Proceedings of the Nutrition Society
A meeting of the Nutrition Society hosted by the Irish Section jointly with the American Society for Nutrition was held at University
College Cork, Republic of Ireland on 15–17 June 2011
70th Anniversary Conference on ‘Vitamins in early development and healthy
aging: impact on infectious and chronic disease’
Symposium 4: Vitamins, infectious and chronic disease during
adulthood and aging
Nutritional influences on epigenetics and age-related disease
Lara K. Park1,2, Simonetta Friso3and Sang-Woon Choi1,2*
1Vitamins and Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts
University, Boston, MA 02111, USA
2Biochemical and Molecular Nutrition Program, Friedman School of Nutrition, Tufts University, Boston, MA 02111, USA
3Department of Medicine, University of Verona School of Medicine, Verona, Italy
Nutritional epigenetics has emerged as a novel mechanism underlying gene–diet interactions,
further elucidating the modulatory role of nutrition in aging and age-related disease develop-
ment. Epigenetics is defined as a heritable modification to the DNA that regulates chromosome
architecture and modulates gene expression without changes in the underlying bp sequence,
ultimately determining phenotype from genotype. DNA methylation and post-translational
histone modifications are classical levels of epigenetic regulation. Epigenetic phenomena are
critical from embryonic development through the aging process, with aberrations in epigenetic
patterns emerging as aetiological mechanisms in many age-related diseases such as
cancer, CVD and neurodegenerative disorders. Nutrients can act as the source of epigenetic
modifications and can regulate the placement of these modifications. Nutrients involved in one-
carbon metabolism, namely folate, vitamin B12, vitamin B6, riboflavin, methionine, choline
and betaine, are involved in DNA methylation by regulating levels of the universal methyl donor
S-adenosylmethionine and methyltransferase inhibitor S-adenosylhomocysteine. Other nutrients
and bioactive food components such as retinoic acid, resveratrol, curcumin, sulforaphane and tea
polyphenols can modulate epigenetic patterns by altering the levels of S-adenosylmethionine and
S-adenosylhomocysteine or directing the enzymes that catalyse DNA methylation and histone
modifications. Aging and age-related diseases are associated with profound changes in epigenetic
patterns, though it is not yet known whether these changes are programmatic or stochastic in
nature. Future work in this field seeks to characterise the epigenetic pattern of healthy aging to
ultimately identify nutritional measures to achieve this pattern.
Nutrition: Aging: Epigenetics: DNA methylation: Histone modifications
In the advent of Genome Wide Association Studies, con-
siderable progress has been made elucidating genetic sus-
ceptibilities to complex chronic diseases(1). Despite this
progress there is still a substantial proportion of phenotypic
disparity that has not been explained by genetics, thus
shifting the focus to environmental influences. Nutrition is
a major environmental exposure that influences all aspects
of health and lifespan(2). Nutrients are known to alter gene
expression and thereby affect phenotype(3). Epigenetics is a
recently highlighted molecular mechanism by which
nutrients can alter gene expression(4). Epigenetic phenom-
ena are heritable and modifiable marks that regulate gene
Abbreviations: CpG, cytosine-guanine dinucleotides; DNMT, DNA methyltransferase; EGCG, epigallocatechin-3-gallate; HAT, histone acetyltransferase;
HDAC, histone deacetylase; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; SIRT1, Sirtuin 1.
