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Calorie Restriction (CR) Effects on Brain Gene Expression & Behavior in Rats (2023 Study)

Calorie restriction (CR) is increasingly recognized for its potential benefits beyond just weight loss, including reducing anxiety, slowing aging, and mitigating the risk of obesity.

Recent research focused on how both short-term and long-term CR affect behavior and gene expression in various brain regions, providing insights into the molecular underpinnings of these effects.


  • Behavioral Impact of CR: Both short-term and long-term calorie restriction (CR) have been shown to reduce anxiety-like behavior in rats, suggesting potential benefits for emotional health.
  • Gene Expression Changes: CR leads to distinct transcriptomic signatures in the brain, with different sets of genes regulated in the short term vs. the long term, highlighting the complex molecular effects of CR.
  • Potential for Drug Repurposing: Literature mining has identified associations between CR-regulated genes and known drugs, suggesting opportunities for repurposing existing medications to mimic the benefits of CR.
  • Insights into Aging & Neurodegeneration: The study’s findings contribute to our understanding of how CR might slow aging and mitigate neurodegeneration, with implications for developing new therapeutic strategies.

Source: Frontiers in Behavioral Neuroscience (2023)

Study Findings: Calorie Restriction (CR) on Gene Expression in Brains of Rats (2023)

The study’s investigation into calorie restriction (CR) reveals a sophisticated orchestration of gene expression modifications across various brain regions, significantly influencing behavior.

  • Transcription Factors as Master Regulators: ZNF45 and ZBTB2 emerge as pivotal in orchestrating the genome-wide responses to short-term and long-term CR, respectively, highlighting their potential as therapeutic targets for mimicking CR’s effects.
  • Complex Modulation of Stress Responses: CR’s interaction with the HPA axis, manifested in differential gene expression in critical brain areas, reveals a sophisticated mechanism by which CR modulates stress, mood, and fear responses.
  • Time-Dependent Gene Regulation: The distinct gene expression profiles associated with short-term versus long-term CR underscore the nuanced, time-dependent genomic impact of CR, offering insights into its broad and varied benefits on mental and physical health.

Gene Transcription Factors: ZNF45 & ZBTB2

Short-term CR & ZNF45

  • Function: ZNF45, a transcription factor with a key role in DNA binding and gene expression regulation, surfaced as a critical gene in short-term CR-induced gene expression alterations.
  • Implication: Its prominence suggests ZNF45’s involvement in initiating the stress response and adaptation processes that CR triggers, potentially acting as a frontline mediator in recalibrating the body’s response to reduced calorie intake.

Long-term CR & ZBTB2

  • Function: In contrast, long-term CR brought ZBTB2 into focus, suggesting its role in maintaining and reinforcing the adaptations to prolonged calorie restriction.
  • Pathways: ZBTB2’s association with long-term CR hints at its involvement in pathways related to cellular stress resistance, longevity, and metabolic regulation, indicating a shift from initial adaptation to sustained response over time.

HPA Axis Interaction

Dynamic Modulation: The study illuminates CR’s complex interaction with the HPA axis, a central component in managing stress and anxiety responses. This interaction is reflected in the varied gene expression across the amygdala, hypothalamus, and prefrontal cortex.

Brain Regions: These regions are pivotal in stress regulation, emotional response, and fear conditioning, underscoring the broad impact of CR on brain function and behavior.

Short-term vs. Long-term CR: The discovery of distinct gene sets regulated by short-term and long-term CR, with minimal overlap, underlines the temporal precision of CR’s effects on the genome.

Caloric Restriction (CR) on Behavior & Gene Expression in the Brain (2023 Study)

Hazi et al. explored the effects of calorie restriction (CR) on behavior and gene expression in various brain regions associated with anxiety, aging, and neurodegeneration.

Specifically, it sought to:

  • Determine the behavioral effects of short-term and long-term CR on anxiety-like behavior in rats.
  • Investigate the transcriptomic changes induced by short-term and long-term CR in the hypothalamus, amygdala, prefrontal cortex, pituitary, and adrenal glands.
  • Identify distinct transcriptomic signatures associated with short-term and long-term CR.
  • Explore the potential for drug repurposing based on interactions between CR-regulated genes and existing drugs.


