Overview: Findings reveal a cellular mechanism that helps improve physical fitness through exercise and identifies an anti-aging intervention that helps slow the decline that occurs with natural aging.
Source: Joslin Diabetes Center
Exercise has been proven to protect against a wide variety of diseases and is perhaps the most powerful anti-aging intervention known to science. While physical activity can improve health with age, the beneficial effects inevitably diminish. The cellular mechanisms underlying the relationship between exercise, fitness and aging remain poorly understood.
In an article published in the Procedures of the National Academy of SciencesResearchers at the Joslin Diabetes Center investigated the role of one cellular mechanism in improving physical fitness through exercise and identified one anti-aging intervention that slowed the decline that occurs with aging in the model organism. Together, the scientists’ findings 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 disease, and in humans a long-term exercise regimen reduces overall mortality,” said co-corresponding author T. Keith Blackwell, MD, PhD, a senior researcher and section chief of Islet Cell and Regenerative Biology at Joslin. “Our data identify an essential mediator of exercise responsiveness and a starting point for interventions to preserve muscle function during aging.”
That essential mediator is the cycle of fragmentation and repair of the mitochondria, the specialized structures or organelles in each cell responsible for producing energy. Mitochondrial function is critical to health, and disruption of mitochondrial dynamics – the cycle of repairing dysfunctional mitochondria and restoring connectivity between the 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 observe that our muscles go through a pattern of fatigue and recovery after a training session, they go through this mitochondrial dynamic cycle,” says Blackwell, who is also Acting Division Chief of Immunobiology at Joslin. “In this process, muscles manage the aftermath of the metabolic demand of exercise and restore their functional capacity.”
Blackwell and colleagues – including co-corresponding author Julio Cesar Batista Ferreira, PhD, Institute of Biomedical Sciences, University of Sao Paulo – investigated the role of mitochondrial dynamics during exercise in the model organism C. elegans, a simple, well-studied microscopic worm species that often used in metabolism and aging research.
By recording wild-type C. elegans worms as they swam or crawled, the researchers observed a typical age-related decline in physical fitness over the animals’ 15 days of maturity. The scientists also showed a significant and progressive shift to fragmented and/or disorganized mitochondria in the aging animals. For example, they saw in young worms on day 1 of adulthood, a single exercise caused fatigue after an hour.
The 60-minute session also caused an increase in mitochondrial fragmentation in the animals’ muscle cells, but a 24-hour period was enough to restore both performance and mitochondrial function.
In older worms (day 5 and day 10), animal performance did not return to baseline within 24 hours. Similarly, 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 found that a single exercise session induces a cycle of fatigue and physical fitness recovery that is accompanied by a cycle of rebuilding the mitochondrial network,” said lead author Juliane Cruz Campos, a postdoctoral researcher at the Joslin Diabetes Center.
“Aging dampened the rate at which this happened and caused a parallel decline in physical fitness. That suggested that mitochondrial dynamics could be important for maintaining physical fitness and possibly improving physical fitness through a period of exercise.
In a second set of experiments, the scientists got wild-type worms to swim for an hour a day for 10 consecutive days, starting at the onset of adulthood. The team found that – as in humans – the long-term exercise program significantly improved the middle-aged animals’ fitness by day 10 and mitigated the impairment of mitochondrial dynamics typical of aging.
Finally, the researchers tested known life-prolonging interventions for their ability to improve exercise capacity during aging. Worms with increased AMPK – a molecule that is an important regulator of energy during exercise and also promotes remodeling of mitochondrial morphology and metabolism – showed improved physical fitness.
They also showed maintenance, but no improvement in exercise performance as they aged. Worms engineered to lack AMPK showed reduced physical fitness during aging, as well as a deterioration in the recovery cycle. They also didn’t get the age-delaying benefits of exercise over the course of their lives.
“An important goal in the aging field is to identify interventions that not only extend longevity but also improve health and quality of life,” said Blackwell, who is also a professor of genetics at Harvard Medical School.
“In aging people, a decline in muscle function and exercise tolerance is a major problem leading to significant morbidity. Our data points to potentially fruitful intervention points to prevent this decline – most likely along with other aspects of aging. It will be of great interest to determine how plasticity of the mitochondrial network affects physical fitness, along with longevity and age-related diseases in humans.”
Other authors included Takafumi Ogawa of the Joslin Diabetes Center; Luiz Henrique Marchesi Bozi (co-first author); Barbara Krum, Luiz Robert Grassmann Poor, Nicholas Dresch Ferreira, Gabriel Santos Arini, Wheel Priests Albuquerque of the University of Sao Paulo; Annika Traa of McGill University; Alexander M. van der Bliek of the David Geffen School of Medicine at the University of California, Los Angeles; Afshin Beheshti of NASA Ames Research Center; and Jeremy M. Van Raamsdonk of Harvard Medical School.
financing: 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) (Awards 303281/2015-4 and 407306/2013-7); Coordination for the Improvement of Higher Education Personnel – Brazil (CAPES) Finance Code 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); the Joslin Diabetes Center (grants P30 DK036836 and R01 GM121756); FAPESP Postgraduate Scholarships 2017/16540-5 and 2019/18444-9, and 2016/09611-0 and 2019/07221-9; the American Heart Association Career Development Award (2022/926512); the Claudia Adams Barr Program; the Lavine Family Fund; the Pew Charitable Foundation. William B. Mair (Harvard TH 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 (P40 OD010440).