This study published in the Aging Cell examined if reducing calorie intake by 12% for two years (caloric restriction) would improve muscle health in humans. While some muscle mass was lost, strength remained unchanged. Researchers analyzed genes in muscle tissue and found changes linked to muscle maintenance, cellular repair, and energy production. These changes suggest that calorie restriction positively impacts muscle health. Additionally, the study observed alterations in how genes are processed, which aligns with what's seen in animals with calorie restriction. Overall, this suggests moderate calorie restriction as a lifestyle change may benefit human muscle health.

Key Findings

Researchers analyzed muscle tissue samples from the CALERIE participants at the beginning, after 1 year, and after 2 years of the study. They compared gene expression between the CR group and the control group.

The analysis revealed significant changes in gene expression related to various biological processes in the CR group. These processes included:

• Maintaining protein balance (proteostasis): Genes involved in protein building and breakdown were affected by CR.

• Regulating sleep-wake cycles (circadian rhythm): CR appeared to influence genes that control our internal body clock.

• Repairing DNA damage: Genes involved in DNA repair were activated by CR, potentially improving cellular health.

• Increasing mitochondrial production (mitochondrial biogenesis): Mitochondria are the cell's powerhouses, and CR seemed to stimulate their production.

• Processing and modifying messenger RNA (mRNA): CR-impacted genes are responsible for handling the instructions encoded in our genes.

• Regulating FOXO3 metabolism: FOXO3 is a protein involved in various cellular functions, and CR appeared to influence its activity.

• Cell death (apoptosis): CR may have affected genes related to programmed cell death.

• Inflammation: Gene expression related to inflammation was altered by CR.

These changes in gene expression suggest that CR positively influences several biological pathways that contribute to muscle health.

Interestingly, the study also found that CR affected the splicing of certain genes. Splicing is a process that modifies genes to create different protein versions. The splicing changes observed were linked to pathways previously known to be affected by CR in animal studies.

Overall, the study suggests that two years of moderate CR in humans can improve muscle quality. The observed changes in gene expression and splicing patterns align with the positive effects of CR seen in animal models. This indicates that achievable levels of CR, implemented as a lifestyle change, can potentially benefit human muscle health.

Calorie restriction (CR) has long been studied as a potential intervention to counteract the effects of aging. Across various animal species, aging is associated with typical anatomical and physiological changes, leading to functional impairments and ultimately, death. However, research suggests that CR may increase health span and longevity in numerous model organisms, ranging from yeast to rodents. The profound health benefits observed in these models have sparked interest in exploring the potential effects of CR on human aging.

Understanding Calorie Restriction: Insights from CALERIE™

The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) was a landmark study designed to evaluate the effects of reducing calorie intake on human health. This randomized controlled trial involved reducing calorie intake by 25% over a period of 2 years while ensuring participants maintained a normal intake of essential nutrients. The study aimed to assess the impact of CR on young and middle-aged nonobese individuals compared to a control group with ad libitum (AL) intake.

The results of the CALERIE intervention were significant, with participants experiencing an average of 12% CR accompanied by sustained weight loss over the study period. Analysis of whole-body MRI scans revealed preferential loss of adipose tissue, reduced visceral fat accumulation, and minor but significant loss of muscle tissue among participants undergoing CR. Moreover, CR led to improvements in cardiometabolic risk profiles and reduced blood pressure without adverse effects on quality of life.

Effects of Calorie Restriction on Skeletal Muscle

Skeletal muscle health is critical for overall physical function and mobility, especially with advancing age. Previous studies in model organisms have shown that CR positively affects skeletal muscle through various mechanisms. These include:

• Improved Satellite Cell Proliferative Capacity: CR has been shown to enhance the proliferative capacity of satellite cells, which play a crucial role in muscle regeneration and repair.

• Reduction in Mitochondrial Proton Leak and Reactive Oxygen Species Production: CR reduces oxidative stress within muscle cells by improving mitochondrial function, thus preserving muscle integrity.

• Prevention of Muscle Fiber Loss: CR helps maintain muscle mass by preventing the degeneration of muscle fibers associated with aging.

• Enhancement of Mitochondrial Efficiency: CR improves the efficiency of the mitochondrial electron transport chain, leading to increased energy production within muscle cells.

Insights from Human Studies

While much of the evidence supporting the benefits of CR comes from studies in model organisms, there is growing interest in understanding its effects on human health. Cross-sectional studies and short-term randomized trials have provided valuable insights into the potential benefits of CR in humans.

For example, comparisons of muscle biopsies between individuals following a CR diet and those on a Western diet have revealed enhanced cellular quality-control processes among CR participants. Additionally, short-term CR interventions have been shown to increase mitochondrial biogenesis and reduce DNA damage in young, nonobese adults. Similarly, CR has been associated with increased mitochondrial content and improved fatty acid oxidation enzyme activities in overweight and obese older individuals.

Exploring Biological Mechanisms: A High-Depth RNA Sequencing Analysis

To further elucidate the molecular mechanisms underlying the effects of CR on muscle health, researchers conducted a comprehensive high-depth RNA sequencing (RNA-Seq) analysis of skeletal muscle samples from participants in the CALERIE 2 study. The aim was to examine changes in gene expression and splicing variants induced by CR over 12 and 24 months and investigate the impact of CR on muscle quality and strength.

