Abstract
As life expectancy increases worldwide, ageing and age-related diseases arise as a major issue for societies around the globe. Understanding the biological mechanisms underlying the ageing process is thus instrumental for the development of efficient interventions aimed to prevent and treat age-related conditions. Current knowledge in the biogerontology field points to epigenetics as a critical component of the ageing process, not only by serving as a bona-fide marker of biological age but also by controlling and conferring inheritability to cellular and organismal ageing. This is reflected by a myriad of evidences demonstrating the relationship between DNA methylation, histone modifications, chromatin remodeling and small non-coding RNAs and several age-related phenotypes. Given the reversibility of epigenetic alterations, epigenetic reprogramming may also be envisioned as a potential approach to treat age-related disorders. Here we review how different types of epigenetic mechanisms are involved in the ageing process. In addition, we highlight how interventions modulate epigenetics and thus promote health- and lifespan.
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References
Aalto AP et al (2018) Opposing roles of microRNA Argonautes during Caenorhabditis elegans aging. PLoS Genet 14(6):1–24. https://doi.org/10.1371/journal.pgen.1007379
Adams PD et al (2013) Lysosome-mediated processing of chromatin in senescence. J Cell Biol 202(1):129–143. https://doi.org/10.1083/jcb.201212110
Aguilar-Arnal L et al (2015) NAD+-SIRT1 control of H3K4 trimethylation through circadian deacetylation of MLL1. Nat Struct Mol Biol 22(4):312–318. https://doi.org/10.1038/nsmb.2990
Barbi E et al (2018) Demography of longevity pioneers. Science 360(6396):1459–1461. https://doi.org/10.1126/science.aat3119
Barrès R, Zierath JR (2016) The role of diet and exercise in the transgenerational epigenetic landscape of T2DM. Nat Rev Endocrinol 12(8):441–451. https://doi.org/10.1038/nrendo.2016.87
Bartel DP (2018) Metazoan microRNAs. Cell 173(1):20–51. https://doi.org/10.1016/j.cell.2018.03.006
Baumgart M et al (2014) RNA-seq of the aging brain in the short-lived fish N. furzeri—conserved pathways and novel genes associated with neurogenesis. Aging Cell 13(6):965–974. https://doi.org/10.1111/acel.12257
Beerman I et al (2013) Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell 12(4):413–425. https://doi.org/10.1016/j.stem.2013.01.017
Bell JT et al (2012) Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. PLoS Genet. https://doi.org/10.1371/journal.pgen.1002629
Benayoun BA, Pollina EA, Brunet A (2015) Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat Rev Mol Cell Biol 16(10):593–610. https://doi.org/10.1038/nrm4048
Boehm M, Slack F (2005) A developmental timing microRNA and its target regulate life span in C. elegans. Science 310(5756):1954–1957. https://doi.org/10.1126/science.1115596
Bollati V et al (2010) Of elderly subjects. October 130(4):234–239. https://doi.org/10.1016/j.mad.2008.12.003.Decline
Bonkowski MS et al (2006) Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction. Proc Natl Acad Sci USA 103(20):7901–7905. https://doi.org/10.1073/pnas.0600161103
Borrás C et al (2017) Centenarians maintain miRNA biogenesis pathway while it is impaired in octogenarians. Mech Ageing Dev 168:54–57. https://doi.org/10.1016/j.mad.2017.07.003
Boucher J et al (2014) Insulin and insulin-like growth factor 1 receptors are required for normal expression of imprinted genes. Proc Natl Acad Sci USA 111(40):14512–14517. https://doi.org/10.1073/pnas.1415475111
Buler M, Andersson U, Hakkola J (2016) Who watches the watchmen? Regulation of the expression and activity of sirtuins. FASEB J 30(12):3942–3960. https://doi.org/10.1096/fj.201600410RR
Cai H et al (2019) Circular RNA involvement in aging: an emerging player with great potential. Mech Ageing Dev. https://doi.org/10.1016/j.mad.2018.11.002
Campisi J et al (2019) From discoveries in ageing research to therapeutics for healthy ageing. Nature 571(7764):183–192. https://doi.org/10.1038/s41586-019-1365-2
Capell BC et al (2016) Mll1 is essential for the senescenceassociated secretory phenotype. Genes Dev 30(3):321–336. https://doi.org/10.1101/gad.271882.115
Cartee GD et al (2016) Exercise promotes healthy aging of skeletal muscle. Cell Metab. https://doi.org/10.1016/j.cmet.2016.05.007
Cech TR, Steitz JA (2014) The noncoding RNA revolution—trashing old rules to forge new ones. Cell. https://doi.org/10.1016/j.cell.2014.03.008
Chen Q et al (2016a) Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science. https://doi.org/10.1126/science.aad7977
Chen Q, Yan W, Duan E (2016b) Epigenetic inheritance of acquired traits through sperm RNAs and sperm RNA modifications. Nat Rev Genet. https://doi.org/10.1038/nrg.2016.106
