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

Abstract

Objective 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. Design Retrospective analysis of tissue bank specimens and pre-mortem data. Methods 58 HIV+ adults underwent medical and neurocognitive evaluation within one 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. Results 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. Conclusions 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.

Fate of microglia during HIV‐1 infection: From activation to senescence?

“…In addition, it seems well-established now that the latter seem to have an effect on the former. Although a large recent study suggested that HIV-1 infection may cause accentuated but not accelerated aging , many others have presented evidence of accelerated aging in chronically HIV-1-infected populations (Angelovich et al, 2015;Cassol et al, 2014;Chou et al, 2013;Gianesin et al, 2016;Horvath and Levine, 2015;Levine et al, 2016;Martin et al, 2013;Pathai et al, 2013Pathai et al, , 2014Pfefferbaum et al, 2014;Schrack et al, 2015), involving multiple immune system-and CNS-related functional deficits. This review highlighted the many commonalities between functional changes of microglia during HIV-1 infection and during aging, including cellular activation, arrested cell cycle progression and altered cellular metabolism.…”

Traumatic Stress and Accelerated Cellular Aging: From Epigenetics to Cardiometabolic Disease

“…Accelerated DNAm age, primarily based on the Horvath algorithm, has been associated with a variety of diseases and health outcomes including cancer [51], HIV- [52] and Alzheimer’s-related [53] neurocognitive impairment, Parkinson’s disease [54] and shortened time to death [55, 56••, 57]. Five studies (Table 1) have evaluated the associations between trauma and/or PTSD and accelerated DNAm age using the Horvath and/or Hannum algorithms.…”

DNA methylation signatures reflect aging in patients with nonalcoholic steatohepatitis

“…For instance, HIV and obesity are associated with increased liver fibrosis, and both accelerate the epigenetic clock more than would be expected compared with age-matched control specimens (11)(12)(13). Interestingly, obesity altered the epigenetic clock of the liver but not for any other tissue sites (11).…”