Effect of caloric restriction on organ-specific biological aging in a randomized clinical trial.

2026-05
Clinical nutrition (Edinburgh, Scotland) 60
- Yucan Li
- Xinming Xu
- Raghav Sehgal
- Xinyi He
- Yi Zheng
- Xingdong Chen
- Kelin Xu

PubMed: 41895150
DOI: 10.1016/j.clnu.2026.106625

Study Design

Type: Randomized Controlled Trial (RCT)
Sample size: n = 185
Population: 185 participants (120 CR, 65 ad libitum) with available organ-specific biomarkers at baseline and at least one follow-up assessment
Methods: Randomized controlled trial, 2 years of sustained CR or an ad libitum diet; intention-to-treat, dose-response, and treatment-on-the-treated analyses
Blinding: Open-label
Duration: 2 years
Funding: Unclear

Large Human Trial

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^-5; -0.63 years at 24 months, P = 3.02 × 10^-7) and cardiovascular system (-0.82, P = 9.55 × 10^-5; -1.00, P = 1.96 × 10^-6), followed by whole body (-1.00, P = 2.53 × 10^-3; -1.27, P = 1.20 × 10^-4) and immune system (-0.65, P = 1.83 × 10^-3; -0.62, P = 2.92 × 10^-3); liver age increase was modestly slowed only at 24 months (-0.54, P = 8.30 × 10^-3), 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.

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).