Life is short, especially for the killifish, Nothobranchius furzeri: It lives for only a few months and then its time is up. During that short lifespan it passes through every phase of life from larva to venerable old fish. Its brief life expectancy – unusual for a vertebrate – has long fascinated Dario Valenzano of the Max Planck Institute for Biology of Ageing in Cologne. During a ten-year period he has made it a model organism for research into ageing.
“Wow, that’s a really old fish!” Valenzano can barely hide his astonishment in the fish basement of the Max Planck Institute in Cologne. Aquariums are lined up end to end on long shelves.
Who, however, was expecting to find a date of birth in the distant past, will be surprised to read September 2014 on the birth certificate stuck on the aquarium pane. The presumed Methuselah was just nine months old on the day of the visit to the fish basement. For a member of this Nothobranchius species, a positively biblical age. No other vertebrate ages so swiftly.
Valenzano encountered the fish – named after its discoverer, Richard Furzer – in 2002, as a student in the laboratory of his mentor Alessandro Cellerino in Pisa. The laboratory had a small aquarium stocked with fish. Cellerino had been given the fish by an acquaintance, a hobby aquarist who had bred killifish for many years. The fish buff drew the two researchers’ attention to the phenomenal rate at which the fish ages.
The young student had no specific interest in fish at the time. He was more focused on the behavior and evolution of apes and humans. For his Master’s thesis work, he studied apes in a zoo for months and analyzed their facial expressions. Nevertheless, the ephemeral fish caught his interest and soon became his passion. Out of curiosity, he looked for signs of ageing in the brains of the fish and found the same protein deposits that are typical of ageing in the human brain.
From then on, Valenzano wanted to solve the puzzle of the short lifespan of Nothobranchius and make it a model organism for research into ageing. Several models already existed: for example, the nematode C. elegans, the fruit fly Drosophila and the mouse. The latter lives for two to three years. That may not sound like much, but that’s also how long researchers have to wait before they can examine a mouse in advanced age. Nematodes and fruit flies live for just a few weeks, but, as non-vertebrates, they significantly differ from humans. “I wanted to develop the vertebrate equivalent of Drosophila to study the biology of vertebrate aging,” explains Valenzano.
Nothobranchius would therefore fill a gap: It has an extremely short lifespan and, as a vertebrate, it is closely related to humans. In just a few months, Nothobranchius undergoes the entire ageing process that takes years or decades in other vertebrates. Why has this fish in particular not been blessed with a long life? After all, some fish become very old. Koi carp, for example, can live for several decades. One species of rockfish in the North Pacific even has a life span of over 200 years.
The short lifespan of the killifish could be correlated to the climate of its habitat in southern Africa, the home of the turquoise killifish, how it is also called. Water is present there for seven months of the year at most; some bodies of water dry up completely after just two months. This is probably not the most auspicious situation for fish longevity. Only fish that are able to develop and reproduce while there is still water available are able to survive. On the other hand, there is no gain for the fish in being longer-lived. Therefore, selection will not favor genes that make it live beyond the point where the water in the puddles dries out. For Valenzano, this could be the key to understanding how a short lifespan evolved in this species.
Due to the short rainy season, Nothobranchius furzeri has evolved to mature quickly: The fish grow into adults capable of reproduction just three to four weeks after hatching. Then, the shimmering colors of youth pale, the fins fray, and the spine becomes progressively curved. The fish passes through every ageing phase, including dotage, rapidly, as in a time-lapse film.
Nature seems indifferent to this, as long as the survival of the next fish generation is ensured. The eggs develop at the bottom of the pond. If the pond dries up, the embryos fall into a state of suspended animation and can survive months of drought.
In advanced age Nothobranchius is rather inflexible. It ages, even when there is no threat of early death due to desiccation. That’s what fascinated Valenzano so much about the fish: “Nothobranchius could give us an answer to the question of why ageing occurs at all. Does ageing confer an advantage on plants and animals? Or is there simply no reason to prevent the inevitable process of decay, once successful reproduction has taken place?”
Although ageing cannot be halted in Nothobranchius, it can be slowed. A number of factors influence the life expectancy of the fish, one being temperature: the cooler the water, the more slowly the fish age. Food supply also plays a role. If there is a scarcity of food, the fish live longer – a phenomenon that researchers have also observed in fruit flies and nematodes. Why this is so has not been fully explained. “Perhaps the temperature and food supply give the fish cues as to whether the environmental conditions are favorable. At low temperatures and when food is scarce, it makes sense to wait awhile before reproducing. Consequently, the fish must stay alive longer to reproduce,” Valenzano suspects.
But the life history of the killifish is not only interesting in itself. To Valenzano, it also offers an opportunity to understand how other organisms age, including humans. Ageing killifish develop cancer, show cognitive decline, become less fertile, lose their pigmentation and become more fragile. These are very general ageing phenotypes, shared by many organisms. “Nothobranchius allows us to study in a short time how these biological mechanisms work,” explains Valenzano.
Many characteristics have to come together for a species to serve as a model organism for science. Nothobranchius furzeri is a success story in this respect. Valenzano has elevated it to an object of global scientific interest. Some 40 laboratories around the world are now working with this species. “Every fortnight or so we receive enquiries from scientists to send them Nothobranchius eggs so that they can breed the fish in their laboratory,” Valenzano says. Now, there is even an international scientific conference on the turquoise killifish held every two years.
Cover image: With its red and black bands and black-yellow patterned fins, the Turquoise killifish doesn't really look turquoise. It gets its name from the greenish-bluish basic colour of its scales. After only a few months, the shining colours of the young fish begin to fade. The rapid physical decline of the fish has aroused the interest of age researchers around the world. Frank Vinken
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