Why do we age (part 2): aging-associated DNA methylation changes

Written by Professor Monika Puzianowska-Kuznicka, Warsaw University, Poland

One of the hallmarks of epigenetic drift is a progressive change in DNA methylation. This was very nicely shown by Fraga and co-workers who discovered that young monozygotic twins are epigenetically very similar, but older monozygotic twins exhibit remarkable differences in their overall content and genomic distribution of 5-methylcytosine DNA (Fraga et al., 2005).

It is believed that the global genome methylation decreases with age (Heyn et al., 2012) in the majority of (if not all) tissues, that loss of 5-methylcytosine content occurs mostly within repeated sequences, and that this might be associated with a reduced expression of DNMT1 (Casillas et al., 2003). It should be remembered, however, that significant inter-individual differences in DNA methylation have been discovered in longitudinal studies with both increase and decrease of the global genome methylation over the period of more than 10 years (Bjornsson et al., 2008), showing that this phenomenon deserves further study. Another DNA methylation-associated feature of epigenetic drift is the age-associated increase of methylation of the regulatory regions of certain genes, partly due to over expression of DNMT3B (Lopatina et al., 2002; Casillas et al., 2008; Heyn et al., 2012). It is, at least in part, tissue-specific. An example is the increased methylation of the ESR1 gene promoter in colon or RARB2, RASSF1A, GSTP1, ESR1 and NKX2-5 in prostate of aged humans (Issa et al., 1994; Kwabi-Addo et al., 2007). It should be noted, though, that the methylation of other genes might remain unchanged or be decreased in aged individuals (Polosak et al., 2011). Notably, methylation changes of certain sequences such as the EDARADD, TOM1L1, NPTX2, ELOVL2 (!), FHL2, and PENK (Bocklandt et al., 2011; Garagnani et al., 2012; Hannum et al., 2013) genes can serve as age-predicting factors. Again, this aspect of epigenetic drift is highly understudied and also requires further attention.

A number of studies suggest that aging-associated DNA methylation changes may direct cells into a “stem-like” state predisposing to cancer (Teschendorff et al., 2010; Rakyan et al., 2010), partly explaining a higher risk of carcinogenesis in aged individuals.

Dietary constituents, by affecting the DNA methylation status, can affect aging. These are enzyme co-factors such as folate and vitamins B12 and B6, as well as methyl group donors such as methionine, choline, betaine and serine that increase methylation, and selenium, green tea polyphenols and bioflavonoids (e.g. epigallocatechin-3-gallate, genistein, quercetin and fisetin) that reduce methylation. However, while some reports indicate that hypomethylation-promoting diet constituents are profitable, others show that in fact methylation-promoting nutrients are beneficial (reviewed in Bacalini et al., 2014). Therefore, due to lack of consistent data, now it is difficult to formulate recommendations regarding the diet that would specifically slow down or even reverse aging-related methylation changes. As I currently see it, Aristotle’s theory of the golden mean should be utilized in planning your diet, that should consist of both methylation- and de-methylation-promoting nutrients; such an approach will allow your endogenous mechanisms to work optimally. I will write more about anti-aging diets in further blog posts.

Figure shows a participant of the Polish Centenarian Programme (PolStu).


Bacalini MG, et al. Present and future of anti-ageing epigenetic diets. Mech Ageing Dev. 2014 Jan 2 [epub ahead of print]. doi:10.1016/j.mad.2013.12.006.

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Bocklandt S, et al. Epigenetic predictor of age. PLoS One. 2011;6(6):e14821. doi:10.1371/journal.pone.0014821.

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Fraga MF, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 2005;102:10604-10609.

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Issa JP, et al. Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet. 1994;7:536-540.

Kwabi-Addo B, et al. Age-related DNA methylation changes in normal human prostate tissues. Clin Cancer Res. 2007;13:3796-3802.

Lopatina N, et al. Differential maintenance and de novo methylating activity by three DNA methyltransferases in aging and immortalized fibroblasts. J Cell Biochem. 2002;84:324-334.

Polosak J, et al. Aging is accompanied by a progressive decrease of expression of the WRN gene in human blood mononuclear cells. J Gerontol A Biol Sci Med Sci. 2011;66:19-25.

Rakyan VK, et al. Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res. 2010;20:434-439.

Teschendorff AE, et al. Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res. 2010;20:440-446.

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