Caloric Restriction

Caloric restriction is one of the oldest and most reproducible interventions in aging research: reducing calorie intake by roughly 20–40% (while maintaining adequate protein, vitamins, and minerals) extends lifespan and healthspan in a wide range of organisms, from yeast and worms to mice, and has been studied for decades in non-human primates with more mixed results between the two major long-running primate studies (the University of Wisconsin and NIA studies reported somewhat different survival outcomes, likely due to differences in diet composition and control-group feeding).

In humans, the most rigorous evidence comes from CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy), an NIA-funded randomized controlled trial. Participants in the caloric restriction arm sustained roughly a 12% reduction in intake over two years and showed improvements in several cardiometabolic risk markers and a reduction in the pace of biological aging measured by an epigenetic clock (DunedinPACE), compared to the control group. This is real human RCT evidence for caloric restriction's effect on biomarkers and aging-pace measures — it is not evidence that caloric restriction extends human lifespan, which cannot ethically or practically be tested with a decades-long randomized trial.

Sustained caloric restriction at the level studied in animals is difficult to maintain long-term and carries real risks, including loss of bone density, reduced muscle mass if protein intake isn't managed carefully, and menstrual irregularities in some women, which is part of why intermittent fasting and fasting-mimicking diets — which aim to capture some of the same signaling changes without permanent daily restriction — have drawn separate research interest.