*Corresponding author: Dr Sang-Woon Choi, fax +1 617 556 3234, email firstname.lastname@example.org
Proceedings of the Nutrition Society (2012), 71, 75–83
gThe Authors 2011 First published online 4 November 2011
Proceedings of the Nutrition Society
DNA methylation and histone modifications are classical
epigenetic phenomena that alter localised DNA compaction
to regulate expression(4). DNA methylation is a biochem-
ical modification of cytosine in DNA with a one-carbon
unit (a methyl group) and is typically associated with
gene repression(4). Post-translation modifications of histone
tails by methylation, acetylation, phosphorylation, biotiny-
lation and ubiquitination modulate the compaction of the
DNA around the core histones and serve as docking sites
for transcriptional regulators(4). Histone modifications can
either activate or repress gene expression depending
on the type of modification and the placement along the
histone tail(4). Extensive synergy exists between levels of
epigenetic marks to determine accessibility of genes to
Nutrition affects epigenetic phenomena at multiple
levels(4). First, nutrients act as a source of methyl groups or
as co-enzymes for one-carbon metabolism that regulates
methyl transfer(6). B-vitamins including folate, vitamin
B12, vitamin B6 and vitamin B2 are involved as co-
enzymes with methionine, choline, betaine and serine as
methyl donors for DNA methylation and histone methyla-
tion(7). Second, nutrients and bioactive food components
can directly affect enzymes that catalyse DNA methylation
and histone modifications(4). Third, diet is the ultimate
input determining systemic metabolism which modifies
cellular milieu leading to alterations in epigenetic pat-
without alteringthe underlying DNA
Although it is known that these epigenetic phenomena
can be modified by nutrients, their role in physiologic and
pathological processes has not been extensively studied
through these mechanisms(4). In this overview, we will
focus on the influences of nutrition on epigenetics and how
these influences affect the age-related diseases.
Nutrition and DNA methylation
Nutrients, one-carbon metabolism and DNA methylation
DNA methylation is the most studied epigenetic mechan-
ism which entails the addition of a methyl group at
cytosine–guanine dinucleotides (CpG)(9). The reactions
involved in DNA methylation are a part of one-carbon
metabolism, which regulates the transfer of the one-carbon
moiety (methyl group) into biological methylation reac-
tions(4). B-vitamins are coenzymes in one-carbon metabo-
lism (Fig. 1), supporting that nutrients regulate epigenetic
reactions(10). The amino acid methionine is converted to
S-adenosylmethionine (SAM), the unique methyl donor for
many biological methylation reactions including DNA
methylation(4). Folate-derived methyl groups are utilised
for remethylation of homocysteine to produce methio-
nine(10). Choline also provides methyl groups for the
folate-independent homocysteine remethylation reaction;
together these demonstrate how nutrients can serve as the
source of epigenetic modifications(11). After transferring
the methyl group, SAM is converted to S-adenosylhomo-
cysteine (SAH), an inhibitor of methyltransferases(11).
5, 10 methyleneTHF
Fig. 1. One-carbon metabolism. S-adenosylmethionine (SAM) is the unique methyl donor for many
biological methylation reactions including DNA and histone methylation. S-adenosylhomocysteine
(SAH) is an inhibitor of methyltransferases such as DNA methyltransferases (DNMT) and histone
methyltransferases. In one-carbon metabolism vitamins B2, B6, B12and folate are coenzymes, while
methionine, choline, betaine and serine are methyl donors. THF, tetrahydrofolate; 5-mTHF, 5-methyl-
tetrahydrofolate; MT, methyltransferases; HMT, histone methyltransferases; MTHFR, methylene-
tetrahydrofolate reductase; MS, methionine synthase; SHMT, serine hydroxymethyltransferase;
GNMT, glycine N-methyltransferase; CBS, cystathionine-b-synthase; MAT, methionine adenosyl-
transferase; SAHH, S-adenosylhomocysteine hydrolase; BHMT, Betaine homocysteine methyl-
transferase; B2, vitamin B2; B6, vitamin B6; B12, vitamin B12.
76 L. K. Park et al.
Proceedings of the Nutrition Society
Deficiency of B-vitamins, methionine and/or choline can
significantly affect DNA methylation by altering the levels
of SAM and SAH(4,12,13).
