To our knowledge, our study represents the first comprehensive analysis of the long-term correlation of HDL-C levels with lung function decline in a population-based cohort. To account for this association, we categorized the participants into different HDL-C trajectory groups based on their repeated HDL-C measurements. This approach revealed that individuals in the low HDL-C trajectory group exhibited a faster decline in lung function. Notably, these results were consistent across the three-, four-, and five-group trajectory models, thus strengthening the robustness of our findings. The consistency of our findings across different covariate combinations in sensitivity analyses further strengthens the robustness of the observed relationship between HDL-C trajectories and lung function decline. Since the mean HDL-C levels in each trajectory group seemed relatively stable, we explored whether baseline HDL-C could predict lung function decline. Individuals with low initial HDL-C (< 36.0 mg/dL) tended to belong to the very low HDL-C trajectory group and showed faster decline in FVC and FEV1 than the reference group, suggesting that low initial HDL-C levels are also associated with rapid lung function decline. Comprehensively, our analysis indicates that low HDL-C trajectories are associated with accelerated lung function decline, suggesting potential relevance of HDL-C levels to pulmonary health throughout aging.

Lung function naturally declines with aging, and individuals exhibit diverse lung function trajectories throughout their lifetimes [1]. Recent studies have highlighted various biological mechanisms contributing to lung function decline, including cellular senescence, oxidative stress, dysregulated inflammatory responses, and extracellular matrix remodeling [2, 32,33,34]. Despite these findings, there are currently no established parameters that represent lung function decline in clinical practice [2]. Given that lung function tests are not routinely performed in the general population, identifying clinically applicable markers for rapid lung function decline is crucial for early intervention and prevention strategies. Based on our analysis, HDL-C might serve as an indicator of lung function decline rate.

Previous cross-sectional studies have demonstrated that high HDL-C levels correlate with higher FVC and FEV1 in adults [13,14,15,16]. Most evidence, including our findings, supports a correlation between low HDL-C levels and reduced lung function, particularly in the context of aging.

Although there are limited known clinical roles of HDL-C in the lungs, potential molecular biological mechanisms can be hypothesized based on current evidence. Pulmonary surfactants play a crucial role in reducing surface tension in the alveolar space and modulating immune and inflammatory responses [3, 5]. Pulmonary cholesterol, which is generally derived from plasma lipoproteins, is an important component of this surfactant [35, 36]. However, dysregulated and abnormally elevated cholesterol levels could impair the self-assembly of pulmonary surfactant, leading to functional failure [37]. Pulmonary cholesterol is thought to be cleared back into the plasma through interactions between plasma HDL-C and the lipid efflux transporter [7, 8, 12, 38]. Therefore, from a biological mechanism perspective, HDL-C is believed to play a crucial role in regulating proper cholesterol levels and maintaining lung health.

The strength of our study lies in having used data from a long-term prospective cohort study conducted over 12 years, which provided a substantial sample size and follow-up duration. This dataset allowed us to effectively demonstrate the long-term correlation of HDL-C levels with lung function.

Given that an individual’s HDL-C levels could change over time, we employed group-based trajectory modeling to categorize participants into different groups reflecting distinct HDL-C trends. Notably, regardless of the number of trajectory groups independently categorized, participants in the low HDL-C trajectory groups consistently showed a faster decline in lung function than those in the other groups did. This consistency across categorizations strengthens the robustness of our conclusions.

Moreover, the observed longitudinal correlation of a low HDL-C trajectory with declining lung function offers new insights into the complex relationship between lipid metabolism and respiratory health. By employing generalized linear mixed models to analyze this relationship over time, we could advance beyond previous cross-sectional observations and demonstrate the long-term correlation of HDL-C trajectories with lung function decline.

Furthermore, the original cohort study applied strict quality control measures to the spirometry results. Participants who failed or refused to adequately perform spirometry were identified and recorded from the first follow-up and their data were excluded from the analysis, enhancing the reliability of the lung function data.

Our study has certain limitations. First, we could not establish a causal relationship. This limitation stems from the observational nature of our study, with the inherent possibility of unmeasured confounding factors. Nevertheless, our results provide important epidemiological insights into the longitudinal association between HDL-C levels and lung function.

Second, the data used in this study were derived from a Korean community-based cohort, which limits the ethnic diversity. This homogeneity may affect the generalizability of our findings to other ethnic groups. However, Lee et al. previously reported a positive association between HDL-C levels and lung function in both American and Korean populations, suggesting this relationship may extend across different ethnicities [15]. Further studies encompassing diverse ethnicities should be conducted to consolidate the longitudinal correlation of HDL-C levels with lung function decline.

Third, a potential weakness of our study is the inability to directly assess dyslipidemia diagnosis and treatment status, relying instead on questionnaire responses. While it is clinically appropriate to consider dyslipidemia as a confounding factor for serum HDL-C level, it is important to note that the baseline survey of the cohort was conducted in 2001–2002, when both the diagnosis and treatment rates of dyslipidemia were relatively low in Korea [29]. This could potentially introduce bias due to the small proportion of diagnosed individuals at baseline. However, additional analyses excluding self-reported dyslipidemia produced similar results, suggesting that this limitation does not affect our main findings.