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Epigenomic, Transcriptome and Image-Based Biomarkers of Aging

  • Yizhen Yan
  • Yonglin Mu
  • Weiyang Chen
  • Jing-Dong J. HanEmail author
Chapter
Part of the Healthy Ageing and Longevity book series (HAL, volume 10)

Abstract

The need to postpone age-associated decline and maintain late life healthspan is generally agreed, however, available tools and methods still lack accuracy. Indicators of biological age, or biomarkers of aging, therefore, have important roles in simplifying clinical diagnostics to allow healthcare to be tailored to individuals. Moreover, biomarkers of aging can alter current approaches to finding solutions to reduce biological age. Several families of biomarkers have emerged, though most of them are diseases-specific, some of them have great potentials as aging indicators. Here we review the current advances in biomarkers of aging. After describing the definition of aging biomarkers, we emphasize the importance of aging diagnostics, and discuss several basic considerations when modeling biological age. Finally, we highlight some biomarker candidates with the highest application potentials, including epigenome, microRNAs especially exosome microRNAs, and recently developed image-based phenome and microbiome markers.

Keywords

Epigenetics Transcriptome Aging marker Bioimage DNA methylation Chromatin structure microRNA Microbiome 

Notes

Acknowledgements

This work was supported by grants from National Natural Science Foundation of China (91749205, 91329302 and 31210103916), China Ministry of Science and Technology (2015CB964803 and 2016YFE0108700) and Max Planck fellowship to J.D.J.H.

References

  1. Armstrong NJ et al (2017) Aging, exceptional longevity and comparisons of the Hannum and Horvath epigenetic clocks. Epigenomics 9(5):689–700PubMedCrossRefGoogle Scholar
  2. Arroyo JD et al (2011) Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci U S A 108(12):5003–5008PubMedPubMedCentralCrossRefGoogle Scholar
  3. Bannister AJ, Kouzarides T (2011) Regulation of chromatin by histone modifications. Cell Res 21(3):381–395PubMedPubMedCentralCrossRefGoogle Scholar
  4. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297PubMedCrossRefGoogle Scholar
  5. Bates DJ et al (2010) MicroRNA regulation in Ames dwarf mouse liver may contribute to delayed aging. Aging Cell 9(1):1–18PubMedCrossRefGoogle Scholar
  6. Battaglia R et al (2016) MicroRNAs are stored in human MII oocyte and their expression profile changes in reproductive aging. Biol Reprod 95(6):131PubMedCrossRefGoogle Scholar
  7. 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):965–974PubMedPubMedCentralCrossRefGoogle Scholar
  8. Becker JS, Nicetto D, Zaret KS (2016) H3K9me3-dependent heterochromatin: barrier to cell fate changes. Trends Genet 32(1):29–41PubMedCrossRefGoogle Scholar
  9. Belsky DW et al (2015) Quantification of biological aging in young adults. Proc Natl Acad Sci U S A 112(30):E4104–E4110PubMedPubMedCentralCrossRefGoogle Scholar
  10. Benayoun BA, Pollina EA, Brunet A (2015) Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat Rev Mol Cell Biol 16(10):593–610PubMedPubMedCentralCrossRefGoogle Scholar
  11. Bergink S, Jentsch S (2009) Principles of ubiquitin and SUMO modifications in DNA repair. Nature 458(7237):461–467PubMedCrossRefGoogle Scholar
  12. Bischoff SC (2016) Microbiota and aging. Curr Opin Clin Nutr Metab Care 19(1):26–30PubMedCrossRefGoogle Scholar
  13. Boehm M, Slack F (2005) A developmental timing microRNA and its target regulate life span in C. elegans. Science 310(5756):1954–1957PubMedCrossRefGoogle Scholar
  14. Boulias K, Horvitz HR (2012) The C. elegans microRNA mir-71 acts in neurons to promote germline-mediated longevity through regulation of DAF-16/FOXO. Cell Metab 15(4):439–450PubMedPubMedCentralCrossRefGoogle Scholar
  15. Cartee GD et al (2016) Exercise promotes healthy aging of skeletal muscle. Cell Metab 23(6):1034–1047PubMedPubMedCentralCrossRefGoogle Scholar
  16. Chan MK et al (2014) Applications of blood-based protein biomarker strategies in the study of psychiatric disorders. Prog Neurobiol 122:45–72PubMedCrossRefGoogle Scholar