Christensen BC et al (2009) Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CPG island context. PLoS Genet. https://doi.org/10.1371/journal.pgen.1000602
Clancy DJ et al (2001) Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 292(5514):104–106. https://doi.org/10.1126/science.1057991
Cohen HY et al (2004) Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305(5682):390–392. https://doi.org/10.1126/science.1099196
Coppé JP et al (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. https://doi.org/10.1371/journal.pbio.0060301
Damelin M et al (2002) The genome-wide localization of Rsc9, a component of the RSC chromatin-remodeling complex, changes in response to stress. Mol Cell 9(3):563–573. https://doi.org/10.1016/S1097-2765(02)00475-6
Dang W et al (2009) Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature 459(7248):802–807. https://doi.org/10.1038/nature08085
Daniel S et al (2018) T cell epigenetic remodeling and accelerated epigenetic aging are linked to long-term immune alterations in childhood cancer survivors 11 medical and health sciences 1107 immunology. Clin Epigenet 10(1):1–13. https://doi.org/10.1186/s13148-018-0561-5
Day K et al (2013) Differential DNA methylation with age displays both common and dynamic features across human tissues that are influenced by CpG landscape. Genome Biol. https://doi.org/10.1186/gb-2013-14-9-r102
De Cecco M et al (2013) Transposable elements become active and mobile in the genomes of aging mammalian somatic tissues. Aging 5(12):867–883. https://doi.org/10.18632/aging.100621
De Lencastre A et al (2010) MicroRNAs both promote and antagonize longevity in C. elegans. Curr Biol 20(24):2159–2168. https://doi.org/10.1016/j.cub.2010.11.015
De Lucia C et al (2017) MicroRNA in cardiovascular aging and age-related cardiovascular diseases. Front Med. https://doi.org/10.3389/fmed.2017.00074
de Magalhães JP, Costa J, Toussaint O (2005) HAGR: the human ageing genomic resources. Nucleic Acids Res 33:537–543. https://doi.org/10.1093/nar/gki017
Deelen J et al (2019) A meta-analysis of genome-wide association studies identifies multiple longevity genes. Nat Commun. https://doi.org/10.1038/s41467-019-11558-2
Dhahbi JM et al (2013) 5’ tRNA halves are present as abundant complexes in serum, concentrated in blood cells, and modulated by aging and calorie restriction. BMC Genomics. https://doi.org/10.1186/1471-2164-14-298
Dong X, Milholland B, Vijg J (2016) Evidence for a limit to human lifespan. Nature 538(7624):257–259. https://doi.org/10.1038/nature19793
Dozmorov MG (2015) Polycomb repressive complex 2 epigenomic signature defines age-associated hypermethylation and gene expression changes. Epigenetics 10(6):484–495. https://doi.org/10.1080/15592294.2015.1040619
Du WW et al (2014) MiR-17 extends mouse lifespan by inhibiting senescence signaling mediated by MKP7. Cell Death Dis 5(7):1–14. https://doi.org/10.1038/cddis.2014.305
Dzakah EE et al (2018) Loss of miR-83 extends lifespan and affects target gene expression in an age-dependent manner in Caenorhabditis elegans. J Genet Genomics 45(45):651–662. https://doi.org/10.1016/j.jgg.2018.11.003
Eisenberg T et al (2009) Induction of autophagy by spermidine promotes longevity. Nat Cell Biol 11(11):1305–1314. https://doi.org/10.1038/ncb1975
Elsharawy A et al (2012) Genome-wide miRNA signatures of human longevity. Aging Cell 11(4):607–616. https://doi.org/10.1111/j.1474-9726.2012.00824.x
Fahy GM et al (2019) Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell 18(6):1–12. https://doi.org/10.1111/acel.13028
Feser J et al (2010) Elevated histone expression promotes life span extension. Mol Cell 39(5):724–735. https://doi.org/10.1016/j.molcel.2010.08.015
Fontana L, Partridge L, Longo VD (2010) Extending healthy life span-from yeast to humans. Science 328(5976):321–326. https://doi.org/10.1126/science.1172539
Fraga MF, Esteller M (2007) Epigenetics and aging: the targets and the marks. Trends Genet 23(8):413–418. https://doi.org/10.1016/j.tig.2007.05.008
Fraga MF et al (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 102(30):10604–10609. https://doi.org/10.1073/pnas.0500398102
Fraga MF, Agrelo R, Esteller M (2007) Cross-talk between aging and cancer: the epigenetic language. Ann N Y Acad Sci 1100:60–74. https://doi.org/10.1196/annals.1395.005
Friedman DB, Johnson TE (1988) Three mutants that extend both mean and maximum life span of the nematode, Caenorhabditis elegans, define the age-1 gene. J Gerontol 43(4):102–109. https://doi.org/10.1093/geronj/43.4.B102
Fries GR et al (2017) Accelerated epigenetic aging and mitochondrial DNA copy number in bipolar disorder. Transl Psychiatry. https://doi.org/10.1038/s41398-017-0048-8
Garatachea N et al (2015) Exercise attenuates the major hallmarks of aging. Rejuvenation Res 18(1):57–89. https://doi.org/10.1089/rej.2014.1623
Gendron CM, Pletcher SD (2017) MicroRNAs mir-184 and let-7 alter Drosophila metabolism and longevity. Aging Cell 16(6):1434–1438. https://doi.org/10.1111/acel.12673
