How African turquoise killifish press the pause button on aging

When the ponds where one African fish lives dry up, its offspring put their lives on pause. And now researchers have a sense for how the creatures do it.  

African turquoise killifish embryos can halt their development during a state of suspended activity called diapause. Now a study shows that the embryos effectively don’t age while in that state. Genetic analyses reveal that, to stay frozen in time, the embryos put functions such as cell growth and organ development on hold, researchers report in the Feb. 21 Science.

“Nature has identified ways to pause the clock,” says Anne Brunet, a geneticist Stanford University. Knowing how killifish pause their lives could help scientists figure out how to treat aging-related diseases or learn how to preserve human organs long-term, she says.

Nematode worm larvae (Caenorhabditis elegans) can also halt development and aging when faced with a lack of food or if their environment is overcrowded. Invertebrates like nematodes, however, lack many of the features that make other animals age, such as an adaptive immune system. More than 130 species of mammals from mice to bears also have some form of diapause.

The killifish (Nothobranchius furzeri) live in ponds in Mozambique and Zimbabwe that disappear for months during the dry season, leaving the fish without a home until the rain returns (SN: 8/6/18). For adults that typically live only four to six months anyway, vanishing ponds don’t pose much of a threat. But some killifish embryos press pause on their development during dry months, until ponds fill up again. 

Killifish embryos can put their growth on hold from five months up to two years, matching or even greatly exceeding their typical adult life span. If humans could do something similar, an 80-year-old person might instead have a life span from 160 to more than 400 years, Brunet says. But if, or how, these animals protect themselves from aging while in this limbo was unknown.

In the study, Brunet and her colleagues compared killifish embryos that halted their growth with those that bypassed diapause and hatched into adults. Diapause didn’t decrease an adult fish’s growth, life span or ability to reproduce — a sign that the animal didn’t age, even if it paused its development for longer than its typical lifetime, the researchers found.

The team then analyzed the genetic blueprint of embryos suspended in diapause to determine which genes were active. Although the young killifish had developing muscles, hearts and brains before diapause, genes involved in organ development and cell proliferation were subsequently turned off. But other genes were cranked up, such as some crucial for turning other sets of genes on or off.

One gene, the chromobox 7 gene, or CBX7, repressed genes involved in metabolism, but turned on those important for maintaining muscle and staying in diapause, the researchers found. Embryos without CBX7 came out of diapause sooner, and their muscles began to deteriorate after one month.

The new study shows that the embryos aren’t passively waiting for better environmental conditions — their cells coordinate responses during diapause that protect killifish from the passage of time. “We have always looked at this diapause state as more passive — nothing happens there,” says Christoph Englert, a molecular geneticist at the Leibniz Institute on Aging in Jena, Germany, who wasn’t involved in the work. But the new research “shifts the paradigm of diapause as a passive, boring state to an active state of embryonic nondevelopment.”

Researchers aren’t sure how things like temperature might spark a developing killifish to begin or end diapause. But understanding what’s going on inside an embryo is a step toward pinpointing how external signals might control when the animals suspend time, Englert says.