  17. Chandra T et al (2015) Global reorganization of the nuclear landscape in senescent cells. Cell Rep 10(4):471–483PubMedPubMedCentralCrossRefGoogle Scholar
  18. Chen W, Han JD (2015) Aging phenomics enabled by quantitative imaging analysis. Oncotarget 6(19):16794–16795PubMedPubMedCentralGoogle Scholar
  19. Chen W et al (2015) Three-dimensional human facial morphologies as robust aging markers. Cell Res 25(5):574–587PubMedPubMedCentralCrossRefGoogle Scholar
  20. Cheng L et al (2014) Exosomes provide a protective and enriched source of miRNA for biomarker profiling compared to intracellular and cell-free blood. J Extracell Vesicles 3CrossRefGoogle Scholar
  21. Cheng H et al (2018) Repression of human and mouse brain inflammaging transcriptome by broad gene-body histone hyperacetylation. Proc Natl Acad Sci U S A 115(29):7611–7616PubMedPubMedCentralCrossRefGoogle Scholar
  22. Claesson MJ et al (2011) Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci U S A 108(Suppl 1):4586–4591PubMedCrossRefGoogle Scholar
  23. Claesson MJ et al (2012) Gut microbiota composition correlates with diet and health in the elderly. Nature 488(7410):178–184PubMedCrossRefGoogle Scholar
  24. Clark RI et al (2015) Distinct shifts in microbiota composition during drosophila aging impair intestinal function and drive mortality. Cell Rep 12(10):1656–1667PubMedPubMedCentralCrossRefGoogle Scholar
  25. Colcombe SJ et al (2003) Aerobic fitness reduces brain tissue loss in aging humans. J Gerontol A Biol Sci Med Sci 58(2):176–180PubMedCrossRefGoogle Scholar
  26. Conley MN et al (2016) Aging and serum MCP-1 are associated with gut microbiome composition in a murine model. PeerJ 4:e1854PubMedPubMedCentralCrossRefGoogle Scholar
  27. Constantinidis C, Klingberg T (2016) The neuroscience of working memory capacity and training. Nat Rev Neurosci 17(7):438–449PubMedCrossRefGoogle Scholar
  28. Contrepois K et al (2017) Histone variant H2A.J accumulates in senescent cells and promotes inflammatory gene expression. Nat Commun 8:14995Google Scholar
  29. Criscione SW et al (2016) Reorganization of chromosome architecture in replicative cellular senescence. Sci Adv 2(2):e1500882PubMedPubMedCentralCrossRefGoogle Scholar
  30. Crossland H et al (2017) A reverse genetics cell-based evaluation of genes linked to healthy human tissue age. FASEB J 31(1):96–108PubMedCrossRefGoogle Scholar
  31. Dang W et al (2009) Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature 459(7248):802–807PubMedPubMedCentralCrossRefGoogle Scholar
  32. de Cabo R et al (2014) The search for antiaging interventions: from elixirs to fasting regimens. Cell 157(7):1515–1526PubMedPubMedCentralCrossRefGoogle Scholar
  33. de Lencastre A et al (2010) MicroRNAs both promote and antagonize longevity in C. elegans. Curr Biol 20(24):2159–2168Google Scholar
  34. de Magalhaes JP (2012) Programmatic features of aging originating in development: aging mechanisms beyond molecular damage? FASEB J 26(12):4821–4826PubMedPubMedCentralCrossRefGoogle Scholar
  35. Deans C, Maggert KA (2015) What do you mean, “epigenetic”? Genetics 199(4):887–896PubMedPubMedCentralCrossRefGoogle Scholar
  36. Deaton AM, Bird A (2011) CpG islands and the regulation of transcription. Genes Dev 25(10):1010–1022PubMedPubMedCentralCrossRefGoogle Scholar
  37. Demark-Wahnefried W et al (2015) Practical clinical interventions for diet, physical activity, and weight control in cancer survivors. CA Cancer J Clin 65(3):167–189PubMedCrossRefGoogle Scholar
  38. Dewey FE et al (2014) Clinical interpretation and implications of whole-genome sequencing. JAMA 311(10):1035–1045PubMedPubMedCentralCrossRefGoogle Scholar
  39. Diabetes Prevention Program Research Group (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):866–875Google Scholar
  40. Dixon JR et al (2012) Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485(7398):376–380PubMedPubMedCentralCrossRefGoogle Scholar
  41. Driscoll I et al (2009) Longitudinal pattern of regional brain volume change differentiates normal aging from MCI. Neurology 72(22):1906–1913PubMedPubMedCentralCrossRefGoogle Scholar
  42. Drummond MJ et al (2011) Aging and microRNA expression in human skeletal muscle: a microarray and bioinformatics analysis. Physiol Genomics 43(10):595–603PubMedCrossRefPubMedCentralGoogle Scholar
  43. Dryden NH et al (2014) Unbiased analysis of potential targets of breast cancer susceptibility loci by capture Hi-C. Genome Res 24(11):1854–1868PubMedPubMedCentralCrossRefGoogle Scholar
  44. Elliott G et al (2015) Intermediate DNA methylation is a conserved signature of genome regulation. Nat Commun 6:6363PubMedPubMedCentralCrossRefGoogle Scholar
  45. ElSharawy A et al (2012) Genome-wide miRNA signatures of human longevity. Aging Cell 11(4):607–616CrossRefGoogle Scholar
  46. Enge M et al (2017) Single-cell analysis of human pancreas reveals transcriptional signatures of aging and somatic mutation patterns. Cell 171(2):321–330 e14PubMedPubMedCentralCrossRefGoogle Scholar
  47. Ewald CY, Marfil V, Li C (2016) Alzheimer-related protein APL-1 modulates lifespan through heterochronic gene regulation in Caenorhabditis elegans. Aging Cell 15(6):1051–1062PubMedPubMedCentralCrossRefGoogle Scholar
  48. Fan W, Evans RM (2017) Exercise mimetics: impact on health and performance. Cell Metab 25(2):242–247PubMedCrossRefGoogle Scholar
  49. Fang R et al (2016) Mapping of long-range chromatin interactions by proximity ligation-assisted ChIP-seq. Cell Res 26(12):1345–1348PubMedPubMedCentralCrossRefGoogle Scholar
  50. Field AE et al (2018) DNA methylation clocks in aging: categories, causes, and consequences. Mol Cell 71(6):882–895PubMedPubMedCentralCrossRefGoogle Scholar
  51. Fitzenberger E et al (2014) The polyphenol quercetin protects the mev-1 mutant of Caenorhabditis elegans from glucose-induced reduction of survival under heat-stress depending on SIR-2.1, DAF-12, and proteasomal activity. Mol Nutr Food Res 58(5):984–994CrossRefGoogle Scholar
  52. Fraga MF, Esteller M (2007) Epigenetics and aging: the targets and the marks. Trends Genet 23(8):413–418PubMedCrossRefPubMedCentralGoogle Scholar
  53. Franceschi C, Campisi J (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 69(Suppl 1):S4–S9PubMedCrossRefPubMedCentralGoogle Scholar
  54. Gladyshev VN (2016) Aging: progressive decline in fitness due to the rising deleteriome adjusted by genetic, environmental, and stochastic processes. Aging Cell 15(4):594–602PubMedPubMedCentralCrossRefGoogle Scholar
  55. Glorioso C, Sibille E (2011) Between destiny and disease: genetics and molecular pathways of human central nervous system aging. Prog Neurobiol 93(2):165–181PubMedCrossRefPubMedCentralGoogle Scholar
  56. Green CD et al (2017) Impact of dietary interventions on noncoding RNA networks and mRNAs encoding chromatin-related factors. Cell Rep 18(12):2957–2968PubMedCrossRefPubMedCentralGoogle Scholar
  57. Greer EL et al (2010) Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature 466(7304):383–387PubMedPubMedCentralCrossRefGoogle Scholar
  58. Gross CP et al (2006) Relation between medicare screening reimbursement and stage at diagnosis for older patients with colon cancer. JAMA 296(23):2815–2822PubMedCrossRefPubMedCentralGoogle Scholar
  59. Gunn DA et al (2008) Perceived age as a biomarker of ageing: a clinical methodology. Biogerontology 9(5):357–364PubMedCrossRefPubMedCentralGoogle Scholar
  60. Han Y et al (2012) Stress-associated H3K4 methylation accumulates during postnatal development and aging of rhesus macaque brain. Aging Cell 11(6):1055–1064PubMedCrossRefPubMedCentralGoogle Scholar
  61. Hansen M, Kennedy BK (2016) Does longer lifespan mean longer healthspan? Trends Cell Biol 26(8):565–568PubMedPubMedCentralCrossRefGoogle Scholar
  62. Haqqani AS et al (2013) Method for isolation and molecular characterization of extracellular microvesicles released from brain endothelial cells. Fluids Barriers CNS 10(1):4PubMedPubMedCentralCrossRefGoogle Scholar
  63. Harrison DE et al (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460(7253):392–395PubMedPubMedCentralCrossRefGoogle Scholar
  64. He L et al (2007) A microRNA component of the p53 tumour suppressor network. Nature 447(7148):1130–1134PubMedPubMedCentralCrossRefGoogle Scholar
  65. Hopkins AL (2008) Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol 4(11):682–690PubMedCrossRefGoogle Scholar
  66. Horvath S (2013) DNA methylation age of human tissues and cell types. Genome Biol 14(10):R115PubMedPubMedCentralCrossRefGoogle Scholar
  67. Horvath S, Raj K (2018) DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet 19(6):371–384PubMedPubMedCentralCrossRefGoogle Scholar
  68. Hoy AM, Buck AH (2012) Extracellular small RNAs: what, where, why? Biochem Soc Trans 40(4):886–890PubMedPubMedCentralCrossRefGoogle Scholar
  69. Hu Z et al (2014) Nucleosome loss leads to global transcriptional up-regulation and genomic instability during yeast aging. Genes Dev 28(4):396–408PubMedPubMedCentralCrossRefGoogle Scholar
  70. Huang X et al (2013) Characterization of human plasma-derived exosomal RNAs by deep sequencing. BMC Genom 14:319CrossRefGoogle Scholar
  71. Hunter MP et al (2008) Detection of microRNA expression in human peripheral blood microvesicles. PLoS ONE 3(11):e3694PubMedPubMedCentralCrossRefGoogle Scholar
  72. Ibanez-Ventoso C et al (2006) Modulated microRNA expression during adult lifespan in Caenorhabditis elegans. Aging Cell 5(3):235–246PubMedCrossRefGoogle Scholar
  73. Integrative Analysis of Lung Cancer E et al (2018) Assessment of lung cancer risk on the basis of a biomarker panel of circulating proteins. JAMA Oncol 4(10):e182078Google Scholar
  74. Inukai S et al (2012) Novel microRNAs differentially expressed during aging in the mouse brain. PLoS ONE 7(7):e40028PubMedPubMedCentralCrossRefGoogle Scholar
  75. Inukai S et al (2018) A microRNA feedback loop regulates global microRNA abundance during aging. RNA 24(2):159–172PubMedPubMedCentralCrossRefGoogle Scholar
  76. Jackson MA et al (2016) Erratum to: signatures of early frailty in the gut microbiota. Genome Med 8(1):21PubMedPubMedCentralCrossRefGoogle Scholar
  77. Jeffery IB, Lynch DB, O’Toole PW (2016) Composition and temporal stability of the gut microbiota in older persons. ISME J 10(1):170–182PubMedCrossRefGoogle Scholar
  78. Jenkins D, Sievenpiper J, Jones P (2018) Primary prevention of cardiovascular disease with a mediterranean diet supplemented with extra-virgin olive oil or nuts. N Engl J Med 379(14):1387–1388PubMedCrossRefGoogle Scholar
  79. 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):161–72PubMedCrossRefGoogle Scholar
  80. Kang HJ et al (2011) Spatio-temporal transcriptome of the human brain. Nature 478(7370):483–489PubMedPubMedCentralCrossRefGoogle Scholar
  81. Kato M et al (2009) The mir-34 microRNA is required for the DNA damage response in vivo in C. elegans and in vitro in human breast cancer cells. Oncogene 28(25):2419–2424PubMedPubMedCentralCrossRefGoogle Scholar
  82. Kato M et al (2011) Age-associated changes in expression of small, noncoding RNAs, including microRNAs in C. elegans. RNA 17(10):1804–1820PubMedPubMedCentralCrossRefGoogle Scholar
  83. Kawakami K et al (2009) Age-related difference of site-specific histone modifications in rat liver. Biogerontology 10(4):415–421PubMedCrossRefGoogle Scholar
  84. Kennedy BK et al (2014) Geroscience: linking aging to chronic disease. Cell 159(4):709–713PubMedPubMedCentralCrossRefGoogle Scholar
  85. Keshishian H et al (2017) Quantitative, multiplexed workflow for deep analysis of human blood plasma and biomarker discovery by mass spectrometry. Nat Protoc 12(8):1683–1701PubMedPubMedCentralCrossRefGoogle Scholar
  86. Khanna A et al (2011) Gain of survival signaling by down-regulation of three key miRNAs in brain of calorie-restricted mice. Aging (Albany NY) 3(3):223–236CrossRefGoogle Scholar
  87. Konturek PC et al (2015) Emerging role of fecal microbiota therapy in the treatment of gastrointestinal and extra-gastrointestinal diseases. J Physiol Pharmacol 66(4):483–491PubMedGoogle Scholar
  88. Kopeina GS, Senichkin VV, Zhivotovsky B (2017) Caloric restriction—a promising anti-cancer approach: from molecular mechanisms to clinical trials. Biochim Biophys Acta Rev Cancer 1867(1):29–41PubMedCrossRefGoogle Scholar
  89. Krishnan V et al (2011) Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice. Proc Natl Acad Sci U S A 108(30):12325–12330PubMedPubMedCentralCrossRefGoogle Scholar
