Mice born without an inflammation protein called STING lived longer and kept healthier livers

In Short. Mice lacking STING, a protein that sets off inflammation when DNA turns up in the wrong part of a cell, lived about two months longer than normal mice. The finding comes from one laboratory and needs repeating.

CELLS KEEP their DNA in the nucleus, a walled compartment at their center. When DNA turns up in the surrounding fluid, the cytoplasm, it usually means a virus has got in, and the cell has a sensor for that. A protein called cGAS detects the stray DNA and makes a small messenger molecule. That molecule switches on a second protein, STING, which starts an inflammatory response. The sensor cannot tell a virus's DNA from the cell's own, and as cells age their own DNA starts to leak into the cytoplasm, from mitochondria (the cell's energy producers), from stretches of DNA that copy themselves around the genome and from broken pieces of chromosome. This is one proposed cause of the low, constant inflammation that accompanies old age.

If that idea is right, mice without the sensor ought to age more slowly. Researchers test such ideas with a knockout mouse, an animal bred so that one gene is missing from birth and the protein it encodes is never made. Earlier this year a group led by Vera Gorbunova and Andrei Seluanov at the University of Rochester reported that mice lacking cGAS in fact died sooner. They attributed this to a second job that cGAS does inside the nucleus, where it helps keep the DNA packed in order. Removing the next step in the chain, STING, might avoid that problem.

The same group has now tested this idea and posted the results on October 19th as a preprint, a paper shared publicly before other scientists have reviewed it (Martinez et al.). The team followed 61 normal mice and 62 STING knockouts until they died and compared their median lifespan, the age by which half of each group had died. For the normal mice this was 712 days. For the knockouts it was 773 days, 61 days or about 9% longer (61 of 712), and the difference was statistically significant (p=0.035).

The knockouts also looked better in old age in some ways. At 25 months their fur had grayed less (9 normal males against 11 knockouts, p=0.037). When the researchers examined the heart, lungs, liver, kidneys and pancreas under a microscope, only the liver differed. Old knockout livers held fewer clumps of inflammatory cells (10 normal mice against 8 knockouts, p=0.008) and less scar tissue on two of three stains used to detect it (4 mice per group). In normal mice the activity of the STING gene increased in the liver with age. In the knockouts, genes linked to scarring and inflammation, such as Col1a1 and IL-6, did not increase with age, although this rests on 3 mice per group.

The results carry several limits. The work comes from a single laboratory and has not been peer reviewed. The normal mice also died early. They were of a strain called C57BL/6, and in a large study at the Jackson Laboratory, which supplied the animals, mice of that strain had a median lifespan of 866 days for females and 901 days for males (Yuan et al., 2009). The Rochester controls died five to six months sooner, so the knockouts may have lived longer partly because the comparison group fared badly. Each liver comparison rests on 3 to 10 animals. A standard frailty index, a score that adds up signs of physical decline, showed only a trend in favor of the knockouts at 25 months, and the difference was not significant (7 normal mice against 9 knockouts, p=0.29).

Independent work points the same way, but it did not measure lifespan. In 2023 Andrea Ablasser's group at EPFL in Lausanne reported in Nature that H-151, an experimental drug that blocks STING, reduced inflammation in old mice and improved their grip strength, the distance they could run on a treadmill and their scores on memory tests (Gulen et al.). Old STING knockout mice in that study also had lower levels of aging-related immune markers.

The Rochester result is therefore a first survival curve for mice without STING. A second laboratory would need to repeat it with control mice that live as long as their strain normally does, and to test whether blocking STING with a drug late in life has a similar effect.