Mitochondrial abnormalities caused by rare genetic mutations lead to increased metabolism in human cells. While this helps with short-term survival, it comes at a high cost: a dramatic increase in the rate at which cells age. Hypermetabolism may also be a major reason why most cells deteriorate as everyone ages.
The answer may lie in mitochondria, the energy-providing organelles in cells. This concept is not new, but until now there has been a lack of direct evidence in human cells.
A recent study published in Communications Biology and led by Columbia University researchers found that human cells with impaired mitochondria respond by going into overdrive and using more energy. This process, known as hypermetabolism, allows cells to survive temporarily, but it also dramatically accelerates the rate at which they age.
“The findings were made in cells from patients with rare mitochondrial diseases, but they may also be relevant to other conditions that affect mitochondria, including neurodegenerative diseases, inflammatory conditions and infections,” says the lead researcher. Martin Picard, Ph.D., partner. professor of behavioral medicine (in psychiatry and neurology) at
While this energy boost keeps cells functioning, it also breaks down cell telomeres (caps that protect the ends of our chromosomes) and activates stress responses and inflammation. The net effect accelerates biological aging.
“When cells expend more energy making proteins and other substances essential for short-term survival, they likely steal resources from processes that ensure long-term survival, such as maintaining telomeres,” says Gabriel. Sturm, graduate student and lead author of this study.
Hypermetabolism, fatigue and aging
This hypermetabolic state could explain why people with mitochondrial diseases experience fatigue and exercise intolerance, among other symptoms. “To compensate for your cells’ extra energy consumption, your body ‘tells’ you not to overwork, to conserve energy. We probably see the same dynamic as people age and their vitality declines,” Picard says.
The study does not indicate any new cures for patients with mitochondrial diseases, which are currently not treatable, but it does reinforce current recommendations for patients to move more. “It may seem counterintuitive because if you’re more active, you’re going to expend more energy and possibly make your symptoms worse,” Sturm says. “But exercise is known to increase the efficiency of an organism. A person who is running, for example, uses less energy to maintain basic bodily processes than someone who is not physically active.
Improving the body’s efficiency, which would reduce energy consumption in cells and improve fatigue and other symptoms, may partly explain the health benefits of exercise in patients with AD. mitochondrial diseases and healthy people.
In their search for new treatments for mitochondrial diseases, researchers should focus on hypermetabolism, Picard says. “Although mitochondrial defects impair the ability of cells to produce energy, the energy deficit may not be the main initiator of the disease. Our study shows that these defects increase energy consumption. To move the needle for therapeutic purposes, we may need to target hypermetabolism.We need more research to find out if this would work.
Hypermetabolism is also common to other diseases. If increased cellular energy expenditure plays a causal role in the aging process, targeting hypermetabolism may be a way to improve fatigue, improve people’s quality of life, or even slow biological aging.
Reference: “OxPhos Defects Cause Hypermetabolism and Shorten Lifespan in Cells and in Patients with Mitochondrial Diseases” by Gabriel Sturm, Kalpita R. Karan, Anna S. Monzel, Balaji Santhanam, Tanja Taivassalo, Céline Bris, Sarah A. Ware, Marissa Cross, Atif Towheed, Albert Higgins-Chen, Meagan J. McManus, Andres Cardenas, Jue Lin, Elissa S. Epel, Shamima Rahman, John Vissing, Bruno Grassi, Morgan Levine, Steve Horvath, Ronald G. Haller, Guy Lenaers, Douglas C. Wallace, Marie-Pierre St-Onge, Saeed Tavazoie, Vincent Procaccio, Brett A. Kaufman, Erin L. Seifert, Michio Hirano and Martin Picard. Communications Biology.
DOI: 10.1038/s42003-022-04303-x
The study was funded by the National Institutes of Health, Baszucki Brain Research Fund, J. Willard and Alice S. Marriott Foundation, Muscular Dystrophy Association, Nicholas Nunno Foundation, JDF Fund for Mitochondrial Research, and Shuman Mitochondrial Disease Fund.