  90. Lamb J et al (2006) The connectivity map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313(5795):1929–1935PubMedCrossRefGoogle Scholar
  91. Larson K et al (2012) Heterochromatin formation promotes longevity and represses ribosomal RNA synthesis. PLoS Genet 8(1):e1002473PubMedPubMedCentralCrossRefGoogle Scholar
  92. Laslett LL et al (2014) Moderate vitamin D deficiency is associated with changes in knee and hip pain in older adults: a 5-year longitudinal study. Ann Rheum Dis 73(4):697–703PubMedCrossRefGoogle Scholar
  93. Lau EM, Humbert M, Celermajer DS (2015) Early detection of pulmonary arterial hypertension. Nat Rev Cardiol 12(3):143–155PubMedCrossRefGoogle Scholar
  94. Lehmann SM et al (2012) An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nat Neurosci 15(6):827–835PubMedCrossRefGoogle Scholar
  95. Levine ME et al (2018) An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY) 10(4):573–591CrossRefGoogle Scholar
  96. Li N et al (2011a) Up-regulation of key microRNAs, and inverse down-regulation of their predicted oxidative phosphorylation target genes, during aging in mouse brain. Neurobiol Aging 32(5):944–955PubMedCrossRefGoogle Scholar
  97. Li N et al (2011b) Increased expression of miR-34a and miR-93 in rat liver during aging, and their impact on the expression of Mgst1 and Sirt1. Mech Ageing Dev 132(3):75–85PubMedCrossRefGoogle Scholar
  98. Li X et al (2011c) Circulatory miR34a as an RNAbased, noninvasive biomarker for brain aging. Aging (Albany NY) 3(10):985–1002CrossRefGoogle Scholar
  99. Li H, Qi Y, Jasper H (2016) Preventing age-related decline of gut compartmentalization limits microbiota dysbiosis and extends lifespan. Cell Host Microbe 19(2):240–253PubMedPubMedCentralCrossRefGoogle Scholar
  100. Liang R et al (2011) Post-transcriptional regulation of IGF1R by key microRNAs in long-lived mutant mice. Aging Cell 10(6):1080–1088PubMedPubMedCentralCrossRefGoogle Scholar
  101. Liao CY et al (2010) Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. Aging Cell 9(1):92–95PubMedCrossRefGoogle Scholar
  102. Liao CY, Johnson TE, Nelson JF (2013) Genetic variation in responses to dietary restriction–an unbiased tool for hypothesis testing. Exp Gerontol 48(10):1025–1029PubMedPubMedCentralCrossRefGoogle Scholar
  103. Lieberman-Aiden E et al (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326(5950):289–293PubMedPubMedCentralCrossRefGoogle Scholar
  104. Liu N et al (2012) The microRNA miR-34 modulates ageing and neurodegeneration in Drosophila. Nature 482(7386):519–523PubMedPubMedCentralCrossRefGoogle Scholar
  105. Liu F et al (2016) The MC1R gene and youthful looks. Curr Biol 26(9):1213–1220PubMedCrossRefGoogle Scholar
  106. Luger K, Dechassa ML, Tremethick DJ (2012) New insights into nucleosome and chromatin structure: an ordered state or a disordered affair? Nat Rev Mol Cell Biol 13(7):436–447PubMedPubMedCentralCrossRefGoogle Scholar
  107. Machida T et al (2015) MicroRNAs in salivary exosome as potential biomarkers of aging. Int J Mol Sci 16(9):21294–21309PubMedPubMedCentralCrossRefGoogle Scholar
  108. Maes OC et al (2008) Murine microRNAs implicated in liver functions and aging process. Mech Ageing Dev 129(9):534–541PubMedCrossRefGoogle Scholar
  109. Mangiola F et al (2018) Gut microbiota and aging. Eur Rev Med Pharmacol Sci 22(21):7404–7413PubMedGoogle Scholar
  110. Marioni RE et al (2015) The epigenetic clock is correlated with physical and cognitive fitness in the Lothian birth cohort 1936. Int J Epidemiol 44(4):1388–1396PubMedPubMedCentralCrossRefGoogle Scholar
  111. 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):980–990PubMedPubMedCentralCrossRefGoogle Scholar
  112. McColl G et al (2008) Pharmacogenetic analysis of lithium-induced delayed aging in Caenorhabditis elegans. J Biol Chem 283(1):350–357PubMedCrossRefGoogle Scholar
  113. McCord RP et al (2013) Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson-Gilford progeria syndrome. Genome Res 23(2):260–269PubMedPubMedCentralCrossRefGoogle Scholar
