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My funny Valentine – or, how a tiny fish will change the world of aging research

YoungFishI admit it. I have crush on a fish. The object of my affection is the African turquoise killifish - a tiny, colorful fish that lives in seasonal ponds and puddles under the hot sun of Mozambique and Zimbabwe. Because the pools dry out regularly, the fish have evolved to have a normal lifespan of only a few months. In fact, it's one of the shortest-lived vertebrates known. It's also zippy, territorial and (maybe it's just me?) seemingly possessing a degree of chutzpah noticeably absent in your average goldfish.

The killifish's compressed lifespan, plus the ease and speed with which it can be housed and bred, make it an ideal model for genetic studies of aging and longevity. But in the absence of a fully sequenced genome and little information about gene expression patterns or a way to introduce selective mutations, it's been difficult for researchers to get a scientific handle on the slippery creature.

Today, geneticists Anne Brunet, PhD, and Itamar Harel, PhD, published a comprehensive genetic toolbox for use by researchers around the world wanting to draw parallels between humans and my tiny, finned crush. The article appears online in Cell; a charming video abstract describing their work is also available.

As I describe in our release:

Although the similarities between fish and humans may not be immediately evident, people have much more in common with the tiny, minnowlike creature than with other short-lived laboratory animals.

“This fish gives us the best of both worlds,” said postdoctoral scholar Itamar Harel, PhD. “As a vertebrate, it shares many critical attributes with humans, including an adaptive immune system, real blood and similar stem cell biology.

At the same time, its very short life span mimics those of the laboratory worms, yeast and fruit flies that until now have served as the traditional models of aging research.”

A short life span allows researchers to quickly assess the effect of genetic variations among different strains of fish. It also allows them to breed and raise hundreds of progeny for study within the span of months, rather than the many years required to conduct similar experiments in other vertebrates.

“The life span of a mouse can be as long as three to four years,” said Anne Brunet, PhD, professor of genetics. “This is close to the average length of a postdoctoral or graduate student position. This means that it would be very difficult for a researcher to conduct a meaningful analysis of aging in the mouse within a reasonable time period.”

Brunet, who is an associate director of Stanford’s Paul F. Glenn Center for the Biology of Aging, and her colleagues used a fully sequenced killifish genome (which will be described later in a separate paper) generated by fellow lab member and study co-author Berenice Benayoun, PhD, to determine the location of the killifish's genes. They analyzed the patterns of gene expression among tissues and devised a way to use a new genome-editing technique called CRISPR to swap out 13 aging-related genes for mutant or inactive version. One, a mutation in a protein called telomerase, resulted in fish with symptoms that mimic a human condition associated with telomerase defects called dyskeratosis congenita. More from our release:

“Very quickly we began to see an effect on rapidly dividing tissues such as the blood, gut and sperm,” said Harel. “The fish rapidly become sterile, their intestines began to atrophy and they made fewer types of blood cells than their peers.”

The researchers conclude that the killifish is currently the fastest way to study diseases of telomere shortening in vertebrates. They are hopeful that the other mutant strains will be equally useful in their lab and in other labs worldwide.

“Itamar has generated a range of tools necessary to study how genetic changes affect physical characteristics of the killifish,” said Brunet. “It’s a true ‘genotype to phenotype’ platform, and is likely to be transformative. Now we have what is essentially a high-throughput vertebrate model for aging research.”

To an outside observer, the killifish's many charms grow dim as it ages. It swims more slowly, its colors begin to fade and it even begins to hunch. But to me, and to a growing number of aging and longevity researchers like Brunet and Halmar, its star continues to shine bright.  I'm eager to see what biological mysteries are lurking just under its shiny scales in the next few months and years. In the meantime, I'll have to see if I can just make room for a fish tank on my desk...

Previously: Tick tock goes the clock – is aging the biggest illness of all?, Male roundworms shorten females' lifespan with soluble compounds, say Stanford researchers and Longevity gene tied to nerve stem cell regeneration, say Stanford researchers
Photo from the Brunet laboratory, used with the permission of Cell Press

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