The telomere, which is a segment located at the terminal end of a chromosome, plays a crucial role in safeguarding genes from harm, thereby ensuring the stability of chromosomes and the integrity of cells (Blackburn, 2001). Telomeres possess significant biological functions, including the stabilization of chromosome functioning, prevention of degradation and fusion at the terminus, protection of chromosome DNA, and regulation of normal cellular processes (Blackburn, 1991). For quite some time, telomeres have been regarded as a dependable biomarker for cellular senescence (López-Otín et al., 2013). In recent years, aside from their correlation with certain age-related diseases (Sanford et al., 2020; Armanios and Blackburn, 2012), telomere shortening has also been linked to an elevated risk of diabetes (Zee et al., 2010) and tumor development (Rode et al., 2016).

The assessment of pulmonary function can serve as an indicator of the respiratory system’s condition in patients. By conducting lung function examinations, healthcare professionals can not only assess the severity of lung diseases and develop targeted treatment strategies but also aid in the early detection of lung and respiratory diseases. A corresponding study has indicated a correlation between prematurely shortened LTL and the presence of idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) (Dai et al., 2015). The decline of lung function is intricately linked to various lung diseases such as COPD, IPF, and emphysema. Recent studies have indicated a connection between telomere biology and the development of several lung diseases, including IPF and COPD (Alder et al., 2008; Duckworth et al., 2021). However, there is currently a lack of research investigating the potential involvement of LTL in the progression of lung-related diseases through their impact on lung function.

Mendelian randomization (MR) serves as a viable approach to address the common issues of unmeasured confounding and reverse correlation encountered in conventional observational epidemiology (Smith and Ebrahim, 2003). In the present investigation, we employed a dual sample MR design to assess the plausible correlation between LTL and lung function.

Based on the results of the MR analysis, a potential correlation was observed between extended LTL and better lung function indicators, FEV1, predicted FEV1, the best measure of FEV1, and FVC. Employing the IVW method, a significant correlation was identified between genetically determined LTL extension and enhanced lung function in FEV1, with ukb-a-336 (P = 0.127, OR = 1.028,95CI% = 1.003–1.042) and ukb-b-19657 (P = 7.26E-05, OR = 1.051,95CI% = 1.025–1.077), in FEV1 predicted, ukb-a-234 (P = 0.013, OR = 1.029,95CI% = 1.003–1.042), ukb-b-8428 (P = 0.001, OR = 1.032,95CI% = 1.012–1.052), in FEV1 best measure, ukb-a-231 (P = 7.24E-05, OR = 1.050,95CI% = 1.025–1.075), ukb-b-11141 (P = 1.40E-09, OR = 1.067,95CI% = 1.045–1.090), in FVC, ukb-a-336 (P = 0.024, OR = 1.022,95CI% = 1.003–1.042), ukb-b-7953 (P = 0.038, OR = 1.018,95CI% = 1.001–1.036) (Table 1).

Furthermore, we employed various methods to assess the results obtained from the IVW method, all of which yielded consistent directions and similar effects (Figure 1). Our analysis of FVC outcomes using Cochran’s Q test and MR Egger test revealed varying degrees of heterogeneity (Table 2). Additionally, we conducted statistical analysis using the intercept term egger of MR egger_ intercept, which yielded a p-value greater than 0.05, indicating the absence of pleiotropy (Table 2). However, we conducted a retest of pleiotropy levels using MR-PRESSO and identified the presence of pleiotropy in FVC-related outcomes (ukb-a-336, P = 0.031, ukb-b-7953, P = 0.0016).

In the context of sensitivity analysis, the exclusion of a single SNP does not significantly alter the correlation estimation of genetic predicted LTL on lung function (Figure 2). This implies that the removal of any specific SNP does not fundamentally impact the results, thereby ensuring the stability of our dual sample MR analysis. Additionally, the Steriger test reveals that the variance explained by instrumental variables estimation in the outcome is lower than that in the exposure. This suggests that the instrumental variables estimation influences the outcome primarily through its effect on the exposure, as supported by the data presented in Supplementary Table S1.

