Immune aging Preprint

Mice lacking the alarm protein STING lived somewhat longer and had healthier old livers

Mice born without STING, a protein that raises the alarm when DNA turns up in the wrong part of the cell, lived a median of 773 days instead of 712 and had less scarring and inflammation in their livers in old age. It is a small, not yet peer-reviewed mouse study using a lifelong genetic change, not a drug.

Mice that lacked a single protein involved in sounding the body's alarm lived about two months longer than normal mice and had noticeably healthier livers in old age, according to a team at the University of Rochester. The result is modest and comes from small groups of mice that carried the change from birth. It is a preprint, not yet peer-reviewed.

Cells keep their DNA in the nucleus (and a little in their mitochondria, the cell's power plants). When DNA shows up in the fluid around them, the cytoplasm, it usually means a virus has got in. A sensor called cGAS detects it and passes the signal to a second protein, STING, which switches on inflammation and antiviral defences. The trouble is that the system can't tell a virus's DNA from the cell's own. In aging cells, bits of DNA leak out of damaged nuclei and mitochondria and can keep STING switched on, feeding the low-grade, chronic inflammation of old age that researchers call "inflammaging".

The same team had earlier found that mice without cGAS lived shorter lives, which they put down to a second job cGAS does inside the nucleus. So they turned to STING, the next step in the chain.

What they did

  • They followed 62 mice born without a working STING gene and 61 normal mice of the same strain for their whole lives.
  • At 25 months, which is old for a mouse, they scored males for frailty and for grey fur.
  • They examined the heart, lungs, liver, kidneys and pancreas of old mice under the microscope, looking for clusters of immune cells and for fibrosis, the build-up of scar tissue.
  • They measured gene activity in livers of middle-aged (12 months) and old (25 months) males, three mice per group.

What they found

  • Longer median life. Half of the normal mice had died by 712 days, half of the STING-less mice by 773 days: about two months, or close to 10%, longer.
  • Frailty: no clear difference. The STING-less males were only slightly less frail at 25 months, a difference that could have been chance. They did keep more of their fur colour.
  • Healthier livers. Most organs looked much the same, but old STING-less male livers had fewer clusters of inflammatory cells and less scarring. Female livers showed a similar but weaker trend in scarring.
  • Quieter genes. In old STING-less livers, genes for inflammation and for building scar tissue were less active. In normal mice, the activated form of STING rose sharply in the liver between 18 and 25 months.
  • Heavier mice. The mice without STING weighed more than normal mice later in life.

What to keep in mind

  • Mice, not people. Nothing here shows that blocking STING would help humans live longer.
  • A lifelong genetic change, not a treatment. The mice lacked STING from birth. Whether a drug that blocks STING later in life would do the same, and whether it would be safe, was not tested.
  • Small groups. The lifespan study used about 60 mice per group, and the lifespan gain was only modestly statistically significant. Many liver measurements came from just three to five mice per group, mostly males. The paper reports the median lifespan, not the longest-lived mice.
  • STING has a job. It is part of the body's defence against viruses. These mice lived in a clean, pathogen-monitored facility; what losing it would cost outside such conditions wasn't studied.
  • Early and short. The preprint is a brief report; the authors say their code will be shared on publication.

Why it matters

Chronic inflammation is one of the main suspects in how bodies age, and STING is one of the switches that can keep it running when cells leak their own DNA. This study is a first sign that turning that switch off for life is compatible with, and may modestly extend, a mouse's lifespan, with the clearest benefit in the liver. Together with the team's earlier finding that losing cGAS shortens mouse life, it suggests that if this pathway is ever targeted, STING rather than cGAS is the step to aim at. Bigger studies, and tests of STING-blocking drugs given later in life, would be needed before that idea moves any closer to people.

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