No significant effect of vitamin D supplementation on circulating Irisin and SIRT1 levels: a systematic review and meta-analysis of randomized controlled trials

Abstract

Vitamin D regulates different metabolic pathways via its interaction with biomarkers such as sirtuin 1 and irisin. However, clinical research evaluating the effects of supplementation with this vitamin on these biomarkers has shown contradictory findings. Therefore, we performed the present research to investigate the effect of vitamin D administration on circulating levels of SIRT1 and irisin. A systematic search of Scopus, Web of Science, and PubMed was carried out from the beginning to 15 June 2026, and randomized controlled trials were included. Two reviewers independently conducted data extraction and risk-of-bias assessment using the Cochrane RoB 2 tool. Weighted mean differences (WMD) with 95% confidence intervals (CI) were computed using a random-effects model to determine pooled effect sizes. I 2 statistic was used to measure heterogeneity. Sensitivity analyses and Subgroup analyses were undertaken to identify the origins of heterogeneity. Clinical trial number: not applicable. Seven RCTs (9 arms) were included. Vitamin D showed no statistically significant impact on circulating irisin compared to placebo (WMD: 1.84 ng/ml; 95% CI: -0.25 to 3.93; P  = 0.084; I² = 95.0%). Also, vitamin D showed no significant changes in circulating SIRT1 levels (WMD: 1.57 ng/ml; 95% CI: −0.18 to 3.31; P  = 0.078; I²=92.3%). In subgroup analyses, vitamin D supplementation was associated with a significant increase in circulating irisin levels among patients with type 2 diabetes mellitus ( P  = 0.029), and in studies conducted in Iran ( P  = 0.025). For SIRT1, significant increases were observed in 12-week trials ( P  = 0.008). Although the subgroup receiving 7,000 IU/week also showed a significant increase in SIRT1 ( P  = 0.008), this estimate was based on only one effect size and should be interpreted as exploratory. Vitamin D supplementation did not significantly affect circulating irisin or SIRT1 levels overall. Although some subgroup analyses suggested potential differences according to population, study location, and intervention duration, these findings should be interpreted cautiously because of the small number of studies, substantial heterogeneity, and the limited evidence underlying several subgroup estimates. Not applicable.