Genome wide hypomethylation and youth-associated DNA gap reduction promoting DNA damage and senescence-associated pathogenesis
Main Article Content
Abstract
Background: Age-associated epigenetic alteration is the underlying cause of DNA damage in aging cells. Two types of youth-associated DNA-protection epigenetic marks, global methylation, and youth-associated genomic stabilization DNA gap (youth-DNA-gap) reduce when cell ages. The epigenomic mark reduction promotes DNA damage and accelerates aging hallmarks. While DNA hypomethylation destabilizes DNA by several mechanisms, the DNA sequence around the youth-DNA-gap is hypermethylated. Therefore, the genomic instability mechanisms underlying DNA hypomethylation and youth-DNA-gap reduction are linked.
Results: DNA gap prevents DNA damage by relieving the torsion forces caused by a twisted wave during DNA strand separation by transcription or replication. When the cells begin to age, hypomethylation and youth-DNA-gap reduction can occur as consequences of the efflux of intranuclear HMGB1. The methylated DNA gaps are formed by several proteins. Box A of HMGB1 possesses a molecular scissor role in producing youth-DNA-gaps. So the lack of a gap-producing role of HMGB1 results in a youth-DNA-gap reduction. The histone deacetylation role of SIRT1, an aging prevention protein, prevents DNA ends of youth-DNA-gaps from being recognized as pathologic DNA breaks. Youth-DNA-gaps are methylated and determined genome distribution by AGO4, an effector protein in RNA-directed DNA methylation. The lack of intranuclear HMGB1 promotes global hypomethylation due to two subsequent mechanisms. First is the loss of AGO4-methylating DNA. The other is the accumulation of DNA damage due to lacking HMGB1-produced DNA gap promoting DNA demethylation while undergoing DNA repair. DNA torsion due to youth-DNA-gap reduction increases DNA damage and, consequently, the DNA damage response (DDR). Persistent DDR promotes cellular senescence. Accumulating senescent cells leads to the deterioration of the structure and function of the human body. Rejuvenating DNA (RED) by adding DNA protection epigenetic marks using genomic stability molecule (GEM) such as box A of HMGB1 increases DNA durability, limits DNA damage, rejuvenates senescence cells, and improves organ structure and function deterioration due to aging.
Conclusion: Reducing youth-associated epigenetic marks is degenerative diseases' primary molecular pathogenesis mechanism. REDGEM is a new therapeutic strategy inhibiting the upstream molecular aging process that will revolutionize the treatment of DNA damage or age-associated diseases and conditions.
Keywords:
DNA protection, DNA methylation, youth-associated genomic stabilization DNA gap, youth-DNA-gap,, global hypomethylation, DNA damage, genomic instability, senescence, aging, rejuvenation, RIND-EDSB, Box A of HMGB1, Rejuvenating DNA by genomic stability molecule, REDGEM
Article Details
How to Cite
WATCHARANURAK, Papitchaya; MUTIRANGURA, Apiwat.
Genome wide hypomethylation and youth-associated DNA gap reduction promoting DNA damage and senescence-associated pathogenesis.
Medical Research Archives, [S.l.], v. 11, n. 12, dec. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4952>. Date accessed: 22 dec. 2024.
doi: https://doi.org/10.18103/mra.v11i12.4952.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Li Z, Zhang Z, Ren Y, Wang Y, Fang J, Yue H, et al. Aging and age-related diseases: from mechanisms to therapeutic strategies. Biogerontology. 2021;22(2):165-87.
2. Jaul E, Barron J. Age-Related Diseases and Clinical and Public Health Implications for the 85 Years Old and Over Population. Front Public Health. 2017;5:335.
3. Tseng WI, Hsu YC, Kao TW. Brain Age Difference at Baseline Predicts Clinical Dementia Rating Change in Approximately Two Years. J Alzheimers Dis. 2022;86(2):613-27.
4. Chae CU, Pfeffer MA, Glynn RJ, Mitchell GF, Taylor JO, Hennekens CH. Increased pulse pressure and risk of heart failure in the elderly. JAMA. 1999;281(7):634-9.
5. Li X, Xu S, Yu M, Wang K, Tao Y, Zhou Y, et al. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. J Allergy Clin Immunol. 2020;146(1):110-8.
6. Crews DE. Senescence, aging, and disease. J Physiol Anthropol. 2007;26(3):365-72.
7. Childs BG, Durik M, Baker DJ, van Deursen JM. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med. 2015;21(12):1424-35.
8. Mutirangura A. Is global hypomethylation a nidus for molecular pathogenesis of age-related noncommunicable diseases? Epigenomics. 2019;11(6):577-9.
9. Yasom S, Watcharanurak P, Bhummaphan N, Thongsroy J, Puttipanyalears C, Settayanon S, et al. The roles of HMGB1-produced DNA gaps in DNA protection and aging biomarker reversal. FASEB BioAdvances. 2022;4(6):408-34.
10. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194-217.
11. Gonzalo S. Epigenetic alterations in aging. J Appl Physiol (1985). 2010;109(2):586-97.
12. Niedernhofer LJ, Gurkar AU, Wang Y, Vijg J, Hoeijmakers JHJ, Robbins PD. Nuclear Genomic Instability and Aging. Annu Rev Biochem. 2018;87:295-322.
13. Ou HL, Schumacher B. DNA damage responses and p53 in the aging process. Blood. 2018;131(5):488-95.
14. Fumagalli M, Rossiello F, Mondello C, d'Adda di Fagagna F. Stable cellular senescence is associated with persistent DDR activation. PLoS One. 2014;9(10):e110969.
15. Galbiati A, Beausejour C, d'Adda di Fagagna F. A novel single-cell method provides direct evidence of persistent DNA damage in senescent cells and aged mammalian tissues. Aging Cell. 2017;16(2): 422-7.
16. Thongsroy J, Patchsung M, Pongpanich M, Settayanon S, Mutirangura A. Reduction in replication-independent endogenous DNA double-strand breaks promotes genomic instability during chronological aging in yeast. The FASEB Journal. 2018;32(11):6252-60.
17. Patchsung M, Settayanon S, Pongpanich M, Mutirangura D, Jintarith P, Mutirangura A. Alu siRNA to increase Alu element methylation and prevent DNA damage. Epigenomics. 2018;10(2):175-85.
18. Wilson VL, Smith RA, Ma S, Cutler RG. Genomic 5-methyldeoxycytidine decreases with age. J Biol Chem. 1987;262(21):9948-51.
19. Jones PA, Takai D. The role of DNA methylation in mammalian epigenetics. Science. 2001;293(5532):1068-70.
20. Zheng Y, Joyce BT, Liu L, Zhang Z, Kibbe WA, Zhang W, Hou L. Prediction of genome-wide DNA methylation in repetitive elements. Nucleic Acids Res. 2017;45(15):8697-711.
21. Aporntewan C, Phokaew C, Piriyapongsa J, Ngamphiw C, Ittiwut C, Tongsima S, Mutirangura A. Hypomethylation of intragenic LINE-1 represses transcription in cancer cells through AGO2. PLoS One. 2011;6(3):e17934.
22. Tirado-Magallanes R, Rebbani K, Lim R, Pradhan S, Benoukraf T. Whole genome DNA methylation: beyond genes silencing. Oncotarget. 2017;8(3):5629-37.
23. Sheaffer KL, Elliott EN, Kaestner KH. DNA Hypomethylation Contributes to Genomic Instability and Intestinal Cancer Initiation. Cancer Prev Res (Phila). 2016;9(7):534-46.
24. Kitkumthorn N, Mutirangura A. Long interspersed nuclear element-1 hypomethylation in cancer: biology and clinical applications. Clin Epigenetics. 2011;2(2):315-30.
25. Eden A, Gaudet F, Waghmare A, Jaenisch R. Chromosomal instability and tumors promoted by DNA hypomethylation. Science. 2003;300(5618):455.
26. Chen RZ, Pettersson U, Beard C, Jackson-Grusby L, Jaenisch R. DNA hypomethylation leads to elevated mutation rates. Nature. 1998;395(6697):89-93.
27. Tongyoo P, Avihingsanon Y, Prom-On S, Mutirangura A, Mhuantong W, Hirankarn N. EnHERV: Enrichment analysis of specific human endogenous retrovirus patterns and their neighboring genes. PLoS One. 2017;12 (5):e0177119.
28. Bollati V, Schwartz J, Wright R, Litonjua A, Tarantini L, Suh H, et al. Decline in genomic DNA methylation through aging in a cohort of elderly subjects. Mech Ageing Dev. 2009;130 (4):234-9.
29. Jintaridth P, Mutirangura A. Distinctive patterns of age-dependent hypomethylation in interspersed repetitive sequences. Physiol Genomics. 2010;41(2):194-200.
30. Cardelli M. The epigenetic alterations of endogenous retroelements in aging. Mech Ageing Dev. 2018;174:30-46.
31. Lu S, Niu Z, Chen Y, Tu Q, Zhang Y, Chen W, et al. Repetitive Element DNA Methylation is Associated with Menopausal Age. Aging Dis. 2018;9(3):435-43.
32. Thongsroy J, Patchsung M, Mutirangura A. The association between Alu hypomethylation and severity of type 2 diabetes mellitus. Clin Epigenetics. 2017;9:93.
33. Jintaridth P, Tungtrongchitr R, Preutthipan S, Mutirangura A. Hypomethylation of Alu elements in post-menopausal women with osteoporosis. PLoS One. 2013;8(8):e70386.
34. Thongsroy J, Mutirangura A. The association between Alu hypomethylation and the severity of hypertension. PLoS One. 2022;17(7):e0270004.
35. Rerkasem K, Rattanatanyong P, Rerkasem A, Wongthanee A, Rungruengthanakit K, Mangklabruks A, Mutirangura A. Higher Alu methylation levels in catch-up growth in twenty-year-old offsprings. PLoS One. 2015; 10(3):e0120032.
36. Pornthanakasem W, Kongruttanachok N, Phuangphairoj C, Suyarnsestakorn C, Sanghangthum T, Oonsiri S, et al. LINE-1 methylation status of endogenous DNA double-strand breaks. Nucleic Acids Res. 2008;36(11):3667-75.
37. Pongpanich M, Patchsung M, Thongsroy J, Mutirangura A. Characteristics of replication-independent endogenous double -strand breaks in Saccharomyces cerevisiae. BMC Genomics. 2014;15:750.
38. Thongsroy J, Mutirangura A. The inverse association between DNA gaps and HbA1c levels in type 2 diabetes mellitus. Sci Rep. 2023;13(1):18987.
39. Kongruttanachok N, Phuangphairoj C, Thongnak A, Ponyeam W, Rattanatanyong P, Pornthanakasem W, Mutirangura A. Replication independent DNA double-strand break retention may prevent genomic instability. Mol Cancer. 2010;9:70.
40. Arand J, Chiang HR, Martin D, Snyder MP, Sage J, Reijo Pera RA, Wossidlo M. Tet enzymes are essential for early embryogenesis and completion of embryonic genome activation. EMBO Rep. 2022;23(2):e53968.
41. Guo JU, Su Y, Zhong C, Ming GL, Song H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell. 2011;145(3):423-34.
42. Schuermann D, Weber AR, Schar P. Active DNA demethylation by DNA repair: Facts and uncertainties. DNA Repair (Amst). 2016;44:92-102.
43. Grin I, Ishchenko AA. An interplay of the base excision repair and mismatch repair pathways in active DNA demethylation. Nucleic Acids Res. 2016;44(8):3713-27.
44. Gehring M, Reik W, Henikoff S. DNA demethylation by DNA repair. Trends Genet. 2009;25(2):82-90.
45. Wu X, Zhang Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat Rev Genet. 2017;18(9):517-34.
46. Melamed P, Yosefzon Y, David C, Tsukerman A, Pnueli L. Tet Enzymes, Variants, and Differential Effects on Function. Front Cell Dev Biol. 2018;6:22.
47. Kafer GR, Li X, Horii T, Suetake I, Tajima S, Hatada I, Carlton PM. 5-Hydroxymethylcytosine Marks Sites of DNA Damage and Promotes Genome Stability. Cell Rep. 2016;14(6):1283-92.
48. Mahmoud AM, Ali MM. Methyl Donor Micronutrients that Modify DNA Methylation and Cancer Outcome. Nutrients. 2019;11(3).
49. Zeisel S. Choline, Other Methyl-Donors and Epigenetics. Nutrients. 2017;9(5).
50. Miller JW, Nadeau MR, Smith J, Smith D, Selhub J. Folate-deficiency-induced homocysteinaemia in rats: disruption of S-adenosylmethionine's co-ordinate regulation of homocysteine metabolism. Biochem J. 1994;298 ( Pt 2):415-9.
51. Yang AS, Doshi KD, Choi SW, Mason JB, Mannari RK, Gharybian V, et al. DNA methylation changes after 5-aza-2'-deoxycytidine therapy in patients with leukemia. Cancer Res. 2006;66(10):5495-503.
