Caloric restriction (15%) — The Foundational Longevity Intervention

Caloric restriction (CR) acts as a mild biological stressor that triggers highly conserved nutrient-sensing pathways. The reduction in energy intake decreases ATP and increases AMP levels, activating AMPK, which in turn inhibits the mTORC1 pathway to upregulate autophagy and reduce cellular senescence. CR also lowers insulin and IGF-1 signaling, reducing downstream FOXO phosphorylation and promoting stress resistance. Furthermore, the shift in the NAD+/NADH ratio activates sirtuins (particularly SIRT1 and SIRT3), which deacetylate target proteins to enhance mitochondrial biogenesis, improve DNA repair, and suppress NF-κB-mediated inflammation.

The CALERIE phase 2 trial is the landmark human study on caloric restriction. In healthy, non-obese adults, two years of ~12% sustained caloric restriction significantly reduced cardiometabolic risk factors, improved insulin sensitivity, and lowered inflammatory markers. A follow-up analysis using the DunedinPACE epigenetic clock showed that the intervention slowed the pace of biological aging.

The CALERIE phase 2 trial prescribed a 25% caloric restriction, but participants achieved an average of 11.9% (roughly 12-15%) sustained restriction over two years. This is typically implemented by reducing daily caloric intake by 300-500 kcal below maintenance levels while ensuring adequate micronutrient intake.

Moderate caloric restriction is generally safe for healthy adults but carries risks of lean muscle mass loss and reduced bone mineral density if not paired with resistance training and adequate protein intake. It is contraindicated in individuals with a history of eating disorders, pregnant or nursing women, and those who are underweight or frail. Extreme restriction can lead to fatigue, cold intolerance, and hormonal imbalances.

Key Papers