Summary: The findings reveal a cellular mechanism that helps improve physical fitness through physical training and identify an anti-aging intervention that helps slow the declines that occur with natural aging.
Source: Joslin Diabetes Center
Proven to protect against a wide range of diseases, exercise may be the most powerful anti-aging intervention known to science. However, although physical activity can improve health as we age, its beneficial effects inevitably wane. The cellular mechanisms underlying the relationship between exercise, physical conditioning and aging remain poorly understood.
In an article published in Annals of the National Academy of Sciences, researchers at the Joslin Diabetes Center investigated the role of a cellular mechanism in improving physical fitness through physical training and identified an antiaging intervention that delayed the declines that occur with aging in the model organism. Together, the scientists’ findings open the door to new strategies for promoting muscle function during aging.
“Exercise has been widely employed to improve quality of life and protect against degenerative disease, and in humans, a long-term exercise regimen reduces overall mortality,” said co-author T. Keith Blackwell, MD, PhD, Senior Research Fellow and Section Chief of Islet Cell and Regenerative Biology at Joslin. “Our data identify a key mediator of exercise responsiveness and an entry point for interventions to maintain muscle function during aging.”
This essential mediator is the breakdown and repair cycle 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 restoring connectivity between energy-producing organelles – has been linked to the development and progression of chronic age-related diseases such as heart disease and type 2 diabetes.
“As we realize that our muscles go through a pattern of fatigue and restoration after an exercise session, they’re going through this dynamic mitochondrial cycle,” said Blackwell, who is also acting chief of immunobiology at Joslin. “In this process, the muscles manage the consequences of the metabolic demand of exercise and restore their functional capacity.”
Blackwell and colleagues—including co-author Julio Cesar Batista Ferreira, PhD, 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 microscopic worm and well-studied species frequently used in metabolic and aging research.
Recording wild-type C. elegans worms as they swam or crawled, the researchers observed a typical age-related decline in the animals’ physical fitness during the 15 days of adulthood. Scientists have also shown a significant and progressive shift towards fragmented and/or disorganized mitochondria in the elderly 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 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, mitochondria from older animals went through a cycle of fragmentation and repair, but the network reorganization that took place was reduced compared to that of younger animals.
“We determined that a single bout of exercise induces a cycle of fatigue and fitness recovery that is accompanied by a cycle of mitochondrial network rebuilding,” said first author Juliane Cruz Campos, postdoctoral fellow at the Joslin Diabetes Center.
“Aging dampened the extent to which this occurred and induced a parallel decline in physical fitness. This suggested that mitochondrial dynamics may be important for maintaining physical fitness and possibly for physical fitness to be enhanced by an exercise bout.”
In a second set of experiments, the scientists allowed wild-type worms to swim for an hour a day for 10 consecutive days, starting in early adulthood. The team found that – as in people – the long-term training program significantly improved the fitness of the middle-aged animals at day 10 and mitigated the impairment of mitochondrial dynamics normally seen during aging.
Finally, the researchers tested interventions known to prolong lifespan 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 remodeling of mitochondrial morphology and metabolism – exhibited better physical fitness.
They also demonstrated maintenance, but not improvement, of exercise performance during aging. Worms engineered to lack AMPK exhibited reduced physical fitness during aging, as well as impaired recovery cycles. They also did not receive the age-delaying benefits of lifelong exercise.
“An important goal of the aging field is to identify interventions that not only extend lifespan but also improve health and quality of life,” said Blackwell, who is also a professor of genetics at Harvard Medical School.
“In elderly humans, a decline in muscle function and exercise tolerance is a major concern that leads to substantial morbidity. Our data point to potentially fruitful points of intervention to prevent this decline – 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 diseases associated with aging in humans.”
Additional authors included Takafumi Ogawa of the Joslin Diabetes Center; Luiz Henrique Marchesi Bozi (co-first author) and Edward Chouchani of the Dana-Farber Cancer Institute; Barbara Krum, Luiz Roberto Grassmann Bechara, Nikolas Dresch Ferreira, Gabriel Santos Arini, Rudá Prestes Albuquerque from the University of São 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 funded by the State of São Paulo Research Foundation (FAPESP) (grants 2013/07937-8, 2015/22814-5, 2017/16694-2 and 2019/25049-9); National Research and Development Council – Brazil (CNPq) (concepts 303281/2015-4 and 407306/2013-7); Coordination for the Improvement of Higher Education Personnel – Brazil (CAPES) Financial 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) (grant R35 GM122610, R01 AG054215, DK123095, AG071966); the Joslin Diabetes Center (grant P30 DK036836 and R01 GM121756); FAPESP postdoctoral grants 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 Trust; Pew Charitable Trust. 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).
See too
Chouchani is a founder and shareholder of Matchpoint Therapeutics. The other authors declare that there are no conflicting interests.
About this research news about aging and exercise
Author: Chloe Meck
Source: Joslin Diabetes Center
Contact: Chloe MeckJoslin Diabetes Center
Image: The image is in the public domain
Original search: Closed access.
“Exercise Preserves Physical Fitness During Aging Through AMPK and Mitochondrial Dynamics” by T. Keith Blackwell et al. PNAS
Summary
Exercise preserves physical fitness during aging through AMPK and mitochondrial dynamics
Exercise is a non-pharmacological intervention that improves health during aging and a valuable tool in diagnosing age-related diseases. In muscle, exercise transiently alters mitochondrial functionality and metabolism. Mitochondrial fission and fusion are critical effectors of mitochondrial plasticity, which allows fine-tuned regulation of organelle connectivity, size, and function.
Here we investigate the role of mitochondrial dynamics during exercise in the model organism. Caenorhabditis elegans. We show that in body wall muscle, a single bout of exercise induces a cycle of mitochondrial fragmentation followed by fusion after a recovery period, and that daily bouts of exercise delay mitochondrial fragmentation and the decline in physical fitness that occur with aging.
Maintaining adequate mitochondrial dynamics is essential for physical fitness, its improvement through physical training and exercise-induced proteome remodeling. Surprisingly, among the long-lived genotypes we analyzed (isp-1,nuo-6, daf-2, eat-2and CA-AAK-2), constitutive activation of AMP-activated protein kinase (AMPK) uniquely preserves physical fitness during aging, a benefit that is abolished by impaired mitochondrial fission or fusion. AMPK is also required for physical fitness to be enhanced by exercise, with our findings suggesting that exercise may improve muscle function through AMPK regulation of mitochondrial dynamics.
Our results indicate that mitochondrial connectivity and mitochondrial dynamic cycling are essential for maintaining physical fitness and exercise responsiveness during aging and suggest that AMPK activation may recap some benefits of exercise.
Targeting mechanisms to optimize mitochondrial fission and fusion, as well as AMPK activation, may represent promising strategies to promote muscle function during aging.
Comments
Post a Comment