Fruit flies are used as a model of intestinal aging primarily because this aspect of aging drives mortality in that species. We can say that flies die from intestinal dysfunction in the same way that we can say that humans die from cardiovascular dysfunction; it isn’t the whole story by any means, but it is a sizable chunk of the story and the most common cause of mortality. So whenever one reads research materials on the topic of the aging of intestinal tissue, it is reasonable to expect fruit flies to be involved in that work at some point.
In today’s open access paper, researchers present an interesting finding regarding mechanisms of intestinal tissue maintenance and aging. Because enterocyte cells in the intestinal epithelium do not turn over all that rapidly, an early life injury that provokes greater turnover for a time has the side-effect of making a fly more resilient to later age-related damage and dysfunction. The intervention doesn’t have to be injury, as fasting also provokes greater turnover of enterocytes. Anything that allows some degree of replacement of enterocytes in adult life will lead to a long-term resilience to age-related intestinal dysfunction.
Age mosaic of gut epithelial cells prevents aging
Similar age-related structural and functional declines have been reported in the aging mammalian and Drosophila intestines. The Drosophila midgut epithelium has emerged as a model system for the study of aging genetically, and contributes to the understanding of the mechanisms of mammalian intestinal aging. The Drosophila midgut epithelium is a monolayer tissue composed of self-renewing intestinal stem cells (ISCs) that divide asymmetrically to give rise to enteroblasts (EBs) that differentiate into absorptive polypoid enterocytes (ECs) or enteroendocrine progenitor cells that give rise to a pair of enteroendocrine cells (EECs). In old flies, the midgut epithelium exhibits hyperplasia and barrier disruption, which associates with fly death.
However, it is still unclear how to limit hyperplasia to extend lifespan. Here, we show that early midgut injury prevents the abrupt onset of aging hyperplasia and extends lifespan in flies. Daily transcriptome profiling and lineage tracing analysis show that the abrupt onset of aging hyperplasia is due to the collective turnover of developmentally generated “old” enterocytes (ECs). Early injury introduces new ECs into the old EC population, forming the epithelial age mosaic. Age mosaic avoids collective EC turnover and facilitates septate junction formation, thereby improving the epithelial barrier and extending lifespan. Furthermore, we found that intermittent time-restricted feeding benefits health by creating an EC age mosaic. Our findings suggest that age mosaic may become a therapeutic approach to reverse aging.
