Calorie Restriction Linked to Reduced Biomarkers of Aging: Can We Slow Aging with Fewer Calories?

New research suggests calorie restriction (CR) may delay aging by lowering cellular senescence markers. This study linked CR to improved metabolic health, raising exciting possibilities for promoting healthy lifespans. Explore the findings and the need for further investigation.

DR T S DIDWAL MD

3/25/20246 min read

Can Calorie Restriction Slow Aging? Study Shows Promise in Reducing Cellular Senescence

A two-year study in Aging Cell investigated the connection between calorie restriction (CR) and cellular senescence, a hallmark of aging where cells stop dividing. Researchers analyzed blood samples from participants in the CALERIE™ trial, the most robust study on CR in humans. The CR group showed significantly reduced levels of various senescence biomarkers compared to the control group, suggesting CR might slow cellular aging. Interestingly, changes in these biomarkers correlated with improvements in metabolic health for the CR group, hinting at a potential link between reduced senescence and better metabolism. The study also found a downregulation of senescence-related genes in fat tissue samples from the CR group, further supporting CR's potential impact on cellular senescence. While limitations exist, such as the use of non-definitive senescence markers and a relatively young study population, this research offers valuable insights. It highlights the need for further studies to validate the biomarkers, explore the mechanisms behind CR's effects, and investigate CR's long-term impact on a broader population. Overall, the study strengthens the evidence for CR as a potential strategy to promote healthy aging by potentially targeting cellular senescence and improving metabolic health.

Key Findings

Calorie Restriction (CR) Lowers Biomarkers of Cellular Senescence: The study found that moderate CR for two years significantly reduced the levels of several biomarkers associated with cellular senescence in the blood of healthy adults, compared to a control group with no calorie restriction. This suggests CR may slow down the aging process at the cellular level in humans.
Potential Link Between CR and Metabolic Health: The study observed that changes in senescence biomarkers were associated with improvements in metabolic health parameters in the CR group. This suggests a potential connection between reduced cellular senescence and better metabolic health, such as improved insulin sensitivity.
CR May Impact Cellular Senescence Gene Expression: Analysis of gene expression data from adipose tissue showed a downregulation of genes associated with cellular senescence in the CR group compared to baseline levels. This finding supports the idea that CR might influence cellular senescence beyond just biomarker levels.
CALERIE™ Study: A Pioneering Investigation: The study utilized data from the CALERIE™ trial, the most rigorous investigation into CR's effects on humans to date. This large-scale study provides valuable insights for further research on CR and aging.
Limitations of the Study: The study acknowledges limitations such as the use of biomarkers that aren't specific to senescent cells and the inability to establish causation between changes and health outcomes. Additionally, the participants were young and healthy, limiting generalizability.
Need for Further Research: The study highlights the need for further research to validate senescence biomarkers, conduct larger and longer-term studies with diverse populations, and explore the mechanisms behind CR's effects.
CR as a Potential Tool for Healthy Aging: This study adds to the evidence that CR may be a promising strategy for promoting healthy aging in humans by potentially reducing cellular senescence, inflammation, and improving metabolic health.

For years, scientists have been fascinated by the idea of extending human lifespan and delaying the onset of age-related diseases. Calorie restriction (CR), a reduction in calorie intake without malnutrition, has emerged as a potential strategy in this pursuit. But how does CR work in humans, and what are the underlying mechanisms? This blog post explores a recent study that sheds light on the connection between CR and cellular senescence, a key hallmark of aging. Cellular senescence is a state where cells stop dividing and can even harm surrounding tissues. As we age, senescent cells accumulate, potentially contributing to chronic inflammation and other age-related problems.

The CALERIE™ Study: Pioneering Research on Calorie Restriction in Humans

The most rigorous investigation into CR's effects on humans is the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) study. Phase 2 of CALERIE™ was a two-year randomized controlled trial involving healthy young-to-middle-aged adults. Participants were divided into two groups: one following a calorie-restricted diet (CR) and the other consuming an ad libitum (AL) diet with no restrictions.

