https://orcid.org/0000-0002-7280-4310
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ABSTRACT
Aging is associated with progressive and site-specific changes in DNA methylation (DNAm). These global changes are captured by DNAm clocks that accurately predict chronological age in humans but relatively little is known about how clocks perform in vitro. Here we culture primary human fibroblasts across the cellular lifespan (~6 months) and use four different DNAm clocks to show that age-related DNAm signatures are conserved and accelerated in vitro. The Skin & Blood clock shows the best linear correlation with chronological time (r = 0.90), including during replicative senescence. Although similar in nature, the rate of epigenetic aging is approximately 62x times faster in cultured cells than in the human body. Consistent with in vivo data, cells aged under hyperglycemic conditions exhibit an approximately three years elevation in baseline DNAm age. Moreover, candidate gene-based analyses further corroborate the conserved but accelerated biological aging process in cultured fibroblasts. Fibroblasts mirror the established DNAm topology of the age-related ELOVL2 gene in human blood and the rapid hypermethylation of its promoter cg16867657, which correlates with a linear decrease in ELOVL2 mRNA levels across the lifespan. Using generalized additive modeling on twelve timepoints across the lifespan, we also show how single CpGs exhibit loci-specific, linear and nonlinear trajectories that reach rates up to −47% (hypomethylation) to +23% (hypermethylation) per month. Together, these high-temporal resolution global, gene-specific, and single CpG data highlight the conserved and accelerated nature of epigenetic aging in cultured fibroblasts, which may constitute a system to evaluate age-modifying interventions across the lifespan.
Acknowledgments
Work of the authors is supported by NIH grants GM119793, MH113011, MH119336 (M.P.); OD021412 (M.A.B.); AG060908 (S.Horvath); HD32062, NS078059; LM013061 (S.W.); and CA226672 (M.H.). The authors are also supported by the Wharton Fund and the Columbia Aging Center (M.P.), the John Harvard Distinguished Science Fellow Program within the FAS Division of Science of Harvard University (M.A.B.); and the J. Willard and Alice S. Marriott Foundation, Muscular Dystrophy Association, Arturo Estopinan TK2 Research Fund, Nicholas Nunno Foundation, JDF Fund for Mitochondrial Research, and Shuman Mitochondrial Disease Fund (M.H.). The SATSA study is supported by NIH grants AG04563; AG10175; AG028555, the MacArthur Foundation Research Network on Successful Aging, the European Union’s Horizon 2020 research and innovation programme No. 634821, the Swedish Council for Working Life and Social Research (FAS/FORTE) 97:0147:1B, 2009-0795, 2013-2292, the Swedish Research Council 825-2007-7460, 825-2009-6141, 521-2013-8689, 2015-03255, 2015-06796, the Karolinska Institutet delfinansiering (KID) grant for doctoral students (Y.W.), the KI Foundation, the Strategic Research Area in Epidemiology at Karolinska Institutet and by Erik Rönnbergs donation for scientific studies in aging and age-related diseases. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Author contributions
G.S. and M.P. designed experiments. G.S. performed tissue culture experiments and collected DNA methylation data. G.S., A.C., and M.A.B. processed and analyzed in vitro DNA methylation data. S.W., S.Horvath, S.Hägg, and Y.W. provided in vivo methylation data and clock algorithms. M.H. provided cells. G.S. and M.P. drafted manuscript and prepared figures. All authors edited and approved the final version of the manuscript.
Data availability
The methylation array data used in this manuscript is available under accession number GSE131280.
Disclosure statement
No potential conflict of interest was reported by the authors..
Supplementary material
Supplemental data for this article can be accessed here.
