How Exercise Preserves Physical Fitness During Aging

How Exercise Preserves Physical Fitness During Aging

Summary: The findings reveal a cellular mechanism that helps improve physical fitness through exercise and identify an antiaging intervention that helps delay the declines that occur with natural aging.

Source: Joslin Diabetes Center

Proven to protect against a number of diseases, exercise may be the most powerful anti-aging intervention known to science. However, while physical activity may improve health during aging, its beneficial effects inevitably decline. The cellular mechanisms underlying the relationship between exercise, fitness and aging remain poorly understood.

In a paper published in the Proceedings of the National Academy of Sciences, researchers at the Joslin Diabetes Center investigated the role of a cellular mechanism in improving physical fitness through exercise 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 for promoting muscle function during aging.

“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 co-corresponding author T. Keith Blackwell, MD, PhD, a senior investigator. and head of the Islet Cell and Regenerative Biology section at Joslin. “Our data identify an essential mediator of the exercise response and an entry point for interventions to preserve muscle function during aging.”

That essential intermediary is the fragmentation 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 re-connecting energy-producing organelles—has been linked to the development and progression of chronic, age-related diseases such as heart disease and diabetes. of type 2.

“While we perceive our muscles to undergo a pattern of fatigue and restoration after an exercise session, they are undergoing this dynamic mitochondrial cycle,” said Blackwell, who is also acting head of the section of Immunobiology at Joslin. “In this process, muscles manage the consequences of the metabolic demand of 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. species frequently used in metabolic and aging research.

By recording wild-type C. elegans worms as they swam or crawled, the investigators observed a typical age-related decline in fitness during the animals’ 15 days of adulthood. The scientists also showed a significant and progressive shift toward fragmented and/or disorganized mitochondria in aging animals. For example, they observed that in young worms on the first day 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 animal’s muscle cells, but a 24-hour period was sufficient to restore mitochondrial performance and function.

In older worms (day 5 and day 10), animal performance did not return to baseline within 24 hours. Likewise, 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 triggers a cycle of exhaustion and recovery of physical fitness that parallels a cycle of mitochondrial network remodeling,” said first author Juliane Cruz Campos, a postdoctoral fellow at the Joslin Diabetes Center.

“Aging reduced the rate at which this occurred and caused a parallel decline in physical fitness. This suggested that mitochondrial dynamics may be important for the maintenance of physical fitness and perhaps that physical fitness is improved by a period of exercise.

In a second set of experiments, the scientists allowed the wild-type worms to swim for an hour a day for 10 consecutive days, beginning at the onset of adulthood. The team found that—as in humans—the long-term training program significantly improved the physical fitness of the middle-aged animals on day 10 and attenuated the impairment of mitochondrial dynamics commonly seen during aging.

That essential intermediary is the fragmentation and repair cycle of mitochondria, the specialized structures or organelles within each cell responsible for energy production. The image is in the public domain

Finally, the researchers tested known lifespan-prolonging interventions for their ability to improve exercise capacity in aging. Worms with increased AMPK—a molecule that is a key regulator of energy during exercise that also promotes remodeling of mitochondrial morphology and metabolism—displayed improved physical performance.

They also demonstrated maintenance but not improvement in exercise performance during aging. Worms engineered to be deficient in AMPK exhibited reduced physical abilities during aging as well as impaired recovery cycles. They also didn’t get the age-delaying benefits of exercise across the lifespan.

“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 older people, a decline in muscle function and exercise tolerance is a major concern that leads to significant morbidity. Our data point toward potentially fruitful points of intervention to prevent this decline—most likely along with other aspects of aging. It will be of great interest to determine how the plasticity of the mitochondrial network affects fitness along with longevity and aging-related diseases 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 of 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 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); 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; 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 the CGC, which is funded by the NIH (P40 OD010440).

See also

Chouchani is a founder and equity holder in Matchpoint Therapeutics. The other authors declare no competing interests.

About this news about aging and exercise research

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

Original Research: Closed Access.
“Exercise maintains fitness during aging through AMPK and mitochondrial dynamics” by T. Keith Blackwell et al. PNAS


Exercise maintains fitness during aging through AMPK and mitochondrial dynamics

Exercise is a nonpharmacological intervention that improves health in aging and a valuable tool in the diagnosis of aging-related diseases. In muscle, exercise transiently alters mitochondrial functionality and metabolism. Mitochondrial fission and fusion are critical effectors of mitochondrial plasticity, which allows fine-tuning of organelle association, 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 muscle, a single exercise session induces a cycle of mitochondrial fragmentation followed by fusion after a recovery period, and that daily exercise sessions delay the mitochondrial fragmentation and decline in fitness that occur with aging.

Maintaining proper mitochondrial dynamics is essential for physical fitness, its improvement with exercise training, and exercise-induced proteome remodeling. Strikingly, among the long-lived genotypes we analyzed (isp-1, nuo-6, daf-2, eat-2, and CA-AAK-2), constitutive activation of AMP-activated protein kinase (AMPK) uniquely preserves fitness. during aging, a benefit that is removed by impaired mitochondrial fission or fusion. AMPK is also required for exercise-enhanced physical performance, with our findings together suggesting that exercise may improve muscle function through AMPK regulation of mitochondrial dynamics.

Our results show that mitochondrial connectivity and the cycle of mitochondrial dynamics are essential for the maintenance of fitness and the response to exercise 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 for promoting muscle function during aging.

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