How exercise preserves physical fitness during aging

Abstract: The findings reveal a cellular mechanism that helps improve physical fitness through exercise and identify one 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 is perhaps the most powerful anti-aging intervention known to science. However, while physical activity can improve health as we age, its beneficial effects inevitably decline. The cellular mechanisms underlying the relationship between exercise, fitness and aging remain poorly understood.

In a paper published in 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 age-related declines in a model organism. Together, the scientists’ findings open the door to new strategies to boost muscle performance during aging.

“Exercise is 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-author T. Keith Blackwell, MD, PhD, senior researcher and head of the Division of Islet and Regenerative Biology at Joslin. “Our data identify an essential mediator of the exercise response and an entry point for interventions to maintain muscle function during aging.”

That key mediator is the cycle of fragmentation and repair 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 among energy-producing organelles—has been linked to the development and progression of age-related chronic diseases, such as heart disease and type 2 diabetes.

“As we observe our muscles go through a pattern of fatigue and recovery after exercise, they go through this mitochondrial dynamic cycle,” said Blackwell, who is also acting head of the department of immunobiology at Joslin. “In the process, muscles manage the consequences of the metabolic demands of exercise and regain their functional capacity.”

Blackwell and colleagues—including co-author Julio Cesar Batista Ferreira, Ph.D., Institute of Biomedical Sciences, University of São Paulo—investigated the role of mitochondrial dynamics during exercise in the model organism C. elegans, a simple, well-studied microscopic worm of a species often used in metabolism and aging research.

By recording wild-type C. elegans worms as they swam or crawled, the researchers observed a typical age-related decline in fitness over the 15 days of the animals’ adulthood. Scientists have also shown a significant and progressive shift toward fragmented and/or disorganized mitochondria in aging animals. For example, they observed 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 animals’ muscle cells, but a 24-hour period was sufficient to restore both mitochondrial performance and function.

In older (day 5 and day 10) worms, animal performance did not return to baseline within 24 hours. Likewise, mitochondria from older animals underwent a cycle of fragmentation and repair, but the network reorganization that occurred was reduced compared to that of younger animals.

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

“Aging moderated the extent to which this occurred and caused a comparative decline in physical fitness. This suggested that mitochondrial dynamics might be important for maintaining physical fitness and possibly for improving physical fitness through exercise.”

In another set of experiments, scientists allowed wild worms to swim for one 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 animals’ midlife fitness at day 10 and mitigated the impairment of mitochondrial dynamics commonly seen during aging.

Finally, the researchers tested known lifespan-extending interventions for their ability to improve exercise capacity during 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—showed improved physical fitness.

They also showed maintenance but not improvement in exercise performance with aging. Worms engineered to lack AMPK showed reduced fitness during aging as well as impaired recovery cycles. They also did not receive the age-delaying benefits of exercise over 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 aging people, a decline in muscle function and exercise tolerance is a major concern that leads to significant morbidity. Our data point to potentially useful 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 physical fitness along with longevity and age-related diseases in humans.”

Additional authors are Takafumi Ogawa of the Joslin Diabetes Center; Luiz Henrique Marchesi Bozi (co-author); Barbara Krum, Luiz Roberto Grassmann Poor, Nicholas Dresch Ferreira, Gabriel Santos Arini, Wheel Priests Albuquerque from the University of Sao Paulo; Annika Traa from 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’s Ames Research Center; and Jeremy M. Van Raamsdonk of Harvard Medical School.

Financing: 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 Advancement of Personnel in Higher Education – 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) (grants R35 GM122610, R01 AG054215, DK123095, AG071966); Joslin Diabetes Center (grants P30 DK036836 and R01 GM121756); FAPESP postdoctoral scholarships 2017/16540-5 and 2019/18444-9, and 2016/09611-0 and 2019/07221-9; American Heart Association Career Development Award (2022/926512); the 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 NIH-funded CGC (P40 OD010440).

Chouchani is the founder and owner of Matchpoint Therapeutics. The other authors declare that they have no conflicting interests.

About this aging and exercise research news

Author: Chloe Meck
Source: Joslin Diabetes Center
Contact: Chloe Meck – Joslin Diabetes Center
Picture: The image is in the public domain

Original research: Closed access.
“Exercise preserves physical fitness during aging via AMPK and mitochondrial dynamics” by T. Keith Blackwell et al. PNAS

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Abstract

Exercise preserves physical fitness during aging via AMPK and mitochondrial dynamics

Exercise is a non-pharmacological intervention that improves health during aging and is a valuable tool in the diagnosis of age-related diseases. In muscle, exercise temporarily alters mitochondrial function and metabolism. Mitochondrial fission and fusion are key effectors of mitochondrial plasticity, enabling fine-tuned regulation of organelle connectivity, size, and function.

Here, we investigated the role of mitochondrial dynamics during exercise in a 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 mitochondrial fragmentation and fitness decline that occur with aging.

Maintaining proper mitochondrial dynamics is crucial for physical fitness, its improvement by exercise, and exercise-induced proteome remodeling. Surprisingly, among the long-lived genotypes we analyzed (isp-1,from-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 abrogated by impairment of mitochondrial fission or fusion. AMPK is also required for fitness to be improved by exercise, and our findings together suggest that exercise may improve muscle function via AMPK regulation of mitochondrial dynamics.

Our results demonstrate that mitochondrial connectivity and the cycle of mitochondrial dynamics are critical for maintaining physical fitness and exercise readiness during aging and suggest that AMPK activation may recapitulate some of the 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.