Serum spermidine increased the short-term risk of incident dyslipidemia: results from a population-based cohort study

Abstract Objective Although spermidine supplementation has demonstrated lipid-lowering effects in animal models, the physiological significance of circulating spermidine in free-living humans remains poorly understood. This study aimed to investigate the longitudinal association between baseline serum spermidine levels and the risk of incident dyslipidemia in a general population. Methods This prospective study utilized data from the China Rural Cohort, including 889 adults aged ≥ 35 years with normal lipid levels at baseline. Serum spermidine was quantified using high-performance liquid chromatography with fluorescence detection (HPLC-FLD). Incident dyslipidemia was ascertained during a 2-year follow-up period according to national guidelines. Results During the follow-up, 89 (10.0%) participants developed dyslipidemia. Multivariable logistic regression revealed a significant positive association: participants in the highest spermidine quartile (Q4) exhibited a nearly twofold increased risk of dyslipidemia compared to the lowest quartile (Q1) (OR = 1.97, 95% CI 1.05–3.70). This association was sexually dimorphic, being markedly stronger in women (Q4 vs. Q1: OR = 2.98, 95% CI 1.40–6.35), who also displayed a significant nonlinear dose–response relationship ( P -nonlinearity = 0.042). Mechanistically, the increased risk was primarily driven by a longitudinal decline in high-density lipoprotein cholesterol (HDL-C) levels. Conclusions Contrasting with the metabolic benefits often observed in supplementation studies, this study provides the first longitudinal evidence that elevated serum spermidine predicts an increased risk of dyslipidemia, particularly HDL-C decline, in women and older adults. We propose that high circulating spermidine levels in a natural state may serve as a compensatory biomarker of underlying metabolic stress. These findings warrant a re-evaluation of polyamine homeostasis in human lipid metabolism.