Calorie Restriction (CR) & Telomeres: Can CR Slow Aging? New Study Unravels the Mystery

Calorie Restriction & Telomeres: Can CR Slow Aging? New Study Unravels the Mystery

DR T S DIDWAL MD

3/25/20246 min read

Calorie Restriction and Telomeres: Does CR Slow Aging? (New Study Findings)

The CALERIE™ 2 trial, published in the journal Aging Cell, examined how moderate calorie restriction (CR) affects telomere length (TL), a marker of cellular aging, in healthy adults. The findings were intriguing but inconclusive. Initial trends suggested faster TL shortening in the CR group, but this might have reversed during weight maintenance. The study acknowledged limitations like measurement challenges and short follow-up duration. Future research is needed to explore how CR impacts telomeres in the long term and if personalized CR approaches based on factors like genetics can optimize its benefits for healthy aging. Ultimately, unlocking the secrets of CR's influence on TL holds promise for developing strategies to promote longevity and well-being.

Key Findings

CALERIE™ 2 Study: Investigated the effects of moderate calorie restriction (CR) on telomere length (TL), a marker of aging, in healthy adults.
Mixed Findings: The study observed mixed results on telomere shortening with CR. There were trends suggesting faster shortening during weight loss but potentially slower shortening during weight maintenance.
Possible Explanations: Short-term stress response (hormesis) from CR, limitations of telomere measurement techniques, and the need for longer-term studies were offered as explanations.
Comparison to Previous Research: CALERIE™ 2 adds to the ongoing debate, with some studies showing benefits and others not.
CR and Weight Loss Phases: The study suggests a two-phase response: possible faster shortening during weight loss and potentially slower shortening during weight maintenance.
Limitations of the Study: No gold standard for TL measurement, limited follow-up duration, and a non-diverse study population were acknowledged limitations.
Future Directions: Longer-term studies, investigating the mechanisms of CR's effects, and personalized CR approaches are crucial for future research.

Calorie restriction (CR), a practice of reducing calorie intake without malnutrition, has been shown to extend lifespan in various animal models. Researchers are eager to understand if CR translates these benefits to humans. The CALERIE™ 2 trial investigated the effects of moderate CR on healthy, non-obese adults. This blog post explores the impact of CR on telomere length, a potential marker of biological aging.

CALERIE™ 2: Exploring the Effects of Calorie Restriction in Humans

CALERIE™ 2 is a landmark study that assessed the long-term effects of CR on human health. Participants were randomized into two groups: one following a 25% calorie restriction diet and the other consuming a control diet ad libitum (meaning they could eat as much as they wanted).

Prior analyses of CALERIE™ 2 data revealed promising results. The CR group displayed improvements in various aspects of health, including cardiometabolic function, liver function, muscle quality, and immune health. Additionally, CR seemed to slow down the biological aging process based on a panel of clinical biomarkers.

The Intricate Relationship Between Aging and Telomeres

Telomeres are protective caps at the ends of chromosomes that shorten with each cell division. This shortening is considered a hallmark of aging. When telomeres become critically short, cells can malfunction or die. Therefore, measuring telomere length can provide insights into biological aging.

Mixed Results on Telomere Shortening

The study employed two methods to measure TL:

Absolute telomere length (aTL) assessed directly using quantitative PCR (qPCR).
DNA methylation-based telomere length (DNAmTL) estimated indirectly using DNA methylation data.

Here's a breakdown of the observed trends:

First Year (Weight Loss Phase): No significant differences in telomere shortening between the CR and control groups were observed using intention-to-treat (ITT) models. However, there were trends suggesting potentially faster telomere shortening in the CR group for both aTL and DNAmTL measurements.
Accounting for Adherence: When adherence to the CR diet was considered (through TOT analyses), researchers estimated that a 20% calorie reduction might be associated with increased DNAmTL shortening between baseline and the 12-month follow-up. This finding was also replicated for aTL measurements when adjusting for inflammation and oxidative stress.
Second Year (Weight Maintenance Phase): The picture became more complex during the weight maintenance phase. CR participants exhibited slower aTL shortening between 12 and 24 months compared to the control group. This pattern held true for those within the CR group with higher adherence (>10% CR).

