EMBO molecular medicineAug 12, 2026

Targeting DNA damage at chromosome ends to treat unexplained lung scarring

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Aug 14, 2026

Abstract

Systemic treatment with telomeric antisense-oligonucleotides (tASOs) reduces damage response markers, inflammation, and lung fibrosis in a genetic model of idiopathic pulmonary fibrosis (IPF).

Telomere dysfunction and the activation of the telomeric DNA damage response (tDDR) are linked to aging and diseases like IPF.
IPF patients often have mutations in telomerase genes and notably short telomeres.
Inhibition of tDDR using tASOs has been shown to reduce markers of damage response and inflammation across different age groups in mice.
Treatment with tASOs normalizes molecular and pathological changes associated with IPF, regardless of telomere length.
Transcriptomic analysis indicates that changes in telomerase knockout mice mirror those in aged mice and IPF patients, which can be reversed with tDDR inhibition.

Simplified

Telomere dysfunction and the telomeric DNA damage response (tDDR) activation correlate with aging and age-related diseases, including idiopathic pulmonary fibrosis (IPF). However, a causal role for tDDR in IPF pathogenesis has not been determined. IPF patients frequently bear germline mutations in telomerase genes, critically short telomeres, and markers of tDDR and cellular senescence. We previously demonstrated that telomeric antisense-oligonucleotides (tASOs) targeting telomeric non-coding RNAs are selective tDDR inhibitors. Here, we employed late-generation telomerase knockout mice as a genetic model of IPF. Systemic tASOs treatment reduces DDR-including in stem/progenitor cells-inflammation, and lung fibrosis in young, adult, and old mice. Markers of DDR correlate with lung pathology, and tDDR inhibition normalizes molecular and pathological phenotypes, uncoupling telomere lengths from their deleterious consequences. Transcriptomic changes in telomerase knockout mice recapitulate those observed in normal aged mice and in IPF patients, and they are reversed upon tDDR inhibition. These results highlight the pathogenic causative relevance of tDDR activation in IPF pathogenesis and support tASOs as a promising therapeutic strategy for IPF and for telomere biology diseases.