Mechanistically, caloric restriction appears to modulate organ size and metabolic adaptation pathways. Falkenhain et al. reported from CALERIE 2 ancillary data that 25% caloric restriction over 24 months was associated with significant reductions in organ mass, contributing to observed metabolic slowing (P < 0.001 for weight and organ changes) (Falkenhain 2025). In a randomized trial, Kroeger et al. found that intermittent fasting combined with caloric restriction produced greater decreases in body weight (4 ± 1 kg) and waist circumference (6 ± 1 cm) compared with intermittent fasting alone (2 ± 1 kg; 3 ± 1 cm; P = 0.04 for weight difference), with improvements in adipokine profiles (P < 0.01 for leptin reduction) (Kroeger 2012).

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