The link between idiopathic pulmonary fibrosis (IPF) and dysfunction of telomeres is gaining widespread recognition and acceptance in the medical community. We will discuss the association in this article, along with its possible genetic roots and clinical implications.

Zhang et al, in their study on telomere dysfunction in IPF, characterized IPF as “an age-dependent progressive and fatal lung disease of unknown etiology.” Multiple studies have shown that telomere dysfunction drives the pathological processes of IPF. Hence, it is vital that we understand the role that telomere dysfunction plays in the pathogenesis of IPF if we are serious about finding a cure for this disease.

Read more about IPF etiology 


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Telomeres are “ribonucleoprotein structural complexes located at eukaryotic chromosomal ends and are mainly composed of tandem DNA repeats (TTAGGG in humans) and their binding proteins,” Zhang et al explained. Their main function is to protect genomic integrity. The ends of telomeres are capped and protected by a specialized shelterin complex. If the shelterin component is compromised, telomere dysfunction can occur, activating a DNA damage response. 

The general rule is that the older you get, the shorter your telomere length becomes. Zhang et al wrote, “When shortened telomeres reach a critical threshold, cellular senescence, and/or apoptosis are triggered by the DNA damage response.” 

Landmark Study Confirms Association

Duckworth et al conducted a landmark study on the association between telomere length and IPF and COPD. They used Mendelian randomization methodology, which is particularly suited to genetic research. They provided some other reasons this technique was used: 

  • It can be used to test whether a causal relationship exists between a phenotype that can be genetically influenced (in this case, telomere length) and a disease outcome (in this case, IPF and COPD). 
  • Causality can be inferred because genetic makeup is allocated at conception, thus making it unlikely to be influenced by diseases in later life. 
  • This method removes potential confounding influences (such as smoking and environmental factors), which in effect creates a natural blind randomized control trial. 

Using the UK Biobank, Duckworth identified 1369 patients with IPF and 13,538 patients with COPD. They recruited 435,866 patients for the control group by removing both “COPD” and “IPF” from the search criteria. They then used the Mendelian randomization method to investigate causality between telomere length and the incidence of IPF and COPD. 

The results demonstrated that shorter telomere length (of one standard deviation) was associated with higher odds of IPF, but not of COPD.

On the significance of their findings, they wrote, “The inference of a cause behind human IPF provides new insights towards beneficial therapies for patients and potential new treatments, bringing us closer to preventing the disease in individuals with prematurely shortened telomeres, and ultimately providing a direction in our search for a cure.” 

Genetic Mutations May Drive Telomere Length 

Let’s explore the association between telomere abnormalities and IPF a little more closely. Scientists achieved a breakthrough discovery that identified genetic mutations linked to IPF. Studies demonstrated that 15% of familial IPF cases and 2% of sporadic IPF cases had either telomerase reverse transcriptase (TERT) or telomerase RNA (TERC) mutations. The significance of this discovery is that patients with heterozygous mutations in either TERT or TERC possessed shortened telomeres.

Another study found that around 25% of sporadic IPF and 37% of familial IPF patients had significantly shorter telomeres, but without either TERT or TERC mutations. This suggests that there are likely other gene mutations in IPF. Either way, these studies strengthen the claim that telomere dysfunction drives IPF. 

Read more about IPF patient education 

But do we have a biologically plausible pathway in which telomere shortening can cause IPF? In this regard, Zhang and colleagues put forward a credible proposal on how telomere dysfunction drives IPF pathogenesis: Telomere shortening preferentially affects alveolar epithelial type 2 cells (AEC2s) in the lungs, causing either senescence or apoptosis. This then generates spontaneous pulmonary fibrosis through two pathways.

“First, cellular senescence and/or cell death of AEC2s leads to a pro-fibrotic niche through the SASP, and fibrocytes capable of differentiating into fibroblasts, myofibroblasts, and innate immune cells are recruited to the fibrotic lesion site,” Zhang et al wrote. 

“Second, the failure of AEC2s compromises the regeneration of new alveoli, which in turn leads to an increase in mechanical tension in a periphery-to-center spatial distribution, which activates the transforming growth factor-beta (TGF-β) signaling loop in AEC2s or other lung cells.” 

Hence, the end result is higher local levels of TGF-β, myofibroblast differentiation, and fibrosis of the lungs—features that are pathognomonic of IPF. 

Moving Closer to a Cure?

Now we come to the focal point of all the evidence accumulated: the clinical implication for patients with IPF. If telomere dysfunction does indeed drive the pathogenesis of IPF, the next job of scientists is to determine how large that role is.

Telomere dysfunction is not just an issue for IPF; since it is related to aging in general, it already has the attention of the medical research community. If data from general telomere studies can be combined with unique telomere studies in relation to IPF, we may be closer to better therapeutics for IPF than we think. 

References

Zhang K, Xu L, Cong YS. Telomere dysfunction in idiopathic pulmonary fibrosis. Front Med (Lausanne). Published online November 11, 2021. doi:10.3389/fmed.2021.739810

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

Armanios MY, Chen JJ, Cogan JD, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007;356(13):1317-26. doi:10.1056/NEJMoa066157

Borie R, Crestani B, Bichat H. Prevalence of telomere shortening in familial and sporadic pulmonary fibrosis is increased in men. Am J Respir Crit Care Med. 2009;179(11):1073. doi:10.1164/ajrccm.179.11.1073