Researchers from the Kapahi Lab at the Buck Institute for Research on Aging have shown in a new study that increased intestinal permeability is caused by the age-related loss of epithelial cells that form the gut membrane [1].

As we age, the integrity of the gut membrane declines, and it becomes more permeable; this is known as “leaky gut” and is thought to contribute to the background of low-grade chronic inflammation known as inflammaging [2]. One emerging theory is that loss of gut membrane integrity is the origin of inflammaging, the place where age-related chronic inflammation begins. Inflammaging precedes many age-related diseases, including atherosclerosis, arthritis, hypertension, and cancer [3-5].

The new study suggests that caloric restriction, or caloric restriction mimetics, may help to prevent the increase of gut permeability in humans and has the potential to increase healthspan, which is the period of life we spend free from illness.

Dr. Kazutaka Akagi, the lead scientist in this study, focused on the dMyc gene, which is a gene that facilitates cell proliferation. He showed that the level of dMyc acts as a barometer for enterocyte cell fitness, which influences intestinal barrier function in response to changes in diet and age. The research team also observed that cells lacking high levels of dMyc are destroyed by their neighbors in order to maintain gut membrane integrity.

However, dMyc declines in these cells as we age, leading to increased cell elimination and, ultimately, leaky gut. In the study, fruit flies given a rich diet saw an increased rate of cell loss, while flies on a caloric restriction diet lost dMyc much more slowly. This delayed onset of leaky gut and increased the healthy lifespan of the animals. Caloric restriction appears to improve gut barrier integrity and slow age-related changes.







The researchers also looked at changes to the microbiome, particularly dysbiosis, an imbalance of gut bacteria. It has been suggested that dysbiosis contributes to leaky gut; however, the researchers found that removing intestinal bacteria using antibiotics gave only a small level of protection and that the age-related loss of cells still occurred, leading to leaky gut. This suggests that diet is the primary determinant of gut membrane integrity, not changes to the microbiome.

Abstract

Loss of gut integrity is linked to various human diseases including inflammatory bowel disease. However, the mechanisms that lead to loss of barrier function remain poorly understood. Using D. melanogaster, we demonstrate that dietary restriction (DR) slows the age-related decline in intestinal integrity by enhancing enterocyte cellular fitness through up-regulation of dMyc in the intestinal epithelium. Reduction of dMyc in enterocytes induced cell death, which leads to increased gut permeability and reduced lifespan upon DR. Genetic mosaic and epistasis analyses suggest that cell competition, whereby neighboring cells eliminate unfit cells by apoptosis, mediates cell death in enterocytes with reduced levels of dMyc. We observed that enterocyte apoptosis was necessary for the increased gut permeability and shortened lifespan upon loss of dMyc. Furthermore, moderate activation of dMyc in the post-mitotic enteroblasts and enterocytes was sufficient to extend health-span on rich nutrient diets. We propose that dMyc acts as a barometer of enterocyte cell fitness impacting intestinal barrier function in response to changes in diet and age.

Conclusion

These new findings suggest that gut integrity is much more reliant on diet than gut flora, although these bacteria are likely to play a role. Once the gut membrane is compromised, however, the gut microbiome takes a primary role in inflammaging, as bacterial products penetrate the gut membrane into the body. It seems that diet may be the key to keeping the bacteria where they should be: in the gut.

Literature

[1] Akagi, K., Wilson, K. A., Katewa, S. D., Ortega, M., Simons, J., Hilsabeck, T. A., … & Kapahi, P. (2018). Dietary restriction improves intestinal cellular fitness to







[2] Franceschi, C., Garagnani, P., Parini, P., Giuliani, C., & Santoro, A. (2018). Inflammaging: a new immune–metabolic viewpoint for age-related diseases. Nature Reviews Endocrinology, 1.

[3] Freund A, Orjalo AV, Desprez PY, Campisi J. Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med (2010) 16(5):238–46. doi: 10.1016/j.molmed.2010.03.003

[4] Childs, B. G., Gluscevic, M., Baker, D. J., Laberge, R. M., Marquess, D., Dananberg, J., & van Deursen, J. M. (2017). Senescent cells: an emerging target for diseases of ageing. Nature Reviews Drug Discovery, 16(10), 718.

[5] He, S., & Sharpless, N. E. (2017). Senescence in health and disease. Cell, 169(6), 1000-1011.