This book focuses on the three most important aspects of ageing research: nutrition, physical exercise and epigenetics. The contributors discuss ways that age-related epigenetic imprints such as DNA methylation and histone acetylation are modified by these two interventions. The emphasis on epigenetics helps to illuminate the underlying mechanisms of anti-ageing interventions, as ageing and disease are predominately epigenetic phenomena.
Skip to main content Skip to table of contents. Advertisement Hide. Nutrition, Exercise and Epigenetics: Ageing Interventions. Front Matter Pages i-viii. In contrary to what has been observed in yeast, in aged mouse brain this modification is reduced Gong et al. N-terminal acetylation is present in all core histones, but is more abundant on histones H4 and H2A, catalyzed by the N-terminal acetyltransferase Nat4 aka NatD, Naa This histone acetyltransferase has high substrate selectivity and its enzymatic activity is conserved from yeast to human Ree et al.
This modification crosstalks with the adjacent arginine 3 asymmetric dimethylation mark H4R3me2a to regulate ribosomal RNA expression in response to glucose levels suggesting that Nat4 and NacH4 act as a sensor for cell growth Schiza et al. Constitutive expression of Nat4 counteracts the longevity effect induced by CR through a mechanism that involves the induction of specific stress-response genes and nicotinamidase Pnc1, a major regulator of Sir2 activity Molina-Serrano et al. H4K12 can be found both in acetylated and methylated forms.
In its acetylated form this residue is associated with active transcription Wang et al. Interestingly, Peleg and colleagues found that old mice have deregulated H4K12ac levels in certain key genes, impairing their ability to learn Peleg et al. Following this observation, they also show that recovering physiological levels of this modification by treatment with the histone deacetylase inhibitor SAHA restores the expression of learning-induced genes and the cognitive abilities of old mice.
In another report, Peleg and colleagues also found that impairing Chameau, the main H4K12 acetyltransferase in D. H4K16 is usually found in an acetylated form and it is implicated in nucleosome—nucleosome interactions as well as higher order chromatin structure. This modification is present in active chromatin Kimura et al. Yeast mutant strains in which lysine 16 on H4 has been substituted by arginine H4K16R or glutamine H4K16Q show a decrease in replicative lifespan Dang et al.
Consistently, deletion of the H4K16 deacetylase Sir2 has been extensively reported to shorten replicative lifespan in yeast Kaeberlein et al. Along the same lines, evidence shows that Sir2 overexpression increases lifespan in yeast, worms and flies Kaeberlein et al. In the brain of aged mice, SIRT1-associated genes are found to be deregulated, and overexpression of this enzyme can suppress this age-dependent deregulation Oberdoerffer et al.
Moreover, mice mildly overexpressing this enzyme have a better overall health, with lower levels of DNA damage and fewer spontaneous carcinomas Herranz et al.
Interestingly, deletion of Rpd3, another H4K16 deacetylase has the opposite effect to Sir2 deletion, increasing lifespan in yeast and D. However, while heterozygous flies have extended longevity, the complete removal of Rpd3 in D. Whether the contradicting effects observed between Rpd3 and Sir2 are a consequence of targeting histones located on different genes is open to discussion.
Notably, supplementing the drinking water of these mice with the histone deacetylase inhibitor sodium butyrate delays premature cellular aging in these mutants and increases lifespan Krishnan et al. Histone H2B monoubiquitination at lysine in yeast and, correspondingly, lysine in vertebrates is required for the trimethylation of both H3K4 and H3K79 Nakanishi et al.
Interestingly, the levels of this H2B modification increase in replicative aged cells Rhie et al. Interestingly, the lifespan extension observed by deletion of each of these three components is dependent on Sir2 and linked to H4K16 acetylation as well as methylation at H3K4 and H3K79 residues Rhie et al. Environmental factors such as exercise Denham et al. However, nutrient availability and diet is to date the most thoroughly studied environmental factor to affect longevity. Additionally, diet is known to significantly affect the epigenome.
Nutrigenomics and epigenetics: INAF
Specifically, Wolff et al. Since then, the scientific community working within this field was interested to determine whether diet can affect chromatin structure and gene transcription through epigenetic changes. In fact, histone PTMs are excellent intermediaries to connect changes between the environmental input nutrient availability and the biological output transcriptional regulation Badeaux and Shi, However, even though dietary interventions, such as CR, have been shown to impact on lifespan, the causal evidence that establishes histone modifications as the molecular bridge between diet and longevity is still underdeveloped.
