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Mounting evidence suggests telomere shortening is an important research focus in interstitial lung disease (ILD) that may soon lead to novel therapeutic options.¹ A recent article published in The Clinical Respiratory Journal reviewed the latest research about telomere shortening in ILD.

The authors began by reviewing the challenges associated with ILD diagnosis. One of the major challenges, they said, is the similar clinical presentations in patients with different types of ILD. However, they noted that telomere shortening occurs in all patients with ILD, but telomere length and telomere shortening cells vary between the different types of ILD.² Thus, they said, measuring telomere length may be a useful tool in diagnosing and differentiating ILD.

In the case of idiopathic pulmonary fibrosis (IPF), previous research has shown that the disease’s development is linked with telomere shortening in peripheral blood leukocytes.³ Conversely, telomere shortening did not play a role in the development of chronic obstructive pulmonary disease (COPD). That research, the authors said, is part of a growing body of evidence that telomere shortening is a “clear risk factor” and valuable diagnostic tool in IPF.

The cause of telomere shortening in IPF has been linked with the presence of telomerase gene mutations, the authors said. A 2007 study looked at the genetic mutations behind IPF and found that mutations in the TERC and TERT genes of telomerase led to telomere shortening, which in turn could make a person much more likely to develop adult-onset IPF.⁴

Yet, there are other possible causes of telomere shortening. For exmaple, one theory is that abnormal epithelial damage-repair causes the telomere shortening.

“Different studies have confirmed that transforming growth factor-beta (TGF-β) inhibits telomerase gene activity via mothers against decapentaplegic homolog 3 (Smad3) in tumor cells and cultured mouse fibroblasts,” they noted.

Smad3 can interfere with the telomerase gene promoter’s transcription and translation, and knocking down the TGF-β receptor in mouse lung epithelial cells has been shown to reduce lung fibrosis in mice.⁵

Turning their attention to the therapeutic implications, the authors noted that current treatments can only delay—and not reverse—ILD. The targeting of telomerase and telomere function “has broad therapeutic promise” for patients with telomere abnormality-related pulmonary fibrosis, according to the authors. They said both molecular and gene therapies have been investigated for this purpose.

For instance, they noted the TERT gene promoter has estrogen receptors. Previous research has shown that estrogen can upregulate TERT expression and therefore increase telomerase activity.⁶

The novel telomerase activator GRN510 has also been used to successfully increase telomerase activity in a mouse model of TERT gene-mutant pulmonary fibrosis.⁷ 

Another option is inhibition of PAP-associated domain-containing protein 5 (PAPD5). The protein opposes the PARN gene, and the PARN gene regulates the function of TERC and thereby helps maintain telomere length.¹ The theory—backed up by early research—is that inhibiting PAPD5 can ultimately result in enhanced telomerase activity.

Aside from the therapeutic implications of telomere length in ILD, the investigators said telomere length also appears to be a predictor of survival in patients with IPF, though not for patients with non-IPF ILDs.

Moving forward, the authors said more investigation is warranted to better understand the relationships between telomeres, telomere-related gene mutations, and ILD. Such investigation, they said, could help predict—and ideally, change—the trajectory of the disease.

References

1. Jin H, Song J, Gao R, et al. Telomere shortening in interstitial lung disease: challenges and promises. Clin Respir J. 2025;19(7):e70103. doi:10.1111/crj.70103

2. Snetselaar R, van Moorsel CHM, Kazemier KM, et al. Telomere length in interstitial lung diseases. Chest. 2015;148(4):1011-1018. doi:10.1378/chest.14-3078

3. Duckworth A, Gibbons MA, Allen RJ, et al. Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease: a mendelian randomisation study. Lancet Respir Med. 2021;9(3):285-294. doi:10.1016/S2213-2600(20)30364-7

4. Tsakiri KD, Cronkhite JT, Kuan PJ, et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci U S A. 2007;104(18):7552-7557. doi:10.1073/pnas.0701009104

5. Li M, Krishnaveni MS, Li C, et al. Epithelium-specific deletion of TGF-β receptor type II protects mice from bleomycin-induced pulmonary fibrosis. J Clin Invest. 2011;121(1):277-287. doi:10.1172/JCI42090

6. Bayne S, Liu JP. Hormones and growth factors regulate telomerase activity in ageing and cancer. Mol Cell Endocrinol. 2005;240(1-2):11-22. doi:10.1016/j.mce.2005.05.009

7. Le Saux CJ, Davy P, Brampton C, et al. A novel telomerase activator suppresses lung damage in a murine model of idiopathic pulmonary fibrosis. PLoS One. 2013;8(3):e58423. doi:10.1371/journal.pone.0058423

Investigators have published new data in the International Journal of Medical Sciences demonstrating a causal link between elevated high-density lipoprotein cholesterol (HDL-C) levels and a reduced risk of stress urinary incontinence (SUI), with heightened protection observed in patients with overweight and/or obesity. The data highlights the unique role of HDL-C levels in preventing SUI, especially in individuals with a high body mass index (BMI).¹