Gensous N et al (2019) Age-related DNA methylation changes: potential impact on skeletal muscle aging in humans. Front Physiol. https://doi.org/10.3389/fphys.2019.00996
Gombar S et al (2012) Comprehensive microRNA profiling in B-cells of human centenarians by massively parallel sequencing. BMC Genomics. https://doi.org/10.1186/1471-2164-13-353
Green CD et al (2017) Impact of dietary interventions on noncoding RNA networks and mRNAs encoding chromatin-related factors. Cell Rep 18(12):2957–2968. https://doi.org/10.1016/j.celrep.2017.03.001
Greer EL et al (2011) Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature 479(7373):365–371. https://doi.org/10.1038/nature10572
Groth A et al (2007) Chromatin challenges during DNA replication and repair. Cell 128(4):721–733. https://doi.org/10.1016/j.cell.2007.01.030
Guarasci F et al (2018) Aging and nutrition induce tissue-specific changes on global DNA methylation status in rats. Mech Ageing Dev 174:47–54. https://doi.org/10.1016/j.mad.2018.02.001
Guerra BA et al (2019) Dietary sulfur amino acid restriction upregulates DICER to confer beneficial effects. Mol Metab 29:124–135. https://doi.org/10.1016/j.molmet.2019.08.017
Hadar A et al (2018) SIRT1, miR-132 and miR-212 link human longevity to Alzheimer’s disease. Sci Rep 8(1):1–10. https://doi.org/10.1038/s41598-018-26547-6
Hahn O et al (2017) Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism. Genome Biol 18(1):1–18. https://doi.org/10.1186/s13059-017-1187-1
Haithcock E et al (2005) Age-related changes of nuclear architecture in Caenorhabditis elegans. Proc Natl Acad Sci USA 102(46):16690–16695. https://doi.org/10.1073/pnas.0506955102
Han S, Brunet A (2012) Histone methylation makes its mark on longevity. Trends Cell Biol 22(1):42–49. https://doi.org/10.1016/j.tcb.2011.11.001
Han LKM et al (2018) Epigenetic aging in major depressive disorder. Am J Psychiatry 175(8):774–782. https://doi.org/10.1176/appi.ajp.2018.17060595
Hannum G et al (2013) Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell. https://doi.org/10.1016/j.molcel.2012.10.016
Hashimoto H et al (2014) Structure of a Naegleria Tet-like dioxygenase in complex with 5-methylcytosine DNA. Nature 506(7488):391–395. https://doi.org/10.1038/nature12905
He Y, Ecker JR (2015) Non-CG methylation in the human genome. Annu Rev Genomics Hum Genet 16(1):55–77. https://doi.org/10.1146/annurev-genom-090413-025437
He J, Tu C, Liu Y (2018) Role of lncRNAs in aging and age-related diseases. Aging Med 1(2):158–175. https://doi.org/10.1002/agm2.12030
Heijmans BT et al (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA 105(44):17046–17049. https://doi.org/10.1073/pnas.0806560105
Herbig U et al (2006) Cellular senescence in aging primates. Science 311(5765):1257. https://doi.org/10.1126/science.1122446
Hernando-Herraez I et al (2019) Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells. Nat Commun 10(1):1–11. https://doi.org/10.1038/s41467-019-12293-4
Herranz D et al (2010) Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun. https://doi.org/10.1038/ncomms1001
Hickson LTJ et al (2019) Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine 47:446–456. https://doi.org/10.1016/j.ebiom.2019.08.069
Horvath S (2013) DNA methylation age of human tissues and cell types. Genome Biol. https://doi.org/10.1186/gb-2013-14-10-r115
Horvath S et al (2012) Aging effects on DNA methylation modules in human brain and blood tissue. Genome Biol 13(10):R97. https://doi.org/10.1186/gb-2012-13-10-r97
Horvath S et al (2014) Obesity accelerates epigenetic aging of human liver. Proc Natl Acad Sci USA 111(43):15538–15543. https://doi.org/10.1073/pnas.1412759111
Houri-Zeevi L, Rechavi O (2017) A matter of time: small RNAs regulate the duration of epigenetic inheritance. Trends Genet 33(1):46–57. https://doi.org/10.1016/j.tig.2016.11.001
Hsin H, Kenyon C (1999) Signals from the reproductive system regulate the lifespan of C. elegans. Nature 399(6734):362–366. https://doi.org/10.1038/20694
Hu L et al (2013) Crystal structure of TET2-DNA complex: insight into TET-mediated 5mC oxidation. Cell 155(7):1545–1555. https://doi.org/10.1016/j.cell.2013.11.020
Hu Z et al (2014) Nucleosome loss leads to global transcriptional up-regulation and genomic instability during yeast aging. Genes Dev 28(4):396–408. https://doi.org/10.1101/gad.233221.113
Huan T et al (2018) Age-associated microRNA expression in human peripheral blood is associated with all-cause mortality and age-related traits. Aging Cell 17(1):1–10. https://doi.org/10.1111/acel.12687
Huang Z, Jebb D, Teeling EC (2016) Blood miRNomes and transcriptomes reveal novel longevity mechanisms in the long-lived bat, Myotis myotis. BMC Genomics 17(1):1–15. https://doi.org/10.1186/s12864-016-3227-8
Huang Y et al (2020) MicroRNA-188 regulates aging-associated metabolic phenotype. Aging Cell 19(1):1–12. https://doi.org/10.1111/acel.13077
