Killifish inspired study shows glimpses of an aging-free future

Nothobranchius furzeri, the African turquoise killifish, is known to have the shortest life span of any vertebrate species. They hatch and rapidly grow in the rainy season and mature in just two weeks, after which they reproduce daily till the end of the season.

However, killifish exhibit symptoms of aging similar to humans. Cancerous lesions in the liver and gonads and a decrease in the regenerative capacity of the limbs paint a prominent resemblance.

“We performed a thorough cellular and molecular characterization of skeletal muscle from early life, aged and extremely old late-life stages, revealing many similarities to sarcopenia in humans and other mammals,” said Dr. Ruparelia, who believes their study of Sarcopenia to be the first using killifish.

In their analysis, the researchers found that these hallmarks of aging reversed in the late-life stage. “In extremely old animals, there may be mechanisms in place that prevent further deterioration of skeletal muscle health, which may ultimately contribute to an extension of their life span,” said Professor Currie.

“During this late-life stage we observed improved muscle health perfectly coinciding with a stage when mortality rates decline. We, therefore, postulate that the improvement in muscle health may be a critical factor contributing to the extension of life span in extremely old individuals,” he added.

In an experiment that studied killifish metabolism across their aging process, the team observed certain features of the metabolism of the oldest fish to resemble their younger counterparts, with certain lipids playing a critical role in this rejuvenation.

“During extreme old age, there is a striking depletion of lipids, which are the main energy reserves in our cells. We believe that this mimics a state of calorie restriction, a process known to extend life span in other organisms, which results in activation of downstream mechanisms ultimately enabling the animal to maintain nutrient balance and live longer. A similar process is seen in the muscle of highly trained athletes,” Professor Currie mused.

The research could prove aging to be reversible and lead to drugs that manipulate a cell’s metabolism. The team looks to study biological processes regulating aging and age-related diseases and investigate strategies to promote healthy aging.

The team’s findings were published in the peer-reviewed scientific journal Aging Cell.

Study Abstract

Sarcopenia, the age-related decline in muscle function, places a considerable burden on health-care systems. While the stereotypic hallmarks of sarcopenia are well characterized, their contribution to muscle wasting remains elusive, which is partly due to the limited availability of animal models. Here, we have performed cellular and molecular characterization of skeletal muscle from the African killifish—an extremely short-lived vertebrate—revealing that while many characteristics deteriorate with increasing age, supporting the use of killifish as a model for sarcopenia research, some features surprisingly reverse to an “early-life” state in the extremely old stages. This suggests that in extremely old animals, there may be mechanisms that prevent further deterioration of skeletal muscle, contributing to an extension of life span. In line with this, we report a reduction in mortality rates in extremely old killifish. To identify mechanisms for this phenomenon, we used a systems metabolomics approach, which revealed that during aging there is a striking depletion of triglycerides, mimicking a state of calorie restriction. This results in the activation of mitohormesis, increasing Sirt1 levels, which improves lipid metabolism and maintains nutrient homeostasis in extremely old animals. Pharmacological induction of Sirt1 in aged animals was sufficient to induce a late life-like metabolic profile, supporting its role in life span extension in vertebrate populations that are naturally long-lived. Collectively, our results demonstrate that killifish are not only a novel model to study the biological processes that govern sarcopenia, but they also provide a unique vertebrate system to dissect the regulation of longevity.