GWAS of epigenetic aging rates in blood reveals a critical role for TERT.
Level 3 - non-randomized controlled study
Observational cohort genome-wide association study with Mendelian randomization and in vitro laboratory validation.
PubMed 29374233 · doi:10.1038/s41467-017-02697-5
What was done
Genome-wide association study (GWAS) of blood epigenetic aging rates, measuring intrinsic epigenetic age acceleration (IEAA) and extrinsic epigenetic age acceleration (EEAA) in 9,907 individuals. The authors performed Mendelian randomization to evaluate causal associations with biological traits and experimentally expressed hTERT in primary human fibroblasts to evaluate its effect on DNA methylation age across cell population doublings.
What was found
Genetic variants mapped to 5 loci associated with IEAA and 3 loci associated with EEAA. Variants in TERT associated with longer leukocyte telomere length were paradoxically associated with higher IEAA (P < 2.7 x 10^-11). Mendelian randomization indicated causal effects of age at menarche and menopause on IEAA, and lipoproteins on both IEAA and EEAA. Experimental hTERT expression in primary human fibroblasts resulted in a linear increase in DNA methylation age with increasing cell population doubling number.
Why it matters
This work identifies genetic determinants of epigenetic aging clocks and demonstrates that TERT promotes DNA methylation aging despite preserving telomere length.
Limits
Exact effect sizes, confidence intervals, and specific variant details for most loci are not reported in the abstract. Measurements of epigenetic aging were restricted to blood, and in vitro fibroblast findings may not fully generalize to in vivo human tissue biology.
Cited by
- supports Certain inherited genetic variants accelerate epigenetic aging in blood without causing accelerated aging in brain tissue.