Do age-related changes in DNA methylation play a role in the development of age-related diseases?

Abstract

DNA methylation is an important epigenetic mechanism in mammalian cells. It occurs almost exclusively at CpG sites and has a key role in a number of biological processes. It plays an important part in regulating chromatin structure and has been best studied for its role in controlling gene expression. In particular, hypermethylation of gene promoters which have high levels of CpG sites, known as CpG islands, leads to gene inactivation. In healthy cells, however, it appears that only a small number of genes are controlled through promoter hypermethylation, such as genes on the inactivated X-chromosome or at imprinted loci, and most promoter-associated CpG islands remain methylation-free regardless of gene expression status. However, a large body of evidence has now shown that this protection from methylation not only breaks down in a number of pathological conditions (e.g. cancer), but also already occurs during the normal process of aging. The present review focuses on the methylation changes that occur during healthy aging and during disease development, and the potential links between them. We focus especially on the extent to which the acquisition of aberrant methylation changes during aging could underlie the development of a number of important age-related pathological conditions.

Full text

Biochemical Society Annual Symposium No. 80
Biochemical Society Annual
Symposium No. 80
Do age-related changes in DNA methylation play a
role in the development of age-related diseases?
Sanne D. van Otterdijk*1, John C. Mathers† and Gordon Strathdee*
*Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, U.K., and †Human Nutrition Research Centre, Centre for Brain
Ageing and Vitality, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE4 5PL, U.K.
Abstract
DNA methylation is an important epigenetic mechanism in mammalian cells. It occurs almost exclusively at
CpG sites and has a key role in a number of biological processes. It plays an important part in regulating
chromatin structure and has been best studied for its role in controlling gene expression. In particular,
hypermethylation of gene promoters which have high levels of CpG sites, known as CpG islands, leads to
gene inactivation. In healthy cells, however, it appears that only a small number of genes are controlled
through promoter hypermethylation, such as genes on the inactivated X-chromosome or at imprinted loci,
and most promoter-associated CpG islands remain methylation-free regardless of gene expression status.
However, a large body of evidence has now shown that this protection from methylation not only breaks
down in a number of pathological conditions (e.g. cancer), but also already occurs during the normal process
of aging. The present review focuses on the methylation changes that occur during healthy aging and during
disease development, and the potential links between them. We focus especially on the extent to which
the acquisition of aberrant methylation changes during aging could underlie the development of a number
of important age-related pathological conditions.
Introduction
Epigenetic mechanisms play an important role in numerous
cellular processes, such as genomic imprinting [1], X-
chromosome inactivation [2] and cell differentiation [3]
(Figure 1). One of the primary epigenetic mechanisms
is DNA methylation, which involves the addition of a
methyl group to the fifth position of a cytosine base by
enzymes called DNMTs (DNA methyltransferases). This
occurs almost exclusively in cytosines that are immediately
followed by a guanine, forming so-called CpG dinucleotides
[4]. CpG dinucleotides are underrepresented throughout the
genome, except for short stretches of DNA known as CpG
islands [5], which are frequently associated with human genes.
The state of methylation of CpG islands near gene promoters
has been associated with the transcriptional activity of a gene
[6], although it has been shown that even methylation levels
in CpG islands further away from the gene promoter, so-
called CpG island shores, are related to gene expression
[7]. However, it remains uncertain whether methylation is
Key words: age-related disease, aging, cancer, DNA methylation, epigenetics.
Abbreviations used: CLL, chronic lymphoblastic leukaemia; MMR, mismatch repair.
1To whom correspondence should be addressed (email s.d.van-otterdijk@ncl.ac.uk).
involved directly in silencing gene expression or whether it
plays a role in maintaining the silenced state which has been
induced by the associated epigenetic marks on histones and
other epigenetic molecules [8].
In healthy individuals, CpG islands remain mostly
methylation-free, whereas most of the non-island-associated
CpG sites in the bulk of the genome are methylated [5].
