The study investigated the effect of a specific cellular mechanism on the improvement of physical fitness through exercise. It also discovered an anti-aging intervention that could slow the aging-related declines in the model organism.
The findings suggest potential approaches to improving muscle function in older adults.
Exercise has been shown to protect against many diseases and is considered a powerful anti-aging intervention by science. Despite its ability to improve the health of older individuals, its positive effects eventually diminish. The relationship between exercise, fitness and aging, as well as the underlying cellular mechanisms, are still not fully understood.
In a paper published in Proceedings of the National Academy of Sciences, researchers at the Joslin Diabetes Center investigated the role of a cellular mechanism in improving physical fitness through exercise and identified an anti-aging intervention that delayed the declines that occur with aging in the model organism. Together, the researchers’ results open the door to new strategies to promote muscle function during aging.
“Exercise has been widely used to improve quality of life and to protect against degenerative diseases, and in humans, a long-term exercise regimen reduces overall mortality,” said corresponding author T. Keith Blackwell, MD, PhD, a senior investigator and section chief of the Islet Cell and Regenerative Biology at Joslin. “Our data identify an important mediator of exercise responsiveness and a starting point for interventions to maintain muscle function during aging.”
The essential mediator is the cycle of fragmentation and repair of the mitochondria, the specialized structures or organelles, inside each cell responsible for producing energy. Mitochondrial function is critical to health, and interruptions in mitochondrial dynamics — the cycle to repair dysfunctional mitochondria and restore connectivity between the energy-producing organelles — have been linked to the development and progression of chronic, age-related diseases, such as heart disease and type 2 diabetes.
“When we perceive our muscles to be going through a pattern of fatigue and recovery after a workout, they’re going through this mitochondrial dynamic cycle,” said Blackwell, who is also acting section chief of immunobiology at Joslin. “In this process, muscles deal with the aftermath of the metabolic demand of exercise and restore their functional capacity.”
Blackwell and colleagues—including co-corresponding author Julio Cesar Batista Ferreira, Ph.D., Institute of Biomedical Sciences, University of Sao Paulo—examined the role of mitochondrial dynamics during exercise in the model organism C. elegans, a simple, well-studied microscopic worm[{” attribute=””>species frequently used in metabolic and aging research.
Recording wild-type C. elegans worms as they swam or crawled, the investigators observed a typical age-related decline in physical fitness over the animals’ 15 days of adulthood. The scientists also showed a significant and progressive shift toward fragmented and/or disorganized mitochondria in the aging animals. For example, they observed in young worms on day 1 of adulthood, a single bout of exercise-induced fatigue after one hour. The 60-minute session also caused an increase in mitochondrial fragmentation in the animals’ muscle cells, but a period of 24 hours was sufficient to restore both performance and mitochondrial function.
In older (day 5 and day 10) worms, the animals’ performance did not return to baseline within 24 hours. Likewise, the older animals’ mitochondria underwent a cycle of fragmentation and repair, but the network reorganization that occurred was reduced compared to that of the younger animals.
“We determined that a single exercise session induces a cycle of fatigue and physical fitness recovery that is paralleled by a cycle of the mitochondrial network rebuilding,” said first author Juliane Cruz Campos, a postdoctoral fellow at Joslin Diabetes Center. “Aging dampened the extent to which this occurred and induced a parallel decline in physical fitness. That suggested that mitochondrial dynamics might be important for maintaining physical fitness and possibly for physical fitness to be enhanced by a bout of exercise.”
In a second set of experiments, the scientists allowed wild-type worms to swim for one hour per day for 10 consecutive days, starting at the onset of adulthood. The team found that — as in people — the long-term training program significantly improved the animals’ middle-aged fitness at day 10, and mitigated the impairment of mitochondrial dynamics typically seen during aging.
Finally, the researchers tested known, lifespan-extending interventions for their ability to improve exercise capacity during aging. Worms with increased AMPK — a molecule that is a key regulator of energy during exercise which also promotes the remodeling of mitochondrial morphology and metabolism — exhibited improved physical fitness. They also demonstrated maintenance of, but not enhancement of, exercise performance during aging. Worms engineered to lack AMPK exhibited reduced physical fitness during aging as well as impairment of the recovery cycle. They also did not receive the age-delaying benefits of exercise over the course of the lifespan.
“An important goal of the aging field is to identify interventions that not only extend lifespan but also enhance health and quality of life,” said Blackwell, who is also a professor of genetics at Harvard Medical School. “In aging humans, a decline in muscle function and exercise tolerance is a major concern that leads to substantial morbidity. Our data point towards potentially fruitful intervention points for forestalling this decline — most likely along with other aspects of aging. It will be of great interest to determine how mitochondrial network plasticity influences physical fitness along with longevity and aging-associated diseases in humans.”
Reference: “Exercise preserves physical fitness during aging through AMPK and mitochondrial dynamics” by Juliane Cruz Campos, Luiz Henrique Marchesi Bozi, Barbara Krum, Luiz Roberto Grassmann Bechara, Nikolas Dresch Ferreira, Gabriel Santos Arini, Rudá Prestes Albuquerque, Annika Traa, Takafumi Ogawa, Alexander M. van der Bliek, Afshin Beheshti, Edward T. Chouchani, Jeremy M. Van Raamsdonk, T. Keith Blackwell and Julio Cesar Batista Ferreira, 3 January 2023, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2204750120
This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); Conselho Nacional de Pesquisa e Desenvolvimento – Brasil (CNPq); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) Finance Code 001 and Instituto Nacional de Ciência e Tecnologia and Centro de Pesquisa e Desenvolvimento de Processos Redox em Biomedicina; National Institutes of Health (NIH); the Joslin Diabetes Center; FAPESP postdoctoral fellowships; the American Heart Association Career Development Award; the Claudia Adams Barr Program; the Lavine Family Fund; the Pew Charitable Trust. William B. Mair (Harvard T.H. Chan School of Public Health) and Malene Hansen (Sanford Burnham Prebys Medical Discovery Institute) provided some of the worm strains used in this study. Other strains were provided by the CGC, which is funded by the NIH.
Chouchani is a founder and equity holder in Matchpoint Therapeutics. The other authors declare no competing interests.
By JOSLIN DIABETES CENTER