes, there exists a large number of crypts to maintain homeostasis, and a higher probability that any one crypt will obtain a rare mutation of large effect that would result in tumorigenesis. As stem cell niche size increases, the number of crypts needed to maintain the same amount of epithelium decreases, and so does the probability of fixing mutations within the crypts, and therefore the chance of fixing a rare mutation of large effect. However, for larger values of stem cell niche size, the strength of selection increases, thus increasing the chance that a fixed mutation was beneficial, leading to higher chances of tumorigenesis. At the observed intermediate population size in mice, the whole tissue size is expected to decline with age as deleterious mutations accumulate in stem cell niches. If selective pressures against tumorigenesis have selected for intermediate stem cell niche population sizes in mammalian species, then it has been at the expense of increasing epithelial attrition.

Link: https://doi.org/10.1111/eva.12476