Nevertheless, below we briefly introduce nutrient-signaling pathways that feed into histone modifications and then summarize the evidence which demonstrate that dietary interventions influence the occurrence of lifespan-associated histone modifications described above. Table 2.
Dietary influences on histone modifications and their cellular effects. Sirtuins are probably the best-studied family of enzymes implicated in changing the epigenome as a response to environmental signals. As NAD-dependent deacetylases, sirtuins are a perfect candidate to mediate lifespan response to nutrients, having a dual role as NAD-sensors and transcriptional regulators trough the deposition of PTMs in histones and other target proteins Houtkooper et al.
Target of Rapamycin TOR is a well-preserved nutrient sensing pathway that has been extensively linked to CR and lifespan regulation, and its inhibition through rapamycin increases lifespan in several organisms Johnson et al. The histone deacetylase Sir2 is phosphorylated by this pathway, which then regulates its ability to mediate lifespan under CR conditions Kang et al. The insulin signaling pathway, conserved from C. Mutations of its different components regulate genes that are involved in lifespan Kenyon, , and genetic interventions that decrease growth hormone and insulin-like growth factor signaling robustly extend longevity in mammals Brown-Borg, Among the various dietary interventions, CR is the best characterized, and it can increase lifespan in yeast, worm, flies, rodents, and primates.
Here we provide an extensive overview of the links to histone modifications Table 2. In yeast, CR has been shown to regulate the expression of stress response genes through changes in the modification of key histone residues. N-terminal acetylation on histone H4 NacH4 and the phosphorylation of H3T11 are two histone residues that have been linked to CR-mediated pathways.
Both PTMs regulate lifespan through the transcriptional regulation of different stress-response genes. Specifically, CR decreases the acetylation levels at the N-terminus of histone H4. This, in turn, upregulates several stress-response genes, including the one encoding for nicotinamidase Pnc1, a main regulator of Sir2 activity and a well-characterized gene involved in replicative lifespan Molina-Serrano et al. CR also affects H3T11 phosphorylation, in this case enhancing the modification. This mechanism regulates the expression of several stress-response genes, which eventually affect chronological lifespan by influencing cell tolerance to media acidification Oh et al.
These are two of the best examples of histone modifications through which a dietary input CR affects the expression of key regulators that eventually impact on cellular longevity. CR stimulates several epigenetic effects in mammals. Rats fed with a diet containing an indigestible starch showed a reduction of the key transcription factor ChREBP carbohydrate response element binding protein and THRSP thyroid hormone-responsive spot 14 protein levels. Another effect of CR is the increase in histone H4 acetylation on the Glut4 glucose transporter 4 gene promoter in adipose tissue of obese mice.
GLUT4 is responsible for regulating glucose metabolism through uptake into adipocytes, and the increased acetylation enhances its expression.
In human cell cultures glucose restriction reduces the expression of the p16 INK4A gene. Additionally, glucose restriction increased H3ac, H4ac and H3K4me2 levels on the Tert promoter and increased its expression in human fetal lung fibroblasts Daniel and Tollefsbol, Free-feeding ad libitum long-lived rats have the same gene expression profile as the ones fed with CR.
These proteins may be implicated in the dietary memory effect Wood et al. CR seems to work through several pathways, including sirtuin activation Herranz and Serrano, ; Li et al. SIRT1 acts as a metabolic sensor of CR and can delay aging by providing increased stress resistance through regulation of the tumor-suppressor protein p53 and the fork head box O gene FOXO3a.
Interestingly, many CR mimetic phytochemicals work as sirtuin activators vel Szic et al. RSV increases lifespan in yeast, worms, flies, and fish Price et al. Other compounds like 2-deoxyglucose, a glucose analog that blocks glucose metabolism, can also induce SIRT1 in mammals Davis and Ross, High-fat diet is another well characterized dietary intervention. Mice fed in these conditions may develop obesity, together with impaired glucose tolerance and enhanced pyruvate tolerance. Rats fed with HF diet that become obese obesity prone — OP show hepatic cellular aging.
However, some mice develop resistance obesity resistant — OR and thus do not show the OP phenotype Zhang et al. These two genes are regulators of cellular aging, and their upregulation is associated with changes in PTM levels. Similar results have been observed in p16 Ink4a expression when comparing OP to control mice Zhang et al. This is one of the earliest examples of how diet affects histone modifications, which in turn impact on specific genes that regulate cellular lifespan Zhang et al.
However, the p21 Cip1 gene results are contradictory. In recent reports, HF feeding in mice has been associated with reduced H3K18ac and H3K23ac levels in white adipose tissue and in the pancreas Carrer et al. In another study using diet-induce obese mice DIO as prediabetic model, the authors analyzed the liver of these mice and found 10 significantly downregulated and 5 significantly upregulated PTMs compared to control Nie et al.
Interestingly, H3K36me2 increase was reversed by metformin, a widely used drug for treating Type 2 Diabetes Nie et al. HF diet has also been shown to affect considerably the expression of neuropeptides in the brain hypothalamus and brain stem , which are responsible for controlling feeding behavior, energy metabolism and body-weight homeostasis Milagro et al. HF diet effects are transmitted from embryonic stages into adulthood, regardless of the dietary choices later in life Howie et al. Maternal HF diet during gestation and lactation is responsible for a plethora of epigenetic changes in the offspring, and some of the HF diet hereditary epigenetic changes can last for up to two generations Dunn and Bale, For example, timed-pregnant rats fed with a HF diet throughout gestation and lactation showed reduced p16 Ink4a levels in the mammary gland.
These changes were associated with reduced H4ac levels and increased HDAC3 recruitment within the p16 Ink4a promoter region Zheng et al. The offspring of HF fed mother rats also have altered PTMs in their livers compared to the offspring from mothers fed with the control diet. Adiponectin regulator of glucose and fatty acid metabolism expression in the adipose tissue was also reduced in the offspring of mice fed with HF diet during pregnancy, due to a decrease in H3K9ac and concomitant increase in H3K9me levels at the gene promoter Masuyama and Hiramatsu, In the same report, the authors observed an increase in leptin levels hormone, regulator of energy balance and inhibitor of hunger in the adipose tissue, combined with increased H4K20me at the promoter of its gene Masuyama and Hiramatsu, Deregulation of thyroid hormones in the offspring of mothers fed with HF diet can lead to obesity Suter et al.
Interestingly, maternal HF diet can affect the offspring in a different manner based on their genders.
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Specifically, HF diet during pregnancy in mice gave birth to male offspring with high triglycerides and increased the expression of the antioxidant genes Pon1 and Pon3 compare to controls. On the contrary, in female offspring the changes in Pon1 and Pon3 mRNA levels were not statistically significant. The hepatic Pon1 promoter had significantly more histone H4 acetylation and H3K4me2 in both genders.
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However, H3K9me3 was only associated with antioxidant genes in females Strakovsky et al. Paternal HF diet changed the epigenome in spermatozoa and offspring liver. In contrast, in the offspring liver, H3K4me was enriched in genes controlling lipid biosynthesis, fatty acid synthesis and the oxidation-reduction process Terashima et al.
Maternal malnutrition may lead to several epigenetic alterations in the offspring.
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For example, gestational protein restriction in mice decreased H3K4me3 and H4K20me3 while it increased H3K9me3 and H3K27me3 levels on the Igf2 Insulin-like growth factor-II locus, resulting in its repression in fetal liver Strakovsky et al. IGF2 deficiency in humans and mice leads to hepatic lipid homeostasis and growth restriction of the embryo Strakovsky et al.
LP diet in pregnant rats also led to hyper-cholesterolemia in postnatal rat offspring d21 , which persisted into adulthood d Specifically, LP diet reduced the acetylation and increased the trimethylation of H3K9 at the Cyp7a1 Cholesterol 7 alpha-hydroxylase gene promoter, causing its transcriptional repression in the rat offspring. The increase in H3K9me3 deposition was preceded by reduction of its demethylase Jmjd2 during fetal life. In embryonic stage D19 , H3K9me3 levels were not increased and Cyp7a1 expression was modestly reduced Sohi et al.