Modifying the intake of these nutrients alters DNA
methylation(14). In animal models, folate deficiency along
with aging(15)and multiple B-vitamins deficiency(16)in-
duced genomic DNA hypomethylation in the colon. It is
also reported that choline deficiency can change DNA
methylation independently(17)or in conjunction with defi-
ciency of other methyl donors(14). Prolonged intake of diets
deficient in sources of methyl groups such as methionine,
choline, folate and vitamin B12induce profound genomic
hepatic DNA hypomethylation in a rodent model(18). This
model has also demonstrated that a methyl-deficient diet
changes histone methylation(19)and microRNA produc-
tion(20), which may potentiate the development of liver
Two previous human studies conducted in a metabolic
unit demonstrated that marginal folate deficiency can
change blood genomic DNA methylation(21,22). Compared
to animal studies, however, evidence demonstrating sig-
nificant effects of folate supplementation on DNA methyl-
ation in free living human subjects is limited. Recently,
Pizzolo et al.(23)reported that 8-week daily supplementa-
tion of 5mg folic acid did not change DNA methylation in
peripheral mononuclear cells despite increases in blood con-
centrations of folate and SAM and decreases in SAH. This
observation suggests that changes in the levels of SAM and
SAH may not always induce changes in DNA methylation.
deficient mouse studies demonstrated that increased levels
of SAM and SAH are not always correlated with DNA
methylation status in a tissue-specific manner(24,25). It
is important to note that different tissues have different
susceptibilities to methyl deficiency and therefore this lack
of response may not be consistent across all tissues(26).
Other specific nutrients can modify one-carbon metabo-
lism to alter DNA methylation(4). Retinoic acid is known
to affect glycine N-methyltransferase which catalyses
DNA methylation assays demonstrated 166 differentially
methylated CpG sites between undifferentiated and retinoic
acid-treated human embryonic stem cells(28). Interestingly,
a high-throughput DNA methylation array with neuro-
blastoma cells in vitro demonstrated that 402 gene
promoters became demethylated and eighty-eight hyper-
methylated following retinoic acid treatment(29). These
studies indicate that nutrients can interact with the path-
ways regulating DNA methylation, though it remains to be
determined how nutrients target specific genes for epige-
netic modification or, alternatively, if these changes are
stochastic in nature.
The trace element Se is an essential component of the
oxidases(30). Se has been known to influence the trans-
sulfuration pathway in one-carbon metabolism which
converts homocysteine to cysteine and ultimately glu-
tathione(31). In a rodent study, Uthus et al.(32)found that
plasma total homocysteine and cysteine were significantly
decreased and glutathione significantly increased by Se
deficiency. They also found significantly decreased genomic
such asglutathione per-
DNA methylation by Se deficiency in the colon, with con-
comitant trend for decreased DNA methyltransferase
(DNMT) activity (P<0.06), suggesting a relationship
between Se metabolism and DNMT function(33). Most
recently, Zeng et al.(34)reported that dietary Se supple-
mentation increases exon-specific DNA methylation of the
tumour suppressor p53 in the rat liver and colon thereby
suggesting the over-supplementation with Se may increase
cancer risk. These observations indicate that Se alters
one-carbon metabolism leading to both genomic and gene-
specific changes in DNA methylation.
Research into the chemopreventive effects of vitamin D
has taken the forefront due to the role of the vitamin D
receptor in cell-cycle regulation and differentiation(35).
Recent evidence demonstrates that incubation of MCF-7
breast cancer cells with vitamin D3, which models oestro-
gen receptor+ non-invasive breast cancer, reduces the
aberrant hypermethylation and restores gene expression of
retinoic acid receptor b2(36)and phosphatase and tensin
homologue(37). Although this mechanism remains to be
validated in vivo, this work indicates that vitamin D can
modify gene-specific DNA methylation.
Bioactive food components and DNA methylation
Bioactive food components are compounds consumed in
the diet that are not essential for life, though they may
have beneficial health effects(4). Numerous bioactive food
components can alter epigenetic patterns through both
direct and indirect interactions with the enzymes regulating
the placement of epigenetic marks(4). Research indicates
that these interactions can be gene specific in nature, sug-
gesting that the bioactive food compounds may target these
enzymes to specific sites within the genome(38).
