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2015

In Short-Lived Fish, Secrets to Aging
New York Times, February 27, 2015
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The turquoise killifish lives in a fleeting world: the ponds that appear only during the rainy season in East Africa.

As a new pond forms, turquoise killifish eggs buried in the mud spring from suspended animation. The eggs hatch, and in just 40 days the fish grow to full size, about 2.5 inches. They feed, mate and lay eggs. By the time the ponds dry up, the fish are all dead.

Even when hobbyists pamper them in aquariums, turquoise killifish survive only a few months, making them among the shortest-lived vertebrates on Earth. So the turquoise killifish may not seem the best animal to study to discover the secrets of a long life.

But researchers are finding that this tiny fish ages much as we do, only at a much faster pace. “It’s a compressed life span,” said Itamar Harel, a postdoctoral researcher at Stanford University. Dr. Harel and his colleagues recently developed a set of tools to probe the biology of the turquoise killifish.

Old people may seem a more logical focus for scientists looking to discover the mechanics of aging, but progress would be glacial.

“Who has 70 years to study somebody else’s aging process?” asked Sarah J. Mitchell, a postdoctoral researcher at the National Institute on Aging.

Instead, scientists have sought the secrets of aging in a series of animal models. But none has perfectly mirrored what happens to humans.

Dr. Mitchell studies mice, which live three to four years. From them, she has learned how genes become more or less active in old age, and she has been able to test drugs that make mice live longer. Last year, Dr. Mitchell and her colleagues showed that a compound called SRT1720 extends the life span of mice by 8.8 percent on average while improving their health.

But even short-lived mice can slow down aging research. So some researchers have turned to a tiny nematode worm called Caenorhabditis elegans, which reaches old age in just a few weeks. Scientists have discovered that some genes that influence its aging also function in humans.

When Anne Brunet arrived at Stanford University in 2004 as an assistant professor of genetics, she started studying both mice and worms. But she felt something was missing. Although worms grow quickly, they couldn’t answer some of her most pressing questions about aging. Since they have no skeleton, for example, there is no way to learn from them why bones get brittle.

But then a graduate student told her about the turquoise killifish. After the species was discovered in 1968, scientists found many parallels between its aging and human aging.

Old turquoise killifish lose muscle mass, as we do. The females stop producing fertile eggs. Their immune systems falter. They even get worse at learning new things later in life.

In 2006, Dr. Brunet starting assembling a team of postdoctoral researchers and graduate students to study turquoise killifish at a new level of detail. But a string of setbacks slowed them down for years.

A parasitic infection wiped out all their fish, for example; after a thorough bleaching of the lab, they had to start from scratch.

Once the scientists figured out how to keep the animals happy, Dr. Brunet’s team got down to the scientific work. They sequenced the entire genome of the turquoise killifish, identifying a number of genes known to influence aging in other species, including mice and humans.

Dr. Harel then built molecular tools the team could use to tinker with the fish’s genes. Using a new technique called Crispr, he created molecular scissors that could snip out any piece of killifish DNA and replace it with a different one.

To test his tools, Dr. Harel and his colleagues tinkered with a gene called TERT, which protects DNA from wear and tear. It encodes a protein that helps build caps at the ends of DNA molecules called telomeres.

Telomeres, like the plastic tips at the ends of shoelaces, keep DNA from fraying. As cells divide, their telomeres get shorter, and this change probably plays a role in aging. But how is still a mystery.

Dr. Harel and his colleagues succeeded in altering the TERT gene so that the fish could no longer make the protein. The engineered fish developed from embryos normally, but as adults they suffered from a number of defects.

The males became almost entirely infertile, for example, while the females made fewer eggs. Their gut linings atrophied, and they made fewer kinds of blood cells.

These results intrigued the researchers. On one hand, the changes they observed in the fish were similar to some of those in humans as they age. Yet the fish didn’t die any sooner than ones with working TERT genes.

Dr. Brunet was thrilled to have gotten these kinds of results so quickly from the fish. “It’s one of those moments you live for in science,” she said. She and her colleagues published their findings this month in the journal Cell.

Dr. Brunet plans to experiment with other turquoise killifish genes implicated in aging in other species, and then search for genes relevant to aging that may have been missed in longer-lived animals.

The researchers also hope to test anti-aging treatments on the fish. A drug that provides even two extra weeks of life may point the way to a compound that extends human lives by years.

“I hope it’s going to open doors for our lab, and for others,” Dr. Brunet said.

Copyright 2015 The New York Times Company. Reproduced with permission.
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