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The cells lining the intestinal tract are replaced every two or three days, a high turnover rate that is based on a healthy population of intestinal stem cells. Biologists at MIT and the University of Tokyo have now discovered that aging has a devastating effect on intestinal stem cells and may contribute to increased susceptibility to gastrointestinal tract disorders.
The researchers also showed that they could reverse this effect in older mice by treating them with a compound that helps stimulate the intestinal stem cell population. The results suggest that this compound, which appears to stimulate a pathway involving longevity-related proteins known as sirtuins, may help protect the gut from age-related damage, say the researchers.
"One of the problems badociated with aging is the dysfunction of an organ, accompanied by a decrease in the activity of the stem cells that nourish and regenerate that organ. It is therefore a potentially very useful intervention point for slowing down or reversing aging, "said Leonard Guarente. the Novartis biology professor at MIT.
Guarente and Toshimasa Yamauchi, a professor at the University of Tokyo, are the main authors of the study, which is published online in the newspaper. Aging cell On March 28, the main author of the article is Masaki Igarashi, a former postdoctoral fellow at MIT, currently at the University of Tokyo.
Population growth
The Guarente laboratory has long been studying the link between aging and sirtuin, a clbad of proteins found in almost all animals. Sirtuins, which have been proven to protect against the effects of aging, can also be stimulated by caloric restriction.
In an article published in 2016, Guarente and Igarashi discovered that in mice, low-calorie diets activated sirtuins in intestinal stem cells, helping cells to proliferate. In their new study, they looked at whether aging contributes to the decline of stem cell populations and whether this decline could be reversed.
Comparing young (aged 3 to 5 months) and elderly (aged 2 years old) mice, the researchers found that intestinal stem cell populations declined with age. In addition, when these stem cells are removed from mice and grown in a culture dish, they are less able to generate intestinal organoids, which mimic the structure of the intestinal mucosa, compared to younger mouse stem cells. The researchers also found a reduction in sirtuin levels in old mouse stem cells.
Once the effects of aging were established, the researchers wanted to see if they could reverse the effects by using a compound called nicotinamide riboside (NR). This compound is a precursor of NAD, a coenzyme that activates sirtuin SIRT1. They found that after six weeks of NR-enriched drinking water, the older mice had normal levels of intestinal stem cells and that these cells were able to generate organelles as well as stem cells from younger mice.
To determine whether this stem cell stimulation actually had beneficial effects on health, the researchers administered NR-aged mice a compound normally inducing colitis. They found that NR protected mice against inflammation and tissue damage usually produced by this compound in older animals.
"This has real health implications because simply having more stem cells is a good thing, but it may not be anything in the real world," said Guarente. "To know that tripe is actually more resistant to stress if it is enriched in NR is quite interesting."
Protective effects
Guarente thinks that it is likely that NR will act through a pathway previously identified by his laboratory, in which activated NAD activates not only SIRT1, but also another gene called mTORC1, which stimulates synthesis of proteins in the cells and helps them to proliferate.
"Our hypothesis is that the reconstitution of NAD in old mice is the engine of this growth path that works through SIRT1 and TOR to reverse the decline that occurred with aging," he said.
The results suggest that NAD may have a protective effect against diseases of the intestine, such as colitis, in the elderly, he says. Guarente and his colleagues have already discovered that NAD precursors can also stimulate the growth of blood vessels and muscles and increase endurance in older mice. A 2016 study by Swiss researchers found that boosting NAD could help rebuild muscle stem cell populations in older mice.
In 2014, Guarente launched a company called Elysium Health, which sells a food supplement containing NR combined with another natural compound called pterostilbene, which is an activator of SIRT1.
The research was funded in part by the National Institutes of Health and the Glenn Foundation for Medical Research.
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