Genistein is an isoflavone belonging to the flavonoids
group of compounds derived from legumes that has
demonstrated great potential to regulate the epigen-
ome(39,40). In the agouti mouse model, it is well established
that maternal dietary genistein increases the level of DNA
methylation at the agouti locus and produces more pseudo-
agouti black coat-coloured offspring(41). In mouse embryo-
nic stem cells, genistein does not affect de novo methylation
occurring between day 0 and day 4, but interferes with sub-
sequent regulatory processes leading to decreased methyla-
tion at the uncoupling protein 1 and synaptotagmin-like 1
promoters(42). This indicates that genistein perturbed the
methylation pattern of differentiated embryonic stem cells
after de novo methylation in a time-dependent manner. Fang
et al.(43,44)reported that genistein dose-dependently inhib-
ited DNMT activity and partially reactivated genes repres-
sed by hypermethylation such as retinoic acid receptor b,
p16 and O-6-methylguanine-DNA methyltransferase in
oesophageal squamous cell carcinoma cell lines. Similar
effects were observed from the cancer cell lines of colon(45),
prostate(46)and cervix(47). These observations indicate that
genistein can modify DNA methylation tissue specifically,
gene specifically and life cycle specifically.
Epigallocatechin-3-gallate (EGCG), the primary poly-
phenol in green tea, is known to have anti-cancer effects
through many different mechanisms(48). One candidate
mechanism is the inhibition of DNMT1 leading to
Nutritional epigenetics and aging 77
Proceedings of the Nutrition Society
silenced genes(49). Nandakumar et al.(50)reported that
EGCG reactivates silenced tumour suppressor genes p21
and p16 by reducing DNA methylation in human skin
cancer cells, resulting in re-expression of mRNA and pro-
teins of silenced tumour suppressors. Wong et al.(51)also
reported that physiologically relevant concentrations of
EGCG can induce the expression of forkhead box P3, a
master switch that controls the development and function
of regulatory T-cells and Jurkat T-cells in vitro. These cells
play a critical role in the maintenance of tolerance and the
control of autoimmunity. The expression of forkhead box
P3 was associated with reduced DNMT expression and
DNA demethylation in EGCG-treated cells, suggesting that
EGCG may epigenetically modify forkhead box P3
methylation and promote regulatory T-cell induction
and expansion to potentially support the immune response
to cancer. The DNMT inhibitory effects of EGCG were not
as potent as pharmacologic agents such as 5-aza-20-
deoxycytidine, though this is not unexpected as nutrients
are not specifically designed as therapeutics. It appears that
EGCG provides potentially sustained and longer-term
exposure effects with lower toxicity compared with phar-
macologic agents, demonstrating the potential benefits of
natural substances as chemotherapeutics.
In addition to the direct inhibitory effects of DNMT1,
it is also reported that consumption of polyphenols
could increase the formation of SAH, which supports an
additional mechanism inhibiting DNA methylation by
EGCG(52). Animal studies also demonstrated that EGCG
consumption through drinking water can moderately
decrease the level of SAM in the intestine(44). Both obser-
vations indicate that the inhibitory effects of EGCG on
DNMT1 could be conveyed indirectly by modifying one-
Apigenin from parsley(44), curcumin from turmeric(53),
lycopene from tomato(54)and sulforaphane from cruciferous
vegetables(55)are also known to have an inhibitory effect
on DNMT, though their effects are weaker than that of
tea polyphenols and genistein. Further studies are needed
to determine the optimal nutrients intakes to effectively
regulate the epigenome in health.
