The practice of calorie restriction, eating up to 40% fewer calories while still maintaining an optimal intake of micronutrients, is well demonstrated to slow aging and extend healthy life span in near all species and lineages tested to date. It produces sweeping effects on the operation of metabolism – near everything changes, which has made it something of a challenge to identify the principal points of action. Nonetheless, more efficient operation of the cellular housekeeping mechanisms of autophagy is the most plausible mechanism to account for the majority of the benefits. That calorie restriction fails to extend life when autophagy is disabled is the most telling evidence.
The open access paper that I’ll point out today is illustrative of a great many similar lines of work, in which researchers dig deeper into one narrow aspect of calorie restriction and its benefits. Here, the focus is on the function of stem cells supporting intestinal tissue. The lining of the intestine, the intestinal barrier, is important in aging. Its decline in effectiveness allows unwanted microbes and compounds to enter tissue and the bloodstream, where they contribute to rising levels of chronic inflammation.
This decline is in part similar to that of tissues throughout the body, caused by a loss of stem cell function. Every tissue is supported by stem cell and progenitor cell populations that provide a steady flow of new somatic cells to make up losses and repair damage. Stem cell activity falls off with age, due to a mix of damage to these cells and reactions to a changing signaling environment. As the supply of new somatic cells declines, so too does tissue function. The process is slowed by calorie restriction, as appears to be the case for all other processes of aging assessed in the context of calorie restriction. Researchers here ask why exactly that is the case for intestinal stem cells, supporting a cell population known to have a high rate of replacement.
Aging and age-related pathologies such as cancer are the consequence of deleterious changes in cells and tissues over time, including the progressive accumulation of DNA mutations. Calorie restriction (CR) can prevent many age-related changes, resulting in extended lifespan and reduced age-related pathologies. Several intracellular mechanisms through which CR can reduce the accumulation of mutations have been identified, including attenuating oxidative stress and enhancing DNA repair. In addition to these intracellular mechanisms, mechanisms that act at the tissue level may be at play. For example, in Drosophila, CR enhances intestinal cellular fitness through outcompetition of less fit cells, thereby preventing age-related decline of intestinal integrity. Whether related mechanisms upon CR in mammals exist that act at a tissue level is currently unknown.
The mammalian intestinal wall is a single layer of epithelial cells curved into so-called crypt-villus units. As a protective barrier against the external environment, this epithelial sheet is constantly exposed to potentially DNA-damaging substances. However, most mutated cells are naturally lost due to the highly dynamic self-renewing nature of the epithelium. Lgr5+ stem cells at the bottom of crypts are long-lived and can thus accumulate mutations. However, these Lgr5+ stem cells compete for niche occupancy, resulting in continuous replacement and loss of neighboring stem cells, which is often referred to as stem cell competition. As a result, most stem cells, including those carrying mutations, will be lost while the progeny of one stem cell ultimately replaces all other stem cells in the crypt. Therefore, mutations will only be retained in the intestine if they are acquired by stem cells that win the stem cell competition.
We and others have recently shown that the chance that a stem cell can outcompete its neighbors can be manipulated by lowering the number of stem cells through pharmacologically inhibiting WNT protein gradients. Mutated stem cells can more rapidly spread within crypts when there are less competing stem cells. Interestingly, CR has been shown to increase the number of stem cells in intestinal crypts. Here we find that CR leads to increased numbers of functional Lgr5+ stem cells that compete for niche occupancy, resulting in slower but stronger stem cell competition. Consequently, stem cells carrying mutations encounter more wild-type competitors, thus increasing the chance that they get displaced from the niche to get lost over time. Thus, our data show that CR not only affects the acquisition of mutations but also leads to lower retention of mutations in the intestine.