While the average calorie reduction achieved in the CR group was lower than initially intended, the study demonstrated the safety and effectiveness of moderate CR in promoting heart health and reducing risk factors for metabolic diseases. However, the long-term impact of CR on lifespan and healthspan (healthy years of life) remains to be determined.

Cellular Senescence and the Potential Benefits of CR

These biomarkers are not exclusive to senescent cells, but they are known to increase in the blood of older individuals and those with signs of advanced biological age. Additionally, these biomarkers are often elevated in mouse models with a high burden of senescent cells.

CR Lowers Biomarkers of Cellular Senescence in Humans

The study's key finding is that CR significantly reduced the levels of several senescence biomarkers in the blood compared to the ad libitum diet group. This reduction was observed at both 12 and 24 months of the study, suggesting a sustained effect of CR.

CR and Metabolic Health: A Potential Link Through Senescence

The researchers also employed machine learning to analyze the data. Interestingly, changes in the levels of senescence biomarkers emerged as significant predictors for improvements in metabolic health parameters in the CR group. This suggests a potential link between reduced cellular senescence and better metabolic health.

Looking Beyond Blood: Gene Expression in Adipose Tissue

Finally, the study looked at gene expression data from adipose tissue samples (a type of fat tissue) collected from a subset of CALERIE™ participants. They found that genes associated with cellular senescence were significantly downregulated in the CR group compared to baseline levels at both 12 and 24 months. This finding provides further evidence for CR's potential to impact cellular senescence at the gene expression level.

Cellular Senescence and the Potential Benefits of CR

Preclinical studies suggest that CR may exert its beneficial effects by delaying or even preventing cellular senescence. This study aimed to gain new insights into this connection in humans. Researchers analyzed blood samples collected from CALERIE™ participants at different time points. They measured the levels of various biomarkers associated with cellular senescence, including cytokines, chemokines, and growth factors. These biomarkers are not exclusive to senescent cells, but they are known to increase in the blood of older individuals and those with signs of advanced biological age. Additionally, these biomarkers are often elevated in mouse models with a high burden of senescent cells.

Looking Beyond Blood: Gene Expression in Adipose Tissue

Limitations and Areas for Further Research

The study acknowledges several limitations. First, none of the measured biomarkers definitively and universally detect senescent cells. Second, the study design cannot establish causation between changes in senescence and metabolic health. Third, the participants were relatively young and healthy, limiting the generalizability of the findings.

Despite these limitations, this study offers valuable insights into the effects of CR on cellular senescence in humans. The observed reduction in senescence biomarkers and the potential link to improved metabolic health are promising findings that warrant further investigation. Additionally, the downregulation of senescence-related genes in adipose tissue strengthens the connection between CR and cellular senescence.

Future research areas include:

Validating the identified senescence biomarkers as reliable indicators of cellular senescence.
Conducting larger and longer-term studies to assess the impact of CR on cellular senescence and healthspan in a more diverse population.
Investigating the mechanisms by which CR reduces cellular senescence.
Exploring the potential of senolytic drugs that target and remove senescent cells as a strategy for promoting healthy aging.

In conclusion, this study adds to the growing body of evidence suggesting that CR may be a valuable tool for promoting healthy aging in humans. By targeting cellular senescence, CR has the potential to reduce chronic inflammation, improve metabolic health, and potentially extend healthspan.

Journal Reference

Aversa, Z., White, T. A., Heeren, A. A., Hulshizer, C. A., Saul, D., Zhang, X., Molina, A. J. A., Redman, L. M., Martin, C. K., Racette, S. B., Huffman, K. M., Bhapkar, M., Khosla, S., Das, S. K., Fielding, R. A., Atkinson, E. J., & LeBrasseur, N. K. (2024). Calorie restriction reduces biomarkers of cellular senescence in humans. Aging cell, 23(2), e14038. https://doi.org/10.1111/acel.14038

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