  • Animal Model & CR Implementation: Adult male Hooded Wistar and Long Evans rats were subjected to either short-term or long-term CR, with a 25% reduction in ad libitum food intake. Control groups were maintained for both durations without food restriction. Behavioral testing for anxiety-like behavior was conducted using the elevated plus maze.
  • Transcriptomic Analysis: Brain tissues (hypothalamus, amygdala, prefrontal cortex, pituitary, and adrenal glands) were collected post-treatment for RNA sequencing. Differential gene expression analysis was performed to identify genes regulated by short-term and long-term CR. Attribute weighting models were employed to determine the transcriptomic signatures of CR.
  • Drug Repurposing Analysis: Literature and text mining techniques were utilized to identify interactions between CR-regulated genes and known drugs, suggesting potential CR mimetics.


  • Behavioral Effects: Both short-term and long-term CR significantly reduced anxiety-like behavior in rats, as evidenced by increased exploration of open arms in the elevated plus maze.
  • Transcriptomic Changes: Distinct sets of genes were regulated by short-term and long-term CR in the studied brain regions, with no overlap between the two durations, indicating duration-specific transcriptomic responses. Key genes identified included transcription factors (e.g., ZNF45 for short-term CR and ZBTB2 for long-term CR), indicating their potential roles in mediating CR’s effects.
  • Drug Repurposing Potential: Literature mining identified associations between CR-regulated genes and known drugs, including CR mimetics like resveratrol and rapamycin, as well as other drugs not traditionally associated with CR, such as doxycycline and dexamethasone.


  • Species Specificity: The study was conducted in rats, and while rodents are a common model for human health research, there may be limitations in directly extrapolating findings to humans.
  • Duration of CR: The study differentiates between short-term and long-term CR but does not explore intermediate durations, which could offer additional insights into the timing of gene expression changes.
  • Behavioral Measures: The study primarily focused on anxiety-like behavior using the elevated plus maze, which may not capture the full spectrum of CR’s effects on mental health.
  • Gene Expression Focus: While the study provided detailed insights into gene expression changes, it did not delve into the functional impacts of these changes at the protein or physiological level, which could provide a more comprehensive understanding of CR’s effects.
  • Drug Repurposing Analysis: The drug repurposing approach, while innovative, relied on literature and text mining, which may not fully capture the complexity of biological interactions and could overlook novel drug candidates not yet extensively studied in the context of CR.

Potential Clinical Applications & Translation to Humans: Anxiety, Neurodegeneration, Obesity Treatment (2023)

The intricate findings from this study illuminate a path towards harnessing calorie restriction’s (CR) health benefits in a clinical context, offering promising strategies for addressing anxiety disorders, neurodegeneration, and obesity.

Medical Conditions

  • Anxiety Disorders: For acute anxiety management, therapies modeled after short-term CR’s gene expression changes could provide rapid symptom relief without the need for dietary changes.
  • Neurodegenerative Diseases: Long-term CR mimetics could target the underlying genetic pathways associated with neurodegeneration, potentially slowing disease progression or reducing the risk of onset.
  • Obesity Management: By modulating the metabolic pathways affected by CR, targeted therapies could offer new strategies for weight management and metabolic health, independent of dietary intake.

Targeted Treatments via Transcription Factors

  • ZNF45 & ZBTB2: Have been spotlighted as critical in mediating the effects of CR, positioning them as attractive targets for developing therapies that could simulate CR’s benefits.
  • Mechanism-Based Interventions: By focusing on drugs that can influence these transcription factors or their signaling pathways, researchers can potentially replicate CR’s effects on stress response, aging, and metabolism without dietary restrictions.
  • Accessibility: Such therapeutic strategies could provide a viable alternative for individuals unable to adhere to strict CR diets due to health, lifestyle, or personal preferences, making the benefits of CR more widely accessible.

Drug Repurposing: A Fast-Track to Clinical Application

  • Repurposing Existing Drugs: The study’s insights into CR-regulated genes and their interactions with existing drugs pave the way for repurposing approved medications to mimic CR’s health effects.
  • Cost-Effective Strategy: This approach significantly reduces the developmental timelines and investment required, accelerating the availability of CR-mimicking therapies to patients.
  • Aging & Metabolic Disorders: Drugs identified to interact with CR-related pathways could offer new therapeutic avenues for aging-associated diseases and metabolic imbalances, where CR’s effects are particularly beneficial.

Timing Interventions: Leveraging Temporal Dynamics

  • Strategic Timing Based on CR Duration: The differentiation between short-term and long-term CR effects provides valuable guidance for the timing of therapeutic interventions.
  • Acute vs. Chronic Management: Short-term CR mimetics could be optimized for immediate relief from conditions like anxiety, whereas long-term mimetics might be more suitable for the prevention and management of chronic diseases, including neurodegenerative disorders and obesity.