  114. Mitchell MJ, Jain RK, Langer R (2017) Engineering and physical sciences in oncology: challenges and opportunities. Nat Rev Cancer 17(11):659–675PubMedPubMedCentralCrossRefGoogle Scholar
  115. Miyawaki S et al (2016) Facial pigmentation as a biomarker of carotid atherosclerosis in middle-aged to elderly healthy Japanese subjects. Skin Res Technol 22(1):20–24PubMedCrossRefGoogle Scholar
  116. Mori MA et al (2012) Role of microRNA processing in adipose tissue in stress defense and longevity. Cell Metab 16(3):336–347PubMedPubMedCentralCrossRefGoogle Scholar
  117. Mumbach MR et al (2016) HiChIP: efficient and sensitive analysis of protein-directed genome architecture. Nat Methods 13(11):919–922PubMedPubMedCentralCrossRefGoogle Scholar
  118. Neff F et al (2013) Rapamycin extends murine lifespan but has limited effects on aging. J Clin Invest 123(8):3272–3291PubMedPubMedCentralCrossRefGoogle Scholar
  119. Neri F et al (2017) Intragenic DNA methylation prevents spurious transcription initiation. Nature 543(7643):72–77PubMedCrossRefGoogle Scholar
  120. Nevalainen T et al (2017) Obesity accelerates epigenetic aging in middle-aged but not in elderly individuals. Clin Epigenetics 9:20PubMedPubMedCentralCrossRefGoogle Scholar
  121. Ni Z et al (2012) Two SET domain containing genes link epigenetic changes and aging in Caenorhabditis elegans. Aging Cell 11(2):315–325PubMedPubMedCentralCrossRefGoogle Scholar
  122. Noren Hooten N et al (2010) MicroRNA expression patterns reveal differential expression of target genes with age. PLoS ONE 5(5):e10724PubMedPubMedCentralCrossRefGoogle Scholar
  123. Olivieri F et al (2017) Circulating miRNAs and miRNA shuttles as biomarkers: perspective trajectories of healthy and unhealthy aging. Mech Ageing Dev 165(Pt B):162–170CrossRefGoogle Scholar
  124. Organization WH (2017) World report on ageing and health. Indian J Med Res 145(1):150–151CrossRefGoogle Scholar
  125. 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):1218–1225PubMedPubMedCentralCrossRefGoogle Scholar
  126. Pandey AC et al (2011) MicroRNA profiling reveals age-dependent differential expression of nuclear factor kappaB and mitogen-activated protein kinase in adipose and bone marrow-derived human mesenchymal stem cells. Stem Cell Res Ther 2(6):49PubMedPubMedCentralCrossRefGoogle Scholar
  127. Partridge L, Deelen J, Slagboom PE (2018) Facing up to the global challenges of ageing. Nature 561(7721):45–56PubMedCrossRefGoogle Scholar
  128. Peleg S et al (2010) Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328(5979):753–756PubMedCrossRefGoogle Scholar
  129. Peleg S et al (2016) The metabolic impact on histone acetylation and transcription in ageing. Trends Biochem Sci 41(8):700–711PubMedCrossRefGoogle Scholar
  130. Peters MJ et al (2015) The transcriptional landscape of age in human peripheral blood. Nat Commun 6:8570PubMedPubMedCentralCrossRefGoogle Scholar
  131. Petkovich DA et al (2017) Using DNA methylation profiling to evaluate biological age and longevity interventions. Cell Metab 25(4):954–960 e6PubMedPubMedCentralCrossRefGoogle Scholar
  132. Piazzesi A et al (2016) Replication-independent histone variant H3.3 controls animal lifespan through the regulation of pro-longevity transcriptional programs. Cell Rep 17(4):987–996PubMedPubMedCentralCrossRefGoogle Scholar
  133. Rae MJ et al (2010) The demographic and biomedical case for late-life interventions in aging. Sci Transl Med 2(40):40cm21PubMedPubMedCentralCrossRefGoogle Scholar
  134. Rao SS et al (2014) A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159(7):1665–1680PubMedPubMedCentralCrossRefGoogle Scholar
  135. Rea SL et al (2005) A stress-sensitive reporter predicts longevity in isogenic populations of Caenorhabditis elegans. Nat Genet 37(8):894–898PubMedPubMedCentralCrossRefGoogle Scholar
  136. Riera CE, Dillin A (2015) Can aging be ‘drugged’? Nat Med 21(12):1400–1405PubMedCrossRefPubMedCentralGoogle Scholar
  137. Robine JM, Cubaynes S (2017) Worldwide demography of centenarians. Mech Ageing Dev 165(Pt B):59–67PubMedCrossRefPubMedCentralGoogle Scholar
  138. Rogina B, Helfand SL (2004) Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci U S A 101(45):15998–16003PubMedPubMedCentralCrossRefGoogle Scholar