Nutrition and histone modifications
Bioactive food components and histone modifications
Histone proteins are essential for the packaging of DNA
into chromosomes within the nucleus of a cell(56). Post-
translational modifications of histones have been high-
lighted due to their function to regulate gene expression,
especially synergistic interactions with DNA methyla-
tion(5). Further, dysregulated histone acetylation patterns
have been associated with many diseases including cancer,
cardiac hypertrophy and asthma(56–58). Among many dif-
ferent types of histone tail modifications, histone acetyla-
tion has been the most frequent target to evaluate the
epigenetic effects of nutrients, bioactive components and
aging(38,59). Histone acetylation is an epigenetic phenom-
enon that acetylates lysine residues at the histone tail
to alter local DNA compaction, leading to site-specific
changes in gene expression(60). The histone acetylation
status is regulated by a family histone acetyltransferases
(HAT) and histone deacetylases (HDAC).
Butyrate is generated during the fermentation of dietary
fibre in the large intestine(61). Early in 1977, Riggs et al.(62)
reported that addition of sodium n-butyrate to tissue cul-
ture media increases global histone acetylation in cancer
cell lines. Thereafter, sulforaphane, an isothiocyanate from
broccoli, broccoli sprouts and cabbage as well as allyl
compounds from garlic such as diallyl disulfide and S-allyl
mercaptocysteine have been demonstrated to have HDAC
inhibitory effects(39). In light of the development of che-
motherapeutic HDAC inhibitors, this suggests potential
functional significance of this family of bioactive food
components as chemopreventive agents to regulate histone
Curcumin, a yellow pigment present in the spice tur-
meric (Curcuma longa), has been linked with multiple
beneficial activities with anti-inflammatory, antioxidant
and anti-cancer properties(64). Curcumin is known to have
inhibitory activity against HDAC and HAT, with a speci-
fically strong inhibition of HAT in cancer models(64,65).
Kang et al.(66)demonstrated that curcumin-mediated HAT
inhibitory activity is associated with decreased histone 3
and 4 acetylation in both glioblastoma cancer cells and
adult neural-derived stem cells. Functionally, these epige-
netic changes were associated with increased apoptosis in
cancer cells and promoted neuronal differentiation in stem
cells, suggesting possible therapeutic potential in cancer
and neurodegenerative diseases.
Aging and nutritional epigenetics
There is a body of literature demonstrating changes in
epigenetic patterns over the aging process. It is currently
unknown whether these changes are programmatic or stoch-
astic, and whether they are causal or resultant of the aging
process in itself(67). Aging is known to affect DNA meth-
ylation in a complex fashion(68). Total methylcytosine
content is prone to decrease by aging, leading to genomic
hypomethylation in most vertebrate tissues(69,70), whereas
promoter regions tend to undergo paradoxical hypermeth-
ylation in many genes(71). The most plausible mechanism
proposes that decreased expression of the maintenance
DNMT1 underlies reduced genomic hypomethylation,
while increased expression of de novo DNMT mediates
In previous studies, aging reduces genomic DNA
methylation and increases promoter methylation of p16
tumour suppressor gene in the mouse colon(15). Dietary
supplementation of the methyl donor folate increased both
genomic and p16 promoter DNA methylation in the aged
mouse colon but not in the young, indicating that DNA
methylation can be modified by diet in an age-dependent
Wallace et al.(74)investigated the association of blood
folate levels with promoter CpG island methylation in
normal colorectal mucosa in a multicentre chemopreven-
tion trial of aspirin or folic acid for the prevention of
colonic adenoma. For each 10-year difference in age,
78L. K. Park et al.
Proceedings of the Nutrition Society
they observed a 1.7% increase in methylation level for
oestrogen receptor a and a 2.9% increase for secreted
frizzled-related protein-1, both of which were statistically
significant (P<0.0001). These genes are particularly rele-
vant because secreted frizzled-related protein-1 acts as an
inhibitor of the Wnt signalling, a pathway that is implicated
in colorectal carcinogenesis(75). Oestrogen receptor a acti-
vates a transcriptional programme regulating cellular pro-
liferation, and this activity changes with aging due to
reductions in sex hormones(76). Erythrocyte folate levels
were positively associated with methylation levels of both
oestrogen receptor a (P<0.03) and secreted frizzled-
related protein-1 (P<0.01)(74). These results suggest that
promoter CpG methylation in normal colorectal mucosa
correlates with age and erythrocyte folate levels and that
erythrocyte folate could be a clinical marker of colorectal
Normal aging is accompanied by a profound loss of his-
tone proteins from the genome that hypothetically would
have a profound effect on genomic structural integrity
and the regulation of transcriptional programmes(77). Pre-
vious work in yeast models demonstrates increased overall
histone expression promotes lifespan, underscoring the
importance of histone-mediated regulation of DNA archi-
tecture in health(78).
