Understanding the Systemic Response to Prolonged Fasting in Humans through Plasma Proteomic Analysis

Pietzner, M., Uluvar, B., Kolnes, K. J., Jeppesen, P. B., Frivold, S. V., Skattebo, Ø., Johansen, E. I., Skålhegg, B. S., Wojtaszewski, J. F. P., Kolnes, A. J., Yeo, G. S. H., O’Rahilly, S., Jensen, J., & Langenberg, C. (2024). Systemic proteome adaptions to 7-day complete caloric restriction in humans. In Nature Metabolism. Springer Science and Business Media LLC. https://doi.org/10.1038/s42255-024-01008-9

This document explores the systemic response to prolonged fasting in humans through a detailed analysis of plasma proteomic changes. The study delves into the molecular adaptations and health implications of fasting, shedding light on its historical context and potential therapeutic applications.

Summary

The document presents findings from a study on the effects of a 7-day water-only fast on 12 volunteers, revealing an average weight loss of 5.7 kg and systemic changes after 3 days of complete calorie restriction. The analysis highlights the enrichment of extracellular matrix proteins and the diverse tissue origins of fasting-induced proteomic changes. The research emphasizes the shift from an energy-centric view of fasting to a broader systemic response with potential therapeutic implications. Notably, the study identifies proteins associated with metabolic adaptations and genetic links to various diseases, providing insights for clinical translation.

Introduction

Fasting has been practiced for centuries, both as a religious ritual and a form of medical treatment. Recent research has shed light on the systemic responses and molecular adaptations that occur during prolonged fasting in humans. This study delves into the plasma proteomic profiles to uncover the intricate changes that take place during a 7-day water-only fast.

Historical Context of Fasting

Fasting emerged as a voluntary religious practice and ancient medical treatment, with applications ranging from achieving purification to managing conditions like childhood epilepsy and rheumatoid arthritis. The document highlights how fasting has been intertwined with human history and evolution, evolving from periods of food scarcity to intentional periods of abstaining from food.

Purpose of the Study

The study aims to advance our understanding of prolonged fasting beyond its energy-centric adaptations. By analyzing the plasma proteomic profiles of individuals undergoing a 7-day water-only fast, the research uncovers a highly conserved, multi-organ response that extends beyond mere weight loss. The goal is to identify potential health benefits of fasting and translate these findings into targeted therapeutic interventions for various health conditions.

Methodology

Fasting has been a practice deeply rooted in human history, serving both religious and medical purposes. Recent studies have delved into the systemic responses of prolonged fasting in humans, shedding light on its potential therapeutic benefits beyond mere weight loss.

Proteomic Analysis

A 7-day water-only fast was found to induce significant changes in the plasma proteome of individuals, with a notable enrichment of extracellular matrix proteins from various body sites. The fasting signature revealed profound non-metabolic adaptations, hinting at a systemic response that goes beyond traditional energy-centric views.

"Our results advance our understanding of prolonged fasting in humans beyond a merely energy-centric adaptions towards a systemic response that can inform targeted therapeutic modulation."

Genetic Studies

Genetic studies have identified potential links between specific genetic variants and plasma protein levels associated with metabolic adaptations during fasting. The INHBC-increasing G-allele of the rs61352607 SNP, for instance, was positively correlated with plasma triglyceride levels, suggesting a genetic influence on metabolic responses to fasting.

"Here we identify proteins possibly causally mediating the metabolic adaptations to prolonged fasting by integrating evidence from the present and a human genetic study."

"We successfully establish putatively causal links by which genetic liability towards higher/lower plasma levels of 212 proteins is linked to almost 500 diseases and health measures."

In conclusion, the comprehensive analysis of proteomic and genetic data provides valuable insights into the multi-organ response of humans to prolonged fasting, offering a foundation for future research and potential clinical interventions.

Results

Fasting has been a practice deeply rooted in history, serving purposes beyond mere weight loss. Recent research delves into the systemic changes that occur during prolonged fasting, shedding light on its potential health implications.

Plasma Proteomic Changes

A 7-day water-only fast was found to result in an average weight loss of 5.7 kg among volunteers, with significant systemic changes becoming evident after 3 days of complete calorie restriction. The fasting signature revealed enrichment for extracellular matrix proteins from various body sites, indicating profound non-metabolic adaptations. Proteomic analysis showed that more than 1,000 plasma proteins exhibited differential abundance following the fast, with the most health-relevant changes occurring after 3 days of consecutive fasting. Notably, proteins related to the extracellular matrix, such as tenascin-R, showed significant associations with fasting-induced adaptations.

