Trends in DNA Methylation with Age Replicate Across Diverse Human Populations

Abstract

Aging is associated with widespread changes in genome-wide patterns of DNA methylation. Thousands of CpG sites whose tissue-specific methylation levels are strongly correlated with chronological age have been previously identified. However, the majority of these studies have focused primarily on cosmopolitan populations living in the developed world; it is not known if age-related patterns of DNA methylation at these loci are similar across a broad range of human genetic and ecological diversity. We investigated genome-wide methylation patterns using saliva- and whole blood-derived DNA from two traditionally hunting and gathering African populations: the Baka of the western Central African rain forest and the ≠Khomani San of the South African Kalahari Desert. We identified hundreds of CpG sites whose methylation levels are significantly associated with age, thousands that are significant in a meta-analysis, and replicate trends previously reported in populations of non-African descent. We confirmed that an age-associated site in the promoter of the gene shows a remarkably congruent relationship with aging in humans, despite extensive genetic and environmental variation across populations. We also demonstrate that genotype state at methylation quantitative trait loci (meQTLs) can affect methylation trends at some age-associated CpG sites. Our study explores the relationship between CpG methylation and chronological age in populations of African hunter-gatherers, who rely on different diets across diverse ecologies. While many age-related CpG sites replicate across populations, we show that considering common genetic variation at meQTLs further improves our ability to detect previously identified age associations.

The lipid elongation enzyme ELOVL2 is a molecular regulator of aging in the retina

“…This work is the first demonstration, to our knowledge, of a functional role for Elovl2 in regulating age‐associated phenotypes in the retina. Methylation of the promoter region of ELOVL2 is well‐established as a robust prognostic biomarker of human aging (Garagnani, ; Gopalan, ), but whether ELOVL2 activity contributes to aging phenotypes had not yet been documented. In this work, we demonstrated that the age‐related methylation of regulatory regions of Elovl2 occurs in the rodent retina and results in age‐related decreases in the expression of Elovl2 .…”

“…This work is the first demonstration, to our knowledge, of a functional role for Elovl2 in regulating age-associated phenotypes in the retina. Methylation of the promoter region of ELOVL2 is wellestablished as a robust prognostic biomarker of human aging (Garagnani, 2012;Gopalan, 2017), but whether ELOVL2 activity contributes to aging phenotypes had not yet been documented. F I G U R E 3 Elovl2 C234W mice show a loss of ELOVL2 enzymatic activity.…”

Epigenetic aging in children from a small‐scale farming society in The Congo Basin: Associations with child growth and family conflict

“…A primary goal of the current analyses was to test whether markers of children's growth and energetic condition and their experiences of family life that could influence their psychosocial stress and health were correlated with higher EAA in a small‐scale society setting, building from recent related research in similar contexts on adults (Fagny et al, ; Gopalan et al, ; Horvath et al, ). A small but growing number of studies of epigenetic aging in children have attempted to explore the developmental origins of EAA given its implications for mortality and morbidity across the life course (Brody, Yu, et al, ; Davis et al, ; Moore et al, ; Simpkin et al, ).…”

“…A small but growing number of studies of epigenetic aging in children have attempted to explore the developmental origins of EAA given its implications for mortality and morbidity across the life course (Brody, Yu, et al, ; Davis et al, ; Moore et al, ; Simpkin et al, ). However, the vast majority of these studies have been conducted with industrialized populations in societies in which under‐nutrition, energy shortfalls, and/or infectious disease stressors are typically absent or minimal (Fagny et al, ; Gopalan et al, ; Horvath et al, ; Ryan et al, ). Because those conditions diverge from the developmental experiences of many global populations as well as the conditions under which human biology evolved (Gurven, ; Horvath et al, ; Lozano et al, ), it is important to understand the role of concurrent experiences of energetic trade‐offs and psychosocial stressors in relationship to EAA.…”

Inferences of African evolutionary history from genomic data

“…Gopalan et al . [72] found patterns of methylation in African hunter-gatherers (Baka CAHG and San) that could be useful for inferring age, particularly in geographic regions where age is often unknown. Taken together, these epigenomic studies highlight how genetic variation and environment can influence methylation patterns, which in turn can influence adaptive trait variation.…”