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How Exercise Preserves Fitness During Aging

Summary: The findings reveal a cellular mechanism that helps improve physical fitness through physical training and identifies an anti-aging 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, while physical activity can improve health as people age, its beneficial effects inevitably diminish. The cellular mechanisms underlying the relationship between exercise, fitness and aging remain poorly understood.

In an article published in the Proceedings of the National Academy of Sciences, researchers from the Joslin Diabetes Center investigated the role of a cellular mechanism in improving fitness through exercise training and identified an anti-aging intervention that delayed the declines that occur with aging in the body. model organism. Together, the scientists’ findings open the door to new strategies for promoting muscle function during aging.

“Exercise has been widely used to improve quality of life and protect against degenerative disease, and in humans, a long-term exercise regimen reduces overall mortality,” said co-corresponding author T. Keith Blackwell, MD, PhD, Principal Investigator and Section Head of Islet Cell and Regenerative Biology at Joslin. “Our data identify a critical mediator of exercise responsiveness and an entry point for interventions to maintain muscle function during aging.”

This essential mediator is the cycle of fragmentation and repair of mitochondria, the specialized structures, or organelles, inside 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 organs – has been linked to the development and progression of disease. age-related chronic conditions, such as heart disease and type 2 diabetes.

“As we perceive that our muscles are going through a pattern of fatigue and recovery after an exercise session, they are going through this dynamic mitochondrial cycle,” said Blackwell, who is also acting section chief of immunobiology at Joslin. “In this process, the muscles manage the consequences of the metabolic demand for 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 and well-studied microscopic worm A species frequently used in research on metabolism and aging.

By recording the wild C. elegans worms as they swam or crawled, the researchers observed a typical age-related decline in the animals’ fitness for 15 days into adulthood. Scientists have also shown a significant and gradual shift towards fragmented and/or disorganized mitochondria in aging animals. For example, they are observed in young worms on day 1 of adulthood, a single exercise session induces 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 sufficient 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 mitochondria of older animals underwent a cycle of fragmentation and repair, but the network reorganization that occurred was reduced compared to that of younger animals.

“We determined that a single exercise session induces a cycle of fatigue and fitness recovery that parallels a cycle of rebuilding the mitochondrial network,” said first author Juliane Cruz Campos, postdoctoral fellow at Joslin. Diabetes Center.

Aging has lessened the extent to which this has occurred and has induced a parallel decline in fitness. This suggests that mitochondrial dynamics might be important for maintaining fitness and possibly for fitness to be improved by an exercise session.

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 humans, the long-term training program significantly improved the fitness of middle-aged animals by day 10 and attenuated the alteration in mitochondrial dynamics typically seen with aging.

It shows a person walking
This essential mediator is the cycle of fragmentation and repair of mitochondria, the specialized structures, or organelles, inside each cell responsible for energy production. Image is in public domain

Finally, the researchers tested known interventions that extend lifespan for their ability to improve exercise capacity during aging. Worms with an increase in AMPK – a molecule that is a key regulator of energy during exercise that also promotes remodeling of mitochondrial morphology and metabolism – showed improved fitness.

They have also demonstrated the maintenance, but not the improvement, of physical performance during aging. Worms engineered to lack AMPK exhibited reduced fitness during aging as well as impaired recovery cycle. They also did not experience the age-delaying benefits of exercise in their lifetime.

“An important goal of the field of aging 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 aging humans, decreased muscle function and exercise tolerance is a major concern that results in substantial morbidity. Our data point to potentially fruitful points of intervention to prevent this decline – most likely with other aspects of aging. It will be of great interest to determine how the plasticity of the mitochondrial network influences fitness as well as longevity and diseases associated with aging in humans.

Other 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 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.

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); Conselho Nacional de Pesquisa e Desenvolvimento – Brasil (CNPq) (grants 303281/2015-4 and 407306/2013-7); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) Finance Code 001 and Instituto Nacional de Ciência e Tecnologia and Centro de Pesquisa e Desenvolvimento de Processos Redox em Biomedicina; 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. 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).

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Chouchani is founder and shareholder of Matchpoint Therapeutics. The other authors declare no competing interests.

About this aging and exercise research news

Author: Chloe Meck
Source: Joslin Diabetes Center
Contact: Chloe Meck – Joslin Diabetes Center
Picture: Image is in public domain

Original research: Access closed.
Exercise Preserves Fitness During Aging Through AMPK and Mitochondrial Dynamicsby T. Keith Blackwell et al. PNAS


Summary

Exercise Preserves Fitness During Aging Through AMPK and Mitochondrial Dynamics

Exercise is a non-pharmacological intervention that improves health during aging and a valuable tool in the diagnosis of age-related diseases. In muscle, exercise transiently alters the function and metabolism of mitochondria. Fission and fusion of mitochondria are critical effects of mitochondrial plasticity, which allows fine regulation of organelle connectivity, size and function.

Here we investigated the role of mitochondrial dynamics during exercise in the model organism Caenorhabditis elegans. We show that in body wall muscles, a single exercise session induces a cycle of mitochondrial fragmentation followed by fusion after a recovery period, and that daily exercise sessions delay mitochondrial fragmentation and the decline of fitness that come with aging.

Maintaining appropriate mitochondrial dynamics is essential for physical fitness, its improvement through exercise 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 fitness during aging, an advantage that is abolished by impaired mitochondrial fission or fusion. AMPK is also required for exercise-enhanced fitness, with our results collectively suggesting that exercise can improve muscle function through AMPK’s regulation of mitochondrial dynamics.

Our results indicate that mitochondrial connectivity and cycling of mitochondrial dynamics are critical for maintaining fitness and exercise responsiveness during aging and suggest that AMPK activation may recapitulate 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.

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