Live Fast, Die Young
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TECHNOLOGY FEATURE LIVE FAST, DIE YOUNG Research into ageing requires patience, but a small cadre of scientists is angling to speed up answers by developing the flamboyant, short-lived turquoise killifish as a new model. SEBASTIAN KAHNERT/DPA/PICTURE ALLIANCE KAHNERT/DPA/PICTURE SEBASTIAN The turquoise killifish (Nothobranchius furzeri ), with its fleeting life, is helping researchers to study the mechanisms that influence human ageing. BY AMBER DANCE were exceptionally short-lived. Of the many To set up a killifish model, researchers have varieties of killifish, the turquoise killifish taken advantage of modern genomic tools hysiologist Alessandro Cellerino has (Nothobranchius furzeri) has the shortest lifes- and drawn techniques from well-established always been an aquarium enthusiast, pan — the briefest of any vertebrate bred in zebrafish protocols, rather than starting from but fish were not originally part of his captivity, ranging from 3 to 12 months depend- scratch. In 2015, the publication of CRISPR– Presearch plan. One afternoon in 2000, hanging ing on strain and living conditions. Cas9-based gene-editing techniques for out in a tank-filled cellar in Canossa, Italy, with Using killifish to study ageing is not a new the killifish1, as well as two complementary breeder Stefano Valdesalici, Cellerino idly asked idea. In the late twentieth century, scientists genome-sequencing efforts2,3, boosted the fish him which fish were the shortest-lived. Valde- studied ageing in one species, Nothobranchius to the status of genetically tractable model. salici pointed to a tank with brightly speckled guentheri, that lives for about 14 months. But The killifish — or Notho, as some scientists African turquoise killifish: “They don’t make it given techniques available at the time, they affectionately call it — is certainly gaining fans. any longer than three months.” could come up with only basic descriptions of Interest has “really exploded over the past few “Are you kidding?” asked Cellerino, who ageing features. When Cellerino encountered years”, says Valenzano, who now works at the works at the Scuola Normale Superiore in Pisa, N. furzeri, timing and luck were on his side: Max Planck Institute for Biology of Ageing in Italy. “OK, I want them.” advances in molecular analysis had set up excel- Cologne, Germany. He estimates that about two So in March 2004, Cellerino and his gradu- lent conditions in which to develop the model dozen scientists have visited his group in the past ate student Dario Riccardo Valenzano found and investigate mechanisms behind its dotage. year to learn killifish husbandry. In June, about themselves bouncing through Mozambique The killifish’s brief lifespan, relative to those of 70 Notho aficionados attended the second in a four-wheel-drive truck with Valdesalici, longer-lived models such as mice and zebrafish, Nothobranchius Symposium in Jena, Germany. who chairs the Italian Killifish Association in enables ageing research to progress apace. And But the challenges of keeping killifish — such as Canossa. They donned chest-high waders and because the fish is a vertebrate, the research is their lack of a standardized diet — and a want gloves to net killifish from the seasonal, cow- more directly relevant to people than are stud- for basic reagents, such as Notho-specific anti- pat-spattered mud holes where the fish live. ies of short-lived organisms such as fruit flies bodies, mean that the fish has a way to go before Like the tank-bred versions, these wild strains or nematodes (see ‘The long and short of it’). it reaches the utility of lab mice. ©2016 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts r21ese rJULYved. 2016 | VOL 535 | NATURE | 453 TECHNOLOGY AGEING The ephemeral existence that so appeals to scientists is an evolutionary adaptation to Scientists studying ageing can select from a variety of model NATURE the fish’s natural environment: their acceler- THE LONG AND organisms, from short-lived yeast and invertebrates to longer-lived ated development enables them to live and vertebrates, or even analyse the life histories of exceptionally reproduce in transient mud pools during the SHORT OF IT long-lived species. wet season in equatorial Africa. The eggs sur- CLAIRE WELSH/ vive in a dormant state during the dry season, Short-lived invertebrates are convenient for genetic screens, but lack key features of vertebrate and once the rains come and pools form, they biology, such as an internal skeleton or adaptive immune system, that are aected by ageing. hatch. The fish have only a few weeks or months to grow up and spawn before the water dries up. Hobbyists, attracted by the males’ flashy 5–4 DAYS appearance, have been collecting turquoise killi- Budding yeast (Saccharomyces cerevisae) fish since they were discovered in Zimbabwe in 2–8 DAYS A ‘mother’ yeast cell divides asymmetrically, 