52. Chalertpet K, Pin-On P, Aporntewan C, Patchsung M, Ingrungruanglert P, Israsena N, Mutirangura A. Argonaute 4 as an Effector Protein in RNA-Directed DNA Methylation in Human Cells. Front Genet. 2019;10:645.
53. Chen L, Dahlstrom JE, Lee SH, Rangasamy D. Naturally occurring endo-siRNA silences LINE-1 retrotransposons in human cells through DNA methylation. Epigenetics. 2012;7(7):758-71.
54. Castanotto D, Tommasi S, Li M, Li H, Yanow S, Pfeifer GP, Rossi JJ. Short hairpin RNA-directed cytosine (CpG) methylation of the RASSF1A gene promoter in HeLa cells. Mol Ther. 2005;12(1):179-83.
55. Watcharanurak P, Mutirangura A. Human RNA-directed DNA methylation methylates high-mobility group box 1 protein-produced DNA gaps. Epigenomics.0(0):null.
56. Caliri AW, Caceres A, Tommasi S, Besaratinia A. Hypomethylation of LINE-1 repeat elements and global loss of DNA hydroxymethylation in vapers and smokers. Epigenetics. 2020;15(8):816-29.
57. Fustinoni S, Rossella F, Polledri E, Bollati V, Campo L, Byun HM, et al. Global DNA methylation and low-level exposure to benzene. Med Lav. 2012;103(2):84-95.
58. Meevassana J, Serirodom S, Prabsattru P, Boonsongserm P, Kamolratanakul S, Siritientong T, et al. Alu repetitive sequence CpG methylation changes in burn scars. Burns. 2021.
59. Wongpaiboonwattana W, Tosukhowong P, Dissayabutra T, Mutirangura A, Boonla C. Oxidative stress induces hypomethylation of LINE-1 and hypermethylation of the RUNX3 promoter in a bladder cancer cell line. Asian Pac J Cancer Prev. 2013;14(6):3773-8.
60. da Silva J. DNA damage induced by occupational and environmental exposure to miscellaneous chemicals. Mutat Res Rev Mutat Res. 2016;770(Pt A):170-82.
61. Davalos AR, Kawahara M, Malhotra GK, Schaum N, Huang J, Ved U, et al. p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes. J Cell Biol. 2013;201(4):613-29.
62. Hu H, Chen C, Shi S, Li B, Duan S. The gene mutations and subtelomeric DNA methylation in immunodeficiency, centromeric instability and facial anomalies syndrome. Autoimmunity. 2019;52(5-6):192-8.
63. Ehrlich M, Jackson K, Weemaes C. Immunodeficiency, centromeric region instability, facial anomalies syndrome (ICF). Orphanet J Rare Dis. 2006;1:2.
64. Tuck-Muller CM, Narayan A, Tsien F, Smeets DF, Sawyer J, Fiala ES, et al. DNA hypomethylation and unusual chromosome instability in cell lines from ICF syndrome patients. Cytogenet Cell Genet. 2000;89(1-2):121-8.
65. Ehrlich M. DNA methylation in cancer: too much, but also too little. Oncogene. 2002;21(35):5400-13.
66. Kim M, Trinh BN, Long TI, Oghamian S, Laird PW. Dnmt1 deficiency leads to enhanced microsatellite instability in mouse embryonic stem cells. Nucleic Acids Res. 2004;32(19):5742-9.
67. Wang KY, James Shen CK. DNA methyltransferase Dnmt1 and mismatch repair. Oncogene. 2004;23(47):7898-902.
68. Loughery JE, Dunne PD, O'Neill KM, Meehan RR, McDaid JR, Walsh CP. DNMT1 deficiency triggers mismatch repair defects in human cells through depletion of repair protein levels in a process involving the DNA damage response. Hum Mol Genet. 2011;20(16):3241-55.
69. Schermelleh L, Haemmer A, Spada F, Rosing N, Meilinger D, Rothbauer U, et al. Dynamics of Dnmt1 interaction with the replication machinery and its role in postreplicative maintenance of DNA methylation. Nucleic Acids Res. 2007;35(13): 4301-12.
70. Kunkel TA, Erie DA. Eukaryotic Mismatch Repair in Relation to DNA Replication. Annu Rev Genet. 2015;49:291-313.
71. De Cecco M, Ito T, Petrashen AP, Elias AE, Skvir NJ, Criscione SW, et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature. 2019;566 (7742):73-8.