In this randomized study utilizing a two-sample MR approach, our findings indicate a positive association between longer LTL and improved lung function indicators, encompassing FEV1, predicted FEV1, and the most accurate measure of FEV1. Consequently, acquiring an in-depth comprehension of the interplay between LTL and lung function holds immense importance in the realm of lung disease prevention and treatment.

LTL functions as a crucial indicator reflecting the cellular biological condition and overall health status. The shortening of LTL is associated with an augmented risk of cardiovascular diseases, diabetes, and certain cancers (Pauleck et al., 2023; Haycock et al., 2014; Ahmed and Lingner, 2018). Relevant studies have demonstrated that neutrophils induce telomere dysfunction through reactive oxygen species (ROS) dependence (Lagnado et al., 2021). Simultaneously, LTL is prone to ROS-induced impairment, and oxidation can result in telomere shortening (Ahmed and Lingner, 2018). Nevertheless, the length of LTL can be maintained via the UFMylation of MRE11 (Lee et al., 2021). The regulatory mechanism of LTL encompasses multiple aspects such as telomerase activity, oxidative stress, inflammatory response, and genetic factors, yet the specific one remains ambiguous. LTL is a vital regulator of Cellular senescence and genome stability. The deterioration of lung function indicates the aging process. Research indicates that individuals aged 25 to 40 with decreased lung function (FEV<80% predicted) in early adulthood have a higher risk of developing respiratory and cardiovascular diseases, as well as a greater all-cause mortality rate (Agustí et al., 2017).Numerous studies have verified the correlation between LTL and the lung disease. Some research disclosed that individuals with shorter telomere length presented reduced lung function and an elevated risk of developing COPD (Rode et al., 2013; Savale et al., 2009). At the same time, forced expiratory volume (FEV) decreased significantly more in smokers with shorter LTL than in smokers with longer LTL (Andujar et al., 2018). Alder et al. conducted research on the role of telomere length as a genetic predisposing factor for Emphysema by inducing a chronic cigarette smoke model (Alder et al., 2011). Both LTL and lung function decline with age. At the same time, there was a moderate correlation between shorter telomere length in middle-aged people and compromised airflow parameters, although there was no significant correlation with FVC, which is consistent with our own findings (Nguyen et al., 2019). Studies have shown that telomere shortening has been identified as a characteristic of idiopathic interstitial pneumonia and may lead to idiopathic sexual organ failure, which is clinically manifested by lung and liver problems (Alder et al., 2008; Duckworth et al., 2021). Additionally, it has been observed that individuals with shorter telomere length have an increased risk of death and a poorer prognosis among lung cancer patients (Zhang et al., 2015; Jang et al., 2008; Doherty et al., 2018; Astuti et al., 2017).

It should be emphasized that telomere length can be affected by various genetic and environmental factors, including age, lifestyle choices, psychological factors, and the existence of other disease conditions. Numerous studies have indicated that although there is currently a lack of direct evidence to prove that exercise can prolong LTL, a significant difference in LTL is observed between regular exercisers and non-exercisers, as demonstrated by comparative analyses of exercise and non-exercise groups (Cherkas et al., 2008; Venturelli et al., 2014; Borghini et al., 2015; Silva et al., 2016). Hence, adopting a healthier lifestyle and avoiding smoking may contribute to maintaining longer telomere length and optimal lung function.

In this study, there are indeed certain limitations. Our investigation was solely centered on the relationship between LTL and lung function. While we recognize that other factors such as genetic variations and environmental influences may also play a role in lung function. Additionally, it should be noted that our study only included individuals of European descent. Hence, future data from other populations are required to verify this result.

Our research findings indicate a correlation between increased LTL and enhanced lung function. Integrating LTL measurement into clinical practice holds promise for valuable insights into individual risk assessment, disease prognosis, and potential treatment approaches. Further investigation is warranted to elucidate the underlying mechanisms and assess the potential of LTL-related interventions in ameliorating lung function and health.