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Hydrogen sulfide (H2S) is an endogenous gasotransmitter that promotes multiple biological effects in many organs and tissues. An imbalanced biosynthesis of H2S has been observed in animal models of age-related pathological conditions. However, the results from human studies are inconsistent. We performed a systematic review with meta-analysis of studies searched in Medline, Embase, Scopus, and CENTRAL databases. We included observational studies on patients with age-related diseases showing levels of H2S in blood, plasma, or serum. All the analyses were carried out with R software. 31 studies were included in the systematic review and 21 in the meta-analysis. The circulating levels of H2S were significantly reduced in patients with progressive, chronic, and degenerative diseases compared with healthy people (standardized mean difference, SMD: −1.25; 95% confidence interval, CI: −1.98; −0.52). When we stratified results by type of disorder, we observed a significant reduction in circulating levels of H2S in patients with vascular disease (e.g., hypertension) (SMD: −1.32; 95% CI: −2.43; −0.22) or kidney disease (SMD: −2.24; 95% CI: −4.40; −0.08) compared with the control group. These results could support the potential use of compounds targeting the "H2S system" to slow down the progression of many diseases in the elderly. [ABSTRACT FROM AUTHOR]