Sirtuins, a group of conserved NAD+-dependent de-
acetylases, promotelongevity inmanyorganisms(79).Sirtuin
1 (SIRT1) is known to deacetylate histones and non-histone
proteins, thereby regulating metabolism, stress resistance,
cellular survival, cellular senescence/aging, inflammation-
immune function, endothelial functions and circadian
rhythms(79). Yeast silent information regulator 2, related to
the mammalian homologue SIRT1, establishes and main-
tains chromatin silencing by removing acetylation at his-
tone H4 at lysine 16 (H4K16)(80). Dang et al.(81)reported
an age-associated decrease in silent information regulator
2 protein accompanied by an increase in acetylation at
H4K16, resulting in compromised transcriptional silencing.
Naturally occurring dietary polyphenols, such as re-
sveratrol, curcumin, quercetin and catechins, have been
shown to activate SIRT1 in a variety of models(82). Since
the activation of SIRT1 by polyphenols is beneficial in
various cellular functions in response to environmental and
pro-inflammatory stimuli, the regulation of SIRT1 activity
by dietary polyphenols is a promising strategy against
chronic inflammation, which plays an aetiological role in
many age-related diseases.
Li et al.(83)found that histone H3 acetylation at lysine
9 and 14 sites, H3K9 and H3K14, respectively, which
can be modulated by extrinsic signals, plays a key role
in regulating mesenchymal stem cell aging and differ-
entiation. Human mesenchymal cells in early and late
passages were examined for their expression of osteogenic
genes and genes involved in self-renewal and proliferation
to determine their in vitro spontaneous differentiation
towards the osteoblast lineage v. multi-potent potential,
respectively. Altered expression of these genes were clo-
sely associated with epigenetic dysregulation of H3K9
and H3K14 acetylation but not with methylation of
CpG islands in the promoter regions of most of these
genes, suggesting that histone acetylation may be more
sensitive to cellular senescence than DNA promoter
Nutritional influences on age-related diseases
Epigenetic patterns are heavily influenced by the environ-
ment; due to dietary requirements for sustenance, it follows
that nutrition represents a substantial daily environmental
input(84). Nutrition influences our physiology over the
course of the entire lifecycle, with particular phases rep-
resenting times that are more sensitive to nutritional
inputs(85). Most recent studies indicate that the effects of
nutrition in early life alters programmes leading to differ-
ential disease susceptibilities later in life which may be
conveyed through epigenetic mechanisms(86). Furthermore,
the majority of age-related chronic diseases in the devel-
oped world are multi-factorial with substantial lifestyle
components, indicating a significant role for nutritional
epigenetics in their development(87).
Sie et al.(88)investigated the effect of maternal and
post-weaning folic acid supplementation on colorectal
cancer risk in the offspring. The data suggested for the first
time that maternal folic acid supplementation at North
American post-fortification levels recommended to women
at reproductive age protects against the development of
colorectal cancer in the offspring. This protective effect
may be mediated in part by increased global DNA
methylation, decreased epithelial proliferation and reduced
DNA damage in the colorectum. However, the same group
reported that high intrauterine and post-weaning dietary
exposure to folic acid may increase the risk of mammary
tumours in the offspring, mediated in part by altered DNA
methylation and DNMT activity(89). These results indicate
that different tissues have variable responses to folic acid
supplementation, again emphasising the tissue specificity
of epigenetic regulation.