Ibáñez-Ventoso C et al (2006) Modulated microRNA expression during adult lifespan in Caenorhabditis elegans. Aging Cell 5(3):235–246. https://doi.org/10.1111/j.1474-9726.2006.00210.x
Inukai S et al (2012) Novel microRNAs differentially expressed during aging in the mouse brain. PLoS ONE. https://doi.org/10.1371/journal.pone.0040028
Inukai S et al (2018) A microRNA feedback loop regulates global microRNA abundance during aging. RNA 24(2):159–172. https://doi.org/10.1261/rna.062190.117
Ions LJ et al (2013) Effects of Sirt1 on DNA methylation and expression of genes affected by dietary restriction. Age 35(5):1835–1849. https://doi.org/10.1007/s11357-012-9485-8
Ito S et al (2010) Role of tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466(7310):1129–1133. https://doi.org/10.1038/nature09303
Jacques M et al (2019) Epigenetic changes in healthy human skeletal muscle following exercise—a systematic review. Epigenetics. https://doi.org/10.1080/15592294.2019.1614416
Jawaid A et al (2019) Memory decline and its reversal in aging and neurodegeneration involve miR-183/96/182 biogenesis. Mol Neurobiol 56(5):3451–3462. https://doi.org/10.1007/s12035-018-1314-3
Jiang N et al (2013) Dietary and genetic effects on age-related loss of gene silencing reveal epigenetic plasticity of chromatin repression during aging. Aging 5(11):813–824. https://doi.org/10.18632/aging.100614
Jin C et al (2011) Histone demethylase UTX-1 regulates C. elegans life span by targeting the insulin/IGF-1 signaling pathway. Cell Metab 14(2):161–172. https://doi.org/10.1016/j.cmet.2011.07.001
Johnson R (2012) Long non-coding RNAs in Huntington’s disease neurodegeneration. Neurobiol Dis. https://doi.org/10.1016/j.nbd.2011.12.006
Jones MJ, Goodman SJ, Kobor MS (2015) DNA methylation and healthy human aging. Aging Cell 14(6):924–932. https://doi.org/10.1111/acel.12349
Jones BC et al (2016) A somatic piRNA pathway in the Drosophila fat body ensures metabolic homeostasis and normal lifespan. Nat Commun 7:1–9. https://doi.org/10.1038/ncomms13856
Justice JN et al (2019) Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine 40:554–563. https://doi.org/10.1016/j.ebiom.2018.12.052
Kaeberlein M, McVey M, Guarente L (1999) The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev 13(19):2570–2580. https://doi.org/10.1101/gad.13.19.2570
Kaplanis J et al. (2018) With millions of relatives 175:171–175.
Kato M, Slack FJ (2013) Ageing and the small, non-coding RNA world. Ageing Res Rev 12(1):429–435. https://doi.org/10.1016/j.arr.2012.03.012
Kato M et al (2011) Age-associated changes in expression of small, noncoding RNAs, including microRNAs, in C. elegans. RNA 17(10):1804–1820. https://doi.org/10.1261/rna.2714411
Kawahara TLA et al (2009) SIRT6 links histone H3 lysine 9 deacetylation to NF-κB-dependent gene expression and organismal life span. Cell 136(1):62–74. https://doi.org/10.1016/j.cell.2008.10.052
Kenyon C et al (1993) A C. elegans mutant that twice as long as wild type. Nature 366(6454):461–464
Khanna A et al (2011) Gain of survival signaling by down-regulation of three key miRNAs in brain of calorie-restricted mice. Aging 3(3):223–236. https://doi.org/10.18632/aging.100276
Kim SS, Lee SJV (2019) Non-coding RNAs in Caenorhabditis elegans aging. Mol Cells 42(5):379–385. https://doi.org/10.14348/molcells.2019.0077
Kinser HE, Pincus Z (2019) MicroRNAs as modulators of longevity and the aging process. Hum Genet. https://doi.org/10.1007/s00439-019-02046-0
Kirchner S, Ignatova Z (2015) Emerging roles of tRNA in adaptive translation, signalling dynamics and disease. Nat Rev Genet 16(2):98–112. https://doi.org/10.1038/nrg3861
Knupp D, Miura P (2018) CircRNA accumulation: a new hallmark of aging? Mech Ageing Dev 173:71–79. https://doi.org/10.1016/j.mad.2018.05.001
Kohli RM, Zhang Y (2014) TET enzymes, TDG and the dynamics of DNA METHYLATION. Nature 502(7472):472–479. https://doi.org/10.1038/nature12750.TET
Kour S, Rath PC (2016) Long noncoding RNAs in aging and age-related diseases. Ageing Res Rev 26:1–21. https://doi.org/10.1016/j.arr.2015.12.001
Kreiling JA et al (2011) Age-associated increase in heterochromatic marks in murine and primate tissues. Aging Cell 10(2):292–304. https://doi.org/10.1111/j.1474-9726.2010.00666.x
Kristensen LS et al (2019) The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet 20(11):675–691. https://doi.org/10.1038/s41576-019-0158-7
Larson K et al (2012) Heterochromatin formation promotes longevity and represses ribosomal RNA synthesis. PLoS Genet. https://doi.org/10.1371/journal.pgen.1002473
Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75(5):843–854. https://doi.org/10.1016/0092-8674(93)90529-Y
Lee BC, Kaya A, Gladyshev VN (2016) Methionine restriction and life-span control. Ann N Y Acad Sci 1363(1):116–124. https://doi.org/10.1111/nyas.12973
