Clue to age-related muscle wasting may lie in killifish

Posted: 23 May 2023

As we age, our muscles start to waste. Called sarcopenia, it happens to us all if we live long enough, but no one has ever understood why it happens. Now new research from the Australian Regenerative Medicine Institute (ARMI) at Monash University, has used a surprising animal model – the African killifish, to study muscle wasting – and revealed that, towards the end of life, our muscles actually reverse to an “early-life” state, slowing mortality. This latter finding may provide a clue to slowing or halting age-related loss of muscle mass and strength.

The research, published in the Aging Cell and led by Professor Peter Currie and Dr Avnika Ruparelia, who is from ARMI and the University of Melbourne, is important because the global population is aging with an expected dramatic increase in the prevalence and severity of sarcopenia is expected, according to Professor Currie. “As such, there is a pressing need to understand the mechanisms that drive sarcopenia, following which suitable medical interventions to promote healthy muscle aging can be identified and implemented,” he said.

The African turquoise killifish, Nothobranchius furzeri has recently emerged as a new model for the study of ageing. Killifish have the shortest known life span of any vertebrate species l which begins when rains fill the pool, the fish hatch, grow rapidly and mature in as few as two weeks, and then reproduce daily until the pool dries out. Importantly, their short life span is accompanied by symptoms of ageing we see in humans – including the appearance of cancerous lesions in the liver and gonads, reduced regenerative capacity of the limbs, in this case, the fin, and genetic characteristics that are the hallmark of human ageing such as a reduction in mitochondrial DNA copy number and function and shortening of telomeres.

According to Dr Ruparelia, this study is the first to use the killifish to study sarcopenia. “In this study, 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,” she said.

Surprisingly the researchers also found these same metabolic hallmarks of aging are reversed during the late-life stage, “suggesting that 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,” Professor Currie said.

“Importantly, this the late-life stage during which we observed improved muscle health perfectly coincides with a stage with 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.”

To better understand the mechanisms behind this, the research team surveyed the metabolism of fish at different stages of the aging process. This experiment surprisingly revealed that certain features of the metabolism of the very oldest fish actually were rejuvenated to resemble those of young fish. The study revealed the critical role of lipid metabolism in this process of rejuvenation. By using drugs that regulate the formation of certain lipids a similar rejuvenation of ageing muscle could be achieved. “During extreme old age, there is a striking depletion of lipids, which are the main energy reserves in our cells” explains senior author Prof Currie. “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.”

“The idea that aging may be reversible, and potentially treatable by drugs that can manipulate a cell’s metabolism, is an exciting prospect, especially given the social, economic and healthcare costs associated with the ever-growing aged population around the world. We are excited by the potential of the Killifish model, and very grateful to the Winston Churchill Trust for funding, and to Hon Dr Kay Patterson for her assistance with establishing the import regulations to establish the first and only Killifish facility in Australia. We now have a unique opportunity to study biological processes regulating aging and age-related diseases, and to investigate strategies to promote healthy aging,” Dr Ruparelia said.

The publication was the cumulation of a collaboration between researchers from: