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Biomolecular Concepts

Editor-in-Chief: Di Cera, Enrico


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Volume 6, Issue 2

Issues

Longevity: epigenetic and biomolecular aspects

Giusi Taormina
  • DiBiMed Universita’ degli Studi Di Palermo, Via Divisi 83, I-90133 Palermo, Italy
  • DICGIM Universita’ degli Studi Di Palermo, I-90100 Palermo, Italy
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Mario G. Mirisola
Published Online: 2015-04-17 | DOI: https://doi.org/10.1515/bmc-2014-0038

Abstract

Many aging theories and their related molecular mechanisms have been proposed. Simple model organisms such as yeasts, worms, fruit flies and others have massively contributed to their clarification, and many genes and pathways have been associated with longevity regulation. Among them, insulin/IGF-1 plays a key and evolutionary conserved role. Interestingly, dietary interventions can modulate this pathway. Calorie restriction (CR), intermittent fasting, and protein and amino acid restriction prolong the lifespan of mammals by IGF-1 regulation. However, some recent findings support the hypothesis that the long-term effects of diet also involve epigenetic mechanisms. In this review, we describe the best characterized aging pathways and highlight the role of epigenetics in diet-mediated longevity.

Keywords: caloric restriction; epigenetics; longevity

Introduction: general features of epigenetics

Twin studies have limited the genetic contribution to longevity at only 25% at birth; it has therefore been proposed that epigenetic factors and lifestyle might also contribute to aging. Epigenetic regulation of gene expression can be elicited by three distinct principal mechanisms: (i) DNA methylation, (ii) post-translational histone modifications and (iii) non-coding RNA interference (1, 2).

  1. DNA methyl transferases (DNMTs) are the key enzymes responsible for DNA methylation. They transfer a methyl group from S-adenosyl-l-methionine to produce 5-methylcytosine (3). DNMTs can be subdivided into two groups: (a) DNMT3a, DNMT3b and cofactor DNMT3L (DNA methyltransferase-like protein), which are capable of de novo DNA methylation during embryogenesis (4); and (b) DNMT1, which, during replication, maintains the methylation pattern of the parental strain on the newly synthesized DNA strand. Methylated DNA can be recognized and bound by specific proteins, collectively referred to as methylated DNA-binding proteins, which can, in turn, recruit transcription regulatory factors and other chromatin remodeling proteins (5). In addition, DNA methylation and histone methylation synergistically ensure de novo DNA methylation (6). Hypermethylated DNA occurs mainly on CpG islands, whereas non-CpG DNA methylation has been limited to embryonic stem cell and neural development. In addition, methylated DNA has been observed in intron/exon junction and associated with alternative splicing (7), whereas the modified 5-methylcytosine (5mC) 5-hydroxymethylcytosine (5hmC) marks active chromatin regions. Methylated DNA is characteristic of heterochromatin and is traditionally believed to be associated with gene silencing. However, more recent data challenge the link between DNA methylation and genome silencing, suggesting a wider role of DNA methylation including a number of biological processes such as genomic imprinting, X-chromosome inactivation, suppression of repetitive elements, alternative splicing, transcriptional activation (5hmC) and carcinogenesis (8, 9).

  2. Histones, the basic proteins responsible for chromatin assembly and remodeling can undergo many reversible posttranslational modifications at both their amino- and their carboxy-terminal tails. Since the discovery of this mechanism, more than 100 distinct histone modifications have been identified. Acetylation on lysine residues, methylation on lysine and arginine residues, ubiquitylation, biotinylation at specific lysine residues as well as phosphorylation or ADP-ribosylation at specific sites normally occur. The best studied modifications are acetylation/deacetylation and methylation/demethylation, whose function is involved in chromatin remodeling. Two enzyme families lead to acetylation/deacetylation: histone acethyltransferases (HACs) and histone deacetylases (HDACs). HACs transfer the acetyl group from acetyl-CoA to the lysine residues of H3 and H4 histones; the insertion of negative charges neutralizes the positive charge on lysine residues and weakens the charge-dependent affinity between histones and DNA, driving chromatin relaxation (euchromatin), which helps in transcription factor binding. On the contrary, HDACs remove the acetyl groups, DNA sticks to histones and nucleosomes and becomes more packed (heterochromatin) and inaccessible to transcription factors (10). A crosstalk between DNA methylation and histone posttranslational modification can occur in two different ways: methylated DNA can recruit histone posttranslational modifying proteins or histone-modifying proteins can directly or indirectly induce a DNA methyl writer, such as DNMTs, to establish the DNA methylation pattern (11).

    Methylation can also occur on histones; however, mono-, di- or tri-methylation of lysine residues does not affect its positive charge and, therefore, the effect on nucleosome dynamics appears to be less direct than the acetylation/deacetylation of histones. In fact, lysine methylation can be associated with both activation (H3K4me and H3K36me) and repression (H3K9 and H3K27) of transcription. Very few data exist on arginine methylation, and thus its role on nucleosome dynamics appears to be even more crucial (12).

  3. miRNAs (micro RNA) and siRNAs (small interfering RNAs) determine the epigenetic regulation at the post-transcriptional level. They target different transcripts, avoiding their translation. miRNAs are the most well-known small non-coding RNA, which influence aging and lifespan. Notably, miRNAs, such as lin-4, miR-1, miR-145 and miR-140, modulate the insulin/IGF-1 pathway, as well as lipid metabolism. Moreover, miR-34a, members of the miR-106b family and miR-449a modulate the p53-p21-pRb and p16-pRb pathways in order to regulate apoptosis and cell proliferation, and class I HDAC and SIRT1 activity.

Biomolecular mechanisms of aging

Thanks to simple model organisms and genetic and molecular biology studies, many genes and pathways involved in longevity have been identified, helping to depict the molecular scenario of aging. The genes and pathways involved in the aging process were previously catalogued as metabolism, proliferation and growth, and cell protection system. However, it is now clear that these three processes are strictly interconnected and such distinction is useless. It is now clear that upstream signals transduced by metabolic pathways modulate stress response converging on the activation/inhibition of transcription factors [mainly belonging to the forkhead transcription factors family (FoxO)], thus linking the regulation of gene expression to nutrients availability and stress inputs (see Figure 1 for a scheme).

Signal transduction, nutrient sensing as well as epigenetic profile are nutrient dependent and converge on longevity regulation.
Figure 1:

Signal transduction, nutrient sensing as well as epigenetic profile are nutrient dependent and converge on longevity regulation.

High metabolic rates are unfavorable for survival. This is consistent with the observation that the conserved mitochondrial protein CLK-1 inhibits metabolism and prolongs Caenorhabditis elegans lifespan from 15% to 30% (13). Proliferation and growth control, which respond to IGF-1-like and GH signals, are very relevant to aging in most species including humans (14–57).

In C. elegans, inactivation of DAF-2 (an ortholog of insulin receptor), IGF-1 and AGE-1 (an ortholog of phosphatidylinositol-3-kinase) prolongs its lifespan (16, 17), whereas loss of function of insulin receptor and CHICO extends survival in Drosophila (18, 19). Mutation of GH receptor and deletion of mTOR or S6 kinase prolong the lifespan of mice and reduce the incidence of age-related disease in them (20–22). Moreover, GH deficiency in humans reduces IGF-1 and insulin levels, resulting in reduction of cancer and diabetes mortality (23).

Many evidences associate the overexpression of stress response genes to increased longevity. Hsp70, MnSOD and catalase in Drosophila (24) and SOD2 (25), HSF1 and YAP-1 in yeast (26, 27) are some consistent examples. Furthermore, the main ability to detoxify xenobiotics (28) or repair DNA damages [e.g., mei-41 in Drosophila or DDR-2 in yeast (29)] has a major role in survival.

Consistent with this scenario, homeostatic genes, such as p53, inhibit the IGF-1 pathway (30) and play a key role in DNA damage repair as well as in the clearance of injured cells, resulting in increased longevity. p53 cooperates with the Ink4/ARF gene product and regulates telomeres length, thus contributing to the prevention of cancer, whereas hypermethylation of this locus, observed in gastric mucosa, has been associated with aging (31).

Similarly, deletion of the two major aging and nutrient-sensing pathways in yeast, the PKA- and TOR-dependent pathways, increase chronological lifespan, inhibiting pro-aging signals with the involvement of key factors of stress response and damage repair (32–38). That confirms how nutrient-sensing pathways are conserved from yeast to humans (15) and their role in the aging process.

The best characterized intervention to prolong lifespan or to delay the onset of age-related diseases in eukaryotes is the reduction of nutrient intake without malnutrition (dietary restriction) (39). Its effects could be due either to a general reduction of metabolic rate and IGF-like signals or to the absence of specific nutrients that would affect survival responses acting as signals (39, 40).

The FOXO transcription factors, conserved in many organisms, regulate several cell functions such as gluconeogenesis, stress resistance, autophagy and apoptosis, and are upstream regulated by insulin, growth signals, nutrients and stress (41). It is therefore believed that these transcription factors play a central role in the regulation of longevity by nutrient intake.

Calorie restriction changes the gene methylation profile, suggesting that one of the mechanisms through which CR exerts its anti-aging effect is epigenetic mechanism. In particular, HRAS in the pancreas and MYC in the liver are hypomethylated in aging mice but are more methylated in animals under CR (42, 43). In addition, CR seems to affect the expression of DNMTs in vivo (44) and in vitro (45), wherein glucose restriction represses p16 and activates human telomerase reverse transcriptase (hTERT) through an epigenetic mechanism (46). In addition, protein restriction as well as mTOR pharmacological inhibition is associated with modulation of specific histone markers (47).

Another link between CR and epigenetic modification is represented by sirtuin deacetylases (48, 49). Increased level of the Sir2 ortholog, which was originally discovered in yeast, where some inconsistencies between the two adopted aging models exist on their role in aging (50–52), and in worms and flies, prolongs lifespan with an insulin/IGF-1-dependent pathway (52), regulated by the histone demethylase UTX-1 (53). These results are confirmed by the lack of CR-induced lifespan extension observed in the absence of Sir2 (48, 54, 55). Loss of SIRTs provokes several developmental and metabolic defects, including genomic instability, in knockout mice (55, 56). Two of the major SIRT1 targets are PGC1α [peroxisome proliferator-activated receptor (PPAR)-γ co-activator 1 α] and FOXO proteins (57, 58). When higher energy is required, such as during exercise or caloric restriction, SIRT1 activation increases mitochondrial respiration and lipid oxidation (59). Furthermore, FoxO3a deacetylation allows the up-regulation of catalase and MnSOD (60). The existence of a PPAR responsive element within the Sirt1 promoter region (61) is consistent with the observation that PPARα-null mice live shorter than their wild-type counterpart (62). However, this observation has two critical limitations: (i) PPARα has many targets involved in ketogenesis and in response to fasting; therefore the association with SIRT1 is purely speculative; (ii) the impairment of many genes results in the reduction of lifespan without being necessarily involved in the regulation of aging. SIRT-1 regulates the lipid profile, inhibits PPAR-γ and decreases the activity of retinoid as well as that of thyroid hormone receptors, thus lowering adipogenesis and increasing adipolysis as well as adiponectin transcription (63, 64). In addition, it inhibits SREBP1 (sterol regulatory element binding protein 1), thus influencing the lipid profile also through the regulation of lipogenic genes (65).

In primates, the role of sirtuins is controversial. It has, in fact, been demonstrated that sirtuins prolong their lifespan, but only of obese animals or those under a high-fat diet (66, 67). Thus, SIRT1 regulates some age-related pathways and its deficiency has been associated with increased replicative senescence in human fibroblasts (68), since it decreases during senescence (59).

Epigenetic variations during development and aging

Different epigenetic patterns (69) contribute to the establishment and maintenance of the differentiated state in cells and tissues (70). It is well known that during gametogenesis and embryogenesis a huge number of epigenetic changes occur. Environmental factors, such as diet, significantly influence the methylation patterns of the fetus, determining its individual epigenetic pattern since intrauterine life. As an example, exposure in utero to a high-fat diet provokes the age-related hypomethylation of the estrogen receptor promoter in rats (71). Likewise, a low-protein diet during pregnancy induces hypomethylation of PPARα and the glucocorticoid receptor loci in the liver tissue of the offspring (72). Histone modifications and altered expression of epigenetic enzymes are observed in primate liver after the consumption of a maternal high-fat diet; these alterations influence the genes involved in lipid metabolism and heat shock response (73). Accordingly, mice under a methyl-donor-rich diet exhibit variations in coat color, body weight and health (74). Lastly, the offspring of sheep under a diet lacking folate, vitamin B12 and methionine, during the conception period, became obese and showed an impaired immune response (75). For these reasons, some authors talk about the ‘fetal basis of adult disease’ (76).

Notably, epigenetic alterations induced during embryogenesis can be reversed by interventions in neonates. Leptin reverses the hypermethylation of the PPARα promoter induced by reduction of food intake in pregnant women (77), an effect similar to that observed after folic acid supplementation in juvenile rats (75).

Observations in humans are consistent with model organisms. Children of pregnant women suffering from nutrient scarcity during the Second World War in Holland between 1944 and 1945 (Dutch hunger winter) were more susceptible to chronic degenerative disease in aging (78) and showed increased mean level of methylation compared with same-sex siblings born in other periods (79). More in-depth studies revealed hypomethylation of the imprinted IGF-2 gene (80). In addition, IL-10, leptin, ATP-binding cassette A1 and guanine nucleotide-binding protein genes are hypermethylated in the offspring of mothers exposed to famine during the conception period (81).

Loss of imprinting has been linked to pediatric diseases and cancer in adulthood (82). It is interesting to note that monozygotic twins display different genome-wide methylation profiles (83), confirming that the ability to preserve epigenetic patterns might be individually determined (84).

Epigenetic modifications accumulate over time, but environmental factors such as visceral adiposity may influence the methylation status of CpG within the RXRA gene promoter at an early age (85). On the contrary, genomic regions that show heritable DNA methylation patterns, such as the IGF2/H19 region and other functionally important regions, show more stable DNA methylation state during life (86).

The DNA epigenetic pattern continues to change during life. Aging DNA becomes hypomethylated (87–89), especially in repetitive sequences such as Alu elements (90), even if some authors report that DNA methyltransferases do not change significantly (87); on the contrary, other researchers showed that Dnmt1 and Dnmt3a levels decrease during aging, whereas Dnmt3b expression increases (91). In contrast, some of the CpG islands are hypermethylated and silenced in a tissue-specific fashion; these regions include transcription factor-binding sites (92) or promoters of genes involved in the regulation of gene expression, senescence, apoptosis and tumorigenesis (93–96). An example is the CR-induced down-regulation of the p16INK4a gene (97), which is a tumor suppressor as well as an aging-associated gene, whose silencing is obtained through hypermethylation of the transcription factor E2F-1 binding site within the gene promoter (42, 98).

A recent study compared the DNA methylation profiles of leukocytes in centenarians, youngsters and their respective offspring. Researchers found that, in the centenarians’ offspring, the characteristic hypomethylation of the elderly was delayed and, interestingly, the genes involved in metabolism, nucleotide biosynthesis and control of signal transduction are differently methylated between the centenarians’ offspring and the controls, suggesting a possible role in human longevity (99). Furthermore, different epigenetic profiles, in particular the methylation pattern, could be associated with the functional, cognitive and physiological status in the elderly and thus with their quality of aging (100).

A previous study compared the genome of centenarians and newborns showing a lower methylation content in the centenarians, whereas newborns had a more homogeneous methylation pattern (101). It has been postulated that aging could be associated with a loss of epigenetic control rather than with an increase or decrease in methylation activity; however, the majority of epigenetic changes do not determine a known age-related phenotype (102). In contrast, Thompson et al. (103) suggested that the epigenomic dysregulation during aging is non-random and tissue specific. Other authors are trying to use methyloma as a biomarker of chronological aging in humans (104, 105). One of the possible epigenetic biomarkers of aging could be ELOVL2 (fatty acid elongase 2), which is unmethylated in newborns, whereas its methylation levels significantly increase with age in different tissues (106). At the same time, several other genes show methylation alteration during aging, including tumor suppressors (COX7A1, LOX, RUNX3, TIG1, p16INK4A, RASSF1, DUSP22) and genes involved in growth and development (IGF2, cFos), cell-cell adhesion (CDH1), metabolism (ELOVL2, SLC38A4, SLC22A18, MGC3207, ECRG4, ATP13A4, AGPAT2, LEP), DNA repair (MLH1) and the control of signal transmission (FZD1, FZD7) (107).

Also, histone modifications and chromatin structure are fundamental for gene expression and during lifespan change in response to environmental conditions. According to Narita et al. (108), aging cells tend to form regions of heterochromatin called senescence-associated heterochromatin foci, which may be involved in gene silencing to stop proliferation (108). In addition, during aging, histone proteins appear reduced, probably leading to an unstable genome structure (109); according to this observation in yeast, histone expression increases its lifespan (110), whereas during normal aging histone deacetylase Sir2 expression decreases (111).

A recent study describes in detail the changes occurring in circulating miRNA during life (112, 113). Differences in circulating miRNAs have been described in many age-associated diseases (112). Some miRNAs, such as miR-93, miR-669c, miR-214, mir-29 and miR-709, are up-regulated during aging (113); the related target genes are linked to proliferation, mitochondrial function and thus oxidative stress (114, 115). In contrast, expression of other senescence-related miRNAs (miR-23a, miR26a, miR-30a and let-7 family miRNAs) could be regulated by HDAC activity (116).

Nutrient modulation of epigenetic patterns

Nutrient deprivation/replenishment has been shown to induce epigenetic rearrangements in several ways (32, 117–119). Glucose availability and epigenetic patterns have been linked to cultured macrophages. High glucose results in increased expression of NF-κB and inflammation mediators (120–122). Dietary restriction increases the lifespan of human cultured cells with a contemporary increase in SIRT1 expression (42, 123, 124). SIRT1 is a NAD-dependent deacetylase whose expression is related to the down-regulation of p53 (125–127), FoxO (128, 129) and Ku70 (130, 131), a protein required during non-homologous end-joining DNA repair, and to the up-regulation of PGC-1α, a regulator of glucose metabolism (132, 133).

Analogously, during dietary restriction, as previously mentioned, H-RAS locus is silenced through DNA methylation (37), whereas the transcription factor RUNX3 as well as TIG1, a tumor suppressor frequently silenced in cancer cells, is up-regulated (134). Furthermore, a change in the methylation status of TNF-α locus occurs during dietary-restricted regimens.

Since the expression/silencing of these loci is associated with nutrient deprivation, they have been proposed as predictive biomarkers of diet-induced obesity/weight loss (135–137).

As mentioned before, caloric restriction is not the only dietary regimen capable of affecting epigenetics, but many other bioactive food components interfere with the epigenetic mechanism that influences, either directly or indirectly, the activity of epigenetic modification enzymes (Table 1).

Table 1

Bioactive food components and their epigenetic functions.

The molecules involved in such regulation may be subdivided into four different subclasses: (a) co-enzymes necessary for methyl-donor metabolism; (b) substances affecting histone modification; (c) molecules acting directly on the methylation/acetylation processes; and (d) factors affecting the epigenetic pattern through modification of the extracellular environment (138). Spermidine, a naturally occurring polyamine, directly inhibits histone acetyltransferases (HATs), thus maintaining the hypoacetylated state of histone H3 (139). This results in higher heat and oxidative stress resistance with contemporary reduced rates of cell necrosis during aging both in human and in yeast cells. Interestingly, this mechanism is evolutionarily conserved across many species, including flies, nematodes and human cells. In addition, age-related histone acetylation may be modified by dietary strategies that deplete cellular acetyl CoA, the sole donor for acetylation reactions. Depletion of acetyl CoA has been recently shown to be sufficient for the induction of autophagy and lifespan extension. Whether these effects are dependent on epigenetic changes is not yet known (140, 141). Spermidine has the potential to be safe for testing its epigenetic-dependent and -independent effects on human health span. In one human study, an enhancement of the blood polyamine concentration due to a polyamine-rich traditional Japanese food showed no obvious adverse effects (142).

Some food seems to be able to inhibit DNMT, such as green tea and soybeans through polyphenols (epigallocatechin gallate) and genistein bioactive molecules, respectively (143–145), or HDAC, such as broccoli sprouts, which contain sulforaphane (146, 147).

Great importance is widely attached to folate in the regulation of epigenome, especially during embryogenesis. In adults, folic acid deficiency is linked to the development of several cancers such as lung, brain, breast, cervix, ovary and colorectal cancer (148, 149). Folate, choline and methionine deficiency cause DNA hypomethylation (150). Blood folate levels have been associated with methylation in CpG islands in colorectal mucosa at the promoter of the estrogen receptor α gene and frizzled-related protein-1, which are both involved in cellular proliferation (151). Piyathilake et al. (152) associated a healthy dietary pattern (rich in folate; vitamins B12, B2, and B6; and other ‘cancer protective’ micronutrients) with decreased risk of developing cervical intraepithelial neoplasia and the methylation level of the long interspersed nucleotide elements (L1s) of peripheral blood mononuclear cells (152).

Many polyphenols, which not only have antioxidant properties, but also regulate gene expression and chromatin structure, have the ability to interfere with epigenetic patterning.

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is the most studied bioactive compound related to aging. It increases longevity in simple model organisms as well as in mammals (153, 154), mimicking the effects of caloric restriction. It is contained in berries, peanuts, grapes and wine. It has been linked to histone modification and DNA methylation, principally through SIRT1 regulation (155, 156). Resveratrol reduces NF-κB activation and has a role in inhibiting the development of breast as well as prostate cancer (157), by regulating cell survival through FOXO deacetylation (158). Resveratrol supplementation reduces inflammation and increases insulin sensitivity (159, 160). Similarly, quercetins, curcumins and catechins activate SIRT1 in different model systems (161). Many other polyphenols influence the SIRT1 activation state (162), and thus they could be of benefit against some chronic diseases (163). Likewise, it has been reported that resveratrol, as well as quercetins, curcumins and catechins, inhibits COX-2, iNOS and adhesion molecules through the suppression of NF-κB and AP-1 (164–166), which determines the anti-inflammatory effect of these polyphenols. Additionally, another flavonoid present in lemons, naringerin, shows an anti-diabetic effect by the promotion of glucose uptake in skeletal muscle cells (167).

Curcumin is known as a natural anti-inflammatory agent; it is a polyphenol extracted from the spice Curcuma longa. It is involved in different epigenetic modifications and regulates H3 and H4 acetylation, DNMT1 and, with a mechanism that involves miRNA, SP1 and PTEN. The most relevant effect is NF-κB inhibition (163). Morimoto et al. (168) linked the effect of curcumins in heart-failure prevention in mice to the inhibition of HATs, HDACs and p300 degradation induction (169).

Many epigenetic targets have been identified for tea polyphenols and catechins: H3 and H4, NF-κB, IL-6, SUZ12/HAT, HDAC, HMT, P16INK4a, RNRβ, RECK1, hTERT, WIF-1, RXRα, RXRβ, CDX2/DNMTI and Bcl-2. Their role in cancer prevention is fundamentally linked to apoptosis and cell-cycle arrest in tumor cells (170). Epigallocatechin binds to the catalytic region of DNMT1 and inhibits its activity (171). Furthermore, it has been shown to decrease DNMT1, DNMT3a, DNMT3b and HDAC levels, whereas it increases the acetylation of particular regions of histones H3 and H4 (172). Epigallocatechin prevents UV-induced carcinogenesis of the skin in mice (173), whereas epicatechins and catechins have shown anti-aging effects in C. elegans (174).

Vegetables such as broccoli, cabbage and cauliflower contain sulforaphane, phenethyl isothiocyanate, indole-3-carbinol and diindolymethane that induce cell-cycle arrest and apoptosis in cancer cells through epigenetic mechanisms (153, 175–177). A similar effect has been detected for quercetin in citrus fruits and buckwheat (178), lycopene in tomato (179) and ellagic acid (pomegranate, walnuts, almonds) (180). Moreover, low doses of sulforaphane inhibit hTERT, allowing the binding of transcriptional repressors to the regulatory region and the reduction of DNMT1 and DNMT3a expression levels (153), whereas it inhibits in vitro melanoma cell growth and proliferation by down-regulating deacetylases (181). In addition, lycopene protects against UV-induced carcinogenesis by inhibition of epidermal ornithine decarboxylase and reduction of inflammation (182). Moreover, as reported by Jones and Hughes (183), black currant juice (which contains flavonoids and quercetin) prolongs the lifespan of female mice, which live longer than male mice, probably through SIRT1 inhibition (184).

Genistein, contained in soybeans, participates in the modulation of chromatin structure and DNA methylation; among its epigenetic targets are histones, SIRT1, p21, p16, PTEN, p53, FOXO3A and hTERT (185, 186), which, in turn, are key regulators of cell-cycle regulation and cell survival. In contrast, studies on mice CD-1 reveal that exposure to genistein during the neonatal period can promote uterine adenocarcinoma, probably due to the atypical hypomethylation of CpG islands in Nsbp1 (nucleosomal binding protein) (187). Organosulfur compounds of onions and garlic inhibit DNA adduct formation through the up-regulation of antioxidant defenses and DNA repair systems (188).

Conclusion

It is becoming evident that not only calorie restriction but also the restriction of selected nutrients increases the lifespan in a wide array of organisms including humans. Recent data suggest that these restrictions not only have a direct effect on metabolism but also are capable of regulating gene expression. Regulation of key transcription factors by nutrient availability through direct interaction of these factors with nutrient-sensing factors occurs. In addition, many data suggest that the amount and quality of nutrients in the diet influence longevity by modifying the epigenetic pattern. A large number of clinical trials are testing the efficacy of phytochemicals and drugs to inhibit HDAC or DNMT (124) on some tumors and degenerative aging-related diseases. In humans, safety concerns and the possibility of off-target effects suggest the use of only natural substances such as spermidine or resveratrol for clinical trials (189).

Finally, it is interesting to note that epigenetic patterns may be heritable in some cases. The combination of heritability and lifestyle-dependent modification of epigenetics makes this mechanism of gene expression regulation a proof of principle of Lamarckian theories.

References

  • 1.

    Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape. Cell 2007; 128: 635–8.CrossrefGoogle Scholar

  • 2.

    Baker LA, Allis CD, Wang GG. PHD fingers in human diseases: disorders arising from misinterpreting epigenetic marks. Mutat Res 2008; 647: 3–12.Google Scholar

  • 3.

    Issa JP, Kantarjian HM. Targeting DNA methylation. Clin Cancer Res 2009; 15: 3938–46.CrossrefGoogle Scholar

  • 4.

    Denis H, Ndlovu MN, Fuks F. Regulation of mammalian DNA methyltransferases: a route to new mechanisms. EMBO Rep 2011; 12: 647–56.CrossrefGoogle Scholar

  • 5.

    Duthie SJ. Epigenetic modifications and human pathologies: cancer and CVD. Proc Nutr Soc 2011; 70: 47–56.CrossrefGoogle Scholar

  • 6.

    Rose NR, Klose RJ. Understanding the relationship between DNA methylation and histone lysine methylation. Biochim Biophys Acta 2014; 1839: 1362–72.Google Scholar

  • 7.

    Wu H, D’Alessio AC, Ito S, Wang Z, Cui K, Zhao K, Sun YE, Zhang Y. Genome-wide analysis of 5-hydroxymethylcytosine distribution reveals its dual function in transcriptional regulation in mouse embryonic stem cells. Genes Dev 2011; 25: 679–84.CrossrefGoogle Scholar

  • 8.

    Gonzalo S, Jaco I, Fraga MF, Chen T, Li E, Esteller M, Blasco MA. DNA methyltransferases control telomere length and telomere recombination in mammalian cells. Nat Cell Biol 2006; 8: 416–24.PubMedCrossrefGoogle Scholar

  • 9.

    Mellén M, Ayata P, Dewell S, Kriaucionis S, Heintz N. MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell 2012; 151: 1417–30.CrossrefGoogle Scholar

  • 10.

    Suganuma T, Workman JL. Signals and combinatorial functions of histone modifications. Annu Rev Biochem 2011; 80: 473–99.CrossrefGoogle Scholar

  • 11.

    Liyanage VRB, Zachariah RM, Delcuve GP, Davie JR, Rastegar M. In: Simpson NM, Stewart VJ, editors. New developments in chromatin research: an epigenetic perspective. Hauppauge, NY, USA: Nova Science Publishers, 2012: 29–58.Google Scholar

  • 12.

    Zentner GE, Henikoff S. Regulation of nucleosome dynamics by histone modifications. Nat Struct Mol Biol 2013; 20: 259–66.CrossrefGoogle Scholar

  • 13.

