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Human Aging DNA Methylation Signatures Are Conserved but Accelerated in Cultured Fibroblasts

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Human Aging DNA Methylation Signatures Are Conserved but Accelerated in Cultured Fibroblasts Epigenetics ISSN: 1559-2294 (Print) 1559-2308 (Online) Journal homepage: https://www.tandfonline.com/loi/kepi20 Human aging DNA methylation signatures are conserved but accelerated in cultured fibroblasts Gabriel Sturm, Andres Cardenas, Marie-Abèle Bind, Steve Horvath, Shuang Wang, Yunzhang Wang, Sara Hägg, Michio Hirano & Martin Picard To cite this article: Gabriel Sturm, Andres Cardenas, Marie-Abèle Bind, Steve Horvath, Shuang Wang, Yunzhang Wang, Sara Hägg, Michio Hirano & Martin Picard (2019) Human aging DNA methylation signatures are conserved but accelerated in cultured fibroblasts, Epigenetics, 14:10, 961-976, DOI: 10.1080/15592294.2019.1626651 To link to this article: https://doi.org/10.1080/15592294.2019.1626651 View supplementary material Accepted author version posted online: 03 Jun 2019. Published online: 12 Jun 2019. Submit your article to this journal Article views: 457 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=kepi20 EPIGENETICS 2019, VOL. 14, NO. 10, 961–976 https://doi.org/10.1080/15592294.2019.1626651 RESEARCH PAPER Human aging DNA methylation signatures are conserved but accelerated in cultured fibroblasts Gabriel Sturm a, Andres Cardenas b, Marie-Abèle Bind c, Steve Horvath d, Shuang Wang e, Yunzhang Wang f, Sara Hägg f, Michio Hirano g, and Martin Picard a,g,h aDepartment of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, NY, USA; bDivision of Environmental Health Sciences, University of California, Berkeley, School of Public Health, Berkeley, CA, USA; cDepartment of Statistics, Harvard University, Cambridge, MA, USA; dHuman Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; eDepartment of Biostatistics, Mailman School of Public Health, Columbia University Medical Center, New York, NY, USA; fDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; gDepartment of Neurology, H. Houston Merritt Center, Columbia Translational Neuroscience Initiative, Columbia University Irving Medical Center, New York, NY, USA; hColumbia Aging Center, Columbia University Mailman School of Public Health, New York, NY, USA ABSTRACT ARTICLE HISTORY Aging is associated with progressive and site-specific changes in DNA methylation (DNAm). These Received 10 April 2019 global changes are captured by DNAm clocks that accurately predict chronological age in humans but Revised 21 May 2019 relatively little is known about how clocks perform in vitro. Here we culture primary human fibroblasts Accepted 24 May 2019 across the cellular lifespan (~6 months) and use four different DNAm clocks to show that age-related KEYWORDS DNAm signatures are conserved and accelerated in vitro. The Skin & Blood clock shows the best linear Aging; DNA methylation; correlation with chronological time (r = 0.90), including during replicative senescence. Although epigenetic age; primary similar in nature, the rate of epigenetic aging is approximately 62x times faster in cultured cells culture; lifespan; accelerated than in the human body. Consistent with in vivo data, cells aged under hyperglycemic conditions aging 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 con- stitute a system to evaluate age-modifying interventions across the lifespan. Introduction of methylation with advancing chronological age. Notably, among the CpGs most consistently found As we attempt to develop increasingly precise and to undergo hypermethylation with age is ELOVL2 sensitive biological age indicators to detect and pre- cg16867657 [5–9], indicating the presence of site- dict disease risk, a particular epigenetic marker that specific alterations in DNAm with age in human has gained interest is methylation of cytosine nucleo- populations. However, despite the availability of tides in DNA (DNAm) [1]. DNAm is a stable epige- longitudinal DNAm datasets in human blood, it netic mark that serves to establish cell lineages has remained challenging to track dynamic changes during differentiation [2]butrapidchangesin in DNAm across the entire human lifespan and to DNAm are also known to occur on the time scale evaluate the effects of age-modifying genes or envir- of days and weeks, including circadian