Possible Explanations for the Findings

The observed inconsistencies in telomere shortening rates with CR could be due to several factors:

Short-term vs. Long-term Effects: The two-year study duration might not be enough to capture the full impact of CR on telomere dynamics. Longer-term studies are needed to clarify these effects.
Hormesis: CR could trigger a short-term stress response (hormesis) leading to faster telomere shortening. However, this stress response might ultimately enhance cellular resilience and slow down telomere attrition in the long run.
Measurement Challenges: Telomere length measurement techniques are still under development, and the two methods used in the study might capture different aspects of telomere biology.

CR and Telomeres in the Context of Previous Research

The CALERIE™ 2 study adds to the ongoing debate on CR's impact on telomere length. Here's how it compares to previous findings:

PREDIMED-Plus Study: reported no effects of CR on TL.
Meta-analysis of Five RCTs: Provided mixed results, with some studies showing slower telomere shortening with CR.
Cross-sectional Analyses: reported shorter average TL in long-term CR practitioners compared to controls.

A crucial distinction in the CALERIE™ 2 design is that all participants were non-obese. This helps separate the effects of CR from those of obesity-related weight loss, which can also influence telomere health.

CR-mediated Weight Loss and Telomere Dynamics

The CALERIE™ 2 findings suggest a possible two-phase response of telomeres to CR:

Phase 1 (Weight Loss): Accelerated TL attrition might occur due to decreased prioritization of telomere maintenance during the metabolic adaptation to lower calorie intake. This aligns with the metabolic telomere attrition hypothesis.
Phase 2 (Weight Maintenance): TL attrition in the CR group might slow down relative to the control group, potentially reflecting an adaptation to the new metabolic state.

Limitations of the Study

The study acknowledges limitations:

No Gold Standard for Telomere Measurement: The two TL measurement methods used have a moderate correlation.
Limited Follow-up Duration: The two-year duration might limit the ability to detect long-term effects.
Potential Measurement Error: Pre-analytical factors and measurement variability could influence results.
Statistical Power: The sample size might not be sufficient to detect small effect sizes.
Generalizability: The study population was predominantly white, female, and non-obese, limiting generalizability to more diverse groups.

Future Directions

Unraveling the complex relationship between CR and telomere length requires further research:

Longer-term Studies: Studies with longer follow-up periods are needed to capture potential long-term benefits of CR on telomere health.
Mechanisms Underlying CR's Effects: Investigating the mechanisms by which CR influences telomeres, including the role of stress response pathways, is crucial.
Genetic and Baseline Telomere Length Influences: Studying how factors like genetics and baseline telomere length influence individual responses to CR is important.

A Look Ahead: Unlocking the Secrets of Healthy Aging

The quest for healthy aging continues, and research on CR holds significant promise. Here's what future research directions might reveal:

Optimizing CR for Telomere Health: Refining CR protocols to potentially mitigate the initial phase of faster telomere shortening and maximize long-term benefits.
Personalized CR Approaches: Tailoring CR interventions based on individual factors like genetics and baseline telomere length to enhance effectiveness.
Combination Strategies: Exploring the potential benefits of combining CR with other interventions like exercise or dietary modifications to promote telomere health.

The Road to Longevity and Well-being

The pursuit of healthy aging is a multifaceted endeavor. While CR offers a promising avenue, it's likely a combination of lifestyle choices and potential interventions that will ultimately hold the key to longevity and well-being.

The CALERIE™ 2 study, along with ongoing research, paves the way for developing evidence-based strategies to promote healthy aging. As the field progresses, we can expect to gain a deeper understanding of how to optimize our cellular health and potentially extend our healthspan.

In Closing...

Calorie restriction and its impact on telomere length remain a subject of ongoing exploration. The CALERIE™ 2 trial, with its mixed findings, highlights the complexity of this relationship. Future research holds the promise of unlocking the secrets of how CR influences telomere health and ultimately contributes to a longer and healthier lifespan.

Journal Reference
Hastings, W. J., Ye, Q., Wolf, S. E., Ryan, C. P., Das, S. K., Huffman, K. M., Kobor, M. S., Kraus, W. E., MacIsaac, J. L., Martin, C. K., Racette, S. B., Redman, L. M., Belsky, D. W., & Shalev, I. (2024). Effect of long-term caloric restriction on telomere length in healthy adults: CALERIE™ 2 trial analysis. Aging cell, e14149. Advance online publication. https://doi.org/10.1111/acel.14149

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