    Branicky R, Bénard C, Hekimi S. clk-1, mitochondria, and physiological rates. Bioessays 2000; 22: 48–56.CrossrefGoogle Scholar

  • 14.

    Barbieri M, Bonafè M, Franceschi C, Paolisso G. Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans. Am J Physiol Endocrinol Metab 2003; 285: E1064–71.Google Scholar

  • 15.

    Fontana L, Partridge L, Longo VD. Extending healthy life span – from yeast to humans. Science 2010; 328: 321–6.Google Scholar

  • 16.

    Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 1997; 277: 942–6.Google Scholar

  • 17.

    Morris JZ, Tissenbaum HA, Ruvkun G. A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 1996; 382: 536–9.Google Scholar

  • 18.

    Clancy DJ, Gems D, Harshman LG, Oldham S, Stocker H, Hafen E, Leevers SJ, Partridge L. Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 2001; 292: 104–6.Google Scholar

  • 19.

    Piper MD, Selman C, McElwee JJ, Partridge L. Separating cause from effect: how does insulin/IGF signalling control lifespan in worms, flies and mice? J Intern Med 2008; 263: 179–91.Google Scholar

  • 20.

    Bartke A. Minireview: role of the growth hormone/insulin-like growth factor system in mammalian aging. Endocrinology 2005; 146: 3718–23.CrossrefGoogle Scholar

  • 21.

    Bartke A, Brown-Borg HM, Bode AM, Carlson J, Hunter WS, Bronson RT. Does growth hormone prevent or accelerate aging? Exp Gerontol 1998; 33: 675–87.CrossrefGoogle Scholar

  • 22.

    Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI, Claret M, Al-Qassab H, Carmignac D, Ramadani F, Woods A, Robinson IC, Schuster E, Batterham RL, Kozma SC, Thomas G, Carling D, Okkenhaug K, Thornton JM, Partridge L, Gems D, Withers DJ. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 2009; 326: 140–4.Google Scholar

  • 23.

    Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng CW, Hwang D, Martin-Montalvo A, Saavedra J, Ingles S, de Cabo R, Cohen P, Longo VD. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med 2011; 3: 70ra13.Google Scholar

  • 24.

    Orr WC, Sohal RS. Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. Science 1994; 263: 1128–30.Google Scholar

  • 25.

    Flattery-O’Brien JA, Grant CM, Dawes IW. Stationary-phase regulation of the Saccharomyces cerevisiae SOD2 gene is dependent on additive effects of HAP2/3/4/5- and STRE-binding elements. Mol Microbiol 1997; 23: 303–12.CrossrefGoogle Scholar

  • 26.

    Harris N, MacLean M, Hatzianthis K, Panaretou B, Piper PW. Increasing Saccharomyces cerevisiae stress resistance, through the overactivation of the heat shock response resulting from defects in the Hsp90 chaperone, does not extend replicative life span but can be associated with slower chronological ageing of nondividing cells. Mol Genet Genomics 2001; 265: 258–63.Google Scholar

  • 27.

    Herker E, Jungwirth H, Lehmann KA, Maldener C, Fröhlich KU, Wissing S, Büttner S, Fehr M, Sigrist S, Madeo F. Chronological aging leads to apoptosis in yeast. J Cell Biol 2004; 164: 501–7.CrossrefGoogle Scholar

  • 28.

    Tullet JM, Hertweck M, An JH, Baker J, Hwang JY, Liu S, Oliveira RP, Baumeister R, Blackwell TK. Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell 2008; 132: 1025–38.CrossrefGoogle Scholar

  • 29.

    Martínez-Pastor MT, Marchler G, Schüller C, Marchler-Bauer A, Ruis H, Estruch F. The Saccharomyces cerevisiae zinc finger proteins Msn2p and Msn4p are required for transcriptional induction through the stress response element (STRE). EMBO J 1996; 15: 2227–35.Google Scholar

  • 30.

    Kavurma MM, Figg N, Bennett MR, Mercer J, Khachigian LM, Littlewood TD. Oxidative stress regulates IGF1R expression in vascular smooth-muscle cells via p53 and HDAC recruitment. Biochem J 2007; 407: 79–87.Google Scholar

  • 31.

    So K, Tamura G, Honda T, Homma N, Waki T, Togawa N, Nishizuka S, Motoyama T. Multiple tumor suppressor genes are increasingly methylated with age in non-neoplastic gastric epithelia. Cancer Sci 2006; 97: 1155–8.CrossrefGoogle Scholar

  • 32.

    Wei M, Fabrizio P, Hu J, Ge H, Cheng C, Li L, Longo VD. Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9. PLOS Genet 2008; 4: e13.Google Scholar

  • 33.

    Longo VD. Ras: the other pro-aging pathway. Sci Aging Knowl Environ 2004; 2004: pe36.CrossrefGoogle Scholar

  • 34.

    Fabrizio P, Pozza F, Pletcher SD, Gendron CM, Longo VD. Regulation of longevity and stress resistance by Sch9 in yeast. Science 2001; 292: 288–90.CrossrefGoogle Scholar

  • 35.

    Pedruzzi I, Bürckert N, Egger P, De Virgilio C. Saccharomyces cerevisiae Ras/cAMP pathway controls post-diauxic shift element-dependent transcription through the zinc finger protein Gis1. EMBO J 2000; 19: 2569–79.CrossrefGoogle Scholar

  • 36.

    Fabrizio P, Liou LL, Moy VN, Diaspro A, Valentine JS, Gralla EB, Longo VD. SOD2 functions downstream of Sch9 to extend longevity in yeast. Genetics 2003; 163: 35–46.Google Scholar

  • 37.

    Urban J, Soulard A, Huber A, Lippman S, Mukhopadhyay D, Deloche O, Wanke V, Anrather D, Ammerer G, Riezman H, Broach JR, De Virgilio C, Hall MN, Loewith R. Sch9 is a major target of TORC1 in Saccharomyces cerevisiae. Mol Cell 2007; 26: 663–74.CrossrefGoogle Scholar

  • 38.

    Powers RW, Kaeberlein M, Caldwell SD, Kennedy BK, Fields S. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev 2006; 20: 174–84.CrossrefGoogle Scholar

  • 39.

    Taormina G, Mirisola MG. Calorie restriction in mammals and simple model organisms. Biomed Res Int 2014; 2014: 308690.Google Scholar

  • 40.

    Mirisola MG, Taormina G, Fabrizio P, Wei M, Hu J, Longo VD. Serine- and threonine/valine-dependent activation of PDK and Tor orthologs converge on Sch9 to promote aging. PLOS Genet 2014; 10: e1004113.Google Scholar

  • 41.

    Salih DAM, Brunet A. FoxO transcription factors in the maintenance of cellular homeostasis during aging. Curr Opin Cell Biol 2008; 20: 126–36.CrossrefGoogle Scholar

  • 42.

    Hass BS, Hart RW, Lu MH, Lyn-Cook BD. Effects of caloric restriction in animals on cellular function, oncogene expression, and DNA methylation in vitro. Mutat Res 1993; 295: 281–9.CrossrefGoogle Scholar

  • 43.

    Miyamura Y, Tawa R, Koizumi A, Uehara Y, Kurishita A, Sakurai H, Kamiyama S, Ono T. Effects of energy restriction on age-associated changes of DNA methylation in mouse liver. Mutat Res 1993; 295: 63–9.Google Scholar

  • 44.

    Chouliaras L, van den Hove DL, Kenis G, Dela Cruz J, Lemmens MA, van Os J, Steinbusch HW, Schmitz C, Rutten BP. Caloric restriction attenuates age-related changes of DNA methyltransferase 3a in mouse hippocampus. Brain Behav Immun 2011; 25: 616–23.CrossrefGoogle Scholar

  • 45.

    Li Y, Liu Y, Strickland FM, Richardson B. 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 2010; 45: 312–22.PubMedCrossrefGoogle Scholar

  • 46.

    Li Y, Liu L, Tollefsbol TO. Glucose restriction can extend normal cell lifespan and impair precancerous cell growth through epigenetic control of hTERT and p16 expression. FASEB J 2010; 24: 1442–53.Google Scholar

  • 47.

    Fontana L, Adelaiye RM, Rastelli AL, Miles KM, Ciamporcero E, Longo VD, Nguyen H, Vessella R, Pili R. Dietary protein restriction inhibits tumor growth in human xenograft models. Oncotarget 2013; 4: 2451–61.Google Scholar

  • 48.

    Bordone L, Cohen D, Robinson A, Motta MC, van Veen E, Czopik A, Steele AD, Crowe H, Marmor S, Luo J, Gu W, Guarente L. SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell 2007; 6: 759–67.Google Scholar

  • 49.

    Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 2004; 305: 390–2.Google Scholar

  • 50.

    Longo VD, Kennedy BK. Sirtuins in aging and age-related disease. Cell 2006; 126: 257–68.CrossrefGoogle Scholar

  • 51.

    Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for lifespan extension by calorie restriction in Saccharomyces cerevisiae. Science 2000; 289: 2126–8.CrossrefGoogle Scholar

  • 52.

    Tissenbaum HA, Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 2001; 410: 227–30.Google Scholar

  • 53.

    Jin C, Li J, Green CD, Yu X, Tang X, Han D, Xian B, Wang D, Huang X, Cao X, Yan Z, Hou L, Liu J, Shukeir N, Khaitovich P, Chen CD, Zhang H, Jenuwein T, Han JD. Histone demethylase UTX-1 regulates C. elegans life span by targeting the insulin/IGF-1 signaling pathway. Cell Metab 2011; 14: 161–72.CrossrefGoogle Scholar

  • 54.

