Caloric Restriction

Animal evidence: in mice, CR of 30-40% extends median lifespan 30-50% and maximum 20-30%. Effects are dose-dependent and timing-dependent (early life onset is more effective). Studies in rhesus monkeys at University of Wisconsin (2009) and NIA (2012) show partially discrepant results — UW showed clear lifespan extension, while NIA showed health improvement without as pronounced lifespan extension.

CALERIE 2 study (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy): 220 healthy non-obese adults assigned to 25% CR for 2 years. Key results (Belsky 2017): significant reduction of metabolic ageing markers, improvement of blood pressure, lipid profile, insulin sensitivity, and reduction of ageing velocity measured by DunedinPACE.

Confirmed mechanisms of CR: mTOR + IGF-1 inhibition: reduction of chronic cellular growth. AMPK + sirtuins + autophagy activation: deep cellular cleanup. Chronic inflammaging reduction: lower baseline IL-6, TNF-α. Epigenetic improvement: preservation of juvenile methylation landscape. Mitochondrial improvement: increased biogenesis via PGC-1α.

Practical limitation: 25% CR is hard to sustain long-term in humans. Therefore interventions that partially mimic its effects without chronic restriction are explored: intermittent fasting, cyclic ketogenic diet, FMD (Fasting-Mimicking Diet from Valter Longo), rapamycin, metformin, and NAD+ precursors. These interventions activate pathways similar to CR without requiring absolute chronic restriction.