Even though patterns of methylation are inherited through
cell divisions, the copying of methylation patterns from
parental to daughter strand is not 100% efficient and
methylation errors accumulate [9]. The rate at which these
errors are accumulated increases with age and during disease
development. In the present review, we focus on the changes
in methylation levels that occur both during healthy aging and
during the development of age-related diseases. In particular,
to what extent do methylation changes during aging influence
the susceptibility to develop age-related diseases?
Methylation levels change during healthy
aging
Because of the important demographic changes occurring
across most of the world which are leading to an increasingly
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804 Biochemical Society Transactions (2013) Volume 41, part 3
Figure 1 Functional roles of DNA methylation
DNA methylation plays important roles in key biological processes, such
as differentiation, which allows stem cells and multipotent progenitor
cells to differentiate into multiple different cell lineages, imprinting,
which allows certain genes to be expressed in a parent-of-origin specific
matter, and silencing of large chromosomal domains, such as inactivation
of the X-chromosome in females.
elderly population [10], aging and age-related diseases are
becoming a major health priority. Life expectancy has
increased steadily over the last two centuries [11], but a
significant proportion of the extra life years is associated
with morbidity. Age-related diseases, including cancers,
cardiovascular disease and dementia, are now the dominant
health problems in most countries. Identifying the underlying
molecular changes that occur as part of the aging process
and how this contributes to the development of age-related
diseases will be critical for improving the health outcome
for elderly patients and also in underpinning potential
preventative strategies.
Alterations in the patterns of DNA methylation are one of
the hallmarks of aging [12]. These changes include reduced
levels of global DNA methylation across the genome, in
conjunction with local areas of hypermethylation, often
centring on promoter-associated CpG islands. Furthermore,
DNA methylation levels have been observed to change
with age in multiple tissue types in both mice and human
studies [13–17], implying that altered patterns of methylation
are an inevitable consequence of aging in mammalian cells.
The exact timing of these changes in methylation, and the
biological driving forces behind them, remains unclear, but
several human and animal studies have suggested that it is
not a process solely associated with old age, but that it
is an ongoing process over the course of life [16,18]. A
previous study by Teschendorff et al. [15] indicated that
increased levels of DNA methylation in promoter regions
are steadily acquired during the course of life and it has
been observed by Talens et al. [19] that epigenetic variation
in the population also increases gradually with age. The
rate at which these changes occurred differed between
different loci and these changes can be substantial at loci
regulating transcription of nearby genes [19]. Whereas several
studies reported that regions near gene promoters become
hypermethylated with age, several repetitive sequences lose
methylation with increasing age, such as the Alu elements
[20], Line-1 [21] and HERV-K [22]. Even though age-related
methylation changes are observed in many tissues, patterns of
DNA methylation are tissue-specific [23], and, during aging,
individual genes acquire differential methylation patterns
in different tissue types [14,24]. However, although it is
clear that altered DNA methylation is linked strongly
with aging, the biological consequences of the observed
DNA methylation changes are far less clear. The advent of
methods for more precise delineation of DNA methylation
levels, such as the use of pyrosequencing, have made age-
related methylation changes at many loci readily detectable.
However, the extent to which this actually alters expression
levels of genes, and, as a consequence, cellular function,
remains largely unknown. Tissue- and cell-type-specific
differences in DNA methylation patterns cause a number
of difficulties in clearly understanding age-related alterations
in DNA methylation. Almost all studies are carried out using
tissue samples, which are a mixture of different cell types. This
means interpretation of the results obtained for methylation
patterns in the tissues may be confounded by age-related
changes in the cellular make-up of tissues. In addition, the
extent of age-related changes may be underestimated if
the changes occur only in one specific cell type in the tissue
being assessed.
Aberrant patterns of methylation are
observed in diseases
An important role for altered DNA methylation in the
development of disease is strongly suggested by the growing
number of human diseases that are known to occur when
the epigenetic information is not properly established during
embryonic and fetal development or maintained later in life.
The importance of DNA methylation was first discovered
in genetic disorders, such as Prader–Willi syndrome and
Angelman syndrome, that result from loss of expression of a
cluster of imprinted genes [25]. Recently, DNA methylation
is most extensively studied in cancers, although changes in
DNA methylation have been described in multiple other
diseases, such as cardiovascular, neurological and metabolic
disorders, and autoimmune diseases.
