The inactive X chromosome accumulates widespread epigenetic variability with age

Abstract

Background: Loss of epigenetic control is a hallmark of aging. Among the most prominent roles of epigenetic mechanisms is the inactivation of one of two copies of the X chromosome in females through DNA methylation. Hence, age-related disruption of X-chromosome inactivation (XCI) may contribute to the ageing process in women. Methods: We analyzed 9,777 CpGs on the X chromosome in whole blood samples from 2343 females and 1688 males. We replicated findings in duplicate using one whole blood and one purified monocyte data set (in total, 991/924 females/males). We used double generalized linear models (DGLM) to detect age-related differentially methylated CpGs (aDMCs), whose mean methylation level differs with age, and age-related variable methylated CpGs (aVMCs), whose methylation level becomes more variable with age. Results: In females, aDMCs were relatively uncommon (n=33) and preferentially occurred in regions known to escape XCI. In contrast, many CpGs (n=987) were found to display an increased variance with age (aVMCs). Of note, the replication rate of aVMCs was also high in purified monocytes (95%), indicating that their occurrence may be independent of cell composition. aVMCs accumulated in CpG islands and regions subject to XCI. Although few aVMCs were associated with X-linked genes in all females studied, an exploratory analysis suggested that such associations may be more common in old females. In males, aDMCs (n=316) were primarily driven by cell composition, while aVMCs replicated well (94%) but were infrequent (n=37). Conclusions: Age-related DNA methylation differences at the inactive X chromosome are dominated by the accumulation of variability.

Altered X-chromosome inactivation predisposes to autoimmunity

“…This perturbation has, however, few effects in immune cells from 3-month-old females—the most marked phenotypic changes are detected around 1-year of age—and does not really affect life expectancy or animal fitness. Whether this evolutive phenotype relates to changes in heterochromatin features that are known to occur during aging ( 61 , 62 ) and/or whether it is accelerated by the gradual loss of immune cell differentiation potential ( 63 ) remains to be determined. In this regard, it is tempting to speculate that deregulation of XCI may also contribute to autoimmune conditions specific to postmenopausal women [rheumatoid arthritis ( 64 ), some forms of Sjögren’s syndrome ( 65 ), atherosclerosis or of ischemic heart diseases ( 43 , 66 ), and inflammaging ( 67 )] when estrogen levels are low and cannot account for the sexual dimorphism observed in these diseases.…”

Altered X-chromosome inactivation predisposes to autoimmunity

“…This perturbation has, however, few effects in immune cells from 3-month-old females – the most dramatic phenotypic changes are detected around 1-year of age – and does not really affect life expectancy or animal fitness. Whether this evolutive phenotype relates to changes in heterochromatin features that are known to occur during aging ( 64, 65 ) and/or whether it is accelerated by the gradual loss of immune cell differentiation potential ( 66 ) remains to be determined. In this regard, it is tempting to speculate that deregulation of XCI may also contribute to autoimmune conditions specific to postmenopausal women (rheumatoid arthritis ( 67 ), some forms of Sjögren’s syndrome ( 68 ), atherosclerosis or of ischemic heart diseases ( 43, 69 ), inflammaging ( 70 )) when estrogen levels are low and cannot account for the sexual dimorphism observed in these diseases.…”

Sex‐associated differences in cardiac ageing: Clinical aspects and molecular mechanisms

“…Chronic activation of the βadrenergic and reninangiotensin systems has also been associated with the pathophysiology of cardiac ageing. Ageing increases human sympathetic nervous activity at rest due to a malfunction of the norepinephrine (NE) clearance system in humans and animals (18). Adrenergic overstimulation can damage the myocardium by increasing oxidative stress and desensitizing elements of the βadrenergic signalling cascade, limiting the increase in heart rate observed with upright postural change or during exercise.…”

“…There are multiple mechanisms by which sex can directly influence cardiovascular epigenetics. For example, the ageing process can be influenced by age‐related disruption in X‐chromosome inactivation in women 18,19 or the expression of non‐pseudoautosomal Y‐chromosomal epigenetic modifiers in men 19 . Moreover, the nongenomic effect of steroid hormones and their receptors on epigenetic regulators, such as DNA methylation enzymes, histone modifiers and microRNA (miRNA) expression, can also impact the progression of senescence and CVD 20–22 …”