URI study seeks to stave off mitochondrial dysfunction believed to cause aging

Dysfunction resulting from mitochondrial DNA mutations has been implicated in multiple human pathologies, including neurodegenerative disorders, metabolic syndromes, cancer and cardiovascular disease. The stress from mtDNA mutations is thought to play a significant role in the aging process and age-related diseases.

New research led by Professors Jaime Ross and Giuseppe Coppotelli in the University of Rhode Island College of Pharmacy and George & Anne Ryan Institute for Neuroscience aims to discover how mitochondrial mutations impact aging. Using a novel mouse model, Ross and Coppotelli are assessing the effects of exercise and calorie restriction on mtDNA mutations. They seek to identify potential targeted interventions to mitigate age-related diseases and improve health and quality of life throughout the lifespan. 

“We’re trying to understand how mitochondria impairment affects aging and sets the tone for age-related disease onset,” Ross said. “Mitochondrial dysfunction has been associated not just with aging, but also in age-related diseases. The potential of this model is huge.”

Based on the Mitochondrial Theory of Aging—which posits that animals, including humans, age due to defective or impaired mitochondria, a dysfunction that accumulates over time, leading to changes in cellular bioenergetics—Ross and Coppotelli aim to understand the mechanisms by which different tissues accumulate and clear mtDNA mutations, and how the timing of mutation-onset on aging is impacted. Their study is funded by a five-year, $2.8 million RO1 grant from the National Institute on Aging, a division of the National Institutes of Health.

Mitochondria, while serving as the energy powerhouses in human cells, contain a second set of genetically inherited DNA (mtDNA) and are involved in functions such as inflammation, cell communications, and amino acidic metabolism. A natural enzyme in human cells most often repairs or clears any mutations to the mtDNA. But when that editing process is disrupted—the reasons for which are not widely understood—mutations can continue to replicate in the cell, causing aging-like mitochondrial dysfunction that affects every cell of the body, Ross said. Such mitochondrial impairment has been found to be a driver in the aging process.

Ross and Coppotelli are working with mice genetically modified with mutated mtDNA molecules to promote premature aging. The mutated mice quickly begin to look and act older, developing gray hair that begins to fall out, and moving more slowly around their enclosure until their death at about 40 weeks.

However, after Coppotelli exposed the modified mice to voluntary exercise at 10 weeks of age by introducing a hamster wheel to their enclosure, the researchers found something astonishing. After a few weeks running on the wheel whenever they wanted, the exercised mice looked and acted significantly more youthful than their more sedentary counterparts. In side-by-side videos comparing mice at the same age, with the same modifications, the differences are stark, both in appearance and behavior.

“They looked beautiful,” Ross said. “Their fur wasn’t graying; they weren’t losing their hair; they were moving well. At first we thought there was a mix-up in the cages, but we kept seeing the same thing time after time.”

The sedentary mice had ashen fur and patches of bare skin as they wandered slowly around their enclosure, mostly just to get food or a drink of water. The exercised mice sported full fur coats and continued to move around quickly, as one would expect of a healthy mouse.

“Exercise is the only intervention that can dramatically improve the phenotype in these mice so that you cannot distinguish a mouse that has this mutation from a normal animal,” Coppotelli said. “What we believe is that when mice exercise, their muscles require more energy and dysfunctional mitochondrial-carrying mtDNA mutations are now spotted and selectively labeled for removal, while new mitochondria are made. This has not been proven. How this is happening we don’t know. Why this is happening is what we’re investigating now.”

The animals’ health was short-lived, however. At about 40 weeks of age, the differences between the two groups of mice diminishes, the disease state catches up to the active mice, and all die around the same age. That is not necessarily bad news, however. Coppotelli explains that while the ultimate biology of the mutations can’t be changed, it appears the resulting symptoms can be eased, temporarily at least.

“The exercise doesn’t prevent the disease, but eases the symptoms,” Coppotelli said. “So they still die, but they live a higher quality of life while they’re alive. Which is really the goal. We are all going to die, but if you can spend the last two decades of your life not being in pain, not being affected by disease, and still be relatively healthy, that is the goal. We are born to die. The goal is to be healthy as long as possible.”

Coppotelli and Ross are continuing to investigate how mitochondrial dysfunction could be prevented. Using novel mouse models with mitochondrial mutations in targeted tissues, the researchers are testing different regimens, including exercise and caloric restriction, to determine how different tissues respond to the regimens, and why.

“The advantage of this new model is that we can study mitochondrial dysfunction in a tissue-specific manner,” Coppotelli said. “Each tissue regulates mitochondria in a different way, so now we can use our model to understand what happens when mitochondrial dysfunction is in different tissues, and what mechanisms are in place to remove bad mitochondria. For example, we can focus only on the heart or the brain and ask whether exercise is equally effective in preventing dysfunction in the brain, or whether supplements, vitamins, or a drug might work better. We can now do this for every system in the body.”