After a young mouse was joined to an old mouse through a shared circulation, its intestine renewed itself less effectively; disabling the receptor for the inflammatory protein TNF (TNFR1) in the intestinal lining preserved the formation of new crypts, the invaginations where cells are produced

After a young mouse was joined to an old mouse through a shared circulation, its intestine renewed itself less effectively; disabling the receptor for the inflammatory protein TNF (TNFR1) in the intestinal lining preserved the formation of new crypts, the invaginations where cells are produced

In mice, sharing a circulation with an old animal for eight weeks impaired intestinal renewal in the young partner. The authors traced one inflammatory pathway: signaling by the protein TNF through the TNFR1 receptor in cells of the intestinal lining reduced fatty acid use and the formation of new crypts.

The intestine continuously renews its inner lining, known as the epithelium. New cells arise in crypts, which are invaginations in the intestinal wall. In a Nature Aging paper published on August 11, researchers tested whether an old animal could alter this process in a young animal through a shared circulation.

To test this, they surgically joined a young mouse to an old mouse so that their blood circulated between them. After approximately eight weeks, the young partner had fewer dividing cells in its crypts, and crypts isolated from its intestine were less able to form organoids, which are miniature tissue models grown in a dish. In the control group, the researchers simulated the surgery and housed the mice together while keeping their circulations separate. This design allowed them to distinguish the effects of shared circulation from those of surgery and co-housing.

The authors then examined inflammatory signals. In old mice, antibodies against TNF improved organoid formation; antibodies against another inflammatory protein, IFNγ, also produced an improvement. To test the specific role of TNF, the researchers disabled TNFR1 in the intestinal epithelium. In young mice with this modification, organoid formation remained intact even after they were joined to an old animal.

In organoids, added TNF reduced the number of new crypts. Analysis of gene activity indicated that TNF suppresses fatty acid oxidation, the process by which cells obtain energy from fatty acids. In a separate experiment using palmitate, a fatty acid, TNF reduced the maximum rate at which mitochondria consumed oxygen. These results linked poor crypt formation to a reduced capacity of the cells to obtain energy from fats.

A 2018 study had already shown in mice that 24-hour fasting increases fatty acid oxidation and improves intestinal stem cell function. In the current mouse model, the old systemic environment acted through TNF and TNFR1 in the epithelium to suppress the same mode of energy production and reduce the formation of new crypts.