Academy

Caloric Restriction and Caloric Restriction Mimetics

Caloric restriction (CR) is the practice of reducing daily calorie intake without malnutrition. Over decades of research, CR has consistently emerged as the most robust intervention to extend lifespan and improve healthspan across multiple species. Scientists aim to understand its underlying mechanisms and develop caloric restriction mimetics (CRMs) that reproduce these benefits without requiring long-term dietary change.

How Caloric Restriction Works

• Metabolic adaptation: CR reduces circulating glucose and insulin levels, enhancing insulin sensitivity and shifting cells toward more efficient energy use.
• Stress response activation: Reduced nutrients trigger protective pathways such as AMPK and SIRT1 signaling, boosting cellular resilience against oxidative stress.
• Growth and repair modulation: Lower energy availability suppresses nutrient-sensing pathways like mTOR, slowing cell growth and protein synthesis in favor of repair processes.

What Are Caloric Restriction Mimetics?

CRMs are small molecules designed to activate key longevity pathways engaged by caloric restriction. A few examples include:

1. Rapamycin: An mTOR inhibitor that extends lifespan by imitating nutrient scarcity, reducing protein synthesis, and promoting autophagy.
2. Metformin: A diabetes drug that activates AMPK, improving metabolic health and insulin sensitivity.
3. Resveratrol: A natural compound that activates sirtuins (SIRT1), mimicking some effects of calorie restriction.
4. Urolithin A: A gut microbiome–derived metabolite that promotes mitochondrial quality control and supports cellular energy balance.

Relevance to Longevity Research

• Preclinical testing: Mouse models help evaluate CRM effects on lifespan, weight change, and health markers. Standardized measurements of dosage, weight loss, and survival curves are crucial for reproducibility.
• Weight-change monitoring: Since weight loss itself can alter longevity, distinguishing direct drug effects from CR-induced benefits ensures accurate interpretation of geroprotective potential.
• Sex-specific considerations: Male and female organisms can respond differently to CR and CRMs due to hormonal and metabolic variations; inclusive testing protocols are essential.

Looking Ahead Combining CRMs with lifestyle interventions and precision dosing may maximize benefits while minimizing side effects. Ongoing research explores novel compounds, optimized treatment timing, and molecular biomarkers to predict and monitor responses. By harnessing insights from caloric restriction, the next generation of longevity therapies aims to promote healthy ageing for diverse populations.

Understanding CR and its mimetics empowers individuals and researchers alike to explore safe, practical strategies for lifespan extension and improved metabolic health.