Results and Implications

The analysis revealed significant changes in gene expression and splicing variants associated with CR, suggesting profound alterations in biological pathways related to muscle health. Despite experiencing declines in muscle mass, participants undergoing CR did not exhibit significant reductions in muscle strength when adjusted for changes in muscle mass, indicating potential preservation of muscle function.

Insights from Human Studies: CALERIE™ Trial

The CALERIE™ trial, a groundbreaking two-year randomized controlled trial, investigated the impact of CR on skeletal muscle health in healthy humans without obesity. Through deep RNA sequencing of skeletal muscle obtained from repeated biopsies, researchers identified significant differential gene expression changes in CR participants compared to controls. These changes point to biological pathways previously associated with CR in laboratory animals, including muscle repair, myogenesis, and mechanisms of aging.

Modulation of Circadian Rhythm by Calorie Restriction

Recent studies suggest that CR-driven life extension may be mediated by preserving the robustness and stability of the circadian rhythm, which is directly implicated in ageing and age-related chronic diseases. The study confirmed that CR modulates the expression of circadian genes in human skeletal muscle, including the upregulation of core circadian genes such as PER1 and PER2. These findings underscore the potential of CR to prevent declines in the circadian amplitude of gene expression, contributing to the overall health span.

Role of FOXO and Mitochondrial Health

CR modulates the expression of key metabolic regulators in skeletal muscle, including FOXO transcription factors, crucial for maintaining metabolic homeostasis and reducing oxidative stress. Additionally, CR improves mitochondrial function and biogenesis, leading to enhanced oxidative phosphorylation, lipid metabolism, and mitochondrial respiration. These effects contribute to the attenuation of age-related declines in mitochondrial function, crucial for maintaining muscle health with aging.

Autophagy and Inflammation: Implications for Muscle Health

Autophagy and mitophagy play pivotal roles in maintaining muscle health by removing toxic proteins and dysfunctional organelles. CR upregulates these processes, along with the SUMOylation pathway, critical for refolding and clearing damaged proteins. Furthermore, CR leads to transcriptional changes in adipose tissue, reducing chronic inflammation and promoting pathways regulating mitochondrial bioenergetics and lifespan.

Alternative Splicing and Muscle Physiology

Evidence suggests that alternative pre-mRNA splicing is necessary for the effect of CR on longevity. CR upregulates many spliceosome protein- and RNA processing-encoding genes, promoting splicing-related pathways. This includes genes affecting skeletal muscle physiology, highlighting the role of alternative splicing in mediating the positive effects of CR on muscle quality and function.

Conclusion and Future Directions

In conclusion, the study provides compelling evidence that even moderate-intensity CR preserves skeletal muscle health through molecular pathways associated with CR in animal models. The identified mechanisms include modulation of circadian rhythm, enhancement of mitochondrial health, promotion of autophagy, and regulation of alternative splicing. Future research should focus on validating these findings at the proteomic level and conducting larger randomized controlled trials to further elucidate the role of CR in human skeletal muscle health and aging.

Limitations and Future Directions

Despite the significant findings, the study has limitations, including a relatively small sample size and the need for validation at the proteomic level. Future research should aim to replicate these findings in larger, more diverse populations over a wider age range to fully understand the impact of CR on human skeletal muscle health.

To Summarize

• Muscle quality preserved: After 2 years of CR, participants lost slight muscle mass but maintained muscle strength, suggesting preserved quality.

• Gene expression changes: CR significantly altered the expression of genes involved in several crucial pathways, including:

  • Proteostasis: maintaining proper protein quality and breakdown.

  • Circadian rhythm regulation: adjusting to light-dark cycles.

  • DNA repair: protecting genetic integrity.

  • Mitochondrial biogenesis: building more energy-producing mitochondria.

  • mRNA processing/splicing: fine-tuning protein production from genes.

  • FOXO3 metabolism: influencing stress resistance and longevity.

  • Apoptosis: controlled cell death.

  • Inflammation: Balancing defence and damage control.

• Splicing variations: CR also affected how genes are spliced, producing different protein variants. These changes mirrored pathways impacted by CR in animal models.

Overall Significance:

This study demonstrates that even moderate CR in humans can positively impact muscle quality, potentially through modifying gene expression and splicing patterns in ways similar to those observed in rodents. These findings suggest that incorporating some level of CR into a lifestyle intervention could benefit muscle health and potentially overall well-being.

Reference Article

1.Das, J. K., Banskota, N., Candia, J., Griswold, M. E., Orenduff, M., de Cabo, R., Corcoran, D. L., Das, S. K., De, S., Huffman, K. M., Kraus, V. B., Kraus, W. E., Martin, C., Racette, S. B., Redman, L. M., Schilling, B., Belsky, D., & Ferrucci, L. (2023, October 12). Calorie restriction modulates the transcription of genes related to stress response and longevity in human muscle: The CALERIE study. Aging Cell, 22(12). https://doi.org/10.1111/acel.13963

Related

https://healthnewstrend.com/vitamin-k-linked-to-lower-heart-disease-risk-danish-study

Medical Disclaimer

The information on this website is for informational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health care provider with any questions you may have regarding a medical condition or treatment. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.