Lenart P, Novak J, Bienertova-Vasku J (2018) PIWI-piRNA pathway: setting the pace of aging by reducing DNA damage. Mech Ageing Dev 173:29–38. https://doi.org/10.1016/j.mad.2018.03.009
Li Y, Daniel M, Tollefsbol TO (2011) Epigenetic regulation of caloric restriction in aging. BMC Med 9:1–12. https://doi.org/10.1186/1741-7015-9-98
Li F et al (2014) Expression and methylation of DNA repair genes in lens epithelium cells of age-related cataract. Mutat Res. https://doi.org/10.1016/jmrfmmm.2014.05.010
Liu B, Yip KH, Zhou Z (2012a) Chromatin remodeling, DNA damage repair and aging. Curr Genomics 13(7):533–547. https://doi.org/10.2174/138920212803251373
Liu N et al (2012b) The microRNA miR-34 modulates ageing and neurodegeneration in Drosophila. Nature 482(7386):519–523. https://doi.org/10.1038/nature10810
Longo VD, Kennedy BK (2006) Sirtuins in aging and age-related disease. Cell. https://doi.org/10.1016/j.cell.2006.07.002
López-Otín C et al (2013) The hallmarks of aging. Cell 153(6):1194. https://doi.org/10.1016/j.cell.2013.05.039
Madeo F et al (2018) Spermidine in health and disease. Science. https://doi.org/10.1126/science.aan2788
Mah LJ, El-Osta A, Karagiannis TC (2010) γh2AX: a sensitive molecular marker of DNA damage and repair. Leukemia. https://doi.org/10.1038/leu.2010.6
Makwana K et al (2017) Aging and calorie restriction regulate the expression of miR-125a-5p and its target genes Stat3 Casp2 and Stard13. Aging 9(7):1825–1843. https://doi.org/10.18632/aging.101270
Mannick JB et al (2014) mTOR inhibition improves immune function in the elderly. Sci Transl Med. https://doi.org/10.1126/scitranslmed.3009892
Mannick JB et al (2018) TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci Transl Med 10(449):1–11. https://doi.org/10.1126/scitranslmed.aaq1564
Mathers JC, Strathdee G, Relton CL (2010) Induction of epigenetic alterations by dietary and other environmental factors. Adv Genet 71:3–39. https://doi.org/10.1016/B978-0-12-380864-6.00001-8
Maures TJ et al (2011) The H3K27 demethylase UTX-1 regulates C. elegans lifespan in a germline-independent, insulin-dependent manner. Aging Cell 10(6):980–990. https://doi.org/10.1111/j.1474-9726.2011.00738.x
McCartney DL et al (2018) Investigating the relationship between DNA methylation age acceleration and risk factors for Alzheimer’s disease. Alzheimer’s Dementia 10:429–437. https://doi.org/10.1016/j.dadm.2018.05.006
McCay CM (1947) Effect of restricted feeding upon aging and chronic diseases in rats and dogs. Am J Public Health Nation’s Health 37(5):521–528. https://doi.org/10.2105/AJPH.37.5.521
McCay CM, Crowell MF, Maynard LA (1935) The effect of retarded growth upon the length of life span and upon the ultimate body size  » In a preliminary report, the literature concerning the effect of retarded growth upon the life span was reviewed (McCay and Crowell,’ 34). In this report w. J Nutr 10(1):63–79
McCay CM et al (1939) Retarded growth, life span, ultimate body size and age changes in the albino rat after feeding diets restricted in calories. J Nutr 18(1):1–13. https://doi.org/10.1093/jn/18.1.1
McColl G et al (2008) Pharmacogenetic analysis of lithium-induced delayed aging in Caenorhabditis elegans. J Biol Chem 283(1):350–357. https://doi.org/10.1074/jbc.M705028200
McGregor RA, Poppitt SD, Cameron-Smith D (2014) Role of microRNAs in the age-related changes in skeletal muscle and diet or exercise interventions to promote healthy aging in humans. Ageing Res Rev. https://doi.org/10.1016/j.arr.2014.05.001
Mehi SJ et al (2014) MicroRNA-339 and microRNA-556 regulate Klotho expression in vitro. Age 36(1):141–149. https://doi.org/10.1007/s11357-013-9555-6
Meier I et al (2010) Expression of the snoRNA host gene gas5 in the hippocampus is upregulated by age and psychogenic stress and correlates with reduced novelty-induced behavior in C57BL/6 mice. Hippocampus. https://doi.org/10.1002/hipo.20701
Mihalas BP et al (2019) The small non-coding RNA profile of mouse oocytes is modified during aging. Aging 11(10):2968–2997. https://doi.org/10.18632/aging.101947
MolinaSerrano D, Kyriakou D, Kirmizis A (2019) Histone modifications as an intersection between diet and longevity. Front Genet. https://doi.org/10.3389/fgene.2019.00192
Mori MA et al (2012) Role of microRNA processing in adipose tissue in stress defense and longevity. Cell Metab 16(3):336–347. https://doi.org/10.1016/j.cmet.2012.07.017
Mori MA et al (2014) Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy. J Clin Investig 124(8):3339–3351. https://doi.org/10.1172/JCI73468
Mori MA et al (2019) Extracellular miRNAs: from biomarkers to mediators of physiology and disease. Cell Metab 30(4):656–673. https://doi.org/10.1016/j.cmet.2019.07.011
Mostoslavsky R et al (2006) Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124(2):315–329. https://doi.org/10.1016/j.cell.2005.11.044
Mozhui K, Pandey AK (2017) Conserved effect of aging on DNA methylation and association with EZH2 polycomb protein in mice and humans. Mech Ageing Dev 162(3):27–37. https://doi.org/10.1016/j.mad.2017.02.006
Murgatroyd C et al (2009) Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat Neurosci 12(12):1559–1566. https://doi.org/10.1038/nn.2436
Mugatroyd C et al (2010) The janus face of DNA methylation in aging. Aging 2(2):107–110. https://doi.org/10.18632/aging.100124
Narita M et al (2003) Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113(6):703–716. https://doi.org/10.1016/S0092-8674(03)00401-X
Narita M et al (2006) A novel role for high-mobility group A proteins in cellular senescence and heterochromatin formation. Cell 126(3):503–514. https://doi.org/10.1016/j.cell.2006.05.052
Nathan DM et al (2015) ‘Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the diabetes prevention program outcomes study. Lancet Diabetes Endocrinol 3(11):866–875. https://doi.org/10.1016/S2213-8587(15)00291-0
Ni Z et al (2012) Two SET domain containing genes link epigenetic changes and aging in Caenorhabditis elegans. Aging Cell 11(2):315–325. https://doi.org/10.1111/j.1474-9726.2011.00785.x
Nielsen S et al (2014) The miRNA plasma signature in response to acute aerobic exercise and endurance training. PLoS ONE 9(2):e87308. https://doi.org/10.1371/journal.pone.0087308
Noren Hooten N et al (2010) microRNA expression patterns reveal differential expression of target genes with age. PLoS ONE. https://doi.org/10.1371/journal.pone.0010724
O’Sullivan RJ et al (2010) Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres. Nat Struct Mol Biol 17(10):1218–1225. https://doi.org/10.1038/nsmb.1897
Oliverio M et al (2016) ‘Dicer1-miR-328-Bace1 signalling controls brown adipose tissue differentiation and function. Nat cell Biol 18(3):328–336. https://doi.org/10.1038/ncb3316
Orentreich N et al (1993) Low methionine ingestion by rats extends life span. J Nutr 123(2):269–274. https://doi.org/10.1093/jn/123.2.269
Ozata DM et al (2019) PIWI-interacting RNAs: small RNAs with big functions. Nat Rev Genet 20(2):89–108. https://doi.org/10.1038/s41576-018-0073-3
Pal S, Tyler JK (2016) Epigenetics and aging. Sci Adv 2(7):e1600584. https://doi.org/10.1126/sciadv.1600584
Peleg S et al (2010) Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328(5979):753–756. https://doi.org/10.1126/science.1186088
Perna L et al (2016) Epigenetic age acceleration predicts cancer, cardiovascular, and all-cause mortality in a German case cohort. Clin Epigenet 8(1):1–7. https://doi.org/10.1186/s13148-016-0228-z
Petkovich DA et al (2018) Using DNA methylation profiling to evaluate biological age and longevity interventions. Cell Metab 25(4):954–960. https://doi.org/10.1016/j.cmet.2017.03.016
Pincus Z, Smith-Vikos T, Slack FJ (2011) MicroRNA predictors of longevity in Caenorhabditis elegans. PLoS Genet. https://doi.org/10.1371/journal.pgen.1002306
Pinto S et al (2018) Enoxacin extends lifespan of C. elegans by inhibiting miR-34-5p and promoting mitohormesis. Redox Biol 18:84–92. https://doi.org/10.1016/j.redox.2018.06.006
Puth MT et al (2017) Prevalence of multimorbidity in Germany: impact of age and educational level in a cross-sectional study on 19,294 adults. BMC Public Health 17(1):1–7. https://doi.org/10.1186/s12889-017-4833-3
Quina AS, Buschbeck M, Di Croce L (2006) Chromatin structure and epigenetics. Biochem Pharmacol 72(11):1563–1569. https://doi.org/10.1016/j.bcp.2006.06.016
Rai TS et al (2014) HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of Neoplasia. Genes Dev 28(24):2712–2725. https://doi.org/10.1101/gad.247528.114
Rasmussen KD, Helin K (2016) Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev 30(7):733–750. https://doi.org/10.1101/gad.276568.115
Recchioni R et al (2017) Epigenetic effects of physical activity in elderly patients with cardiovascular disease. Exp Gerontol. https://doi.org/10.1016/j.exger.2017.10.016
Rechavi O et al (2014) Starvation-induced transgenerational inheritance of small RNAs in C. elegans. Cell 158(2):277–287. https://doi.org/10.1016/j.cell.2014.06.020
Reis FCG et al (2016) Fat-specific Dicer deficiency accelerates aging and mitigates several effects of dietary restriction in mice. Aging 8(6):1201–1222. https://doi.org/10.18632/aging.100970
Riedel CG et al (2013) DAF-16 employs the chromatin remodeller SWI/SNF to promote stress resistance and longevity. Nat Cell Biol 15(5):491–501. https://doi.org/10.1038/ncb2720
Rogina B, Helfand SL, Frankel S (2002) Longevity regulation by Drosophila Rpd3 deacetylase and caloric restriction. Science 298(5599):1745. https://doi.org/10.1126/science.1078986
Rohde JR, Cardenas ME (2003) The tor pathway regulates gene expression by linking nutrient sensing to histone acetylation. Mol Cell Biol 23(2):629–635. https://doi.org/10.1128/mcb.23.2.629-635.2003
Rojas-Rıós P, Simonelig M (2018) piRNAs and PIWI proteins: regulators of gene expression in development and stem cells. Development (Cambridge). https://doi.org/10.1242/dev.161786
