The cerebellum ages slowly according to the epigenetic clock

Horvath, Steve; Mah, Vei; Lu, Ake T.; Woo, Jennifer S; Choi, Oi-Wa; Jasinska, Anna J.; Riancho, José A.; Coles, Natalie S.; Braun, Jonathan; Vinters, Harry V.; Coles, L. Stephen

doi:10.18632/aging.100742

Cited by 155 publications

(121 citation statements)

References 59 publications

(61 reference statements)

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“…It is in agreement with a previous study of DNAm age in multiple tissues of centenarians, which revealed that the cerebellum is ~15 years younger than other tissues [13]. Of interest, the cerebellum in C9orf72 cases is free from TDP-43 inclusions and neurodegeneration [20]; despite having a heavily misregulated transcriptome [23] and a high load of dipeptide repeat proteins (translated from the repeat expansion), which has been suggested to be toxic in some cell/animal models [19].…”

Section: Discussionsupporting

confidence: 93%

DNA methylation age-acceleration is associated with disease duration and age at onset in C9orf72 patients

et al. 2017

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The repeat expansion in C9orf72 is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia. C9orf72 patients present with a wide range in disease duration and age of onset. The strongest risk factor for both syndromes is aging, which was linked to DNA methylation (DNAm) age based on the cumulative assessment of the methylation levels of 353 CpGs included on the genome-wide 450k BeadChip. DNAm age may reflect biological age better than chronological age. We conducted a genome-wide blood DNA methylation study of 46 unrelated C9orf72 patients. After correction for multiple testing, none of the CpGs demonstrated association between its methylation level and disease duration or age of onset. However, we detected a significant reverse correlation of DNAm age-acceleration with disease duration and age of onset, suggesting that for every 5-year increase in DNAm age-acceleration there is a 3.2-year earlier age of onset and 1.5-year shorter disease duration. The significant correlations remain after adjusting for gender, TMEM106B genotypes, disease phenotype and C9orf72 5′CpG island methylation status. A similar trend was observed for the blood DNA of affected members of an extended C9orf72 family; and tissues from the central nervous system of C9orf72 autopsy cases. For instance, regression analysis suggested that a 5-year increase in DNAm age-acceleration is linked to an earlier age of onset by 4.7 or 5.5 years for frontal cortex or spinal cord, respectively. Blood DNAm age may be a useful biomarker for biological age, because blood DNAm age-acceleration was similar to all investigated brain tissues, except for cerebellum that ages more slowly. In conclusion, DNA methylation analysis of C9orf72 patients revealed that increased DNAm age-acceleration is associated with a more severe disease phenotype with a shorter disease duration and earlier age of onset.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1713-y) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 93%

DNA methylation age-acceleration is associated with disease duration and age at onset in C9orf72 patients

et al. 2017

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“…Second, it might reflect the severe loss of neurons even though moderate changes in cell composition do not seem to affect the estimate of DNAm age [18, 20]. However, we observe the same effect when using our cell intrinsic measure of age acceleration that adjusts for the proportion of neurons (Figure 1F).…”

Section: Resultssupporting

confidence: 53%

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

Horvath

Langfelder

Kwak

et al. 2016

Aging

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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.

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“…Further exploring the possible importance of tissue specific aging, obesity has been associated with an increased biological age of the liver (Horvath et al, 2014). And recently, Horvath et al (2015b) applied the 'epigenetic clock' to a number of tissues and found that the cerebellum ages at an increasingly slower rate in 80+ years individuals compared to other brain regions. While the conclusions that can be drawn from this finding are still highly speculative, it does suggest that DNAm age of also specific tissues could be a sign of biological age .…”

Section: Discussionmentioning

confidence: 99%

DNA methylation age is associated with mortality in a longitudinal Danish twin study

et al. 2015

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SummaryAn epigenetic profile defining the DNA methylation age (DNAm age) of an individual has been suggested to be a biomarker of aging, and thus possibly providing a tool for assessment of health and mortality. In this study, we estimated the DNAm age of 378 Danish twins, age 30-82 years, and furthermore included a 10-year longitudinal study of the 86 oldest-old twins (mean age of 86.1 at follow-up), which subsequently were followed for mortality for 8 years. We found that the DNAm age is highly correlated with chronological age across all age groups (r = 0.97), but that the rate of change of DNAm age decreases with age. The results may in part be explained by selective mortality of those with a high DNAm age. This hypothesis was supported by a classical survival analysis showing a 35% (4-77%) increased mortality risk for each 5-year increase in the DNAm age vs. chronological age. Furthermore, the intrapair twin analysis revealed a more-than-double mortality risk for the DNAm oldest twin compared to the co-twin and a 'doseresponse pattern' with the odds of dying first increasing 3.2 (1.05-10.1) times per 5-year DNAm age difference within twin pairs, thus showing a stronger association of DNAm age with mortality in the oldest-old when controlling for familial factors. In conclusion, our results support that DNAm age qualifies as a biomarker of aging.

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The cerebellum ages slowly according to the epigenetic clock

Cited by 155 publications

References 59 publications

DNA methylation age-acceleration is associated with disease duration and age at onset in C9orf72 patients

DNA methylation age-acceleration is associated with disease duration and age at onset in C9orf72 patients

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

DNA methylation age is associated with mortality in a longitudinal Danish twin study

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