  139. Rutherford MJ et al (2015) The impact of eliminating age inequalities in stage at diagnosis on breast cancer survival for older women. Br J Cancer 112(Suppl 1):S124–S128PubMedPubMedCentralCrossRefGoogle Scholar
  140. Santoro A et al (2018) Gut microbiota changes in the extreme decades of human life: a focus on centenarians. Cell Mol Life Sci 75(1):129–148PubMedCrossRefPubMedCentralGoogle Scholar
  141. Sarfati D, Koczwara B, Jackson C (2016) The impact of comorbidity on cancer and its treatment. CA Cancer J Clin 66(4):337–350PubMedCrossRefPubMedCentralGoogle Scholar
  142. Scaffidi P, Misteli T (2006) Lamin A-dependent nuclear defects in human aging. Science 312(5776):1059–1063PubMedPubMedCentralCrossRefGoogle Scholar
  143. Scahill RI et al (2003) A longitudinal study of brain volume changes in normal aging using serial registered magnetic resonance imaging. Arch Neurol 60(7):989–994PubMedCrossRefGoogle Scholar
  144. Scherbov S, Sanderson WC (2016) New approaches to the conceptualization and measurement of age and aging. J Aging Health 28(7):1159–1177PubMedCrossRefGoogle Scholar
  145. Schmid G et al (2016) Expression and promotor hypermethylation of miR-34a in the various histological subtypes of ovarian cancer. BMC Cancer 16:102PubMedPubMedCentralCrossRefGoogle Scholar
  146. Schoenborn NL et al (2018) Preferred clinician communication about stopping cancer screening among older US adults: results from a national survey. JAMA Oncol 4(8):1126–1128PubMedPubMedCentralCrossRefGoogle Scholar
  147. Schubeler D (2015) Function and information content of DNA methylation. Nature 517(7534):321–326PubMedCrossRefGoogle Scholar
  148. Sen P et al (2015) H3K36 methylation promotes longevity by enhancing transcriptional fidelity. Genes Dev 29(13):1362–1376PubMedPubMedCentralCrossRefGoogle Scholar
  149. Shirakabe A et al (2016) Aging and autophagy in the heart. Circ Res 118(10):1563–1576PubMedPubMedCentralCrossRefGoogle Scholar
  150. Shumaker DK et al (2006) Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging. Proc Natl Acad Sci U S A 103(23):8703–8708PubMedPubMedCentralCrossRefGoogle Scholar
  151. Siebold AP et al (2010) Polycomb repressive complex 2 and trithorax modulate drosophila longevity and stress resistance. Proc Natl Acad Sci U S A 107(1):169–174PubMedCrossRefGoogle Scholar
  152. Singh J et al (2016) Aging-associated changes in microRNA expression profile of internal anal sphincter smooth muscle: role of microRNA-133a. Am J Physiol Gastrointest Liver Physiol 311(5):G964–G973PubMedPubMedCentralCrossRefGoogle Scholar
  153. 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):2238–2246PubMedPubMedCentralCrossRefGoogle Scholar
  154. Smith-Vikos T et al (2016) A serum miRNA profile of human longevity: findings from the Baltimore longitudinal study of aging (BLSA). Aging (Albany NY) 8(11):2971–2987CrossRefGoogle Scholar
  155. Sood S et al (2015) A novel multi-tissue RNA diagnostic of healthy ageing relates to cognitive health status. Genome Biol 16:185PubMedPubMedCentralCrossRefGoogle Scholar
  156. Stadler MB et al (2011) DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature 480(7378):490–495PubMedCrossRefGoogle Scholar
  157. Stubbs TM et al (2017) Multi-tissue DNA methylation age predictor in mouse. Genome Biol 18(1):68PubMedPubMedCentralCrossRefGoogle Scholar
  158. 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):673–688PubMedPubMedCentralCrossRefGoogle Scholar
  159. Sun L, Yu R, Dang W (2018) Chromatin architectural changes during cellular senescence and aging. Genes 9(4). (Basel)PubMedCentralCrossRefPubMedGoogle Scholar
  160. Talbert PB, Henikoff S (2017) Histone variants on the move: substrates for chromatin dynamics. Nat Rev Mol Cell Biol 18(2):115–126PubMedCrossRefGoogle Scholar
  161. Tatar M, Bartke A, Antebi A (2003) The endocrine regulation of aging by insulin-like signals. Science 299(5611):1346–1351PubMedCrossRefPubMedCentralGoogle Scholar
  162. Tazawa H et al (2007) Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc Natl Acad Sci U S A 104(39):15472–15477PubMedPubMedCentralCrossRefGoogle Scholar
