Epigenetic Age Acceleration Assessed with Human White-Matter Images

Abstract

The accurate estimation of age using methylation data has proved a useful and heritable biomarker, with acceleration in epigenetic age predicting a number of age-related phenotypes. Measures of white matter integrity in the brain are also heritable and highly sensitive to both normal and pathological aging processes across adulthood. We consider the phenotypic and genetic interrelationships between epigenetic age acceleration and white matter integrity in humans. Our goal was to investigate processes that underlie interindividual variability in age-related changes in the brain. Using blood taken from a Mexican-American extended pedigree sample (n = 628; age = 23.28-93.11 years), epigenetic age was estimated using the method developed by Horvath (2013). For n = 376 individuals, diffusion tensor imaging scans were also available. The interrelationship between epigenetic age acceleration and global white matter integrity was investigated with variance decomposition methods. To test for neuroanatomical specificity, 16 specific tracts were additionally considered. We observed negative phenotypic correlations between epigenetic age acceleration and global white matter tract integrity (ρ_pheno = -0.119, p = 0.028), with evidence of shared genetic (ρ_gene = -0.463, p = 0.013) but not environmental influences. Negative phenotypic and genetic correlations with age acceleration were also seen for a number of specific white matter tracts, along with additional negative phenotypic correlations between granulocyte abundance and white matter integrity. These findings (i.e., increased acceleration in epigenetic age in peripheral blood correlates with reduced white matter integrity in the brain and shares common genetic influences) provide a window into the neurobiology of aging processes within the brain and a potential biomarker of normal and pathological brain aging.SIGNIFICANCE STATEMENT Epigenetic measures can be used to predict age with a high degree of accuracy and so capture acceleration in biological age, relative to chronological age. The white matter tracts within the brain are also highly sensitive to aging processes. We show that increased biological aging (measured using epigenetic data from blood samples) is correlated with reduced integrity of white matter tracts within the human brain (measured using diffusion tensor imaging) with data from a large sample of Mexican-American families. Given the family design of the sample, we are also able to demonstrate that epigenetic aging and white matter tract integrity also share common genetic influences. Therefore, epigenetic age may be a potential, and accessible, biomarker of brain aging.

Keywords: aging; epigenetics; genetics; white matter integrity.

Figure 1.

Epigenetic age measures. Top, Chronological age compared with epigenetic age estimates; correlation slope shown. Light gray represents females. Dark gray represents males. Bottom, Distribution of epigenetic age acceleration measure (i.e., epigenetic age covarying for age, sex, age × sex, age², and age² × sex, and cell composition in blood). If values are >0 (to the right of the vertical line), this indicates individuals have epigenetic age estimates that are older than would be expected given the covariates; if values are <0, this indicates that epigenetic age estimates are younger than expected.

Figure 2.

Relationship between chronological age and global white matter integrity. Light gray represents females. Dark gray represents males.

Figure 3.

Relationship between chronological age and white matter hyperintensity volume. Light gray represents females. Dark gray represents males.