72. Janssen A, Colmenares SU, Karpen GH. Heterochromatin: Guardian of the Genome. Annu Rev Cell Dev Biol. 2018;34:265-88.
73. Goodarzi AA, Noon AT, Deckbar D, Ziv Y, Shiloh Y, Lobrich M, Jeggo PA. ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. Mol Cell. 2008;31(2):167-77.
74. Goodarzi AA, Jeggo PA. The heterochromatic barrier to DNA double strand break repair: how to get the entry visa. Int J Mol Sci. 2012;13(9):11844-60.
75. Wang HC, Chou WC, Shieh SY, Shen CY. Ataxia telangiectasia mutated and checkpoint kinase 2 regulate BRCA1 to promote the fidelity of DNA end-joining. Cancer Res. 2006;66(3):1391-400.
76. Suyarnsestakorn C, Thanasupawat T, Leelahavanichkul K, Gutkind JS, Mutirangura A. Ataxia telangiectasia mutated nuclear localization in head and neck cancer cells is PPP2R2B-dependent. Asian Biomedicine. 2010;4(3):373-83.
77. Phokaew C, Kowudtitham S, Subbalekha K, Shuangshoti S, Mutirangura A. LINE-1 methylation patterns of different loci in normal and cancerous cells. Nucleic Acids Res. 2008;36(17):5704-12.
78. Yasom S, Khumsri W, Boonsongserm P, Kitkumthorn N, Ruangvejvorachai P, Sooksamran A, et al. B1 siRNA Increases de novo DNA Methylation of B1 Elements and Promotes Wound Healing in Diabetic Rats. Front Cell Dev Biol. 2021;9:802024.
79. Meevassana J, Nacharoenkul P, Wititsuwannakul J, Kitkumthorn N, Hamill KJ, Angspatt A, Mutirangura A. B1 repetitive sequence methylation enhances wound healing of second-degree burns in rats. Biomed Rep. 2022;16(3):20.
80. Skoruppa E, Nomidis SK, Marko JF, Carlon E. Bend-Induced Twist Waves and the Structure of Nucleosomal DNA. Phys Rev Lett. 2018;121(8):088101.
81. Ramstein J, Lavery R. Energetic coupling between DNA bending and base pair opening. Proc Natl Acad Sci U S A. 1988;85(19):7231-5.
82. Teves SS, Henikoff S. DNA torsion as a feedback mediator of transcription and chromatin dynamics. Nucleus. 2014;5(3):211-8.
83. Roca J. Transcriptional inhibition by DNA torsional stress. Transcription. 2011;2(2):82-5.
84. Joshi RS, Pina B, Roca J. Positional dependence of transcriptional inhibition by DNA torsional stress in yeast chromosomes. EMBO J. 2010;29(4):740-8.
85. Vilenchik MM, Knudson AG. Endogenous DNA double-strand breaks: production, fidelity of repair, and induction of cancer. Proc Natl Acad Sci U S A. 2003;100(22):12871-6.
86. Pongpanich M, Patchsung M, Mutirangura A. Pathologic Replication-Independent Endogenous DNA Double-Strand Breaks Repair Defect in Chronological Aging Yeast. Front Genet. 2018;9:501.
87. Lange SS, Mitchell DL, Vasquez KM. High mobility group protein B1 enhances DNA repair and chromatin modification after DNA damage. Proc Natl Acad Sci U S A. 2008;105(30):10320-5.
88. Chen C, Zhou M, Ge Y, Wang X. SIRT1 and aging related signaling pathways. Mech Ageing Dev. 2020;187:111215.
89. Alcendor RR, Gao S, Zhai P, Zablocki D, Holle E, Yu X, et al. Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ Res. 2007;100(10):1512-21.
90. Moazed D. Small RNAs in transcriptional gene silencing and genome defence. Nature. 2009;457(7228):413-20.
91. Ei ZZ, Mutirangura A, Arunmanee W, Chanvorachote P. The Role of Box A of HMGB1 in Enhancing Stem Cell Properties of Human Mesenchymal Cells: A Novel Approach for the Pursuit of Anti-aging Therapy. In Vivo. 2023;37(5):2006-17.
92. Takahashi T, Shishido T, Kinoshita D, Watanabe K, Toshima T, Sugai T, et al. Cardiac Nuclear High-Mobility Group Box 1 Ameliorates Pathological Cardiac Hypertrophy by Inhibiting DNA Damage Response. JACC Basic Transl Sci. 2019;4(2):234-47.
