Accelerated epigenetic aging in brain is associated with pre-mortem HIV-associated neurocognitive disorders

Abstract

HIV infection leads to age-related conditions in relatively young persons. HIV-associated neurocognitive disorders (HAND) are considered among the most prevalent of these conditions. To study the mechanisms underlying this disorder, researchers need an accurate method for measuring biological aging. Here, we apply a recently developed measure of biological aging, based on DNA methylation, to the study of biological aging in HIV+ brains. Retrospective analysis of tissue bank specimens and pre-mortem data was carried out. Fifty-eight HIV+ adults underwent a medical and neurocognitive evaluation within 1 year of death. DNA was obtained from occipital cortex and analyzed with the Illumina Infinium Human Methylation 450K platform. Biological age determined via the epigenetic clock was contrasted with chronological age to obtain a measure of age acceleration, which was then compared between those with HAND and neurocognitively normal individuals. The HAND and neurocognitively normal groups did not differ with regard to demographic, histologic, neuropathologic, or virologic variables. HAND was associated with accelerated aging relative to neurocognitively normal individuals, with average relative acceleration of 3.5 years. Age acceleration did not correlate with pre-mortem neurocognitive functioning or HAND severity. This is the first study to demonstrate that the epigenetic age of occipital cortex samples is associated with HAND status in HIV+ individuals pre-mortem. While these results suggest that the increased risk of a neurocognitive disorder due to HIV might be mediated by an epigenetic aging mechanism, future studies will be needed to validate the findings and dissect causal relationships and downstream effects.

Keywords: Epigenetic; Epigenetic clock; HANA; HAND; HIV; HIV-associated neurocognitive disorder.

FIGURE 1

Panel A and B: DNA methylation age (y-axis) versus chronological age in A) all brain samples and B) those brains from individuals who died past age 33 (this analysis was undertaken due to the outlier shown in panel A). Red circles and black squares in the scatter plot denote samples from HAND and neurocognitively normal HIV+ cases, respectively. The orange line depicts a linear regression line through HAND samples. Similarly, the black solid line corresponds to a regression line of DNA methylation age on chronological age in neurocognitively normal samples. For each sample, age acceleration is defined as the vertical distance to the relevant regression line (i.e. DNA methylation age minus the expected value based on HIV-samples). Panels C: Mean age acceleration (y-axis) versus HAND status in all brain samples. Each bar plot depicts one standard error around the mean value and reports the Kruskal Wallis (non-parametric) group comparison test p-value. Panel D: Analogous results can be obtained when restricting the analysis to those over age 33 (due to outlier values in younger cases). The number of samples in each group is reported by the rotated number under each bar.