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German Research Team Finds Link Between Gene Expression and Longevity in Killifish

NEW YORK (GenomeWeb) – A team led by researchers from the Leibniz Institute on Aging has discovered that when genes involved in a cell's energy production are less active at a young age, the short-lived African turquoise killifish (Nothobranchius furzeri) lives longer.

African turquoise killifish are exceptionally short-lived, and even when they live in optimal conditions, their lifespan usually lasts between four and 12 months. That short lifespan makes them an ideal species in which to study aging.

While it's well known that genetic differences among individuals influence lifespan, the study published today in Cell Systems further suggests that differences in patterns of gene expression in youth may predict longevity.

The research team analyzed the lifespan of 152 single-housed male killifish by taking small biopsies from their fins at age 10 weeks and 20 weeks. Then 45 of the fish were divided into three groups based on longevity — short-lived (age of death 28 to 36 weeks), long-lived (age of death 45 to 50 weeks), and longest-lived (age of death 57 to 71 weeks).

The researchers extracted RNA from the biopsy samples and sequenced the samples on the Illumina HiSeq 2500. Once the sequence reads were mapped, the researchers clustered genes according to their temporal profiles.

During their initial analysis, the research team discovered that when the genes that are responsible for cellular respiration were less active at a young age, the fish lived longer than those that had more gene expression related to cellular respiration at a young age.

Once they determined that there was a clear difference between gene expression in long-lived and short-lived individuals, the researchers decided to give diluted doses of rotenone, a natural poison that inhibits the proteins that collectively form mitochondrial complex I and are responsible for the first step of cellular respiration, to some of the fish.

After analyzing samples from these fish, the researchers found that those exposed to rotenone lived longer than those that were not exposed to the poison.

It's not yet clear if these findings will apply to humans, but the function of mitochondria decreases with age in both humans and killifish alike, Alessandro Cellerino, lead author and researcher at the Leibniz Institute on Aging in Jena, Germany, and the Scuola Normale Superiore in Pisa, Italy, said in a statement.

"Up to the present, it was thought that improving mitochondrial function would improve health in aged people; however, our results indicate a more complex scenario where the partial inhibition of mitochondrial function paradoxically has beneficial effects," Cellerino said.

This latest research suggests that the effects of aging on mitochondria may involve a compensatory response rather than one that causes problems. "This obviously has implications on the development of strategies to improve health in older people and prevent aging-associated diseases," he said.

Cellerino also noted that there are FDA-approved drugs that inhibit mitochondrial complex I, such as metformin, a drug that is prescribed to treat type 2 diabetes and has been shown to extend the lifespan of mice. "Based on our data, we strongly suspect that the effect of metformin was due to inhibition of complex I and not to its anti-diabetic action," he said.