Aging inevitably leads to muscle wasting, a condition known as sarcopenia. Until recently, the scientific world lacked a comprehensive understanding of why and how this occurs.
However, recent research from the Australian Regenerative Medicine Institute (ARMI) at Monash University has made strides in unraveling this mystery, thanks to an unusual subject – the African killifish.
The research suggests that towards the end of life, our muscles may revert to an “early-life” state, which could slow mortality. This groundbreaking revelation potentially opens doors to new approaches that could slow, halt or even reverse the age-related loss of muscle mass and strength.
Published in the journal Aging Cell, the study was led by Professor Peter Currie and Dr. Avnika Ruparelia from ARMI and the University of Melbourne. The importance of this research becomes increasingly evident in the face of a predicted global surge in the prevalence and severity of sarcopenia.
“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,” said Professor Currie.
The African turquoise killifish, known scientifically as Nothobranchius furzeri, is a recent addition to the pantheon of model organisms used in aging studies. With the shortest known lifespan among captive-breedable vertebrates, killifish make for an intriguing research subject.
Spawned by the African rains, killifish live in seasonal rain pools. Their life cycle is rapid, hatching, growing, and reaching maturity in just two weeks, after which they reproduce daily until the pool evaporates.
What makes them particularly useful in aging research is the manifestation of human-like aging symptoms – cancerous liver and gonad lesions, diminished limb regenerative abilities (in their case, the fin), and genetic hallmarks of aging such as decreased mitochondrial DNA copy number and function, and telomere shortening.
Dr. Ruparelia notes that the study is the first to use killifish in sarcopenia research. “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.”
Remarkably, the researchers also discovered these metabolic signs of aging seemingly reversed during the late-life stage.
Dr. Ruparelia suggests 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.”
Drawing a correlation between improved muscle health and declining mortality rates in old age, the team hypothesizes that enhanced muscle health could be a significant factor in prolonging the lifespan of the extremely elderly.
To further investigate this phenomenon, the researchers embarked on a metabolic survey of killifish at different aging stages. This exploration revealed a surprising rejuvenation of certain metabolic features in the oldest fish, mirroring those seen in young fish.
The investigation underscored the crucial role of lipid metabolism in this rejuvenation process. Through regulating the formation of certain lipids with drugs, the researchers achieved a similar rejuvenation of aging muscle.
“During extreme old age, there is a striking depletion of lipids, which are the main energy reserves in our cells,” said Professor Currie. “We believe that this mimics a state of calorie restriction, a process known to extend lifespan 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 muscle 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,” said Dr. Ruparelia.
“We are excited by the potential of the killifish model, and very grateful to the Winston Churchill Trust for funding, and to 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 heathy aging.”
Anti-aging research is an incredibly broad field, encompassing many different disciplines. From genetics and cell biology to pharmacology and lifestyle modification, many promising advances are being made.
One important area of anti-aging research revolves around understanding the underlying biological processes of aging.
Scientists have identified several key hallmarks of aging, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.
By targeting these fundamental processes, researchers hope to slow down or even reverse the signs of aging.
These protective end caps of chromosomes that shorten as cells divide, are a major focus in this research. Scientists have discovered that by manipulating an enzyme called telomerase, they can extend the lifespan of cells in the lab. This has the potential to slow down or reverse certain aging processes, although this approach is still being studied for safety and efficacy.
The practice of reducing daily calorie intake without malnutrition, has been shown to extend lifespan in multiple organisms, from yeast and worms to mice and monkeys. This has led to interest in drugs that can mimic the effects of caloric restriction, such as metformin and rapamycin. These drugs have shown promise in preclinical studies and are now being tested in human trials.
This is a state in which cells can no longer divide and accumulate with age, contributing to tissue dysfunction. Scientists are exploring drugs known as senolytics that selectively eliminate these senescent cells, thereby improving health and lifespan in animal models.
The idea is to use stem cells to replace damaged or aged cells in the body, effectively rejuvenating tissues and organs. Techniques such as induced pluripotent stem cells (iPSCs), which can theoretically produce any cell type in the body, hold great promise in this area.
Understanding the role of the microbiome, the community of microbes living in our gut, in aging has gained considerable attention. Studies suggest that the composition of the gut microbiota changes with age and influences health and lifespan. Therefore, interventions that modify the gut microbiota, such as probiotics, prebiotics, and fecal microbiota transplants, may have potential anti-aging effects.
Despite these exciting developments, it’s important to remember that aging is a complex process that is unlikely to have a simple, one-size-fits-all solution.
However, the research being done in this field could not only increase lifespan but also “healthspan,” the period of life spent in good health, free from the chronic diseases and disabilities of aging.