Huntington's disease accelerates epigenetic aging of human brain and disrupts DNA methylation levels

Abstract

Age of Huntington's disease (HD) motoric onset is strongly related to the number of CAG trinucleotide repeats in the huntingtin gene, suggesting that biological tissue age plays an important role in disease etiology. Recently, a DNA methylation based biomarker of tissue age has been advanced as an epigenetic aging clock. We sought to inquire if HD is associated with an accelerated epigenetic age. DNA methylation data was generated for 475 brain samples from various brain regions of 26 HD cases and 39 controls. Overall, brain regions from HD cases exhibit a significant epigenetic age acceleration effect (p=0.0012). A multivariate model analysis suggests that HD status increases biological age by 3.2 years. Accelerated epigenetic age can be observed in specific brain regions (frontal lobe, parietal lobe, and cingulate gyrus). After excluding controls, we observe a negative correlation (r=−0.41, p=5.5×10−8) between HD gene CAG repeat length and the epigenetic age of HD brain samples. Using correlation network analysis, we identify 11 co-methylation modules with a significant association with HD status across 3 broad cortical regions. In conclusion, HD is associated with an accelerated epigenetic age of specific brain regions and more broadly with substantial changes in brain methylation levels.

The interaction of aging and oxidative stress contributes to pathogenesis in mouse and human Huntington disease neurons

“…Interestingly, we also saw that HD neurons basally had a trend toward decreased NMDAR1 (Figure 4B, Hu97/18 nGFP vs. Hu18/18 nGFP p=0.3485), a significant decrease in dynamin 1 (Figure 4C, Hu97/18 nGFP vs. Hu18/18 nGFP p= p=0.03572), and a strong trend toward decreased Lamin B1 (Figure 4D, Hu97/18 nGFP vs. Hu18/18 nGFP p= p=0.0605). These results are consistent with other reports of advanced biological age in HD brain and neurons (Grima et al, 2017;Horvath et al, 2016). It is also important to note that in mature neurons, treatment with progerin caused cellular rearrangement of HD neurons (Figure S3), which has previously been observed in Hu97/18 primary neurons treated with poorly tolerated antisense oligonucleotides (Skotte et al, 2014).…”

“…Additionally, oxidative and DNA damage as well as somatic expansion, potential drivers of HD pathogenesis, increase with aging. Combined with evidence of advanced biological age in HD brains (Grima et al, 2017;Horvath et al, 2016), age-related defects in the nuclear pore complex of HD neurons (Grima et al, 2017), and the fact that aging can render MSNs to mutant HTT (mtHTT) toxicity (Diguet et al, 2009) this suggests an interplay between age, oxidative stress, and mutant HTT in HD neurodegeneration and thus onset and/or progression.…”

Polyglutamine-Expanded Huntingtin Exacerbates Age-Related Disruption of Nuclear Integrity and Nucleocytoplasmic Transport

“…Indeed, several common hallmarks of aging, including mitochondria dysfunction, impaired protein homeostasis and degradation have previously been are associated with HD (Jenkins et al, 1993, Hay et al, 2004, Lin and Beal, 2006, Bennett et al, 2007). In addition, consistent with mutant Huntingtin accelerating cellular aging, a recent study reported an accumulation of epigenetic markers of aging in the brain of HD patients as compared to control subjects (Horvath et al, 2016). In line with this notion, several genetic, pharmacological and dietary anti-aging interventions have been reported to ameliorate aspects of HD in mouse models (Duan et al, 2003, Ma et al, 2007, Sadagurski et al, 2011, Tallaksen-Greene et al, 2014, Moreno et al, 2016).…”

DNA methylation‐based biological aging and cancer risk and survival: Pooled analysis of seven prospective studies

“…Conversely, previous studies have suggested that strong genetic determinants of epigenetic aging exist, as illustrated by high heritability estimates of 0.43 and 0.65 although these studies could not account for environmental effects shared within families . Observed associations with more strongly genetically determined characteristics, such as age at menopause and obesity, or with certain genetic or neurodegenerative conditions may also point to a genetic component of age acceleration. Few studies have attempted to assess associations with common genetic variants …”