During cancer development, reduced levels of global DNA
methylation is observed, together with hypermethylation of
some CpG islands in gene promoters [26]. Hypermethylation
is frequently observed in the same genes that are often
mutated in familial cancers, emphasizing their causal
importance in tumorigenesis. For example, loss of function
of DNA MMR (mismatch repair) genes, including MLH1,
are causal for HNPCC (hereditary non-polyposis colorectal
cancer) [27], whereas, in sporadic colorectal cancer, loss
of microsatellite instability (an effect of MMR) is due to
hypermethylation of MLH1 [28]. Another example is the
congenital BRCA1 mutation, which is a cause of breast and
ovarian cancer. It is the same gene, however, that becomes
frequently hypermethylated in sporadic breast and ovarian
cancers [29,30]. In some cases, frequent hypermethylation
of genes can be used to identify novel tumour-suppressor
genes, as was the case for RASSF1 [31], HACE1 [32]
and TWIST2 [33]. Hypermethylation of tumour-suppressor
genes is a feature of several cancers, including the p15 gene
in leukaemia [34], the Rb gene in retinoblastoma [35] and
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Biochemical Society Annual Symposium No. 80: Epigenetic Mechanisms in Development and Disease 805
the VHL gene in renal tumours [36]. On the other hand,
hypomethylation was observed in several cancers in tumour-
promoting or metastasis-promoting genes, such as the uPA
gene in breast cancer [37] and the MAGEB2 gene in head and
neck squamous cell carcinomas [38].
Whereas many genes that have similar functional roles
are methylated during cancer development, some of the
specific genes which are methylated are tumour-type-specific,
whereas others are shared by multiple tumour types [39], such
as the p16/CDKN2 gene [40], the RASSF1 gene and HIC1
gene [41].
Aberrant methylation patterns occur in other pathologies
in addition to cancers. And, whereas in tumours, the causal
methylation changes are in tumour-suppressor genes and
in oncogenes, in cardiovascular diseases, the genes that
change methylation patterns are thought to be involved
in lipid oxidation, inhibition of endothelial cell migration
and formation, the control of cell proliferation and
angiogenesis [42–45]. However, whereas for cancers, the
causal role of DNA methylation is well established, for
cardiovascular diseases, the direct functional link of these
altered methylation patterns is not as clear. The role of DNA
methylation in cardiovascular diseases is discussed in a recent
review [46], and is not reviewed further in the present article.
Neither do we expand on the role of DNA methylation in
other diseases, such as neurological disorders [47], metabolic
disorders [48] and autoimmune disorders [49].
Cross-talk between methylation changes
during aging and disease susceptibility
The changes in DNA methylation patterns observed during
aging are reminiscent of the methylation alterations seen
during cancer development, i.e. loss of DNA methylation
at the genome-wide level in combination with gains in
methylation levels in CpG islands in or near gene promoters.
This raises the possibility that the acquisition of methylation
changes during healthy aging and during the development of
a disease might be linked to each other. The methylation
patterns of functionally important promoter regions are
reported to be more stable as opposed to non-promoter
regions and the corresponding genes might be involved
in longevity [16,50]. Global DNA methylation levels were
reported to correlate negatively with frailty measurements in
individuals over 65 years of age [51]. Indeed, there is some
evidence that genes that are differentially methylated during
healthy aging and during the development of diseases show
a degree of overlap. Teschendorff et al. [15] showed that
there was an overlap between the genes that showed age-
related methylation changes and genes that were reported
previously to be methylated in cancers, such as the genes
TP73 and SFRP1, two genes that were shown to become
methylated in different types of cancers. Rakyan et al.
[52] showed a significant correlation specifically between
bivalent chromatin domain DMRs that showed age-related
hypermethylation and aberrantly methylated promoters in
primary AML (acute myeloid leukaemia).
Before being able to understand the link between aging
and disease development, it is first necessary to understand
the precise role that DNA methylation plays during disease
development. Currently, this remains uncertain, although
several plausible hypotheses can be suggested. The first
hypothesis describes the changes in methylation levels as
events that occur during the process of clonal expansion. This
suggests that methylation changes are not the driving force
behind the development of the disease, but rather a side effect
of disease development. In the second hypothesis, methyla-
tion changes occur during the process of clonal expansion.