  163. Thevaranjan N et al (2017) Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe 21(4):455–466 e4CrossRefGoogle Scholar
  164. Thom G, Lean M (2017) Is there an optimal diet for weight management and metabolic health? Gastroenterology 152(7):1739–1751PubMedCrossRefGoogle Scholar
  165. Tian Y et al (2016) Mitochondrial stress induces chromatin reorganization to promote longevity and UPR (mt). Cell 165(5):1197–1208PubMedPubMedCentralCrossRefGoogle Scholar
  166. Timmons JA (2017) Molecular diagnostics of ageing and tackling age-related disease. Trends Pharmacol Sci 38(1):67–80PubMedCrossRefPubMedCentralGoogle Scholar
  167. Tissenbaum HA, Guarente L (2001) Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410(6825):227–230PubMedCrossRefPubMedCentralGoogle Scholar
  168. van der Stok EP et al (2017) Surveillance after curative treatment for colorectal cancer. Nat Rev Clin Oncol 14(5):297–315PubMedCrossRefPubMedCentralGoogle Scholar
  169. Venkatesh S, Workman JL (2015) Histone exchange, chromatin structure and the regulation of transcription. Nat Rev Mol Cell Biol 16(3):178–189PubMedCrossRefPubMedCentralGoogle Scholar
  170. Vickers KC et al (2011) MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol 13(4):423–433PubMedPubMedCentralCrossRefGoogle Scholar
  171. Wagner W (2017) Epigenetic aging clocks in mice and men. Genome Biol 18(1):107PubMedPubMedCentralCrossRefGoogle Scholar
  172. Wang T et al (2017) Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment. Genome Biol 18(1):57PubMedPubMedCentralCrossRefGoogle Scholar
  173. Wang Y, Yuan Q, Xie L (2018) Histone modifications in aging: the underlying mechanisms and implications. Curr Stem Cell Res Ther 13(2):125–135PubMedCrossRefGoogle Scholar
  174. Weber JA et al (2010) The microRNA spectrum in 12 body fluids. Clin Chem 56(11):1733–1741PubMedPubMedCentralCrossRefGoogle Scholar
  175. Wilkinson JE et al (2012) Rapamycin slows aging in mice. Aging Cell 11(4):675–682PubMedPubMedCentralCrossRefGoogle Scholar
  176. Wong HR et al (2017) Improved risk stratification in pediatric septic shock using both protein and mRNA biomarkers. PERSEVERE-XP. Am J Respir Crit Care Med 196(4):494–501PubMedPubMedCentralCrossRefGoogle Scholar
  177. Wood JG et al (2010) Chromatin remodeling in the aging genome of Drosophila. Aging Cell 9(6):971–978PubMedPubMedCentralCrossRefGoogle Scholar
  178. Wu X, Zhang Y (2017) TET-mediated active DNA demethylation: mechanism, function and beyond. Nat Rev Genet 18(9):517–534PubMedCrossRefGoogle Scholar
  179. Xia X et al (2017) Molecular and phenotypic biomarkers of aging. F1000Res 6:860PubMedPubMedCentralCrossRefGoogle Scholar
  180. Yang J et al (2013) MiR-34 modulates Caenorhabditis elegans lifespan via repressing the autophagy gene atg9. Age (Dordr) 35(1):11–22CrossRefGoogle Scholar
  181. Yang X et al (2014) Gene body methylation can alter gene expression and is a therapeutic target in cancer. Cancer Cell 26(4):577–590PubMedPubMedCentralCrossRefGoogle Scholar
  182. Young AL et al (2014) A data-driven model of biomarker changes in sporadic Alzheimer’s disease. Brain 137(Pt 9):2564–2577PubMedPubMedCentralCrossRefGoogle Scholar
  183. Zhang W et al (2015) Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science 348(6239):1160–1163Google Scholar
  184. Zhao Y, Garcia BA (2015) Comprehensive catalog of currently documented histone modifications. Cold Spring Harb Perspect Biol 7(9):a025064PubMedPubMedCentralCrossRefGoogle Scholar
  185. Zhao Q et al (2016) Dissecting the precise role of H3K9 methylation in crosstalk with DNA maintenance methylation in mammals. Nat Commun 7:12464PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Yizhen Yan
    • 1
    • 2
  • Yonglin Mu
    • 1
    • 2
  • Weiyang Chen
    • 2
    • 3
  • Jing-Dong J. Han
    • 1
    • 2
    Email author
  1. 1.Key Laboratory of Computational BiologyCAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of SciencesShanghaiChina
  2. 2.University of Chinese Academy of SciencesBeijingChina
  3. 3.School of Computer Science and TechnologyQilu University of Technology (Shandong Academy of Sciences)JinanChina

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