The disruption of the HAT and HDAC balance can also
be a major mechanism underlying changing epigenetic
patterns with functional disease output, including cancer
and neurodegeneration(90). In a rodent study, aged mice
display specific deregulation of histone H4 at lysine 12
(H4K12) acetylation during learning and fail to initiate a
hippocampal gene expression programme associated with
memory consolidation. Restoration of deregulated histone
acetylation reinstates the expression of learning-induced
genes and recovers cognitive functions, purporting the
importance of epigenetic histone regulation in neurological
function(91). Interestingly, Govindarajan et al.(92)reported
that butyrate, which is known to have an HDAC inhibitory
effect, improves memory function in an Alzheimer’s dis-
ease mouse model when administered at an advanced stage
As aberrant histone deacetylation has been demonstrated
to silence critical genes in carcinogenesis, HDAC inhibi-
tors have great potential as new anti-cancer drugs due to
their ability to modulate transcription(93). HDAC inhibitors
such as trichostatin-A induce apoptosis and suppress can-
cer cell growth by affecting the acetylation status of
tumour suppressor genes in cancer cell lines, though their
specificity to gene targets is not well understood(94,95).
Nutritional epigenetics and aging79
Proceedings of the Nutrition Society
Sulforaphane and curcumin have similar effects on cancer
cells by modifying histone acetylation(64,96). Sulforaphane
inhibits HDAC activity in vivo and suppresses tumorigen-
esis in APCminmice(97). In vitro, sulforaphane exerts dif-
ferential effects on cell proliferation, HDAC activity and
downstream targets in both normal and cancer cells(96).
Accompanied by reduced HDAC4 expression and activity,
curcumin induces apoptosis and cell cycle arrest in
medulloblastoma cells in vitro and reduced tumour growth
in in vivo medulloblastoma xenografts(98). These observ-
ations indicate that both sulforaphane and curcumin or any
other bioactive components that have histone modification
effects have the potential to be developed as cancer che-
motherapeutic agents. Similar to trichostatin-A, it is
important to determine the gene specificity of this nutrient-
induced HDAC repression. Furthermore, studies need to
determine whether the amounts of these nutrients can be
consumed in the whole diet at physiological quantities or if
supraphysiological supplements are required. The timing
of nutrient exposure needs to be determined as well; are
these nutrients effective at reducing carcinogenesis prior to
cancer development, during early carcinogenesis or in late-
Nutrition, systemic metabolism and epigenetics
In contrast to single-nutrient–single-gene interactions,
systemic metabolism also plays a role in determining diet–
gene interactions(8). In light of the increasing prevalence of
obesity and subsequent development of type II diabetes
mellitus, a large proportion of the population is being
exposed to chronic hyperglycaemia and impaired lipid
homoeostasis leading to a substantially different cellular
milieu(99). Epigenetic mechanisms are currently being
investigated within the scope of the metabolic profiles
characteristic of obesity and its associated sequellae(100).
Exposure of macrophages to high glucose to model
demethylase 1H3 and a reduction in H3K9 methylation at
the NF-kB-p65 gene promoter leading to an increased
expression of this transcription factor(100). Similar results
were observed in both endothelial cells and vascular
smooth muscle cells(101). These epigenetic marks were
sustained following return to normoglycaemic conditions,
lending support to the notion of metabolic memory that has
been observed in clinical studies describing persistent
vascular injury following previous poor metabolic con-
trol(102). Furthermore, human vascular smooth muscle cells
treated with high-glucose conditions demonstrated activat-
ing histone 3 at lysine 4 (H3K4) dimethylation marks and
increased gene expression at the NF-kB targets, monocyte
chemotactic protein-1 and IL-6, indicating epigenetic
mechanisms underlying the hyperglycaemia-induced vas-
Hypercholesterolaemia and circulating oxidised LDL
are also systemic metabolic characteristics that potentiate
the development of age- and obesity-related chronic dis-
eases(104). Consistent with the notion that chronic in-
flammation plays an aetiological role in atherogenesis,
incubation of human umbilical-cord vein endothelial
cells with oxidized LDL also led to altered epigenetic
marks at inflammation-related genes(105). Cells exposed
to oxidized LDL demonstrated recruitment of cAMP-
response-element-binding protein-binding protein/p300 and
reduced HDAC1 and HDAC2 binding leading to increased
activating histone marks at the IL-8 and monocyte che-
moattractant protein-1 promoters. In utero exposure to
hypercholesterolemia from ApoE- / -mothers led to dif-
ferential global histone methylation patterns in offspring
vascular smooth muscle cells and endothelial cells(106).
