The vibrantly coloured and short-lived African killfish may hold secrets to reversing muscle ageing, say researchers.
As we age, our muscles start to waste. Called sarcopenia, it happens to everyone, but no-one has ever understood how and why it occurs.
Now new research from the Australian Regenerative Medicine Institute (ARMI) at Monash University in Melbourne, has used a surprising animal model – the African killfish – to reveal that towards the end of life, our muscles actually reverse to an ‘early-life’ state, slowing mortality.
This finding could provide a clue to slowing, halting or even reversing age-related loss of muscle mass and strength.
The research, published in the monthly peer-reviewed Aging Cell and led by Professor Peter Currie and Dr Avnika Ruparelia, who are from ARMI and the University of Melbourne, is important because of the expected dramatic increase in the prevalence and severity of sarcopenia with those aged over 60 expected to rise from one billion to 1.4 billion by 2030.
By 2050 the World Health Organisation predicts the global population of people aged 60 and over will have doubled to 2.1 billion.
According to Professor Currie, “…there is a pressing need to understand the mechanisms that drive sarcopenia, so that we can identify and implement suitable medical interventions to promote healthy muscle ageing.”
The African turquoise killifish, scientifically known as 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 that can be bred in captivity. Life for a killifish begins with the African rains. The drought-resistant eggs and embyros enter a state of suspended animation, entombed in hard mud until the next rainfall creates water pools – which can be months or even years.
The arrival of the rain then triggers the eggs into hatching, They grow, mature, reach sexual maturity and mate in just 14 days, reproducing daily until the rain pool dries. In all, the killfish will only live for around nine or ten weeks. Even those bred in captivity will only survive for between four and six months.
Importantly for scientists, their short life span is accompanied with symptoms of ageing seen in humans. These include 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 getting old such as a reduction in mitochondrial DNA copy number and function and shortening of telomeres – the protective caps on the ends of chromosomes that affect how quickly cells age.
A just-hatched killifish larvae. Image: Dr Avnika Ruparelia
According to Dr Ruparelia, this study is the first to use the killifish to examine sarcopenia, which can affect not only muscle mass, but also impact on gait, balance and people’s ability to go about daily tasks and physical activities, exacerbating the problem.
She explained: “In this study, we performed a thorough cellular and molecular characterisation of skeletal muscle from early life, aged and extremely old late-life stages, revealing many similarities to sarcopenia in humans and other mammals.”
Surprisingly the researchers also found these same metabolic hallmarks of ageing 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,” Dr Ruparelia added.
“Importantly, the late-life stage during which we observed improved muscle health perfectly coincides 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.”
To better understand the mechanisms behind this, the research team surveyed the metabolism of fish at different stages of the ageing 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.
It highlighted 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.
Senior author, Prof Currie., said: “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 organsims, 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.”
Dr Ruparelia went on to say: “The idea that muscle ageing 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 ageing and age-related diseases, and to investigate strategies to promote heathy ageing.”