Association Between SUI and HDL-C Warrants Further Research

SUI, a condition that particularly impacts women, involves the involuntary leakage of urine during physical acts. Examples include laughing, coughing, or sneezing. With up to 10% to 40% of women globally affected by SUI—and prevalence increasing with age and obesity—there is a critical need for research on prevention strategies and risk factor amelioration. Factors such as pelvic floor dysfunction and childbirth are established risks for SUI, but more recent evidence points to metabolic health as a potential new avenue for SUI prevention.^1-3

HDL-C is known as an indicator of cardiovascular protection in contrast to low-density lipoprotein cholesterol (LDL-C). More recent analyses have begun to uncover the involvement of HDL-C in non-cardiovascular settings, including infections, diabetes, and chronic kidney disease, offering potential for HDL-C to serve as a predictive measure of SUI development. Unfortunately, available evidence on the relationship between HDL-C and SUI is conflicting, with numerous investigative groups coming to varying conclusions.^1,4

A dual-evidence study, integrating cross-sectional analyses from the National Health and Nutrition Examination Survey (NHANES) and a 2-sample Mendelian randomization, was imitated by the current authors to evaluate the association between HDL-C levels and SUI prevalence, with particular focus on patients with overweight or obesity. Furthermore, the authors sought to explore whether BMI levels can modify the protective effect of HDL-C. In total, 18,415 women from the NHANES survey were included in the analysis, of which 7658 (41.59%) reported SUI.¹

Higher HDL-C Levels Reduced Risk of SUI

Firstly, HDL-C and SUI associations were examined. Restricted cubic splines (RCS) analysis demonstrated a nonlinear association between HDL-C and SUI in a crude model (P for overall < .001; P for nonlinear < .001). There was a steep risk decrease observed at lower HDL-C levels, with a plateau in risk reduction at higher HDL-C. A stepwise weighted multivariate logistic regression indicated that, for each 1 mg/dL increase in HDL-C, SUI risk decreased by 0.8% (95% CI, 0.989—0.994; P < .001), which remained significant in the partially adjusted and fully adjusted models.¹

Regarding specific HDL-C thresholds, individuals with HDL-C of 67 mg/dL or more had a 17.3% (95% CI, 0.747—0.917) reduced risk of SUI. The authors also conducted a stepwise analysis investigating the risk of SUI with increasing HDL-C levels, with Q4 indicating the highest LDL-C level and Q1 indicating the lowest. Observations from a fully adjusted model indicate that the risk of SUI in the highest LDL-C level was 25.1% (95% CI, 0.652—0.859) lower compared with the lowest level, while the second level indicated no meaningful protective effect (odds ratio [OR] = 0.950 [95% CI, 0.847—1.066]; P = .380).¹

A subgroup analysis was conducted across demographic and clinical data, which revealed that the protective effect of HDL-C was especially strong in individuals with overweight or obesity (BMI of 25 kg/m² or more: OR = 0.992, P = .006; BMI of 30 kg/m² or more: OR = 0.991, P = .001). Notably, younger women—aged 60 or less—demonstrated a heightened risk reduction of SUI. The authors also determined that, when SUI was stratified by varying leakage frequencies, HDL-C levels were inversely related with all frequency levels of SUI, with increasing HDL-C levels inducing a parallel decrease in the frequency of SUI.¹

A causal relationship between HDL-C and SUI was indeed observed by the study authors, suggesting a protective effect with HDL-C against SUI. The investigators caution, however, that these protective effects are not linear across the board; they noted an “HDL-C” paradox observed in their unadjusted RCS analysis, which underscores the need for precision and thorough further investigation. Despite this limitation, the use of a large, nationally representative sample from a large-scale analysis allows for these observations to be deemed reliable and a solid base for future research.¹

“These robust findings suggest that maintaining optimal HDL-C levels may serve as an effective preventive strategy against SUI, especially in high-BMI populations,” the study authors concluded. “While our results highlight the therapeutic potential of HDL-C, future studies should further elucidate the underlying mechanisms and validate these associations across diverse demographic groups.”¹

REFERENCES

1. Huang J, Wang Z, Liu Z, et al. Protective Role of High-Density Lipoprotein Cholesterol in Stress Urinary Incontinence with Special Emphasis on Overweight/Obese Individuals. Int J Med Sci. 2025;22(12):3304-3315. doi:10.7150/ijms.116324

2. Li J, Wang D, Tian H, et al. Association between lipid accumulation products and stress urinary incontinence: a cross-sectional study from NHANES 2005 to 2018. Lipids in Health and Disease. 2024;23(358). doi:10.1186/s12944-024-02350-3

3. Bo K, Frawley HC, Haylen BT. An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for the conservative and nonpharmacological management of female pelvic floor dysfunction. Neurourol Urodyn. 2017;36(2):221-244. doi:10.1002/nau.23107

4. Eckardstein AV, Nordestgaard BG, Remaley AT, Catapano AL. High-density lipoprotein revisited: biological functions and clinical relevance. Eur Heart J. 2023;44(16):1394-1407. doi:10.1093/eurheartj/ehac605