Summary: The findings reveal a cellular mechanism that helps improve physical activity through training and identify an antiaging intervention that helps delay 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 diminish. The cellular mechanisms underlying the relationship between exercise, fitness and aging are poorly understood.
in a paper published in the journal Proceedings of the National Academy of Sciences, Joslin Diabetes Center researchers investigated the role of a cellular mechanism in enhancing exercise training and identified an antiaging intervention that delayed the declines that occur with aging in a model organism. Together, the scientists’ findings open the door to new strategies to promote muscle function in old age.
“Exercise has been widely used to improve quality of life and protect against degenerative diseases, and in humans, a long-term exercise regimen reduces overall mortality,” said lead researcher T. Keith Blackwell, MD, PhD. and Chair of Islet Cell and Regenerative Biology at Joslin. “Our data identify a key mediator of the exercise response and an entry point for interventions to maintain muscle function in aging.”
This essential mediator is the division and repair cycle of mitochondria, 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 age-related chronic diseases such as heart disease and type 2 diabetes.
“When we sense that our muscles are going through a pattern of fatigue and recovery after an exercise session, they’re going through this dynamic mitochondrial cycle,” said Blackwell, who also heads Joslin’s Division of Immunobiology. “In this process, muscles manage the effects of the metabolic demand of exercise and regain functional capacity.”
Blackwell and colleagues—including co-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 well-studied simple microscopic worm. species frequently used in metabolic 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 within 15 days of the animals’ adulthood. The scientists also showed a significant and progressive shift to fragmented and/or disorganized mitochondria in aging animals. For example, in young worms on day 1 of adulthood, they found that a single exercise induced fatigue after one hour.
A 60-minute session increased mitochondrial fission in animal muscle cells, but a 24-hour period was sufficient to restore both performance and mitochondrial function.
In old worms (day 5 and day 10), animal performance did not return to baseline within 24 hours. Likewise, the mitochondria of the older animals underwent a cycle of division 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 fitness recovery in parallel with a cycle of mitochondrial network rebuilding,” said first author Juliane Cruz Campos, a postdoctoral fellow at the Joslin Diabetes Center.
“Aging slowed the rate at which this occurred and caused a parallel decline in physical capacity. This suggested that mitochondrial dynamics may be important for maintaining physical fitness and possibly improving exercise performance.
In a second set of experiments, the scientists allowed wild-type worms to swim for an hour a day for 10 consecutive days, starting at the beginning of adulthood. The team found that – as in humans – the long-term training program significantly improved the animals’ middle-aged fitness on day 10, and mitigated the deterioration of mitochondrial dynamics normally seen in aging.
Finally, the researchers tested known lifespan-extending interventions for their ability to improve exercise capacity in aging. Worms with increased AMPK – the molecule that is the main regulator of energy during exercise and promotes the remodeling of mitochondrial morphology and metabolism – improved physical condition.
They also demonstrated maintenance, but not improvement, of exercise performance with aging. Worms engineered to lack AMPK showed reduced physical capacity as they aged, as well as impaired recovery cycles. Furthermore, they did not receive any age-delaying benefits of physical exercise over the life course.
“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.
“The decline in muscle function and exercise tolerance in aging humans is a major concern that leads to significant disease. Our data point to potentially fruitful interventions to prevent this decline, possibly along with other aspects of aging. It will be of great interest to understand how plasticity of the mitochondrial network is affected.” in its physical condition along with the diseases associated with longevity and aging in humans.
Additional authors were Takafumi Ogawa of the Joslin Diabetes Center; Luiz Henrique Marchesi Bozi (first author); Barbara Krum, Luiz Roberto Grassmann Poor, Nicholas Dresch Ferreira, Gabriel Santos Arini, University of Sao Paulo Wheel Priests Albuquerque; Annika Traa of McGill University; Alexander M. van der Bliek of the David Geffen School of Medicine, University of California, Los Angeles; Afshin Beheshti of the NASA Ames Research Center; and Jeremy M. Van Raamsdonk of Harvard Medical School.
Funding: 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 Research and Development Council – Brazil (CNPq) (grants 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 Biomedical Redox Processes; National Institutes of Health (NIH) (grants R35 GM122610, R01 AG054215, DK123095, AG071966); Joslin Diabetes Center (grants P30 DK036836 and R01 GM121756); FAPESP postdoctoral grants 2017/16540-5 and 2019/18444-9, and 2016/09611-0 and 2019/07221-9; American Heart Association Career Development Award (2022/926512); Claudia Adams Barr Program; Lavine Family Fund; 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 CGC, funded by NIH (P40 OD010440).
About this new study on aging and exercise
Author: Chloe Meck
Source: Joslin Diabetes Center
Contact: Chloe Meck – Joslin Diabetes Center
Image: The image is in the public domain
Original research: Closed access
“Exercise maintains fitness in aging through AMPK and mitochondrial dynamics” T. Keith Blackwell et al. PNAS
abstract
Exercise maintains fitness in aging through AMPK and mitochondrial dynamics
Physical exercise is a non-pharmacological intervention that improves health in aging and is a valuable tool for the diagnosis of aging-related diseases. In muscle, exercise alters mitochondrial functionality and metabolism. Mitochondrial fission and fusion are critical effectors of mitochondrial plasticity, which enables precise regulation of organelle connectivity, size, and function.
Here we investigated the role of mitochondrial dynamics during exercise in a model organism Caenorhabditis elegans. In body wall muscle, we show that a single bout of exercise induces a cycle of mitochondrial fission followed by fusion, followed by a recovery period, and that daily bouts of exercise delay age-related mitochondrial fission and fitness decline.
Maintaining appropriate mitochondrial dynamics is essential for fitness, improvement through exercise training, and exercise-induced remodeling of the proteome. Surprisingly, among the long-lived genotypes we studied (isp-1,– from 6, daf-2, eat-2and CA-AAK-2), constitutive activation of AMP-activated protein kinase (AMPK) maintains fitness in old age, a benefit that is abolished by impairment of mitochondrial fission or fusion. AMPK is also required to enhance exercise, our findings together suggest that exercise may improve muscle function through AMPK regulation of mitochondrial dynamics.
Our results indicate that mitochondrial connectivity and the mitochondrial dynamic cycle are essential for maintaining fitness and exercise response in old age and suggest that AMPK activation may restore some of the benefits of exercise.
Targeting mechanisms to optimize mitochondrial fission and fusion, as well as AMPK activation, may be promising strategies to promote muscle function in aging.