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# Short telomeres, not epigenetic or proteomic ageing, raise interstitial lung disease risk
- URL: https://www.coios.me/short-telomeres-not-epigenetic-or-proteomic-ageing-raise/
- Published: 2026-10-17T09:09:26.000Z
- Updated: 2026-10-17T09:51:26.000Z
- Description: Of six ageing measures tested against six immune-mediated diseases, only longer leukocyte telomeres lowered interstitial lung disease risk.
- Author: Daniel Ryan
- Tags: Tomorrow's world, Slowing ageing itself, What linked data reveals, Finland, #preprint, #refines, #item, #source-2026-10, #score-68

Two-sample Mendelian randomisation tested six ageing measures against six immune-mediated diseases in FinnGen R12\. The measures were GrimAge, PhenoAge, Hannum age, intrinsic epigenetic and proteomic age acceleration, and leukocyte telomere length. Of 36 pairs, only longer telomeres passed correction, lowering interstitial lung disease risk (OR 0.59, 95% CI 0.49-0.71, 77 instruments). Four pleiotropic instruments in TERT, TERC, APOE and ATM accounted for all heterogeneity in the unfiltered estimate. The effect replicated in 5,159 European (OR 0.18) and 1,210 East Asian idiopathic pulmonary fibrosis cases (OR 0.54). Excluding telomere-maintenance and fibrosis loci left OR 0.26, though estimates rest on genetic proxies, not measured telomere length.

*Why it is interesting: It separates telomere length from the telomerase pathway as the operative exposure in fibrotic lung disease. The epigenetic and proteomic ageing clocks showed no such effect across the six diseases tested.*

Source

[medRxiv, 15 October 2026](https://doi.org/10.64898/2026.10.14.26364960?ref=coios.me)

Paper

Short telomeres, but not accelerated epigenetic or proteomic age, increase fibrotic lung disease risk: Mendelian randomisation with pleiotropy dissection and independent replication

Authors

Hanke S

DOI

10.64898/2026.10.14.26364960

Type

Preprint

Design

Two-sample bidirectional Mendelian randomisation, six ageing measures against six immune-mediated diseases (36 pairs) in FinnGen R12, with pleiotropy dissection and replication in 5,159 European and 1,210 East Asian IPF cases

Verdict

Refines prior evidence

Driver

[Slowing ageing itself](https://www.coios.me/d-ageing/)

Driver

[What linked data reveals](https://www.coios.me/d-linked-data/)

Abstract — the authors' own words, CC BY

Background:

Short telomeres are an established cause of idiopathic pulmonary fibrosis (IPF), but the genetic evidence rests on seven instruments, six of which lie at telomere-maintenance loci, and so cannot separate an effect of telomere length from an effect of the telomerase pathway itself - a distinction that determines whether telomere length is a tractable target or only a marker of the pathway. Whether other measures of biological ageing share the effect, and whether accelerated ageing causes immune-mediated disease more generally, has not been tested systematically. Methods. Two-sample Mendelian randomisation of six ageing measures - GrimAge, PhenoAge, Hannum-age and intrinsic epigenetic age acceleration, proteomic age acceleration, and leukocyte telomere length - against six immune-mediated diseases in FinnGen R12: giant cell arteritis (GCA), polymyalgia rheumatica, primary Sjoegren's disease, interstitial lung disease (ILD), Crohn's disease and ulcerative colitis. All 36 pairs were analysed in both directions using inverse-variance weighted (IVW), MR-Egger, weighted-median and weighted-mode estimators, with Cochran's Q, I2, leave-one-out and single-variant diagnostics, a pre-specified analysis excluding HLA-region instruments, and iterative Q-based outlier removal. Instruments were annotated against telomere-maintenance and pulmonary-fibrosis loci and that class excluded. Minimum detectable effects were computed for every pair before estimates were examined. Any pair surviving correction was re-estimated in two independent IPF case-control datasets. A two-step analysis tested mediation of ILD risk by seven gut microbial taxa acting through telomere length. Results. One of 36 forward pairs survived correction. Longer telomeres reduced ILD risk: outlier-robust IVW odds ratio (OR) 0.59 per standard deviation (SD), 95% CI 0.49-0.71, p = 2.7 x 10^-8, on 77 instruments, with no residual heterogeneity (I2 = 6%) and concordance across estimators. Four pleiotropic instruments - in TERT, TERC, APOE and ATM - inflated the unfiltered estimate to OR 0.46 (0.37-0.57) and accounted for all of its heterogeneity. The effect was reproduced in 5,159 clinician-diagnosed European IPF cases (OR 0.18, 0.12-0.25, p = 5.0 x 10^-23) and in 1,210 East Asian cases (OR 0.54, 0.35-0.83, p = 0.005). Excluding every telomere-maintenance and pulmonary-fibrosis locus left OR 0.26 (0.17-0.40), p = 1.6 x 10^-9, on 72 instruments, establishing that the effect does not depend on TERT or TERC. The effect was three times larger for clinically defined IPF than for the broad registry ILD endpoint (p = 1.8 x 10^-9), consistent with dilution of a fibrosis-specific mechanism by case mix. No methylation clock and no proteomic age measure affected any disease; smallest detectable ORs ranged from 1.29 to 5.24 per SD, so these nulls exclude only large effects. The reverse direction could not be tested at informative precision. One apparent clock-autoimmunity association was produced entirely by a single HLA-region instrument. Mediation was null at its first step. Conclusions. Telomere attrition causally increases fibrotic lung disease risk, with an effect that concentrates in clinically defined IPF and that survives removal of every telomere-maintenance locus - shown here for the first time - and is therefore attributable to telomere length rather than to the telomerase genes that dominate conventional instrument sets. Four methylation clocks and proteomic age acceleration show no such effect, so these measures cannot be treated as interchangeable proxies for biological ageing.