93. Funayama A, Shishido T, Netsu S, Narumi T, Kadowaki S, Takahashi H, et al. Cardiac nuclear high mobility group box 1 prevents the development of cardiac hypertrophy and heart failure. Cardiovasc Res. 2013;99(4):657-64.
94. Serrano M, Barzilai N. Targeting senescence. Nat Med. 2018;24(8):1092-4.
95. Di Micco R, Krizhanovsky V, Baker D, d'Adda di Fagagna F. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat Rev Mol Cell Biol. 2021;22(2):75-95.
96. Amaya-Montoya M, Perez-Londono A, Guatibonza-Garcia V, Vargas-Villanueva A, Mendivil CO. Cellular Senescence as a Therapeutic Target for Age-Related Diseases: A Review. Adv Ther. 2020;37(4):1407-24.
97. Ying W, Alano CC, Garnier P, Swanson RA. NAD+ as a metabolic link between DNA damage and cell death. J Neurosci Res. 2005;79(1-2):216-23.
98. Shimizu I, Yoshida Y, Suda M, Minamino T. DNA damage response and metabolic disease. Cell Metab. 2014;20(6):967-77.
99. Chen RJ, Wu PH, Ho CT, Way TD, Pan MH, Chen HM, et al. P53-dependent downregulation of hTERT protein expression and telomerase activity induces senescence in lung cancer cells as a result of pterostilbene treatment. Cell Death Dis. 2017;8(8):e2985.
100. Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, Moll UM. p53 has a direct apoptogenic role at the mitochondria. Mol Cell. 2003;11(3):577-90.
101. White E. Autophagy and p53. Cold Spring Harb Perspect Med. 2016;6(4): a026120.
102. Mirzayans R, Andrais B, Hansen G, Murray D. Role of p16(INK4A) in Replicative Senescence and DNA Damage-Induced Premature Senescence in p53-Deficient Human Cells. Biochem Res Int. 2012;2012:951574.
103. Belenky P, Bogan KL, Brenner C. NAD+ metabolism in health and disease. Trends Biochem Sci. 2007;32(1):12-9.
104. Mendelsohn AR, Larrick JW. Interacting NAD(+) and Cell Senescence Pathways Complicate Antiaging Therapies. Rejuvenation Res. 2019;22(3):261-6.
105. Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000;403(6771): 795-800.
106. Canto C, Auwerx J. Targeting sirtuin 1 to improve metabolism: all you need is NAD(+)? Pharmacol Rev. 2012;64(1):166-87.
107. Rayess H, Wang MB, Srivatsan ES. Cellular senescence and tumor suppressor gene p16. Int J Cancer. 2012;130(8):1715-25.
108. Papadopoli D, Boulay K, Kazak L, Pollak M, Mallette F, Topisirovic I, Hulea L. mTOR as a central regulator of lifespan and aging. F1000Res. 2019;8.
109. Buj R, Chen CW, Dahl ES, Leon KE, Kuskovsky R, Maglakelidze N, et al. Suppression of p16 Induces mTORC1-Mediated Nucleotide Metabolic Reprogramming. Cell Rep. 2019;28(8):1971-80 e8.
110. Grosse L, Wagner N, Emelyanov A, Molina C, Lacas-Gervais S, Wagner KD, Bulavin DV. Defined p16(High) Senescent Cell Types Are Indispensable for Mouse Healthspan. Cell Metab. 2020;32(1):87-99 e6.
111. Thongsroy J, Matangkasombut O, Thongnak A, Rattanatanyong P, Jirawatnotai S, Mutirangura A. Replication-independent endogenous DNA double-strand breaks in Saccharomyces cerevisiae model. PLoS One. 2013;8(8):e72706.
112. Yu Y, Tang D, Kang R. Oxidative stress-mediated HMGB1 biology. Front Physiol. 2015;6:93.
113. Vaziri C, Saxena S, Jeon Y, Lee C, Murata K, Machida Y, et al. A p53-dependent checkpoint pathway prevents rereplication. Mol Cell. 2003;11(4):997-1008.
114. Horvath S, Raj K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet. 2018;19(6):371-84.
115. Rakyan VK, Down TA, Maslau S, Andrew T, Yang TP, Beyan H, et al. Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res. 2010;20(4):434-9.