    Lin SJ, Kaeberlein M, Andalis AA, Sturtz LA, Defossez PA, Culotta VC, Fink GR, Guarente L. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 2002; 418: 344–8.Google Scholar

  • 55.

    Finkel T, Deng CX, Mostoslavsky R. Recent progress in the biology and physiology of sirtuins. Nature 2009; 460: 587–91.Google Scholar

  • 56.

    Kim HS, Vassilopoulos A, Wang RH, Lahusen T, Xiao Z, Xu X, Li C, Veenstra TD, Li B, Yu H, Ji J, Wang XW, Park SH, Cha YI, Gius D, Deng CX. SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell 2011; 20: 487–99.CrossrefGoogle Scholar

  • 57.

    Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 2006; 127: 1109–22.CrossrefGoogle Scholar

  • 58.

    Guarente L. Franklin H. Epstein Lecture: Sirtuins, aging and medicine. N Engl J Med 2011; 364: 2235–44.Google Scholar

  • 59.

    Gurd BJ, Yoshida Y, McFarlan JT, Holloway GP, Moyes CD, Heigenhauser GJ, Spriet L, Bonen A. Nuclear SIRT1 activity, but not protein content, regulates mitochondrial biogenesis in rat and human skeletal muscle. Am J Physiol Regul Integr Comp Physiol 2011; 301: R67–75.Google Scholar

  • 60.

    Sundaresan NR, Gupta M, Kim G, Rajamohan SB, Isbatan A, Gupta MP. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J Clin Invest 2009; 119: 2758–71.Google Scholar

  • 61.

    Masternak MM, Bartke A. PPARs in calorie restricted and genetically long-lived mice. PPAR Res 2007; 2007: 28436.Google Scholar

  • 62.

    Howroyd P, Swanson C, Dunn C, Cattley RC, Corton JC. Decreased longevity and enhancement of age-dependent lesions in mice lacking the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα). Toxicol Pathol 2004; 32: 591–9.CrossrefGoogle Scholar

  • 63.

    Kadowaki T, Yamauchi T, Waki H, Iwabu M, Okada-Iwabu M, Nakamura M. Adiponectin, adiponectin receptors, and epigenetic regulation of adipogenesis. Cold Spring Harb Symp Quant Biol 2011; 76: 257–65.CrossrefGoogle Scholar

  • 64.

    Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R, Leid M, McBurney MW, Guarente L. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ. Nature 2004; 429: 771–6.Google Scholar

  • 65.

    Wang GL, Fu YC, Xu WC, Feng YQ, Fang SR, Zhou XH. Resveratrol inhibits the expression of SREBP1 in cell model of steatosis via Sirt1-FOXO1 signaling pathway. Biochem Biophys Res Commun 2009; 380: 644–9.Google Scholar

  • 66.

    Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 2008; 8: 157–68.CrossrefGoogle Scholar

  • 67.

    Jimenez-Gomez Y, Mattison JA, Pearson KJ, Martin-Montalvo A, Palacios HH, Sossong AM, Ward TM, Younts CM, Lewis K, Allard JS, Longo DL, Belman JP, Malagon MM, Navas P, Sanghvi M, Moaddel R, Tilmont EM, Herbert RL, Morrell CH, Egan JM, Baur JA, Ferrucci L, Bogan JS, Bernier M, de Cabo R. Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet. Cell Metab 2013; 18: 533–45.CrossrefGoogle Scholar

  • 68.

    Han L, Zhou R, Niu J, McNutt MA, Wang P, Tong T. SIRT1 is regulated by a PPAR{γ}-SIRT1 negative feedback loop associated with senescence. Nucleic Acids Res 2010; 38: 7458–71.CrossrefGoogle Scholar

  • 69.

    Berdasco M, Esteller M. Aberrant epigenetic landscape in cancer: how cellular identity goes awry. Dev Cell 2010; 19: 698–711.CrossrefGoogle Scholar

  • 70.

    Mendelsohn AR, Larrick JW. The DNA methylome as a biomarker for epigenetic instability and human aging. Rejuvenation Res 2013; 16: 74–7.CrossrefGoogle Scholar

  • 71.

    Yenbutr P, Hilakivi-Clarke L, Passaniti A. Hypomethylation of an exon I estrogen receptor CpG island in spontaneous and carcinogen-induced mammary tumorigenesis in the rat. Mech Ageing Dev 1998; 106: 93–102.CrossrefGoogle Scholar

  • 72.

    Burdge GC, Lillycrop KA, Phillips ES, Slater-Jefferies JL, Jackson AA, Hanson MA. Folic acid supplementation during the juvenile-pubertal period in rats modifies the phenotype and epigenotype induced by prenatal nutrition. J Nutr 2009; 139: 1054–60.CrossrefGoogle Scholar

  • 73.

    Aagaard-Tillery KM, Grove K, Bishop J, Ke X, Fu Q, McKnight R, Lane RH. Developmental origins of disease and determinants of chromatin structure: maternal diet modifies the primate fetal epigenome. J Mol Endocrinol 2008; 41: 91–102.CrossrefGoogle Scholar

  • 74.

    Weaver IC, Diorio J, Seckl JR, Szyf M, Meaney MJ. Early environmental regulation of hippocampal glucocorticoid receptor gene expression: characterization of intracellular mediators and potential genomic target sites. Ann N Y Acad Sci 2004; 1024: 182–212.Google Scholar

  • 75.

    Sinclair KD, Allegrucci C, Singh R, Gardner DS, Sebastian S, Bispham J, Thurston A, Huntley JF, Rees WD, Maloney CA, Lea RG, Craigon J, McEvoy TG, Young LE. DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc Natl Acad Sci USA 2007; 104: 19351–6.CrossrefGoogle Scholar

  • 76.

    Morley R. Fetal origins of adult disease. Semin Fetal Neonatal Med 2006; 11: 73–8.CrossrefGoogle Scholar

  • 77.

    Gluckman PD, Lillycrop KA, Vickers MH, Pleasants AB, Phillips ES, Beedle AS, Burdge GC, Hanson MA. Metabolic plasticity during mammalian development is directionally dependent on early nutritional status. Proc Natl Acad Sci USA 2007; 104: 12796–800.CrossrefGoogle Scholar

  • 78.

    Lumey LH, Stein AD. In utero exposure to famine and subsequent fertility: the Dutch famine birth cohort study. Am J Public Health 1997; 87: 1962–6.CrossrefGoogle Scholar

  • 79.

    Painter RC, Roseboom TJ, Bleker OP. Prenatal exposure to the Dutch famine and disease in later life: an overview. Reprod Toxicol 2005; 20: 345–52.CrossrefGoogle Scholar

  • 80.

    Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, Susser ES, Slagboom PE, Lumey LH. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA 2008; 105: 17046–9.CrossrefGoogle Scholar

  • 81.

    Tobi EW, Lumey LH, Talens RP, Kremer D, Putter H, Stein AD, Slagboom PE, Heijmans BT. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet 2009; 18: 4046–53.CrossrefGoogle Scholar

  • 82.

    Steegers-Theunissen RP, Obermann-Borst SA, Kremer D, Lindemans J, Siebel C, Steegers EA, Slagboom PE, Heijmans BT. Periconceptional maternal folic acid use of 400 μg per day is related to increased methylation of the IGF2 gene in the very young child. PLOS One 2009; 4: e7845.CrossrefGoogle Scholar

  • 83.

    Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suñer D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 2005; 102: 10604–9.CrossrefGoogle Scholar

  • 84.

    Bjornsson HT, Sigurdsson MI, Fallin MD, Irizarry RA, Aspelund T, Cui H, Yu W, Rongione MA, Ekström TJ, Harris TB, Launer LJ, Eiriksdottir G, Leppert MF, Sapienza C, Gudnason V, Feinberg AP. Intra-individual change over time in DNA methylation with familial clustering. J Am Med Assoc 2008; 299: 2877–83.Google Scholar

  • 85.

    Godfrey KM, Sheppard A, Gluckman PD, Lillycrop KA, Burdge GC, McLean C, Rodford J, Slater-Jefferies JL, Garratt E, Crozier SR, Emerald BS, Gale CR, Inskip HM, Cooper C, Hanson MA. Epigenetic gene promoter methylation at birth is associated with child’s later adiposity. Diabetes 2011; 60: 1528–34.CrossrefGoogle Scholar

  • 86.

    Kaminsky ZA, Tang T, Wang SC, Ptak C, Oh GH, Wong AH, Feldcamp LA, Virtanen C, Halfvarson J, Tysk C, McRae AF, Visscher PM, Montgomery GW, Gottesman II, Martin NG, Petronis A. DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet 2009; 41: 240–5.CrossrefGoogle Scholar

  • 87.

    Maegawa S, Hinkal G, Kim HS, Shen L, Zhang L, Zhang J, Liang S, Donehower LA, Issa JP. Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res 2010; 20: 332–40.CrossrefGoogle Scholar

  • 88.

    Wilson VL, Smith RA, Ma S, Cutler RG. Genomic 5-methyldeoxycytidine decreases with age. J Biol Chem 1987; 262: 9948–51.Google Scholar

  • 89.

    Richardson B. Impact of aging on DNA methylation. Ageing Res Rev 2003; 2: 245–61.CrossrefGoogle Scholar

  • 90.

    Bollati V, Schwartz J, Wright R, Litonjua A, Tarantini L, Suh H, Sparrow D, Vokonas P, Baccarelli A. Decline in genomic DNA methylation through aging in a cohort of elderly subjects. Mech Ageing Dev 2009; 130: 234–9.CrossrefGoogle Scholar

  • 91.

    Casillas MA, Lopatina N, Andrews LG, Tollefsbol TO. Transcriptional control of the DNA methyltransferases is altered in aging and neoplastically-transformed human fibroblasts. Mol Cell Biochem 2003; 252: 33–43.Google Scholar

  • 92.