However, the methylation event could be aetiologically
important, e.g. in producing further growth and proliferative
advantages of the targeted cells over the non-targeted cells
and so promote disease development. A third hypothesis
states that diseases develop in cells that are pre-primed by
aberrant patterns of DNA methylation. In this hypothesis,
altered patterns of methylation pre-exist in a subset of appar-
ently normal cells. If cancer-driving mutations occur in a cell
with a pre-existing methylation pattern, this cell can rapidly
proliferate and lead to disease (Figure 2). This hypothesis
is supported by the observation that methylation patterns
are already present in apparently normal tissues from those
at higher cancer risk [53] and in pre-cancerous tissues [54].
However, these three hypotheses are not mutually exclusive
and a combination of these hypotheses might be possible.
Two possible hypotheses can explain the link between
the methylation changes that occur during aging and during
disease development. First, both age-related and cancer-
related DNA methylation changes might be driven by similar
mechanisms, which is causing the similar patterns of altered
methylation during cancer and aging. This hypothesis is
supported by the evidence that the same lifestyle factors
which influence the aging process influence the risk of cancer
and of other age-related diseases and modulate patterns of
DNA methylation [55,56]. The second hypothesis states that
age-related DNA methylation may underlie the development
of cancer, and possibly other age-related diseases. This
suggests that methylation is already present in apparently
healthy individuals before the development of the disease and
the disease then develops from cells with altered methylation
patterns (Figure 2). This hypothesis is supported by the
observation that in CLL (chronic lymphoblastic leukaemia),
global DNA methylation was shown to be relatively stable
over time and similar within different CLL compartments
[57], suggesting that cancer cells are not necessarily highly
methylation unstable. However, more research is necessary to
determine what the precise link is between DNA methylation
changes seen in aging and disease development.
Conclusion
DNA methylation levels change during healthy aging.
These changes in methylation levels during aging are
reminiscent of methylation alterations observed during
disease development. The precise mechanisms behind this
link remain unclear. In the present review, we have suggested
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806 Biochemical Society Transactions (2013) Volume 41, part 3
Figure 2 Possible role of DNA methylation during disease development and the link with aging
Three possible hypotheses can explain the role of DNA methylation in disease development. (A) Methylation changes are
an effect of the clonal expansion of cells before disease development, but it does not play a role in the development of
the disease. (B) Methylation changes occur during the clonal expansion of cells that occur before disease development. The
methylation events will then produce further growth advantages, promoting development of disease. (C) Methylation levels
are already present in a subset of normal cells. Disease develops when these ‘methylation-primed’ cells clonally expand.
These three hypotheses lead to new hypotheses explaining the link between DNA methylation changes during healthy
aging and disease: (i) in the case of (A)or(B), both aging and disease-related DNA methylation changes are driven by
similar mechanisms; (ii) in the case of hypothesis (C), age-related DNA methylation underlies the development of cancer,
and possibly other diseases.
two possible hypotheses in understanding the link that exists
between healthy aging and disease development. First, both
age-related and cancer-related DNA methylation changes
are driven by similar mechanisms. The second possible
hypothesis is that age-related DNA methylation underlies
the development of cancer, and possibly other diseases.
Funding
The work of G.S. and S.D.v.O. is supported by the Newcastle National
Institute for Health Research (NIHR) Biomedical Research Centre,
Tyneside Leukaemia Research Association, Dunhill Medical Trust,
Biotechnology and Biological Sciences Research Council and Children
with Cancer. The work of J.C.M. is supported by the Biotechnology
and Biological Sciences Research Council [grant number BH090948]
and through the Centre for Brain Ageing and Vitality which is funded
through the Lifelong Health and Wellbeing cross-council initiative by
the Medical Research Council, Biotechnology and Biological Sciences
Research Council, Engineering and Physical Sciences Research
Council and Economic and Social Research Council and by the U.K.
Department of Health.
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Received 21 December 2012
doi:10.1042/BST20120358
C
The Authors Journal compilation C
2013 Biochemical Society