oscillations in onmental perturbations without appropriate labora- cells and animals [3], and over years with cellular tory-based experimental systems. aging [4]. In human tissues, specific cytosine- In human tissues, epigenetic biomarkers, or bio- guanine dinucleotides (CpGs) undergo stereotypic logical ‘clocks’ have been developed that reliably loss (hypomethylation) or gain (hypermethylation) track chronological age [1]. DNAm clocks use CONTACT Martin Picard [email protected] Columbia University Irving Medical Center, 622 W 168th street, New York, NY 10032, USA Supplemental data for this article can be accessed here. © 2019 Informa UK Limited, trading as Taylor & Francis Group 962 G. STURM ET AL. penalized linear regression models, such as elastic- compare the rate of aging in vivo and in vitro.We net regression to select CpGs whose change in use repeated DNAm measurements across the cel- DNAm correlate (either positively or negatively) lular lifespan to define the spectrum and rate of with chronological age. For example, the Horvath both linear and nonlinear, hypo- and hypermethy- pan-tissue clock [10] and the Hannum clock [11] lation kinetics of individual CpGs. Overall, our have been widely used in epidemiological studies. findings reveal that DNAm aging signatures They provide moderate to excellent estimates of between primary cultured fibroblasts and human chronological age (r > 0.90) in human tissues [1]. blood leukocytes are conserved and accelerated, Subsequent minimalist algorithms have also suggesting that human fibroblast aging exhibits shown that the methylation levels of only three key molecular events that recapitulate human to eleven CpGs from human blood can provide aging (Figure 1(a)). This study demonstrates that fairly accurate age predictions (mean absolute human biological aging in the order of decades can error 2.72–5.4 years) or predict mortality [12– be mimicked with in vitro laboratory experiments 14]. However, little is known about the kinetics over a few months. of DNAmAge and DNAm levels at single-CpG resolution across the human lifespan, in part because it is difficult to repeatedly obtain biologi- Results cal samples from a given individual across Primary human fibroblasts grown across the a sufficiently long period to robustly characterize cellular lifespan DNAm kinetics. Primary human fibroblasts are derived from mini- To examine the kinetics of DNA methylation mally invasive skin biopsies, can be grown in vitro, across the lifespan, primary fibroblasts from a - and have been used as an experimental model of 29 year-old male were cultured and aged by con- aging [15]. Fibroblasts divide at a regular rate and tinuous passaging until replicative senescence. The undergo a specific number of division (i.e. the maximal linear rate of cell division was 0.75 divi- Hayflick limit) before reaching senescence, a state sions/day. In total, cells doubled approximately 56 characterized by replicative arrest and metabolic times in 110 days, before reaching a plateau mark- remodeling [16]. In this system, senescence can ing replicative senescence (Figure 1(b)). As also be induced by genotoxic stress, such as irradia- expected, cellular senescence was associated with tion and DNA damage [17], providing an appealing distinct cellular characteristics including loss of model to study factors that influence the biological spindle-shaped cell morphology, appendage asym- aging process. Previous studies have identified CpGs metry, nuclear flatness, and reduced maximal con- whose methylation levels distinguish cultured senes- fluency (Figure 1(c)). cent from younger cells [18,19], and shown a certain degree of overlap with aging human tissues [20]. Whole methylome analysis across the cellular Other work has also provided preliminary evidence lifespan that DNA methylation age (DNAmAge) algorithms may be sensitive to replicative and radiation-induced DNA methylation was quantified for 866,736 CpG senescence [21–23]. Although fibroblasts from older sites using the Illumina MethylationEPIC array at donors show reproducible differences in metabolic twelve timepoints collected approximately every function and transcriptional state [24,B.D.25], it is 11 days across the cellular lifespan. When consider- unclear whether age-related DNAm changes in pri- ing global DNAm variation for all CpGs together
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