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

Yucan Li; Xinming Xu; Raghav Sehgal; Xinyi He; Yi Zheng; Xingdong Chen; Kelin Xu

doi:10.1016/j.clnu.2026.106625

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

Clin Nutr. 2026 May:60:106625. doi: 10.1016/j.clnu.2026.106625. Epub 2026 Mar 14.

Authors

Yucan Li¹, Xinming Xu², Raghav Sehgal³, Xinyi He⁴, Yi Zheng⁴, Xingdong Chen⁵, Kelin Xu⁶

Affiliations

¹ State Key Laboratory of Genetics and Development of Complex Phenotypes, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, Shanghai, 201203, China; Department of Biostatistics, School of Public Health, The Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, 200032, China.
² Department of Nutrition and Food Hygiene, Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Institute of Nutrition, Fudan University, Shanghai, 200032, China.
³ Department of Psychiatry, Yale University, New Haven, CT, USA.
⁴ State Key Laboratory of Genetics and Development of Complex Phenotypes, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, Shanghai, 201203, China.
⁵ State Key Laboratory of Genetics and Development of Complex Phenotypes, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, Shanghai, 201203, China; Fudan University Taizhou Institute of Health Sciences, Taizhou, Jiangsu, 225300, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China; Yiwu Research Institute of Fudan University, Yiwu, Zhejiang, 322000, China. Electronic address: xingdongchen@fudan.edu.cn.
⁶ Department of Biostatistics, School of Public Health, The Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, 200032, China; Fudan University Taizhou Institute of Health Sciences, Taizhou, Jiangsu, 225300, China. Electronic address: xukelin@fudan.edu.cn.

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

Abstract

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).

Keywords: Aging; Biological age; CALERIE™ phase 2; Caloric restriction; Organ-specific biological age.

Publication types

Randomized Controlled Trial
Clinical Trial, Phase II

MeSH terms

Aged
Aging* / physiology
Biomarkers / blood
Caloric Restriction* / methods
Female
Humans
Liver
Male
Middle Aged
Organ Specificity

Substances

Biomarkers

Associated data

ClinicalTrials.gov/NCT00427193