Drug Candidates for CR Mimetics: Mechanisms & Therapeutic Potential

The exploration into calorie restriction (CR) mimetics has highlighted several drug candidates, including resveratrol, rapamycin, doxycycline, and dexamethasone.

These drugs, identified through their interaction with CR-regulated genes, offer diverse mechanisms of action that could replicate the beneficial effects of CR in managing neurodegeneration, anxiety, and promoting aging and longevity.

1. Tamoxifen & EID1

Mechanism: Tamoxifen may interact with EID1, a gene implicated in DNA binding and regulation of gene expression, to modulate pathways involved in cellular stress responses and adaptation.

Effect: The hypothesized effect is a modulation of the body’s stress response mechanisms, potentially offering neuroprotective benefits similar to those observed in CR.

2. Tacrolimus & CARHSP1

Mechanism: Tacrolimus potentially affects CARHSP1, which is involved in calcium signaling and stress responses, suggesting an influence on neuroinflammation and cellular stress pathways.

Effect: This interaction may reduce neuroinflammatory responses and enhance stress resilience, aligning with the neuroprotective aspects of CR.

3. Rapamycin & HLA-A

Mechanism: Rapamycin interacts with HLA-A by modulating immune responses, potentially mimicking CR’s effects on reducing inflammation and cellular aging.

Effect: The expected outcome is a decreased risk of age-related diseases and an extension of healthspan, mirroring the longevity benefits of CR.

4. Valproic Acid & CRY2

Mechanism: Valproic acid’s regulation of CRY2, a clock gene involved in circadian rhythms, suggests impacts on mood regulation and stress responses.

Effect: Hypothesized to stabilize mood and improve circadian rhythm synchronization, potentially offering a therapeutic strategy for mood disorders influenced by CR.

5. Doxycycline & Various CR-Related Genes

Mechanism: Doxycycline’s anti-inflammatory and neuroprotective properties may influence genes associated with neuroinflammation and synaptic health, implicated in both short-term and long-term CR effects.

Effect: It could help maintain neuronal integrity and combat neurodegenerative processes, contributing to CR’s neuroprotective effects.

6. Dexamethasone & Multiple CR-Regulated Genes

Mechanism: Dexamethasone’s potent anti-inflammatory action is likely to interact with CR-regulated genes involved in immune response and inflammation, particularly those like C1QA, which are implicated in neuroprotective pathways.

Effect: This interaction is hypothesized to reduce chronic inflammation and stress responses, offering protection against neurodegeneration and potentially extending lifespan.

7. Resveratrol & CR-Regulated Pathways

Mechanism: Through activation of sirtuin pathways, resveratrol mimics CR’s metabolic and stress resistance effects, impacting genes involved in longevity and mitochondrial function.

Effect: The anticipated effect is enhanced metabolic health, stress resilience, and possibly an extension of lifespan, akin to the benefits of CR.

8. Tetracycline & CR-Associated Genes

Mechanism: As an antibiotic with anti-inflammatory properties, tetracycline may influence genes related to inflammation and cellular stress, similar to doxycycline.

Effect: Potential reduction in neuroinflammation and support for neuronal health, aligning with CR’s effects on neuroprotection.

9. Quercetin & CR-Impacted Genes

Mechanism: Quercetin’s antioxidant and anti-inflammatory effects could affect multiple pathways altered by CR, including those related to aging and immune response.

Effect: It may offer protective effects against cellular aging and neurodegeneration, mirroring CR’s broad health-promoting impacts.

10. Forskolin & Long-Term CR Targets

Mechanism: Forskolin may stimulate cAMP pathways, affecting genes involved in metabolism and cellular stress responses identified in long-term CR.

Effect: The hypothesized benefit includes improved metabolic regulation and cellular resilience, contributing to the health and longevity effects of CR.

Takeaway: Calorie Restriction & Gene Expression in the Brain (2023)

This study determined the complex molecular underpinnings of calorie restriction’s (CR) beneficial effects, revealing distinct transcriptomic signatures for short-term and long-term CR in rats.

Key findings, such as the identification of transcription factors ZNF45 and ZBTB2 as pivotal in these processes, pave the way for novel therapeutic targets and strategies.

The potential for drug repurposing offers an exciting avenue for rapid translation of these findings into clinical practice, promising new treatments for anxiety, neurodegeneration, and obesity.

Moreover, the insights into the temporal specificity of CR’s effects provide a basis for personalized and timed interventions.

While further research is needed to translate these findings fully into human applications, the study marks a significant step forward in our understanding of CR’s role in health and disease, offering hope for new, effective treatments derived from dietary intervention strategies.


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