In flies, the declining state of the intestine is a critical aspect of aging, the strongest determinant of mortality. This central position of the intestine in aging is not the case in mammals, but loss of integrity of the intestinal wall is still a major driver of chronic inflammation. That inflammation in turn accelerates progression of all of the common age-related diseases; it is a major aspect of aging, and control of inflammation is a goal well worth chasing. The practice of calorie restriction has been shown to slow down near all measurable aspects of aging, and the aging of the intestinal wall is no exception, as researchers demonstrate here. The noteworthy aspect of this research is the demonstration that the microbes of the gut do not seem to be all that involved in the pace of decline, which is not what one might expect based on recent years of work on the role of the gut microbiome in aging.
Flies eating a Spartan diet are protected from leaky gut and the systemic inflammation associated with it as they age. Conversely, flies on a rich diet are more prone to developing intestinal permeability, a condition linked to a variety of human conditions including inflammatory bowel disease. Researchers have shown that gaps in the intestinal barrier are caused by an age-related increase in the death of intestinal epithelial cells, also known as enterocytes.
The researchers zeroed in on dMyc, a gene involved in cell proliferation. They observed that levels of dMyc act as a barometer of cellular fitness in enterocytes, post-mitotic intestinal cells. They found that cells that have too little dMyc get eliminated by neighboring cells through a process termed cell competition in an attempt to maintain gut health. Levels of dMyc naturally decline with age in enterocytes, leading to excessive cell loss and thus a leaky gut. This decline in dMyc was enhanced by a rich diet, while dietary restriction maintained dMyc level in the flies, preventing leaky gut and extending the lifespan of the animals.
The researchers also looked at the role of dysbiosis, an imbalance in the intestinal bacteria or microbiome of the flies, as a potential contributor to leaky gut. Even though dysbiosis has been proposed as a leading cause of leaky gut, researchers found that removing intestinal bacteria with antibiotics conferred only minimal protection to the animals and did not prevent age-related damage to enterocytes. “The intestinal epithelium is affected by everything that moves through the gut. It would make sense that diet would have major impact on the health of those cells, especially over a lifetime of eating. While we understand the interest in the role of the microbiome, we think that diet may ultimately be the primary driver in cellular changes leading to leaky gut.”