Rose M, Charlesworth B (1980) A test of evolutionary theories of senescence. Nature. https://doi.org/10.1038/287141a0
Ryu SH et al (2011) Transcriptional repression of repeat-derived transcripts correlates with histone hypoacetylation at repetitive DNA elements in aged mice brain. Exp Gerontol 46(10):811–818. https://doi.org/10.1016/j.exger.2011.07.001
Sae-Lee C et al (2018) Dietary intervention modifies DNA methylation age assessed by the epigenetic clock. Mol Nutr Food Res 62(23):1–7. https://doi.org/10.1002/mnfr.201800092
Sarker G et al (2019) Maternal overnutrition programs hedonic and metabolic phenotypes across generations through sperm tsRNAs. Proc Natl Acad Sci USA 116(21):10547–10556. https://doi.org/10.1073/pnas.1820810116
Scaffidi P, Misteli T (2006) Lamin A-dependent nuclear defects in human aging. Science 312(5776):1059–1063. https://doi.org/10.1126/science.1127168
Schmidt E, Kornfeld JW (2016) Decoding Lamarck—transgenerational control of metabolism by noncoding RNAs. Pflügers Archiv 468(6):959–969. https://doi.org/10.1007/s00424-016-1807-8
Schneider A et al (2017) Caloric restriction impacts plasma microRNAs in rhesus monkeys. Aging Cell 16(5):1200–1203. https://doi.org/10.1111/acel.12636
Sedivy JM et al (2013) Death by transposition—the enemy within? BioEssays 35(12):1035–1043. https://doi.org/10.1002/bies.201300097
Sen P, Shah PP et al (2016) Epigenetic mechanisms of longevity and aging. Cell 166(4):822–839. https://doi.org/10.1016/j.cell.2016.07.050
Serna E et al (2012) Centenarians, but not octogenarians, up-regulate the expression of microRNAs. Sci Rep 2:1–6. https://doi.org/10.1038/srep00961
Shah PP et al (2013) Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes Dev 27(16):1787–1799. https://doi.org/10.1101/gad.223834.113
Sharma M et al (2014) Mega roles of microRNAs in regulation of skeletal muscle health and disease. Front Physiol. https://doi.org/10.3389/fphys.2014.00239
Siebold AP et al (2010) Polycomb repressive complex 2 and Trithorax modulate Drosophila longevity and stress resistance. Proc Natl Acad Sci USA 107(1):169–174. https://doi.org/10.1073/pnas.0907739107
Sierra H et al (2015) Confocal imaging-guided laser ablation of basal cell carcinomas: an ex vivo study. J Investig Dermatol 135(2):612–615. https://doi.org/10.1038/jid.2014.371
Silva GJJ et al (2017) MicroRNAs as important regulators of exercise adaptation. Progr Cardiovasc Dis. https://doi.org/10.1016/j.pcad.2017.06.003
Skvortsova K, Iovino N, Bogdanović O (2018) Functions and mechanisms of epigenetic inheritance in animals. Nat Rev Mol Cell Biol 19(12):774–790. https://doi.org/10.1038/s41580-018-0074-2
Smith-Vikos T et al (2014) MicroRNAs mediate dietary-restriction-induced longevity through PHA-4/FOXA and SKN-1/Nrf transcription factors. Curr Biol 24(19):2238–2246. https://doi.org/10.1016/j.cub.2014.08.013
Smith-Vikos T et al (2016) A serum miRNA profile of human longevity: findings from the Baltimore longitudinal study of aging (BLSA). Aging 8(11):2971–2987. https://doi.org/10.18632/aging.101106
Sousa-Victor P et al (2017) Piwi is required to limit exhaustion of aging somatic stem cells. Cell Rep 20(11):2527–2537. https://doi.org/10.1016/j.celrep.2017.08.059
Steves CJ, Spector TD, Jackson SHD (2012) Ageing, genes, environment and epigenetics: what twin studies tell us now, and in the future. Age Ageing 41(5):581–586. https://doi.org/10.1093/ageing/afs097
Sturm Á et al (2017) The Piwi-piRNA pathway: road to immortality. Aging Cell 16(5):906–911. https://doi.org/10.1111/acel.12630
Sun D et al (2014) Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell 14(5):673–688. https://doi.org/10.1016/j.stem.2014.03.002
Talbert PB, Henikoff S (2017) Histone variants on the move: Substrates for chromatin dynamics. Nat Rev Mol Cell Biol 18(2):115–126. https://doi.org/10.1038/nrm.2016.148
Tan J et al (2020) miRNA expression profiling uncovers a role of miR-302b-3p in regulating skin fibroblasts senescence. J Cell Biochem 121(1):70–80. https://doi.org/10.1002/jcb.28862
Teschendorff AE et al (2010) Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res 20(4):440–446. https://doi.org/10.1101/gr.103606.109
Teschendorff AE et al (2013) A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450 k DNA methylation data. Bioinformatics 29(2):189–196. https://doi.org/10.1093/bioinformatics/bts680
Tian X et al (2019) SIRT6 is responsible for more efficient DNA double-strand break repair in long-lived species. Cell 177(3):622–638. https://doi.org/10.1016/j.cell.2019.03.043
Tissenbaum HA, Guarente L (2001) Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410(6825):227–230. https://doi.org/10.1038/35065638
Tsuchiya M et al (2006) Sirtuin-independent effects of nicotinamide on lifespan extension from calorie restriction in yeast. Aging Cell 5(6):505–514. https://doi.org/10.1111/j.1474-9726.2006.00240.x
