Exercise may be the most effective anti-aging treatment now known to science because it has been shown to protect against a wide range of ailments. However, despite the fact that exercise might boost health as we age, its positive effects gradually wane. It is yet unclear what biological processes underlie the connection between exercise, fitness, and aging.
In a paper published in the Proceedings of the National Academy of Sciences, researchers at Joslin Diabetes Center investigated the role of one cellular mechanism in improving physical fitness by exercise training and identified one anti-aging intervention that delayed the declines that occur with aging in the model organism.
The researchers’ findings pave the way for fresh approaches to preserving muscular function as we age.
“Exercise has been widely employed to improve quality of life and to protect against degenerative diseases, and in humans, a long-term exercise regimen reduces overall mortality,” said co-corresponding author T. Keith Blackwell, MD, PhD, a senior investigator and section head of Islet Cell and Regenerative Biology at Joslin. “Our data identify an essential mediator of exercise responsiveness and an entry point for interventions to maintain muscle function during aging.”
In the cycle of mitochondrial fragmentation and repair, the specialized organelles inside every cell that are in charge of generating energy, is the crucial mediator. Mitochondrial dynamics, the cycle of repairing dysfunctional mitochondria and restoring the connectivity among the energy-producing organelles, are crucial to health, and disruption of these dynamics has been linked to the onset and progression of chronic, age-related diseases like heart disease and type 2 diabetes.
“As we perceive that our muscles undergo a pattern of fatigue and restoration after an exercise session, they are undergoing this mitochondrial dynamic cycle,” said Blackwell, who is also acting section head of Immunobiology at Joslin. “In this process, muscles manage the aftermath of the metabolic demand of exercise and restore their functional capability.”
An important goal of the aging field is to identify interventions that not only extend lifespan but also enhance health and quality of life. 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.
T. Keith Blackwell
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 frequently used in metabolic and aging research.
The researchers found a typical age-related drop in physical performance over the animals’ 15 days of adulthood by recording wild-type C. elegans worms as they crawled or swam. Additionally, the aging animals’ mitochondria were found to be increasingly fragmented and/or disordered, according to the researchers.
For instance, they saw that a single round of activity caused weariness in young worms on the first day of adulthood after one hour. The animals’ muscle cells saw an increase in mitochondrial fragmentation after the 60-minute session, but after 24 hours, both performance and mitochondrial function were fully recovered.
In older (day 5 and day 10) worms, the animals’ performance did not return to baseline within 24 hours. Similar to younger animals, the older animals’ mitochondria went through a cycle of fragmentation and repair, although the amount of network reconfiguration was less than in 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 tests, starting at the beginning of adulthood, the researchers gave wild-type worms permission to swim for an hour every day for ten straight days. Like in humans, the team discovered that a long-term training program at day 10 dramatically increased the animals’ middle-aged fitness and reduced the impairment of mitochondrial dynamics that is generally seen as people age.
The ability of well-known therapies to lengthen lifespan to enhance exercise capacity during aging was also investigated by the researchers. Worms with higher levels of AMPK, a crucial energy-regulating protein that also encourages modification of mitochondrial architecture and metabolism, showed greater physical fitness. They also showed that exercise performance may be maintained during aging but not improved.
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 their 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.”
Additional authors included Takafumi Ogawa of Joslin Diabetes Center; Luiz Henrique Marchesi Bozi (co-first author) and Edward Chouchani of Dana-Farber Cancer Institute; Barbara Krum, Luiz Roberto Grassmann Bechara, Nikolas Dresch Ferreira, Gabriel Santos Arini, Rudá Prestes Albuquerque of the University of Sao Paulo; Annika Traa of McGill University; Alexander M. van der Bliek of David Geffen School of Medicine at University of California, Los Angeles; Afshin Beheshti of NASA Ames Research Center; and Jeremy M. Van Raamsdonk of Harvard Medical School.