1968. Consequently, Cellerino’s first challenge Nematode (Caenorhabditis elegans) budding o ‘daughters’, but the mother can was to confirm that their lifespan was not a side replicate only a limited number of times. Some of the same genes involved in worm effect of decades of breeding in tanks. Most of senescence control the hibernation-like the wild N. furzeri that Cellerino’s team caught dauer state. in Mozambique lived for about eight months — not as brief a time as the inbred Zimbabwe line, 30–40 DAYS but still short enough to interest scientists. Fruit y (Drosophila melanogaster) But that begged another question: would Flies and vertebrates share some common killifish age in a way that parallels the human features, such as a brain, a heart and adult process? Yes, says Valenzano: the fish do get stem cells. ‘old’ before they die. “They don’t drop dead Vertebrates with mid-range lifespans are suitable for experimentation, and their biology after four months,” he says. “They slowly dete- 2 is closer to that of a human. riorate.” The fish become duller in colour, lose muscle mass and body weight, develop cancers and swim around less. 3–2 MONTHS The brain shows typical signs of ageing, too, Turquoise killish (Nothobranchius furzeri) says Livia D’Angelo, an anatomist at the Univer- Killish, vertebrates with a remarkably short sity of Naples Federico II in Italy. Glia — brain lifespan, are garnering attention from researchers studying ageing. cells that provide support and protection for 2–3 YEARS neurons — upregulate the glial fibrillary acidic 3–5 YEARS Mouse (Mus musculus) protein GFAP, as happens in mammalian age- Zebrash (Danio rerio) Mice share many features with humans, but ing, and age-associated, lipid-rich pigment are expensive to maintain and relatively slow Although it is easy to perform genetic to breed. granules called lipofuscin accumulate. Neurons modications on zebrash, their relatively degenerate and deposit amyloid molecules that long lifespan precludes many ageing studies. aggregate, resembling the plaques seen in peo- 5–20 YEARS ple with Alzheimer’s disease, Valenzano adds. Dog (Canis lupus familiaris) He has also found that old fish don’t learn as well Pet canines share their environments, lifestyle as young ones. Young fish rapidly work out how habits and many common age-related diseases to avoid an unpleasant stimulus, such as a plastic with people, and so they serve as practical stick swirling in their tank, whereas old-timers models for healthy-ageing treatments. take longer to catch on4. “It’s a very good model for neuroscience research,” D’Angelo says. The fish also respond to anti-ageing interven- 3 With longer-lived species, researchers can perform comparative studies. tions much as some short-lived vertebrates do. Resveratrol — the stuff in red wine that prolongs 28–3 YEARS life in nematodes and fruit flies — can lengthen Naked mole-rat (Heterocephalus glaber) their lifespan by up to 59%4. Restricting feed- The naked mole-rat resists age-related disease; ings to every other day creates a caloric deficit for example, cancer is extremely rare. UP TO ~4 YEARS known to extend lifespan in organisms ranging Brandt’s bat (Myotis brandtii) from yeast to rodents, and it does the same for 5 Precise gures are scarce and come from wild killifish, although the effects vary by strain . animals, but 40 years is the oldest age yet ~7 YEARS known. Low levels of reproduction and hibernation might contribute to bats’ GONE FISHING Human (Homo sapiens) Having shown that killifish decline with age, lengthy lives. scientists now want to understand how the pro- Life expectancy varies geographically; at its extremes, it is 50 years in Chad and 90 in cess occurs. One key resource is the collection of Monaco. several strains from Africa whose genomes are ~200 YEARS not identical. Notho scientists have four main Bowhead whale (Balaena mysticetus) strains to choose from, Cellerino says: the origi- nal Zimbabwe line, and three derived from fish This estimate is based on chemical changes to amino acids in whale eyes, but living whales caught in Mozambique in 2004 and 2007, which have also been found toting whaling tools that have slightly longer lifespans. are more than a century out of date. By cross-breeding two strains, Cellerino and 454 | NATURE | VOL 535 | 21 JULY ©20162016 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. AGEING TECHNOLOGY his team created fish with a range of lifespans. has two. But at the Jena meeting, geneticist surgeon diagnosed the parasite Glugea, which They then compared the genomes and longevi- John Postlethwait of the University of Oregon the scientists suspect came in with other species ties of parent and second-generation progeny, in Eugene offered a potential solution. The trick, of killifish that they bought from a fish store. and identified a few chromosomal regions, each he explains, is to use an intermediate genome “That was the lowest point,” Brunet says.