116. Horvath S, Zhang Y, Langfelder P, Kahn RS, Boks MP, van Eijk K, et al. Aging effects on DNA methylation modules in human brain and blood tissue. Genome Biol. 2012;13 (10):R97.
117. Debes C, Papadakis A, Gronke S, Karalay O, Tain LS, Mizi A, et al. Ageing-associated changes in transcriptional elongation influence longevity. Nature. 2023;616(7958): 814-21.
118. Tang D, Kang R, Livesey KM, Cheh CW, Farkas A, Loughran P, et al. Endogenous HMGB1 regulates autophagy. J Cell Biol. 2010;190(5):881-92.
119. Lu H, Zhang Z, Barnie PA, Su Z. Dual faced HMGB1 plays multiple roles in cardiomyocyte senescence and cardiac inflammatory injury. Cytokine Growth Factor Rev. 2019;47:74-82.
120. Andersson U, Yang H, Harris H. Extracellular HMGB1 as a therapeutic target in inflammatory diseases. Expert Opin Ther Targets. 2018;22(3):263-77.
121. Paudel YN, Angelopoulou E, Piperi C, Othman I, Aamir K, Shaikh MF. Impact of HMGB1, RAGE, and TLR4 in Alzheimer's Disease (AD): From Risk Factors to Therapeutic Targeting. Cells. 2020;9(2).
2. Jaul E, Barron J. Age-Related Diseases and Clinical and Public Health Implications for the 85 Years Old and Over Population. Front Public Health. 2017;5:335.
3. Tseng WI, Hsu YC, Kao TW. Brain Age Difference at Baseline Predicts Clinical Dementia Rating Change in Approximately Two Years. J Alzheimers Dis. 2022;86(2):613-27.
4. Chae CU, Pfeffer MA, Glynn RJ, Mitchell GF, Taylor JO, Hennekens CH. Increased pulse pressure and risk of heart failure in the elderly. JAMA. 1999;281(7):634-9.
5. Li X, Xu S, Yu M, Wang K, Tao Y, Zhou Y, et al. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. J Allergy Clin Immunol. 2020;146(1):110-8.
6. Crews DE. Senescence, aging, and disease. J Physiol Anthropol. 2007;26(3):365-72.
7. Childs BG, Durik M, Baker DJ, van Deursen JM. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med. 2015;21(12):1424-35.
8. Mutirangura A. Is global hypomethylation a nidus for molecular pathogenesis of age-related noncommunicable diseases? Epigenomics. 2019;11(6):577-9.
9. Yasom S, Watcharanurak P, Bhummaphan N, Thongsroy J, Puttipanyalears C, Settayanon S, et al. The roles of HMGB1-produced DNA gaps in DNA protection and aging biomarker reversal. FASEB BioAdvances. 2022;4(6):408-34.
10. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194-217.
11. Gonzalo S. Epigenetic alterations in aging. J Appl Physiol (1985). 2010;109(2):586-97.
12. Niedernhofer LJ, Gurkar AU, Wang Y, Vijg J, Hoeijmakers JHJ, Robbins PD. Nuclear Genomic Instability and Aging. Annu Rev Biochem. 2018;87:295-322.
13. Ou HL, Schumacher B. DNA damage responses and p53 in the aging process. Blood. 2018;131(5):488-95.
14. Fumagalli M, Rossiello F, Mondello C, d'Adda di Fagagna F. Stable cellular senescence is associated with persistent DDR activation. PLoS One. 2014;9(10):e110969.
15. Galbiati A, Beausejour C, d'Adda di Fagagna F. A novel single-cell method provides direct evidence of persistent DNA damage in senescent cells and aged mammalian tissues. Aging Cell. 2017;16(2): 422-7.
16. Thongsroy J, Patchsung M, Pongpanich M, Settayanon S, Mutirangura A. Reduction in replication-independent endogenous DNA double-strand breaks promotes genomic instability during chronological aging in yeast. The FASEB Journal. 2018;32(11):6252-60.
17. Patchsung M, Settayanon S, Pongpanich M, Mutirangura D, Jintarith P, Mutirangura A. Alu siRNA to increase Alu element methylation and prevent DNA damage. Epigenomics. 2018;10(2):175-85.
18. Wilson VL, Smith RA, Ma S, Cutler RG. Genomic 5-methyldeoxycytidine decreases with age. J Biol Chem. 1987;262(21):9948-51.
