Epigenetic influences on aging: a longitudinal genome-wide methylation study in old Swedish twins

Abstract

Age-related changes in DNA methylation were observed in cross-sectional studies, but longitudinal evidence is still limited. Here, we aimed to characterize longitudinal age-related methylation patterns using 1011 blood samples collected from 385 Swedish twins (age at entry: mean 69 and standard deviation 9.7, 73 monozygotic and 96 dizygotic pairs) up to five times (mean 2.6) over 20 years (mean 8.7). We identified 1316 age-associated methylation sites (P<1.3×10−7) using a longitudinal epigenome-wide association study design. We measured how estimated cellular compositions changed with age and how much they confounded the age effect. We validated the results in two independent longitudinal cohorts, where 118 CpGs were replicated in Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, 390 samples) (P<3.9×10−5), 594 in Lothian Birth Cohort (LBC, 3018 samples) (P<5.1×10−5) and 63 in both. Functional annotation of age-associated CpGs showed enrichment in CCCTC-binding factor (CTCF) and other transcription factor binding sites. We further investigated genetic influences on methylation and found no interaction between age and genetic effects in the 1316 age-associated CpGs. Moreover, in the same CpGs, methylation differences within twin pairs increased with 6.4% over 10 years, where monozygotic twins had smaller intra-pair differences than dizygotic twins. In conclusion, we show that age-related methylation changes persist in a longitudinal perspective, and are fairly stable across cohorts. The changes are under genetic influence, although this effect is independent of age. Moreover, methylation variability increase over time, especially in age-associated CpGs, indicating the increase of environmental contributions on DNA methylation with age.

Epigenetic mutation load is weakly correlated with epigenetic age acceleration

“…Furthermore, EML was negatively correlated with CD4+ T cells (meta r = -0.121, meta P-value = 4.24E-22), plasmablasts (meta r = -0.085, meta P-value = 1.14E-11), and granulocytes (meta r = -0.064, meta P-value = 3.70E-07), but positively with exhausted CD8+ (defined as CD8+CD28-CD45RA-) T cells. These results are consistent with known age-related changes in blood cell composition [ 34 , 35 ].…”

Developments in molecular epidemiology of aging

“…Meanwhile, the same type of study design is now seen for projects in epigenetics, where population-based cohorts with similar genome-wide DNA methylation data join forces to identify methylation marks associated with a trait of interest. Aging studies on the epigenome have been far more successful; thousands of DNA methylation changes have been associated with the aging process in humans and validated across different cohorts [63][64][65]. Another type of study using recent GWAS findings within genetic and molecular epidemiology is the application of Mendelian randomizations to assess causal associations in aging.…”

DNA Methylation Biomarkers in Aging and Age-Related Diseases

“…This notion proposes an increased rate of stochastic methylation errors across the entire genome during aging. Indeed, several reports provided compelling evidence that older monozygotic twins exhibit global differences in DNA methylation (DNAm) patterns when compared to their younger counterparts (Fraga et al, 2005;Lévesque et al, 2014;Tan et al, 2016;Wang et al, 2018). Similarly, a centenarian's methylome displays reduced DNA methylation levels as well as a decreased pair-wise correlation in the methylation status of neighboring CpG sites relative to the methylome of a newborn (Heyn et al, 2012).…”