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Lu, Ake T.; Xue, Luting; Salfati, Elias L.; Chen, Brian H.; Ferrucci, Luigi; Levy, Daniel; Joehanes, Roby; Murabito, Joanne M.; Kiel, Douglas P.; & Tsai, Pei-Chien, et al. (2018). GWAS of Epigenetic Aging Rates in Blood Reveals a Critical Role for TERT. Nature Communications, 9, 387. PMCID: PMC5786029


DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9907 individuals, we find gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggests causal influences of menarche and menopause on IEAA and lipoproteins on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) paradoxically confer higher IEAA (P < 2.7 x 10(-11)). Causal modeling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT-expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the epigenetic clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.


Reference Type

Journal Article

Year Published


Journal Title

Nature Communications


Lu, Ake T.
Xue, Luting
Salfati, Elias L.
Chen, Brian H.
Ferrucci, Luigi
Levy, Daniel
Joehanes, Roby
Murabito, Joanne M.
Kiel, Douglas P.
Tsai, Pei-Chien
Yet, Idil
Bell, Jordana T.
Mangino, Massimo
Tanaka, Toshiko
McRae, Allan F.
Marioni, Riccardo E.
Visscher, Peter M.
Wray, Naomi R.
Deary, Ian J.
Levine, Morgan E.
Quach, Austin
Assimes, Themistocles L.
Tsao, Philip S.
Absher, Devin M.
Stewart, James D.
Li, Yun
Reiner, Alexander P.
Hou, Lifang
Baccarelli, Andrea A.
Whitsel, Eric A.
Aviv, Abraham
Cardona, Alexia
Day, Felix R.
Wareham, Nicholas J.
Perry, John R. B.
Ong, Ken K.
Raj, Kenneth
Lunetta, Kathryn L.
Horvath, Steve