Tsurumi A, Li WX (2012) Global heterochromatin loss: a unifying theory of aging? Epigenetics 7(7):680–688. https://doi.org/10.4161/epi.20540
Tvardovskiy A et al (2017) Accumulation of histone variant H3.3 with age is associated with profound changes in the histone methylation landscape. Nucleic Acids Res 45(16):9272–9289. https://doi.org/10.1093/nar/gkx696
Unnikrishnan A et al (2019) The role of DNA methylation in epigenetics of aging. Pharmacol Ther 195:172–185. https://doi.org/10.1016/j.pharmthera.2018.11.001
Victoria B et al (2015) Circulating microRNA signature of genotype-by-age interactions in the long-lived Ames dwarf mouse. Aging Cell. https://doi.org/10.1111/acel.12373
Vijg J, Campisi J (2008) Puzzles, promises and a cure for ageing. Nature. https://doi.org/10.1038/nature07216
Villeponteau B (1997) The heterochromatin loss model of aging. Exp Gerontol. https://doi.org/10.1016/S0531-5565(96)00155-6
Vyas CM et al (2019) Pilot study of DNA methylation, molecular aging markers and measures of health and well-being in aging. Transl Psychiatry 9(1):1–9. https://doi.org/10.1038/s41398-019-0446-1
Wang Y, Guan H (2017) The role of DNA methylation in lens development and cataract formation. Cell Mol Neurobiol. https://doi.org/10.1007/s10571-016-0447-z
Wang Y et al (2016) Ultraviolet-B induces ERCC6 repression in lens epithelium cells of age-related nuclear cataract through coordinated DNA hypermethylation and histone deacetylation. Clin Epigenet 8(1):1–15. https://doi.org/10.1186/s13148-016-0229-y
Wątroba M et al (2017) Sirtuins, epigenetics and longevity. Ageing Res Rev 40:11–19. https://doi.org/10.1016/j.arr.2017.08.001
Wei JW et al (2017) Non-coding RNAs as regulators in epigenetics (review). Oncol Rep 37(1):3–9. https://doi.org/10.3892/or.2016.5236
Weidner CI et al (2014) Aging of blood can be tracked by DNA methylation changes at just three CpG sites. Genome Biol. https://doi.org/10.1186/gb-2014-15-2-r24
Wood JG, Helfand SL (2013) Chromatin structure and transposable elements in organismal aging. Front Genet. https://doi.org/10.3389/fgene.2013.00274
Wood JG et al (2010) Chromatin remodeling in the aging genome of Drosophila. Aging Cell 9(6):971–978. https://doi.org/10.1111/j.1474-9726.2010.00624.x
Woolf SH, Schoomaker H (2019) Life Expectancy and mortality rates in the united states, 1959–2017. JAMA 322(20):1996. https://doi.org/10.1001/jama.2019.16932
World Health Organization (2015) WHO facts about ageing. WHO, Geneva
Xiao FH et al (2018) Accelerated DNA methylation changes in middle-aged men define sexual dimorphism in human lifespans. Clin Epigenet 10(1):1–6. https://doi.org/10.1186/s13148-018-0573-1
Xu Y et al (2019) A micro RNA switch controls dietary restriction-induced longevity through Wnt signaling. EMBO Rep. https://doi.org/10.15252/embr.201846888
Yang J et al (2013) MiR-34 modulates Caenorhabditis elegans lifespan via repressing the autophagy gene atg9. Age 35(1):11–22. https://doi.org/10.1007/s11357-011-9324-3
Yao Y et al (2019) Integrative analysis of miRNA and mRNA expression profiles associated with human atrial aging. Front Physiol 10:1–12. https://doi.org/10.3389/fphys.2019.01226
Yoshino J, Baur JA, Imai SI (2018) NAD + intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab 27(3):513–528. https://doi.org/10.1016/j.cmet.2017.11.002
Yu Y et al (2015) Panoramix enforces piRNA-dependent cotranscriptional silencing. Science 350(6258):339–342. https://doi.org/10.1126/science.aab0700
Zampieri M et al (2015) Reconfiguration of DNA methylation in aging. Mech Ageing Dev 151:60–70. https://doi.org/10.1016/j.mad.2015.02.002
Zhang R et al (2005) Formation of macroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev Cell 8(1):19–30. https://doi.org/10.1016/j.devcel.2004.10.019
Zhang R et al (2019) Caloric restriction induces microRNAs to improve mitochondrial proteostasis. iScience 17:155–166. https://doi.org/10.1016/j.isci.2019.06.028
Zhou Y et al (2019) ‘A secreted microRNA disrupts autophagy in distinct tissues of Caenorhabditis elegans upon ageing. Nat Commun 10(1):1–14. https://doi.org/10.1038/s41467-019-12821-2
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The authors are funded by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (2019/14391-8, 2018/11672-3, 2018/11792-9, 2017/08829-5, 2017/01184-9, and 2017/22057-5), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (310287/2018-9), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (88887.143923/2017-00 and scholarships).
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Braga, D.L., Mousovich-Neto, F., Tonon-da-Silva, G. et al. Epigenetic changes during ageing and their underlying mechanisms. Biogerontology 21, 423–443 (2020). https://doi.org/10.1007/s10522-020-09874-y
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DOI: https://doi.org/10.1007/s10522-020-09874-y