Old Muscles Reverse to “Early Life” State in Model of Aging

Researchers from the Australian Regenerative Medicine Institute (AMRI) at Monash University find that, towards the end of life, muscles “rejuvenate” to resemble their early-life metabolic state in an animal model of aging. The research is published in Aging Cell.

Using animal models to study aging

Scientists rely on laboratory models, such as animals, to conduct biomedical research that furthers our understanding of human biology. Laboratory models are often selected due to their biological similarities to humans, susceptibility to diseases that are prevalent in humans and their shorter lifecycles.

The African turquoise killifish, Nothobranchius furzeri, has the shortest known lifespan of any vertebrate species that can be successfully bred in a laboratory environment. The killifish also presents with biological hallmarks of aging that we see in humans, such as cancer in the liver and the gonads, reduced regenerative capacity in the limbs and shortening of telomeres. These characteristics have led to its increased adoption as a laboratory model for human aging, which is recognized as a key societal challenge.

In the new study, renowned developmental evolutionary and stem cell biologist Professor Peter Currie at AMRI and Dr. Avnika Ruparelia, senior lecturer in anatomy and physiology at the University of Melbourne, led scientists in using the killifish to study sarcopenia, a gradual loss of muscle mass and strength that occurs in aging.

How sarcopenia contributes to the wasting of muscles is not clear. “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 aging,” Currie said. The research team, which included collaborators from institutes in Australia and Germany, says this is the first time the model has been utilized to study the condition.

Older mammals carry a mechanism to prevent deterioration of skeletal muscle

Currie and colleagues conducted experiments to characterize skeletal muscle from early life to late-life in the African killifish at the molecular and cellular level. “We reveal that many of the characteristics examined, including muscle stem cell number and muscle innervation deteriorate with increasing age, consistent with the presentation of sarcopenia,” the scientists write in the paper.

To their surprise, the scientists discovered that some of these hallmarks of aging actually reverse during the late-life stage: “We reveal a second subset of characteristics, composed of muscle fiber size and proteolysis, that deteriorated in aged fish but were found to improve in the extremely old late-life fish,” they describe.

Ruparelia says that this trait suggests extremely old animals may carry a mechanism whereby further deterioration of skeletal muscle is prevented, ultimately contributing to an extension of their lifespan. “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 lifespan in extremely old individuals,” she said.

Muscles “rejuvenate” in late-life – but how?

After discovering this surprising finding, the team wanted to know why it could be happening. They used a systems metabolomics approach, which provides insights into all known metabolomic reactions occurring in a cell or a tissue sample at a given timepoint.

Studying the metabolism at different stages of the killifish’s aging process, Currie and colleagues found that metabolic characteristics of the very oldest fish appear to “rejuvenate” to resemble those of younger fish. Specifically, they witnessed the activation of mitohormesis, a stress resistance mechanism. “We postulate that this results in improved lipid metabolism and a maintenance in nutrient homeostasis in the extremely old cohort thus providing a mechanism for their increased longevity,” the researchers explained.

“During extreme old age, there is a striking depletion of lipids, which are the main energy reserves in our cells,” Currie said. “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.”

Can we reverse muscle aging? 

The researchers hypothesized that applying a drug capable of regulating the formation of certain lipids could pharmacologically induce this rejuvenation process. They tested resveratrol, which produced a significant increase in the body weight of treated killifish compared to controls.

“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,” Ruparelia said. “We now have a unique opportunity to study biological processes regulating aging and age-related diseases, and to investigate strategies to promote healthy aging.”

Reference: Ruparelia AA, Salavaty A, Barlow CK, et al. The African killifish: A short-lived vertebrate model to study the biology of sarcopenia and longevity. Aging Cell. 2023:e13862. doi: 10.1111/acel.13862

This article is a rework of a press release issued by Monash University. Material has been edited for length and content.