Human aging DNA methylation signatures are conserved but accelerated in cultured fibroblasts
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 a...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2019-10-01
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| Series: | Epigenetics |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/15592294.2019.1626651 |
| _version_ | 1827811533774651392 |
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| author | Gabriel Sturm Andres Cardenas Marie-Abèle Bind Steve Horvath Shuang Wang Yunzhang Wang Sara Hägg Michio Hirano Martin Picard |
| author_facet | Gabriel Sturm Andres Cardenas Marie-Abèle Bind Steve Horvath Shuang Wang Yunzhang Wang Sara Hägg Michio Hirano Martin Picard |
| author_sort | Gabriel Sturm |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T23:06:21Z |
| format | Article |
| id | doaj.art-42ef42540e03474eae2c15fa04ffc5ce |
| institution | Directory Open Access Journal |
| issn | 1559-2294 1559-2308 |
| language | English |
| last_indexed | 2024-03-11T23:06:21Z |
| publishDate | 2019-10-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Epigenetics |
| spelling | doaj.art-42ef42540e03474eae2c15fa04ffc5ce2023-09-21T13:09:22ZengTaylor & Francis GroupEpigenetics1559-22941559-23082019-10-01141096197610.1080/15592294.2019.16266511626651Human aging DNA methylation signatures are conserved but accelerated in cultured fibroblastsGabriel Sturm0Andres Cardenas1Marie-Abèle Bind2Steve Horvath3Shuang Wang4Yunzhang Wang5Sara Hägg6Michio Hirano7Martin Picard8Columbia University Irving Medical CenterUniversity of California, Berkeley, School of Public HealthHarvard UniversityUniversity of California Los AngelesMailman School of Public Health, Columbia University Medical CenterKarolinska InstitutetKarolinska InstitutetH. Houston Merritt Center, Columbia Translational Neuroscience Initiative, Columbia University Irving Medical CenterColumbia University Irving Medical CenterAging 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.http://dx.doi.org/10.1080/15592294.2019.1626651agingdna methylationepigenetic ageprimary culturelifespanaccelerated aging |
| spellingShingle | Gabriel Sturm Andres Cardenas Marie-Abèle Bind Steve Horvath Shuang Wang Yunzhang Wang Sara Hägg Michio Hirano Martin Picard Human aging DNA methylation signatures are conserved but accelerated in cultured fibroblasts Epigenetics aging dna methylation epigenetic age primary culture lifespan accelerated aging |
| title | Human aging DNA methylation signatures are conserved but accelerated in cultured fibroblasts |
| title_full | Human aging DNA methylation signatures are conserved but accelerated in cultured fibroblasts |
| title_fullStr | Human aging DNA methylation signatures are conserved but accelerated in cultured fibroblasts |
| title_full_unstemmed | Human aging DNA methylation signatures are conserved but accelerated in cultured fibroblasts |
| title_short | Human aging DNA methylation signatures are conserved but accelerated in cultured fibroblasts |
| title_sort | human aging dna methylation signatures are conserved but accelerated in cultured fibroblasts |
| topic | aging dna methylation epigenetic age primary culture lifespan accelerated aging |
| url | http://dx.doi.org/10.1080/15592294.2019.1626651 |
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