Digestive Enzyme Escaping from the Gut and into Many Organs May Cause Aging in Rats

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• Ioana Patringenaru- [email protected]

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The mucosal layer in the small intestine degrades with age in rats, allowing digestive enzymes to slowly escape and leak into organs outside the intestine, including the liver, lung, heart, kidney and brain.

As the enzymes are unable to distinguish tissues from food, they break down collagen and destroy many receptors on cell membranes, such as the insulin receptor which leads to Type II Diabetes. The researchers call this process autodigestion.

They present their work in the Oct. 18 issue of the journal PLOSOne.

"These results support the hypothesis that in addition to oxidative stress, radiation, or an accumulation of microinjuries, aging is due to autodigestion and a consequence of the fundamental requirement for digestion," said Geert Schmid-Schoenbein, a distinguished professor in the Shu Chien-Gene Lay Department of Bioengineering at the University of California San Diego.

Digestion requires powerful enzymes that are synthesized in the pancreas. They are delivered from the pancreas into the lumen of the small intestine, where they digest all the food we eat. The digestive enzymes are capable of degrading most sources of food into their molecular building blocks, whether from plants or animals. Notably, they are able to digest the intestines of other animals, such as sausage casing.

A barrier consisting of epithelial cells with a thin slimy carbohydrate layer, known as the mucosal layer, keeps these digestive enzymes from escaping outside of the intestine. But the thin mucosal layer can be damaged by the food that passes through the intestine. While the barrier is capable of repairing itself, over a lifetime, these repairs become less and less effective.

In the PLOSOne study, researchers compared the guts of 4-month-old and 24-month-old rats. The team also looked for digestive enzymes in the organs of both sets of rats. They found that the older rats had high levels of digestiveenzymes in their organs which were undetectable in young ones. The gut barrier was alsoan order of magnitude moredamaged in older versus younger rats.

What can be done to minimize autodigestion-and therefore aging? In a study of 24-month-old rats, equivalent to human centenarians, the team blocked one of the digestive enzymes, pancreatic trypsin, using a two-week oral treatment with a serine protease inhibitor, tranexamic acid. This was designed to prevent autodigestion but not normal digestion. This intervention reduced the accumulation of pancreatic digestive enzymes in organs outside the intestine and allowed repair of damaged tissue in the older rat population.

"This research brings to light that whereas life is only possible with digestion (of the food we eat) there is a price to pay in the form of autodigestion (of one's own tissue) by the pancreatic digestive enzymes," Schmid-Schoenbein said.

Autodigestion during aging is consistent with the central role of pancreatic digestive enzymes during multi organ failure at the end of life, which the team previously demonstrated. The team is now exploring new methods to block digestive enzymes without stopping digestion and to better preserve the important mucosal layer in the intestine. They test blockades of digestive enzymes that could be applied in humans.

This work was funded partially by UC San Diego and from the NIH National Institute of Aging.

Aging by autodigestion

Geert W. Schmid-Schönbein and Frank De Lano
Center for Autodigestion Innovation
Shu Chien-Gene Ley Department of Bioengineering University of California San Diego

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