Summary:
Researchers at Joslin Diabetes Center have identified a cellular mechanism that could improve physical fitness through exercise training and delay declines that occur with aging. In a study published in the Proceedings of the National Academy of Sciences, the team investigated the role of the cycle of fragmentation and repair of the mitochondria, the organelles that produce energy in cells, during exercise in the model organism C. elegans. They found that a single bout of exercise caused fatigue and an increase in mitochondrial fragmentation in young worms, but that a period of 24 hours was sufficient to restore both performance and mitochondrial function. In older worms, performance did not return to normal within 24 hours and there was a reduced network reorganization of mitochondria compared to younger worms. The team also found that long-term exercise training improved middle-aged fitness in worms and mitigated the impairment of mitochondrial dynamics typically seen during aging. The absence of the molecule AMPK resulted in reduced physical fitness and impaired recovery after exercise, and these worms did not experience the age-delaying benefits of exercise.
Source: Joslin Diabetes Center
Exercise has been shown to be effective in protecting against various diseases and is potentially the most effective way to slow the aging process. However, the benefits of physical activity on health tend to decrease with age. Despite the known benefits of exercise on aging, the exact relationship between exercise, fitness, and the aging process is not fully understood at the cellular level.
In a study published in the Proceedings of the National Academy of Sciences, researchers at Joslin Diabetes Center looked at how a specific cellular mechanism can improve physical fitness through exercise and identified a method of delaying the negative effects of aging on muscle function in a model organism. These findings may lead to new approaches for maintaining muscle health as we age.
T. Keith Blackwell, a senior investigator and section head of Islet Cell and Regenerative Biology at Joslin, said, “Exercise is often used to improve quality of life and prevent degenerative diseases. In humans, long-term exercise has been shown to decrease overall mortality. Our research identified a key factor in the body’s response to exercise and a potential point for interventions to preserve muscle function during aging.”
The key factor that helps the body respond to exercise is the cycle of fragmentation and repair of the mitochondria, which are organelles inside cells that produce energy. The health of the mitochondria is important, and disruption of the cycle of repairing damaged mitochondria and maintaining connectivity among these energy-producing organelles has been connected to the onset and progression of chronic age-related diseases like heart disease and type 2 diabetes.
Blackwell, who is also acting section head of Immunobiology at Joslin, explained, “When we feel our muscles become tired and then recover after a workout, they are going through this cycle of fragmentation and repair of the mitochondria. This process allows muscles to recover their functional ability after the demands of exercise.”
Blackwell and his team, which included co-corresponding author Julio Cesar Batista Ferreira from the Institute of Biomedical Sciences at the University of Sao Paulo, studied the role of mitochondrial dynamics during exercise in the model organism C. elegans, a simple microscopic worm often used in research on metabolism and aging.
The researchers recorded wild type C. elegans worms as they moved, and noticed a decline in physical fitness over the worms’ 15-day adult lifespan, which is typical of aging. They also found a significant and progressive shift towards fragmented and disorganized mitochondria in the aging worms. For instance, they observed that in young worms on the first day of adulthood, a single bout of exercise caused fatigue after one hour.
The 60-minute exercise session also led to an increase in mitochondrial fragmentation in the worms’ muscle cells. However, a period of 24 hours was enough to restore both physical performance and mitochondrial function.
In older worms (on day 5 and day 10), their physical performance did not return to normal within 24 hours. Additionally, the older worms’ mitochondria went through the cycle of fragmentation and repair, but the network reorganization that occurred was less compared to that of the younger worms.
First author Juliane Cruz Campos, a postdoctoral fellow at Joslin Diabetes Center, stated, “We found that a single exercise session causes a cycle of fatigue and physical fitness recovery that is accompanied by a cycle of rebuilding the mitochondrial network.”
Campos added, “Aging decreased the extent to which this occurred and led to a parallel decline in physical fitness. This suggests that mitochondrial dynamics may be important for maintaining physical fitness and possibly for improving physical fitness through exercise.”
In a second set of experiments, the researchers let wild type worms swim for one hour per day for 10 consecutive days, starting at the beginning of their adult lifespan. They found that, similar to humans, the long-term training program significantly improved the worms’ middle-aged fitness at day 10 and reduced the impairment of mitochondrial dynamics typically seen during aging.
Finally, the researchers tested known interventions that can extend lifespan to see if they could improve exercise capacity during aging. They found that worms with increased AMPK (a molecule that regulates energy during exercise and promotes remodeling of mitochondrial morphology and metabolism) had improved physical fitness.
The researchers also found that the absence of AMPK resulted in reduced physical fitness during aging and impaired recovery after exercise. These worms did not experience the age-delaying benefits of exercise over their lifespan.
Blackwell, who is also a professor of genetics at Harvard Medical School, commented, “One important goal in the field of aging research is to find interventions that not only extend lifespan but also improve health and quality of life.”
Blackwell continued, “In aging humans, a decrease in muscle function and exercise tolerance is a major concern that leads to significant morbidity. Our data suggest promising intervention points for preventing this decline, possibly along with other aspects of aging. It will be interesting to see how plasticity in the mitochondrial network affects physical fitness, lifespan, and aging-related diseases in humans.”
Other authors of the study include 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 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.
Funding: This work was supported by the 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), the Conselho Nacional de Pesquisa e Desenvolvimento – Brasil (CNPq) (grants 303281/2015-4 and 407306/2013-7), the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) Finance Code 001, the Instituto Nacional de Ciência e Tecnologia and Centro de Pesquisa e Desenvolvimento de Processos Redox em Biomedicina, the National Institutes of Health (NIH) (grants R35 GM122610, R01 AG054215, DK123095, AG071966), the 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, the American Heart Association Career Development Award (2022/926512), the Claudia Adams Barr Program, the Lavine Family Fund, the Pew Charitable Trust, and William B. Mair (Harvard T.H. Chan School of Public Health) and Malene Hansen (Sanford Burnham Prebys Medical Discovery Institute). Some of the worm strains used in the study were provided by the CGC, which is funded by the NIH (P40 OD010440).