Newswise from BOSTON “Exercise has been proven to protect against a wide range of diseases and may be the most powerful anti-aging agent known to science. However, while physical activity may improve health as we age, its beneficial effects inevitably decline. The cellular mechanisms underlying the relationship between exercise, fitness and aging remain poorly understood.
In an article published in Proceedings of the National Academy of Sciences, researchers at the Joslin Diabetes Center investigated the role of a single cellular mechanism in improving fitness through exercise and identified one anti-aging intervention that delayed the decline that occurs with aging in a model organism. Together, scientists’ discoveries open the door to new strategies to improve muscle function during aging.
“Exercise is widely used to improve quality of life and protect against degenerative diseases, and in humans, a long-term exercise regimen reduces overall mortality,” said co-author T. Keith Blackwell, MD, senior investigator. and head of the department of islet cells and regenerative biology at Joslyn. “Our data define an important mediator of exercise response and a starting point for interventions aimed at maintaining muscle function during aging.”
This important mediator is the cycle of fragmentation and repair of mitochondria, the specialized structures or organelles within each cell responsible for energy production. Mitochondrial function is critical to health, and disruption of mitochondrial dynamics—the cycle of repairing dysfunctional mitochondria and reconnecting energy-producing organelles—has been linked to the development and progression of chronic age-related diseases such as heart disease and type 2 diabetes.
“Because we understand that our muscles experience fatigue and recovery after exercise, they go through this mitochondrial dynamic cycle,” said Blackwell, who is also the acting head of immunobiology at Joslyn. “In this process, the muscles deal with the effects of the metabolic demands of exercise and regain their functionality.”
Blackwell and colleagues, including co-author Julio Cesar Batista Ferreira, Ph.D. from the Institute of Biomedical Sciences at the University of São Paulo, investigated the role of mitochondrial dynamics during exercise in the model organism C. elegans, a simple, well-studied microscopic worm. species often used in metabolism and aging research.
By recording wild-type C. elegans worms as they swam or crawled, the researchers observed the animals’ typical age-related decline in fitness over 15 days of adulthood. The scientists also showed a significant and progressive shift towards fragmented and/or disorganized mitochondria in aging animals. For example, they observed in young worms on the 1st day of adulthood: a single exercise caused fatigue after an hour. The 60-minute session also caused an increase in mitochondrial fragmentation in animal muscle cells, but a 24-hour period was sufficient to restore both performance and mitochondrial function.
In older (5th and 10th day) worms, the productivity of animals did not return to the initial level within 24 hours. Similarly, the mitochondria of older animals underwent a cycle of fragmentation and repair, but the network reorganization that occurred was less than in younger animals.
“We determined that a single exercise session induces a cycle of fatigue and fitness recovery that parallels the mitochondrial network repair cycle,” said first author Julian Cruz Campos, a postdoctoral fellow at the Joslin Diabetes Center. “Aging has reduced the extent of this phenomenon and caused a parallel decline in fitness. This suggests that mitochondrial dynamics may be important for maintaining fitness and possibly improving fitness through exercise.”
In a second series of experiments, the scientists allowed wild-type worms to swim for one hour a day for 10 consecutive days, starting at the onset of adulthood. The team found that, as in humans, the long-term training program significantly improved the average-aged animals’ fitness at day 10 and mitigated the disruption of mitochondrial dynamics commonly seen with aging.
Finally, the researchers tested known life-extending drugs for their ability to improve exercise capacity during aging. Worms with increased levels of AMPK — a molecule that is a key regulator of energy during exercise and also promotes remodeling of mitochondrial morphology and metabolism — showed improved physical fitness. They also demonstrated the maintenance, but not the increase, of physical performance during aging. Worms lacking AMPK have shown a decline in fitness during aging as well as a disruption in the repair cycle. They also didn’t get the anti-aging benefits of exercise throughout their lives.
“An important goal in the field of aging is to identify interventions that not only increase life expectancy, but also improve health and quality of life,” said Blackwell, who is also a professor of genetics at Harvard Medical School. “In aging people, the decline in muscle function and exercise tolerance is a major problem that leads to significant morbidity. Our data point to potentially fruitful intervention points to prevent this decline, most likely along with other aspects of aging. It will be very interesting to determine how the plasticity of the mitochondrial network affects fitness, as well as life expectancy and aging-related diseases in humans.”
Other contributors included Takafumi Ogawa of the Joslin Diabetes Center; Luis Enrique Marchesi Bosi (co-author); Barbara Krum, Luis Roberto Grassmann Pour, Nicholas Dres Ferreira, Gabriel Santos Arini, Wheel Priests Albuquerque of the University of São Paulo; Annika Traa from McGill University; Alexander M. van der Bleek of the UCLA David Geffen School of Medicine; Afshin Beheshti of NASA Ames Research Center; and Jeremy M. Van Ramsdonk of Harvard Medical School.
This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (grants 2013/07937-8, 2015/22814-5, 2017/16694-2 and 2019/25049-9); National Council for Research and Development – Brazil (CNPq) (grants 303281/2015-4 and 407306/2013-7); Higher Education Workforce Improvement Coordination – Brazilian Financial Code (CAPES) 001 and National Institute of Science and Technology and Center for Research and Development of Redox Processes in Biomedicine; National Institutes of Health (NIH) (grants R35 GM122610, R01 AG054215, DK123095, AG071966); Joslin Diabetes Center (grants P30 DK036836 and R01 GM121756); FAPESP Postdoctoral Fellowships 2017/16540-5 and 2019/18444-9, and 2016/09611-0 and 2019/07221-9; American Heart Association Career Development Award (2022/926512); the Claudia Adams Barr program; the Lavigne Family Foundation; Pew Charitable Foundation. William B. Mair (Harvard T. H. Chan School of Public Health) and Malene Hansen (Sanford Burnham Prebys Medical Discovery Institute) provided several of the worm strains used in this study. Other strains were provided by NIH funded CGC (P40 OD010440).
Chouchani is the founder and shareholder of Matchpoint Therapeutics. The remaining authors declare no competing interests.
About Joslin Diabetes Center
The Joslin Diabetes Center is world renowned for its deep expertise in diabetes care and research. As part of Beth Israel Lahey Health, Joslyn is dedicated to finding a cure for diabetes and ensuring long and healthy lives for people with diabetes. We develop and distribute innovative patient treatments and scientific discoveries around the world. Joslin is affiliated with Harvard Medical School and is one of 18 diabetes research centers designated by the US National Institutes of Health.
Joslin Diabetes Center is part of Beth Israel Lahey Health, a healthcare system that brings together academic medical centers and teaching hospitals, community and specialty hospitals, over 4,800 physicians, and 36,000 employees in a shared mission to expand access to excellent care and progress. science and practice of medicine through innovative research and education.