These effects were further potentiated when offspring were
fed a high-fat diet inducing hypercholesterolemia. Studies
in primate models have demonstrated that maternal high-
fat diet leads to altered hepatic histone modifications and
epigenetic enzyme expression, with gene-specific changes
localised to genes involved in circadian rhythms, lipid
metabolism and heat shock responses(107). Taken together,
these studies demonstrate that both trans-generational and
post-natal exposure to the metabolic characteristics of high-
fat diet and hypercholesterolaemia lead to differential epi-
genetic patterns in various tissues which may potentiate
chronic disease development later in life.
Conclusion and future perspectives
The field of nutritional epigenetics is further elucidating
the nature of gene–diet interaction, thus providing support
for the role of nutrition and lifestyle in determining
phenotype from genotype(10). Aging is associated with
substantial changes in epigenetic patterns and recent work
is implicating epigenetic mechanisms in the aetiology of
many age-related diseases(108). In some cases, evidence
suggests that nutrients may slow down the age-related
epigenetic changes and delay disease onset, though it is too
soon to draw broad conclusions(86). Future work seeks to
characterise the epigenetic pattern of healthy aging and to
identify nutritional measures to achieve this pattern.
Nutritional epigenetics is a field in its infancy; there
is much research to be done that has great potential to
yield findings with significant public health implications.
Questions that remain to be answered include determining
the tissue specificity of nutrient exposures, particularly as
many studies have been performed in vitro with single-cell
types. Specific timing of nutritional exposures and their
concomitant efficacy of epigenetic regulations needs to be
examined. Accumulating evidence supports the notion that
maternal nutrition is critical in epigenetic programming of
offspring(109), but other time periods of the lifecycle need
to be investigated. This is particularly critical with respect
to nutritional epigenetic interventions for diseases; should
exposure be prior to disease development, implicating the
importance of lifetime dietary patterns, or can there be
effective therapeutic effects following disease diagnosis?
Last, the question remains as to whether nutrition and
aging modulate epigenetic patterns in a programmatic
fashion or if the effects are more stochastic in nature.
Genome Wide Association Studies technology that identi-
fied original gene–diet interactions is now being applied
to nutritional epigenetics, embarking into the arena of
Epigenome-Wide Association Studies which will support
80 L. K. Park et al.
Proceedings of the Nutrition Society
There is significant impetus to continue research within
the field of nutritional epigenetics as the findings may
support significant public health applications. While DNA
sequences cannot be changed and aging cannot be avoided,
individuals have the ability to change their diet. Nutrition
has the potential to modulate the interactions between
genes, aging and disease susceptibility through epigenetic
mechanisms. Future work promises fruitful results under-
lying the role of nutrition guiding healthful aging pheno-
types from genotype.
This material is based on work supported by the U.S.
Department of Agriculture, under agreement no. 58-1950-
7-707. Any opinions, findings, conclusion, or recommen-
dations expressed in this publication are those of the
author(s) and do not necessarily reflect the view of the U.S.
Department of Agriculture. The authors declare no con-
flicts of interest. This project was supported in part by
the National Institute of Health Grant R01 AG025834
(to S.W.C.). L.K.P., S.F. and S.W.C. participated in the
conception, design and drafting of the manuscript.
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