Aging of blood can be tracked by DNA methylation changes at just three CpG sites

Abstract

BackgroundHuman aging is associated with DNA methylation changes at specific sites in the genome. These epigenetic modifications may be used to track donor age for forensic analysis or to estimate biological age.ResultsWe perform a comprehensive analysis of methylation profiles to narrow down 102 age-related CpG sites in blood. We demonstrate that most of these age-associated methylation changes are reversed in induced pluripotent stem cells (iPSCs). Methylation levels at three age-related CpGs - located in the genes ITGA2B, ASPA and PDE4C - were subsequently analyzed by bisulfite pyrosequencing of 151 blood samples. This epigenetic aging signature facilitates age predictions with a mean absolute deviation from chronological age of less than 5 years. This precision is higher than age predictions based on telomere length. Variation of age predictions correlates moderately with clinical and lifestyle parameters supporting the notion that age-associated methylation changes are associated more with biological age than with chronological age. Furthermore, patients with acquired aplastic anemia or dyskeratosis congenita - two diseases associated with progressive bone marrow failure and severe telomere attrition - are predicted to be prematurely aged.ConclusionsOur epigenetic aging signature provides a simple biomarker to estimate the state of aging in blood. Age-associated DNA methylation changes are counteracted in iPSCs. On the other hand, over-estimation of chronological age in bone marrow failure syndromes is indicative for exhaustion of the hematopoietic cell pool. Thus, epigenetic changes upon aging seem to reflect biological aging of blood.

DNA methylation and healthy human aging

“…Studies that examined this period of human development have reported that DNA methylation levels increase rapidly and then stabilize by adulthood in both brain and blood (Alisch et al ., 2012; Lister et al ., 2013). From adulthood to advanced age, overall levels of DNA methylation remain stable in blood, while interindividual variability increases over that time (Talens et al ., 2012; Weidner et al ., 2014). Postadulthood, many studies have found a mean decrease in blood DNA methylation with increasing age (Bjornsson et al ., 2004; Boks et al ., 2009; Heyn et al ., 2012; Horvath et al ., 2012; Hannum et al ., 2013; Johansson et al ., 2013; Florath et al ., 2014; Weidner et al ., 2014).…”

“…From adulthood to advanced age, overall levels of DNA methylation remain stable in blood, while interindividual variability increases over that time (Talens et al ., 2012; Weidner et al ., 2014). Postadulthood, many studies have found a mean decrease in blood DNA methylation with increasing age (Bjornsson et al ., 2004; Boks et al ., 2009; Heyn et al ., 2012; Horvath et al ., 2012; Hannum et al ., 2013; Johansson et al ., 2013; Florath et al ., 2014; Weidner et al ., 2014). These changes are less likely to occur in promoters and more likely to be observed in enhancers (Johansson et al ., 2013).…”

“…These changes are less likely to occur in promoters and more likely to be observed in enhancers (Johansson et al ., 2013). Regions that gain DNA methylation with age are enriched for CpG islands, while nonislands tend to lose DNA methylation with age (Rakyan et al ., 2010; Heyn et al ., 2012; Horvath et al ., 2012; Florath et al ., 2014; Weidner et al ., 2014). …”

“…As most CpGs are located outside of CpG islands and are highly methylated, this translates to an overall loss of DNA methylation in later life as well as a tendency for DNA methylation levels to shift toward the mean with increased age (Saxonov et al ., 2006; Weber et al ., 2007; Illingworth & Bird, 2009; Hannum et al ., 2013; Teschendorff et al ., 2013; Weidner et al ., 2014). …”

Reduced DNA methylation patterning and transcriptional connectivity define human skin aging

“…While the key features of epigenetic drift remain to be defined, several observations have been made that characterize age‐related methylation changes across human tissues. These include the hypermethylation of stem cell genes (Rakyan et al ., 2010; Teschendorff et al ., 2010), a general linear correlation between the methylation level of certain CpGs and the chronological age (Hannum et al ., 2013; Horvath, 2013; Weidner et al ., 2014), and the hypermethylation of CpG islands (Yuan et al ., 2015). The molecular and phenotypic consequences of these alterations remain a topic of active research.…”