Inhibiting Age-Related Inflammation Extends Lifespan
Aging is associated with a wide range of tissue dysfunctions. Among these are metaplasias – conditions in which one kind of tissue is replaced by another type, causing misregulation of regional tissue functions. Metaplasias in the gastrointestinal (GI) tract are common maladies that have been associated with cancers and other diseases. Research at the Buck Institute for Research on Aging uses the fruit fly Drosophila to study the origin of metaplasias and to identify ways to reverse or delay them.
Publishing in Cell Host & Microbe in February 2016, the Jasper lab showed that age-related inflammation drives metaplasia in the fly equivalent of the stomach. This gastric metaplasia causes changes in the regional distribution of the commensal microbiota, the total species of gut bacteria, resulting in age-related intestinal pathologies and a shorter lifespan. Strikingly, the research shows the effects are reversible. Using genetic tools to reduce inflammatory signaling in the gastric region of the gut, researchers prevented metaplasia, maintained a healthy commensal population, and extended lifespan in the flies by up to 18%.
A release from the institute reports that senior scientist and Buck faculty Heinrich Jasper PhD said the findings have implications for human disease, adding that metaplasia is the first step in the development of Barrett’s Esophagus, whereby cells in the esophagus take on the characteristics of the stomach, and that some forms of colon cancer begin with metaplasia. “We don’t really understand the cellular processes underlying these diseases yet,” Jasper said. “What this study shows is that chronic age-related inflammation may drive a natural predisposition to metaplasia. In the fly, this metaplasia causes an imbalance or dysbiosis of the microbiota, resulting in pathologies that include stem cell deregulation along the gastrointestinal tract.”
Researchers found that the age-related metaplasia is initiated by chronic activation of a well-characterized inflammatory response JAK/Stat signaling pathway. Activation of this pathway is implicated in age-related inflammation, and its chronic activation disrupted normal cellular composition and activity of the stomach-like copper cell region in the middle midgut of the fly. When JAK/Stat signaling was inhibited in this region specifically, the flies lived longer. “Interestingly, these flies also lived longer when we cultured them in a germ-free condition,” said Hongjie Li, a graduate student in the Jasper lab. “This indicates that activity in the gastric region contributes to gut homeostasis in addition to its role in controlling gut microbiota.”