    Hernandez DG, Nalls MA, Gibbs JR, Arepalli S, van der Brug M, Chong S, Moore M, Longo DL, Cookson MR, Traynor BJ, Singleton AB. Distinct DNA methylation changes highly correlated with chronological age in the human brain. Hum Mol Genet 2011; 20: 1164–72.CrossrefGoogle Scholar

  • 93.

    Salminen A, Ojala J, Kaarniranta K. Apoptosis and aging: increased resistance to apoptosis enhances the aging process. Cell Mol Life Sci 2011; 68: 1021–31.CrossrefGoogle Scholar

  • 94.

    Kwabi-Addo B, Chung W, Shen L, Ittmann M, Wheeler T, Jelinek J, Issa JP. Age-related DNA methylation changes in normal human prostate tissues. Clin Cancer Res 2007; 13: 3796–802.CrossrefGoogle Scholar

  • 95.

    Grönniger E, Weber B, Heil O, Peters N, Stäb F, Wenck H, Korn B, Winnefeld M, Lyko F. Aging and chronic sun exposure cause distinct epigenetic changes in human skin. PLOS Genet 2010; 6: e1000971.CrossrefGoogle Scholar

  • 96.

    Waki T, Tamura G, Sato M, Motoyama T. Age-related methylation of tumor suppressor and tumor-related genes: an analysis of autopsy samples. Oncogene 2003; 22: 4128–33.CrossrefGoogle Scholar

  • 97.

    Keyes MK, Jang H, Mason JB, Liu Z, Crott JW, Smith DE, Friso S, Choi SW. Older age and dietary folate are determinants of genomic and p16-specific DNA methylation in mouse colon. J Nutr 2007; 137: 1713–7.Google Scholar

  • 98.

    Li Y, Tollefsbol TO. p16(INK4a) suppression by glucose restriction contributes to human cellular lifespan extension through SIRT1-mediated epigenetic and genetic mechanisms. PLOS One 2011; 6: e17421.Google Scholar

  • 99.

    Gentilini D, Mari D, Castaldi D, Remondini D, Ogliari G, Ostan R, Bucci L, Sirchia SM, Tabano S, Cavagnini F, Monti D, Franceschi C, Di Blasio AM, Vitale G. Role of epigenetics in human aging and longevity: genome-wide DNA methylation profile in centenarians and centenarians’ offspring. Age (Dordr) 2013; 35: 1961–73.CrossrefGoogle Scholar

  • 100.

    Bellizzi D, D’Aquila P, Montesanto A, Corsonello A, Mari V, Mazzei B, Lattanzio F, Passarino G. Global DNA methylation in old subjects is correlated with frailty. Age (Dordr) 2012; 34: 169–79.CrossrefGoogle Scholar

  • 101.

    Heyna H, Lib N, Ferreiraa HJ, Morana S, Pisanoe DG, Gomeza A, Dieza J, Sanchez-Muta JV, Setiena F, Carmonaa FJ, Puca AA, Sayolsa S, Pujanah MA, Serra-Musachh J, Iglesias-Platasi I, Formigaj F, Fernandezk AF, Fragak MF, Heathm SC, Valenciae A, Gutm IG, Wangn J, Estellera M. Distinct DNA methylomes of newborns and centenarians. Proc Natl Acad Sci USA 2012; 109: 10522–27.CrossrefGoogle Scholar

  • 102.

    Bell JT, Tsai PC, Yang TP, Pidsley R, Nisbet J, Glass D, Mangino M, Zhai G, Zhang F, Valdes A, Shin SY, Dempster EL, Murray RM, Grundberg E, Hedman AK, Nica A, Small KS; MuTHER Consortium, Dermitzakis ET, McCarthy MI, Mill J, Spector TD, Deloukas P. Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. PLOS Genet 2012; 8: e1002629.CrossrefGoogle Scholar

  • 103.

    Thompson RF, Atzmon G, Gheorghe C, Liang HQ, Lowes C, Greally JM, Barzilai N. Tissue-specific dysregulation of DNA methylation in aging. Aging Cell 2010; 9: 506–18.CrossrefGoogle Scholar

  • 104.

    Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda S, Klotzle B, Bibikova M, Fan JB, Gao Y, Deconde R, Chen M, Rajapakse I, Friend S, Ideker T, Zhang K. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell 2013; 49: 359–67.CrossrefGoogle Scholar

  • 105.

    Bocklandt S, Lin W, Sehl ME, Sánchez FJ, Sinsheimer JS, Horvath S, Vilain E. Epigenetic predictor of age. PLOS One 2011; 6: e14821.CrossrefGoogle Scholar

  • 106.

    Garagnani P, Bacalini MG, Pirazzini C, Gori D, Giuliani C, Mari D, Di Blasio AM, Gentilini D, Vitale G, Collino S, Rezzi S, Castellani G, Capri M, Salvioli S, Franceschi C. Methylation of ELOVL2 gene as a new epigenetic marker of age. Aging Cell 2012; 11: 1132–4.CrossrefGoogle Scholar

  • 107.

    Christensen BC, Houseman EA, Marsit CJ, Zheng S, Wrensch MR, Wiemels JL, Nelson HH, Karagas MR, Padbury JF, Bueno R, Sugarbaker DJ, Yeh RF, Wiencke JK, Kelsey KT. Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLOS Genet 2009; 5: e1000602.CrossrefGoogle Scholar

  • 108.

    Narita M, Nũnez S, Heard E, Lin AW, Hearn SA, Spector DL, Hannon GJ, Lowe SW. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 2003; 113: 703–16.CrossrefGoogle Scholar

  • 109.

    Das C, Tyler JK. Histone exchange and histone modifications during transcription and aging. Biochim Biophys Acta 2013; 1819: 332–42.Google Scholar

  • 110.

    Feser J, Truong D, Das C, Carson JJ, Kieft J, Harkness T, Tyler JK. Elevated histone expression promotes life span extension. Mol Cell 2010; 39: 724–35.CrossrefGoogle Scholar

  • 111.

    Dang W, Steffen KK, Perry R, Dorsey JA, Johnson FB, Shilatifard A, Kaeberlein M, Kennedy BK, Berger SL. Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature 2009; 459: 802–7.Google Scholar

  • 112.

    Lai CY, Wu YT, Yu SL, Yu YH, Lee SY, Liu CM, Hsieh WS, Hwu HG, Chen PC, Jeng SF, Chen WJ. Modulated expression of human peripheral blood microRNAs from infancy to adulthood and its role in aging. Aging Cell 2014; 13: 679–89.CrossrefGoogle Scholar

  • 113.

    Weilner S, Schraml E, Redl H, Grillari-Voglauer R, Grillari J. Secretion of microvesicular miRNAs in cellular and organismal aging. Exp Gerontol 2013; 48: 626–33.CrossrefGoogle Scholar

  • 114.

    Maes OC, An J, Sarojini H, Wang E. Murine microRNAs implicated in liver functions and aging process. Mech Ageing Dev 2008; 129: 534–41.CrossrefGoogle Scholar

  • 115.

    Ugalde AP, Ramsay AJ, de la Rosa J, Varela I, Mariño G, Cadiñanos J, Lu J, Freije JM, López-Otín C. Aging and chronic DNA damage response activate a regulatory pathway involving miR-29 and p53. EMBO J 2011; 30: 2219–32.CrossrefGoogle Scholar

  • 116.

    Lee S, Jung JW, Park SB, Roh K, Lee SY, Kim JH, Kang SK, Kang KS. Histone deacetylase regulates high mobility group A2-targeting microRNAs in human cord blood-derived multipotent stem cell aging. Cell Mol Life Sci 2011; 68: 325–36.CrossrefGoogle Scholar

  • 117.

    Houthoofd K, Vanfleteren JR. The longevity effect of dietary restriction in Caenorhabditis elegans. Exp Gerontol 2006; 41: 1026–31.CrossrefGoogle Scholar

  • 118.

    Clancy DJ, Gems D, Hafen E, Leevers SJ, Partridge L. Dietary restriction in long-lived dwarf flies. Science 2002; 296: 319.Google Scholar

  • 119.

    Giannakou ME, Goss M, Partridge L. Role of dFOXO in lifespan extension by dietary restriction in Drosophila melanogaster: not required, but its activity modulates the response. Aging Cell 2008; 7: 187–98.CrossrefGoogle Scholar

  • 120.

    Cooper ME, El-Osta A. Epigenetics: mechanisms and implications for diabetic complications. Circ Res 2010; 107: 1403–13.CrossrefGoogle Scholar

  • 121.

    Fernandez AZ, Siebel AL, El-Osta A. Atherogenic factors and their epigenetic relationships. Int J Vasc Med 2010; 2010: 437809.Google Scholar

  • 122.

    Teperino R, Schoonjans K, Auwerx J. Histone methyl transferases and demethylases; can they link metabolism and transcription? Cell Metab 2010; 12: 321–7.CrossrefGoogle Scholar

  • 123.

    Li Y, Daniel M, Tollefsbol TO. Epigenetic regulation of caloric restriction in aging. BMC Med 2011; 9: 98.CrossrefGoogle Scholar

  • 124.

    Sandovici I, Smith NH, Nitert MD, Ackers-Johnson M, Uribe-Lewis S, Ito Y, Jones RH, Marquez VE, Cairns W, Tadayyon M, O’Neill LP, Murrell A, Ling C, Constância M, Ozanne SE. Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets. Proc Natl Acad Sci USA 2011; 108: 5449–54.CrossrefGoogle Scholar

  • 125.

    Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, Guarente L, Gu W. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 2001; 107: 137–48.CrossrefGoogle Scholar

  • 126.

