BACKGROUND AND AIMS: Caloric restriction (CR) has demonstrated benefits in improving individual biomarkers and longevity, but its organ-specific systemic effects remain unclear. We aimed to quantify the effects of long-term CR on longitudinal changes in organ-specific biological age across multiple physiological systems.
METHODS: In the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Phase 2 randomized controlled trial, a subset of 185 participants (120 CR, 65 ad libitum) with available organ-specific biomarkers at baseline and at least one follow-up assessment at 12 or 24 months was analyzed. Participants were assigned to 2 years of sustained CR or an ad libitum diet. Five organ-specific biological ages (cardiovascular, immune, kidney, liver, metabolic) and the whole body age were assessed at both time points. Intention-to-treat, dose-response, and treatment-on-the-treated analyses were performed to evaluate changes in these biological age measures over time.
RESULTS: CR mitigated organ-specific increases in biological age relative to the ad libitum diet, with the most robust effects in metabolic system (-0.54 years at 12 months, P = 1.26 × 10; -0.63 years at 24 months, P = 3.02 × 10) and cardiovascular system (-0.82, P = 9.55 × 10; -1.00, P = 1.96 × 10), followed by whole body (-1.00, P = 2.53 × 10; -1.27, P = 1.20 × 10) and immune system (-0.65, P = 1.83 × 10; -0.62, P = 2.92 × 10); liver age increase was modestly slowed only at 24 months (-0.54, P = 8.30 × 10), while kidney age remained unaffected. Participants with a higher dose of CR (≥12.4%) showed a more pronounced attenuation of increases in metabolic and whole body age. Adherence analysis further showed that achieving the 20% CR target led to significant declines in multiple biological ages. -5 -7 -5 -6 -3 -4 -3 -3 -3
CONCLUSION: CR exerts heterogeneous effects on biological aging across organ systems, with the most pronounced responses in metabolic, cardiovascular, immune, and whole body systems. These findings support organ-specific biological ages as sensitive surrogate endpoints for detecting early responses to anti-aging interventions and as practical tools for monitoring or targeting organ-specific aging in future efforts.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00427193 (registered January 25, 2007; URL: https://clinicaltrials.gov/study/NCT00427193).
Longevity & Aging