Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 16 No. 5 • May 2013


The Methylome DNA

Methylation Changes with Age Reveals Dynamic Landscape

Changes in DNA methylation (the methylome) with time are being studied for insights into aging and age-related diseases. A recent study reported some initial findings of a quantitative model of aging using measurements at more than 450,000 CpG markers (hot spots where DNA methylation takes place) from the whole blood of 656 people.1 These subjects were aged 19 to 101 years.

The model was designed to “measure [ ] the rate at which an individual’s methylome ages.” The authors report that differences in aging rates were affected by gender and genetic variants and that, very interestingly, tumors reveal an accelerated aging rate.®

Changes in methylation are one reason that identical twins, which start out with the same DNA blueprint, become different with age (for example, becoming divergent in their susceptibility to various diseases), a phenomenon called “epigenetic drift.” Environmental factors, such as the dietary supply of methyl donating nutrients (e.g., choline and methionine) can also modulate gene expression via changes in DNA methylation.

The authors found that their model was able to predict the age of most individuals with high accuracy, with a correlation between age and predicted age of 96% and an error of 3.9 years. “The methylome of men appeared to age approximately 4% faster than that of women, even though the overall distributions of age were not significantly different between the men and women in the cohort (p > 0.05, KS test).”1 On the other hand, BMI did not contribute significantly to aging rate.

The authors report that “[n]early all markers in the model lay within or near genes with known functions in aging-related conditions ...” However, “none of the genetic variants were significant predictors of age itself,” indicating that there was a pattern of changes in methylation that predicted age, but that methylation changes in a single gene did not do so. Examining all 70,387 markers of global methylation levels showed that 44% tend to increase and 56% tend to decrease with age. “[T]umors coincide with older values for 74% of the markers regardless of the trending direction.”1

“Interestingly, use of our aging model indicated that tumors appear to have aged 40% more than matched normal tissue from the same individual (Wilcox test, p<10-41).”1

One other interesting finding1 was that there was a loss of information (increase in entropy) in the methylome over time. “An increase in entropy of a CpG marker means that its methylation state becomes less predictable across the population of cells, i.e., its methylation fraction tends toward 50%. Indeed, over all markers associated with a change in methylation fraction in the sample cohort, 70% tended toward a methylation fraction of 50%.” “Furthermore, extreme methylome entropy for an individual was highly correlated with accelerated aging rate ...”1

Another paper on DNA methylation changes with age reported on changes in development and aging of the human prefrontal cortex.2 “The human prefrontal cortex (PFC) plays a critical role in complex cognitive behaviors, personality, decision making, and orchestration of thoughts and actions and thus has been referred to as the CEO of the brain.”2

In this study, the researchers “investigated the genome-wide temporal dynamics of DNA methylation in a large cohort of well-characterized human PFC specimens from the second trimester of gestation until old age ...” “DNA methylation at CpG dinucleotides has long been considered a key mechanism of transcriptional regulation and a critical factor in embryonic development and in cancer.”2

The researchers divided the PFC specimens by age into the fetal period, the childhood period, and those over ten years of age. The overall methylation changes were much greater during the fetal period, but involved fewer loci than in other life stages. During childhood and in later life, methylation changes occurred at a much slower rate (2–3 orders of magnitude slower).

One interesting finding was that many of the cancer-related genes began showing methylation changes during childhood and continuing into old age. Important tumor suppressor genes were found to have increased methylation levels during aging of adults. Hypermethylation silences the tumor suppressor genes, thereby increasing the risk of cancer.

We are beginning to see a deluge of papers on methylation changes with age. For example, another paper3 reported that age-dependent decreases in DNA methyltransferase and low transmethylation micronutrient levels (methyl donors) synergize to promote increased expression of genes implicated in autoimmunity and acute coronary syndromes. Generally, hypomethylation increases gene expression while hypermethylation silences genes by decreasing expression. Here, the researchers found that the age-associated decrease in DNA methyltransferase was synergistic with low folate, low methionine, or high homocysteine levels that demethylate and activate methylation-sensitive genes. Hypomethylation has also been shown to reactivate hypermethylated (silenced) tumor suppressor genes and that curcumin and EGCG are two natural materials that act as hypomethylating agents.5A,5B An additional paper4 reported that axonal regeneration in the repair of the adult central nervous system in rodents was mediated at least in part through DNA methylation and that folic acid, as a methyl donor, promotes methylation.

References

1. Hannum et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell. 49:359-67 (2013).
2. Numata et al. DNA methylation signatures in development and aging of the human prefrontal cortex. Am J Hum Genet. 90:260-72 (2012).
3. Li et al. Age-dependent decreases in DNA methyltransferase levels and low transmethylation micronutrient levels synergize to promote overexpression of genes implicated in autoimmunity and acute coronary syndromes. Exp Gerontol. 45:312-22 (2010).
4. Iskandar et al. Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation. J Clin Invest. 120(5):1603-16 (2010).
5A. Liu et al. Curcumin is a potent DNA hypomethylation agent. Bioorg Med Chem Lett. 19(3):706-9 (2009).
5B. Fang et al. Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res. 63(22):7563-70 (2003).

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