    Langley E, Pearson M, Faretta M, Bauer UM, Frye RA, Minucci S, Pelicci PG, Kouzarides T. Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J 2002; 21: 2383–96.CrossrefGoogle Scholar

  • 127.

    Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK, Guarente L, Weinberg RA. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 2001; 107: 149–59.Google Scholar

  • 128.

    Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, Gygi SP, Sinclair DA, Alt FW, Greenberg ME. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 2004; 303: 2011–5.Google Scholar

  • 129.

    Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W, Bultsma Y, McBurney M, Guarente L. Mammalian SIRT1 represses forkhead transcription factors. Cell 2004; 116: 551–63.CrossrefGoogle Scholar

  • 130.

    Jeong J, Juhn K, Lee H, Kim SH, Min BH, Lee KM, Cho MH, Park GH, Lee KH. SIRT1 promotes DNA repair activity and deacetylation of Ku70. Exp Mol Med 2007; 39: 8–13.CrossrefGoogle Scholar

  • 131.

    Cohen HY, Lavu S, Bitterman KJ, Hekking B, Imahiyerobo TA, Miller C, Frye R, Ploegh H, Kessler BM, Sinclair DA. Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol Cell 2004; 13: 627–38.CrossrefGoogle Scholar

  • 132.

    Wakeling LA, Ions LJ, Ford D. Could Sirt1-mediated epigenetic effects contribute to the longevity response to dietary restriction and be mimicked by other dietary interventions? Age (Dordr) 2009; 31: 327–41.CrossrefGoogle Scholar

  • 133.

    Schilling MM, Oeser JK, Boustead JN, Flemming BP, O’Brien RM. Gluconeogenesis: re-evaluating the FOXO1-PGC-1alpha connection. Nature 2006; 443: E10–1.Google Scholar

  • 134.

    Kim TY, Lee HJ, Hwang KS, Lee M, Kim JW, Bang YJ, Kang GH. Methylation of RUNX3 in various types of human cancers and premalignant stages of gastric carcinoma. Lab Invest 2004; 84: 479–84.CrossrefGoogle Scholar

  • 135.

    Milagro FI, Campión J, Cordero P, Goyenechea E, Gómez-Uriz AM, Abete I, Zulet MA, Martínez JA. A dual epigenomic approach for the search of obesity biomarkers: DNA methylation in relation to diet-induced weight loss. FASEB J 2011; 25: 1378–89.CrossrefGoogle Scholar

  • 136.

    Bouchard L, Rabasa-Lhoret R, Faraj M, Lavoie ME, Mill J, Pérusse L, Vohl MC. Differential epigenomic and transcriptomic responses in subcutaneous adipose tissue between low and high responders to caloric restriction. Am J Clin Nutr 2010; 91: 309–20.CrossrefGoogle Scholar

  • 137.

    Campión J, Milagro FI, Goyenechea E, Martínez JA. TNF-alpha promoter methylation as a predictive biomarker for weight-loss response. Obesity (Silver Spring) 2009; 17: 1293–7.Google Scholar

  • 138.

    Cyr AR, Domann FE. The redox basis of epigenetic modifications: from mechanisms to functional consequences. Antioxid Redox Sign 2011; 15: 551–89.CrossrefGoogle Scholar

  • 139.

    Eisenberg T, Knauer H, Schauer A, Büttner S, Ruckenstuhl C, Carmona-Gutierrez D, Ring J, Schroeder S, Magnes C, Antonacci L, Fussi H, Deszcz L, Hartl R, Schraml E, Criollo A, Megalou E, Weiskopf D, Laun P, Heeren G, Breitenbach M, Grubeck-Loebenstein B, Herker E, Fahrenkrog B, Fröhlich KU, Sinner F, Tavernarakis N, Minois N, Kroemer G, Madeo F. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol 2009; 11: 1305–14.CrossrefGoogle Scholar

  • 140.

    Eisenberg T, Schroeder S, Andryushkova A, Pendl T, Küttner V, Bhukel A, Mariño G, Pietrocola F, Harger A, Zimmermann A, Moustafa T, Sprenger A, Jany E, Büttner S, Carmona-Gutierrez D, Ruckenstuhl C, Ring J, Reichelt W, Schimmel K, Leeb T, Moser C, Schatz S, Kamolz LP, Magnes C, Sinner F, Sedej S, Fröhlich KU, Juhasz G, Pieber TR, Dengjel J, Sigrist SJ, Kroemer G, Madeo F. Nucleocytosolic depletion of the energy metabolite acetyl-coenzyme a stimulates autophagy and prolongs lifespan. Cell Metab 2014; 19: 431–44.CrossrefGoogle Scholar

  • 141.

    Mariño G, Pietrocola F, Eisenberg T, Kong Y, Malik SA, Andryushkova A, Schroeder S, Pendl T, Harger A, Niso-Santano M, Zamzami N, Scoazec M, Durand S, Enot DP, Fernández ÁF, Martins I, Kepp O, Senovilla L, Bauvy C, Morselli E, Vacchelli E, Bennetzen M, Magnes C, Sinner F, Pieber T, López-Otín C, Maiuri MC, Codogno P, Andersen JS, Hill JA, Madeo F, Kroemer G. Regulation of autophagy by cytosolic acetyl-coenzyme A. Mol Cell 2014; 53: 710–25.CrossrefGoogle Scholar

  • 142.

    Soda K, Kano Y, Sakuragi M, Takao K, Lefor A, Konishi F. Long-term oral polyamine intake increases blood polyamine concentrations. J Nutr Sci Vitaminol (Tokyo) 2009; 55: 361–6.CrossrefGoogle Scholar

  • 143.

    Li Y, Tollefsbol TO. Impact on DNA methylation in cancer prevention and therapy by bioactive dietary components. Curr Med Chem 2010; 17: 2141–51.CrossrefGoogle Scholar

  • 144.

    Li Y, Yuan YY, Meeran SM, Tollefsbol TO. Synergistic epigenetic reactivation of estrogen receptor-α (ERα) by combined green tea polyphenol and histone deacetylase inhibitor in ERα-negative breast cancer cells. Mol Cancer 2010; 9: 274.CrossrefGoogle Scholar

  • 145.

    Li Y, Liu L, Andrews LG, Tollefsbol TO. Genistein depletes telomerase activity through cross-talk between genetic and epigenetic mechanisms. Int J Cancer 2009; 125: 286–96.CrossrefGoogle Scholar

  • 146.

    Meeran SM, Ahmed A, Tollefsbol TO. Epigenetic targets of bioactive dietary components for cancer prevention and therapy. Clin Epigenetics 2010; 1: 101–16.CrossrefGoogle Scholar

  • 147.

    Meeran SM, Patel SN, Tollefsbol TO. Sulforaphane causes epigenetic repression of hTERT expression in human breast cancer cell lines. PLOS One 2010; 5: e11457.CrossrefGoogle Scholar

  • 148.

    Kim YI. Folate and colorectal cancer: an evidence-based critical review. Mol Nutr Food Res 2007; 51: 267–92.CrossrefGoogle Scholar

  • 149.

    Yang Q, Bostick RM, Friedman JM, Flanders WD. Serum folate and cancer mortality among U.S. adults: findings from the Third National Health and Nutritional Examination Survey linked mortality file. Cancer Epidemiol Biomarkers Prev 2009; 18: 1439–47.CrossrefGoogle Scholar

  • 150.

    Waterland RA, Lin JR, Smith CA, Jirtle RL. Post-weaning diet affects genomic imprinting at the insulin-like growth factor 2 (Igf2) locus. Hum Mol Genet 2006; 15: 705–16.CrossrefGoogle Scholar

  • 151.

    Wallace K, Grau MV, Levine AJ, Shen L, Hamdan R, Chen X, Gui J, Haile RW, Barry EL, Ahnen D, McKeown-Eyssen G, Baron JA, Issa JP. Association between folate levels and CpG Island hypermethylation in normal colorectal mucosa. Cancer Prev Res 2010; 3: 1552–64.CrossrefGoogle Scholar

  • 152.

    Piyathilake CJ, Badiga S, Kabagambe EK, Azuero A, Alvarez RD, Johanning GL, Partridge EE. A dietary pattern associated with LINE-1 methylation alters the risk of developing cervical intraepithelial neoplasia. Cancer Prev Res 2012; 5: 385–92.CrossrefGoogle Scholar

  • 153.

    Barger JL, Kayo T, Vann JM, Arias EB, Wang J, Hacker TA, Wang Y, Raederstorff D, Morrow JD, Leeuwenburgh C, Allison DB, Saupe KW, Cartee GD, Weindruch R, Prolla TA. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLOS One 2008; 3: e2264.CrossrefGoogle Scholar

  • 154.

    Agarwal B, Baur JA. Resveratrol and life extension. Ann NY Acad Sci 2011; 1215: 138–43.Google Scholar

  • 155.

    Patel KR, Scott E, Brown VA, Gescher AJ, Steward WP, Brown K. Clinical trials of resveratrol. Ann NY Acad Sci 2011; 1215: 161–9.Google Scholar

  • 156.

    Subramanian L, Youssef S, Bhattacharya S, Kenealey J, Polans AS, van Ginkel PR. Resveratrol: challenges in translation to the clinic – a critical discussion. Clin Cancer Res 2010; 16: 5942–8.CrossrefGoogle Scholar

  • 157.

    Tili E, Michaille JJ, Alder H, Volinia S, Delmas D, Latruffe N, Croce CM. Resveratrol modulates the levels of microRNAs targeting genes encoding tumor-suppressors and effectors of TGFβ signaling pathway in SW480 cells. Biochem Pharmacol 2010; 80: 2057–65.CrossrefGoogle Scholar

  • 158.