Health Implications

The study's findings provide a novel perspective on prolonged fasting in humans, highlighting a multi-organ response that extends beyond energy-centric views. The observed rise in plasma 3-hydroxybutyrate was linked to lower levels of brain-specific extracellular matrix proteins and neurotrophic factors, suggesting a potential mechanism for the success of fasting as a therapeutic intervention. Additionally, the identification of proteins possibly mediating metabolic adaptations during fasting opens avenues for understanding the health benefits associated with fasting and developing targeted interventions for individuals who may not adhere to prolonged fasting schemes. This research sets a foundation for interpreting future studies on fasting and weight loss, offering insights for clinical translation and potential applications in intermittent fasting regimens.

Discussion

Fasting has been a practice deeply rooted in human history, serving both religious and medical purposes. The recent study delves into the systemic responses of humans to prolonged fasting, shedding light on the molecular adaptations beyond mere energy-centric perspectives. The findings highlight the profound non-metabolic adaptations that occur during fasting, providing valuable insights for potential therapeutic interventions.

Interpretation of Findings

The study reveals that a 7-day water-only fast induces significant weight loss and systemic changes in volunteers, with notable adaptations observed after 3 days of complete calorie restriction. Proteomic analysis demonstrates a strong enrichment of extracellular matrix proteins from various body sites, indicating a comprehensive systemic response to fasting. Notably, the fasting signature encompasses proteins primarily expressed in specific tissues, spanning all major organ systems, suggesting a multi-organ response to prolonged fasting.

Distinct trajectories of proteomic changes were observed during fasting, with a subset of proteins showing delayed alterations beyond the initial days of fasting. The enrichment of extracellular matrix proteins, such as tenascin-R, and the association between plasma 3-hydroxybutyrate levels and brain-specific ECM proteins offer novel insights into the mechanisms underlying the success of fasting as a therapeutic approach.

Clinical Applications

The study paves the way for identifying potential health benefits associated with fasting and translating these findings into targeted interventions. By elucidating the temporal dynamics of plasma proteomic profiles during fasting, the research provides a foundation for understanding the systemic effects of prolonged fasting in humans. These insights could inform the development of interventions for individuals who may not be able to adhere to extended fasting regimens, including fasting-mimicking diets.

Moreover, the establishment of putative causal links between genetic variants, plasma protein levels, and various diseases offers a promising avenue for personalized medicine. The study's comprehensive analysis of over 1,000 plasma proteins following prolonged fasting underscores the potential clinical relevance of fasting-induced molecular adaptations. These findings serve as a valuable reference for future studies investigating fasting, weight loss, and intermittent fasting schemes of varying durations.

Conclusion

Fasting has been a practice deeply rooted in human history, serving both religious and medical purposes. Recent research has shed light on the systemic responses and molecular adaptations that occur during prolonged fasting, going beyond mere weight loss to reveal profound non-metabolic changes in the body. This study provides valuable insights into the potential health benefits of fasting and offers a new perspective on its therapeutic applications.

Key Takeaways

• A 7-day water-only fast can lead to an average weight loss of 5.7 kg, with systemic changes becoming evident after 3 days of complete calorie restriction.
• The fasting signature is enriched for extracellular matrix proteins from various body sites, indicating significant non-metabolic adaptations.
• Plasma proteomic profiles show more than 1,000 proteins with altered abundance following prolonged fasting, with the most health-relevant changes occurring after 3 days of consecutive fasting.
• Proteins associated with the extracellular matrix, such as tenascin-R, show significant changes during fasting, suggesting a potential link to the success of this ancient treatment scheme.

Future Research Directions

• Further exploration is needed to establish causal links between fasting schemes and health benefits through large prospective clinical trials.
• Integrating evidence from genetic studies can help identify proteins that mediate metabolic adaptations to fasting and their potential implications for various diseases.
• Investigating the tissue origin of changes in the plasma proteome during fasting can provide insights into the multi-organ response observed in humans.
• Continued research into fasting-related pathways and molecular adaptions may pave the way for targeted therapeutic interventions for individuals who cannot adhere to prolonged fasting regimens.

Frequently Asked Questions

What were the main findings of the study?

The study revealed significant weight loss and systemic changes in response to a 7-day water-only fast, with a focus on proteomic alterations and potential health benefits.

How do the findings contribute to our understanding of fasting?

The findings expand our knowledge beyond energy-centric views, providing insights into the systemic response to fasting and its implications for therapeutic interventions.

What future research is suggested by the study?

The study suggests further investigations into the molecular mechanisms of fasting, potential interventions for patients unable to fast, and the translation of findings into clinical practice.

Highlighted Quotes

"Our results advance our understanding of prolonged fasting in humans beyond a merely energy-centric adaptions towards a systemic response that can inform targeted therapeutic modulation." (PDF p. 0)

"Distinct trajectories of proteomic changes" (PDF p. 1)

"Our results provide the opportunity to systematically identify the potential health benefits from fasting and translate this knowledge into putative interventions, including for patients who cannot adhere to prolonged fasting schemes or fasting-mimicking diets." (PDF p. 3)