URI study seeks to stave off mitochondrial dysfunction believed to cause aging
Researchers at the University of Rhode Island College of Pharmacy and the George & Anne Ryan Institute for Neuroscience, led by Professors Jaime Ross and Giuseppe Coppotelli, are investigating how mitochondrial DNA mutations contribute to aging and related diseases, including neurodegenerative, metabolic, cardiovascular disorders, and cancer. Using a novel mouse model, the team is studying the impact of exercise and calorie restriction on mitochondrial dysfunction to identify potential interventions that could delay age related disease onset and improve healthspan and quality of life.
Based on the Mitochondrial Theory of Aging, which suggests that aging results from the gradual accumulation of mitochondrial dysfunction due to mtDNA mutations that disrupt cellular energy production, Ross and Coppotelli are investigating how different tissues accumulate and eliminate these mutations and how their onset influences aging. Supported by a five year, $2.8 million R01 grant from the National Institute on Aging (NIH), their research focuses on mitochondrial roles in energy metabolism, inflammation, and cellular communication, as well as how impaired DNA repair mechanisms allow harmful mutations to persist and drive age related decline. Using genetically modified mice carrying mtDNA mutations that induce premature aging characterized by early graying, hair loss, reduced mobility, and shortened lifespan the team aims to better understand mitochondrial dysfunction as a key driver of aging and identify potential therapeutic targets.
When Coppotelli introduced voluntary exercise via running wheels to genetically modified mice at 10 weeks of age, the results were unexpectedly striking. After several weeks of activity, exercised mice appeared markedly younger than sedentary counterparts, showing healthier coats, reduced hair loss, and more active behavior, while inactive mice exhibited signs of accelerated aging such as thinning fur, skin patches, and lethargy. According to Ross and Coppotelli, exercise was the only intervention that nearly normalized the aging like phenotype, making mutated mice indistinguishable from healthy controls. The researchers hypothesize that increased muscular energy demand during exercise may trigger the selective identification and removal of dysfunctional mitochondria while promoting the generation of new ones, although the exact mechanisms remain under investigation.
The researchers observed that the benefits of exercise in the genetically modified mice were temporary, as by around 40 weeks of age the differences between exercised and sedentary groups diminished, with both ultimately showing similar disease progression and lifespan. However, Coppotelli noted that while exercise does not prevent the underlying mitochondrial mutations, it can significantly reduce symptoms and improve quality of life during aging. He emphasized that the goal is not necessarily to extend lifespan, but to maintain health and functionality for as long as possible. The team is now using tissue-specific mouse models to further explore how mitochondrial dysfunction develops and responds to interventions such as exercise and caloric restriction in different organs, including the brain and heart, to determine whether alternative treatments like drugs, supplements, or lifestyle changes may be more effective depending on the tissue involved.