    Chen Q, Ganapathy S, Singh KP, Shankar S, Srivastava RK. Resveratrol induces growth arrest and apoptosis through activation of FOXO transcription factors in prostate cancer cells. PLOS ONE 2010; 5: e15288.CrossrefGoogle Scholar

  • 159.

    Bertelli AA, Das DK. Grapes, wines, resveratrol, and heart health. J Cardiovasc Pharmacol 2009; 54: 468–76.CrossrefGoogle Scholar

  • 160.

    Boccardi V, Esposito A, Rizzo MR, Marfella R, Barbieri M, Paolisso G. Mediterranean diet, telomere maintenance and health status among elderly. PLOS One 2013; 8: e62781.CrossrefGoogle Scholar

  • 161.

    Chung S, Yao H, Caito S, Hwang JW, Arunachalam G, Rahman I. Regulation of SIRT1 in cellular functions: role of polyphenols. Arch Biochem Biophys 2010; 501: 79–90.Google Scholar

  • 162.

    Ayissi VB, Ebrahimi A, Schluesenner H. Epigenetic effects of natural polyphenols: a focus on SIRT1-mediated mechanisms. Mol Nutr Food Res 2014; 58: 22–32.CrossrefGoogle Scholar

  • 163.

    Mudduluru G, George-William JN, Muppala S, Asangani IA, Kumarswamy R, Nelson LD, Allgayer H. Curcumin regulates miR-21 expression and inhibits invasion and metastasis in colorectal cancer. Biosci Rep 2011; 31: 185–97.CrossrefGoogle Scholar

  • 164.

    Biesalski HK. Polyphenols and inflammation: basic interactions. Curr Opin Clin Nutr Metab Care 2007; 10: 724–8.CrossrefGoogle Scholar

  • 165.

    Coward WR, Watts K, Feghali-Bostwick CA, Knox A, Pang L. Defective histone acetylation is responsible for the diminished expression of cyclooxygenase 2 in idiopathic pulmonary fibrosis. Mol Cell Biol 2009; 29: 4325–39.CrossrefGoogle Scholar

  • 166.

    Zhang R, Chen HZ, Liu JJ, Jia YY, Zhang ZQ, Yang RF, Zhang Y, Xu J, Wei YS, Liu DP, Liang CC. SIRT1 suppresses activator protein-1 transcriptional activity and cyclooxygenase-2 expression in macrophages. J Biol Chem 2010; 285: 7097–110.Google Scholar

  • 167.

    Zygmunt K, Faubert B, MacNeil J, Tsiani E. Naringenin, a citrus flavonoid, increases muscle cell glucose uptake via AMPK. Biochem Biophys Res Commun 2010; 398: 178–83.Google Scholar

  • 168.

    Morimoto T, Sunagawa Y, Kawamura T, Takaya T, Wada H, Nagasawa A, Komeda M, Fujita M, Shimatsu A, Kita T, Hasegawa K. The dietary compound curcumin inhibits p300 histone acetyltransferase activity and prevents heart failure in rats. J Clin Invest 2008; 118: 868–78.Google Scholar

  • 169.

    Marcu MG, Jung YJ, Lee S, Chung EJ, Lee MJ, Trepel J, Neckers L. Curcumin is an inhibitor of p300 histone acetyltransferase. Med Chem 2006; 2: 169–74.Google Scholar

  • 170.

    Tsang WP, Kwok TT. Epigallocatechin gallate up-regulation of miR-16 and induction of apoptosis in human cancer cells. J Nutr Biochem 2010; 21: 140–6.CrossrefGoogle Scholar

  • 171.

    Fang MZ, Wang Y, Ai N, Hou Z, Sun Y, Lu H, Welsh W, Yang CS. Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res 2003; 63: 7563–70.Google Scholar

  • 172.

    Nandakumar V, Vaid M, Katiyar SK. (-)-Epigallocatechin-3-gallate reactivates silenced tumor suppressor genes, Cip1/p21 and p16INK4a, by reducing DNA methylation and increasing histones acetylation in human skin cancer cells. Carcinogenesis 2011; 32: 537–44.Google Scholar

  • 173.

    Katiyar S, Elmets CA, Katiyar SK. Green tea and skin cancer: photoimmunology, angiogenesis and DNA repair. J Nutr Biochem 2007; 18: 287–96.CrossrefGoogle Scholar

  • 174.

    Sunagawa T, Shimizu T, Kanda T, Tagashira M, Sami M, Shirasawa T. Procyanidins from apples (Malus pumila Mill.) extend the lifespan of Caenorhabditis elegans. Planta Med 2011; 77: 122–7.CrossrefGoogle Scholar

  • 175.

    Li Y, Vandenboom TG, Wang Z, Kong D, Ali S, Philip PA, Sarkar FH. miR-146a suppresses invasion of pancreatic cancer cells. Cancer Res 2010; 70: 1486–95.CrossrefGoogle Scholar

  • 176.

    Wang LG, Beklemisheva A, Liu XM, Ferrari AC, Feng J, Chiao JW. Dual action on promoter demethylation and chromatin by an isothiocyanate restored GSTP1 silenced in prostate cancer. Mol Carcinog 2007; 46: 24–31.CrossrefGoogle Scholar

  • 177.

    Izzotti A, Larghero P, Cartiglia C, Longobardi M, Pfeffer U, Steele VE, De Flora S. Modulation of microRNA expression by budesonide, phenethyl isothiocyanate and cigarette smoke in mouse liver and lung. Carcinogenesis 2010; 31: 894–901.CrossrefGoogle Scholar

  • 178.

    Priyadarsini RV, Vinothini G, Murugan RS, Manikandan P, Nagini S. The flavonoid quercetin modulates the hallmark capabilities of hamster buccal pouch tumors. Nutr Cancer 2011; 63: 218–26.CrossrefGoogle Scholar

  • 179.

    King-Batoon A, Leszczynska JM, Klein CB. Modulation of gene methylation by genistein or lycopene in breast cancer cells. Environ Mol Mutagen 2008; 49: 36–45.CrossrefGoogle Scholar

  • 180.

    Wen XY, Wu SY, Li ZQ, Liu ZQ, Zhang JJ, Wang GF, Jiang ZH, Wu SG. Ellagitannin (BJA3121), an anti-proliferative natural polyphenol compound, can regulate the expression of MiRNAs in HepG2 cancer cells. Phytother Res 2009; 23: 778–84.Google Scholar

  • 181.

    Do DP, Pai SB, Rizvi SA, D’Souza MJ. Development of sulforaphane-encapsulated microspheres for cancer epigenetic therapy. Int J Pharm 2010; 386: 114–21.Google Scholar

  • 182.

    Fazekas Z, Gao D, Saladi RN, Lu Y, Lebwohl M, Wei H. Protective effects of lycopene against ultraviolet B-induced photodamage. Nutr Cancer 2003; 47: 181–7.CrossrefGoogle Scholar

  • 183.

    Jones E, Hughes RE. Quercetin, flavonoids and the life-span of mice. Exp Gerontol 1982; 17: 213–7.CrossrefGoogle Scholar

  • 184.

    De Boer VC, De Goffau MC, Arts IC, Hollman PC, Keijer J. SIRT1 stimulation by polyphenols is affected by their stability and metabolism. Mech Ageing Dev 2006: 127; 618–27.Google Scholar

  • 185.

    Fang MZ, Chen D, Sun Y, Jin Z, Christman JK, Yang CS. Reversal of hypermethylation and reactivation of p16INK4a, RARbeta, and MGMT genes by genistein and other isoflavones from soy. Clin Cancer Res 2005; 11: 7033–41.CrossrefGoogle Scholar

  • 186.

    Majid S, Dar AA, Ahmad AE, Hirata H, Kawakami K, Shahryari V, Saini S, Tanaka Y, Dahiya AV, Khatri G, Dahiya R. BTG3 tumor suppressor gene promoter demethylation, histone modification and cell cycle arrest by genistein in renal cancer. Carcinogenesis 2009; 30: 662–70.CrossrefGoogle Scholar

  • 187.

    Tang WY, Newbold R, Mardilovich K, Jefferson W, Cheng RY, Medvedovic M, Ho SM. Persistent hypomethylation in the promoter of nucleosomal binding protein 1 (Nsbp1) correlates with overexpression of Nsbp1 in mouse uteri neonatally exposed to diethylstilbestrol or genistein. Endocrinology 2008; 149: 5922–31.CrossrefGoogle Scholar

  • 188.

    Druesne N, Pagniez A, Mayeur C, Thomas M, Cherbuy C, Duée PH, Martel P, Chaumontet C. Diallyl disulfide (DADS) increases histone acetylation and p21(waf1/cip1) expression in human colon tumor cell lines. Carcinogenesis 2004; 25: 1227–36.Google Scholar

  • 189.

    Morselli E, Mariño G, Bennetzen MV, Eisenberg T, Megalou E, Schroeder S, Cabrera S, Bénit P, Rustin P, Criollo A, Kepp O, Galluzzi L, Shen S, Malik SA, Maiuri MC, Horio Y, López-Otín C, Andersen JS, Tavernarakis N, Madeo F, Kroemer G. Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome. J Cell Biol 2011; 192: 615–29.Google Scholar

About the article

Corresponding author: Mario G. Mirisola, DiBiMed Universita’ degli Studi Di Palermo, Via Divisi 83, I-90133 Palermo, Italy, e-mail:


Received: 2014-11-14

Accepted: 2015-03-04

Published Online: 2015-04-17

Published in Print: 2015-04-01


Citation Information: Biomolecular Concepts, Volume 6, Issue 2, Pages 105–117, ISSN (Online) 1868-503X, ISSN (Print) 1868-5021, DOI: https://doi.org/10.1515/bmc-2014-0038.

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