19. Jones PA, Takai D. The role of DNA methylation in mammalian epigenetics. Science. 2001;293(5532):1068-70.
20. Zheng Y, Joyce BT, Liu L, Zhang Z, Kibbe WA, Zhang W, Hou L. Prediction of genome-wide DNA methylation in repetitive elements. Nucleic Acids Res. 2017;45(15):8697-711.
21. Aporntewan C, Phokaew C, Piriyapongsa J, Ngamphiw C, Ittiwut C, Tongsima S, Mutirangura A. Hypomethylation of intragenic LINE-1 represses transcription in cancer cells through AGO2. PLoS One. 2011;6(3):e17934.
22. Tirado-Magallanes R, Rebbani K, Lim R, Pradhan S, Benoukraf T. Whole genome DNA methylation: beyond genes silencing. Oncotarget. 2017;8(3):5629-37.
23. Sheaffer KL, Elliott EN, Kaestner KH. DNA Hypomethylation Contributes to Genomic Instability and Intestinal Cancer Initiation. Cancer Prev Res (Phila). 2016;9(7):534-46.
24. Kitkumthorn N, Mutirangura A. Long interspersed nuclear element-1 hypomethylation in cancer: biology and clinical applications. Clin Epigenetics. 2011;2(2):315-30.
25. Eden A, Gaudet F, Waghmare A, Jaenisch R. Chromosomal instability and tumors promoted by DNA hypomethylation. Science. 2003;300(5618):455.
26. Chen RZ, Pettersson U, Beard C, Jackson-Grusby L, Jaenisch R. DNA hypomethylation leads to elevated mutation rates. Nature. 1998;395(6697):89-93.
27. Tongyoo P, Avihingsanon Y, Prom-On S, Mutirangura A, Mhuantong W, Hirankarn N. EnHERV: Enrichment analysis of specific human endogenous retrovirus patterns and their neighboring genes. PLoS One. 2017;12 (5):e0177119.
28. Bollati V, Schwartz J, Wright R, Litonjua A, Tarantini L, Suh H, et al. Decline in genomic DNA methylation through aging in a cohort of elderly subjects. Mech Ageing Dev. 2009;130 (4):234-9.
29. Jintaridth P, Mutirangura A. Distinctive patterns of age-dependent hypomethylation in interspersed repetitive sequences. Physiol Genomics. 2010;41(2):194-200.
30. Cardelli M. The epigenetic alterations of endogenous retroelements in aging. Mech Ageing Dev. 2018;174:30-46.
31. Lu S, Niu Z, Chen Y, Tu Q, Zhang Y, Chen W, et al. Repetitive Element DNA Methylation is Associated with Menopausal Age. Aging Dis. 2018;9(3):435-43.
32. Thongsroy J, Patchsung M, Mutirangura A. The association between Alu hypomethylation and severity of type 2 diabetes mellitus. Clin Epigenetics. 2017;9:93.
33. Jintaridth P, Tungtrongchitr R, Preutthipan S, Mutirangura A. Hypomethylation of Alu elements in post-menopausal women with osteoporosis. PLoS One. 2013;8(8):e70386.
34. Thongsroy J, Mutirangura A. The association between Alu hypomethylation and the severity of hypertension. PLoS One. 2022;17(7):e0270004.
35. Rerkasem K, Rattanatanyong P, Rerkasem A, Wongthanee A, Rungruengthanakit K, Mangklabruks A, Mutirangura A. Higher Alu methylation levels in catch-up growth in twenty-year-old offsprings. PLoS One. 2015; 10(3):e0120032.
36. Pornthanakasem W, Kongruttanachok N, Phuangphairoj C, Suyarnsestakorn C, Sanghangthum T, Oonsiri S, et al. LINE-1 methylation status of endogenous DNA double-strand breaks. Nucleic Acids Res. 2008;36(11):3667-75.
37. Pongpanich M, Patchsung M, Thongsroy J, Mutirangura A. Characteristics of replication-independent endogenous double -strand breaks in Saccharomyces cerevisiae. BMC Genomics. 2014;15:750.
38. Thongsroy J, Mutirangura A. The inverse association between DNA gaps and HbA1c levels in type 2 diabetes mellitus. Sci Rep. 2023;13(1):18987.
39. Kongruttanachok N, Phuangphairoj C, Thongnak A, Ponyeam W, Rattanatanyong P, Pornthanakasem W, Mutirangura A. Replication independent DNA double-strand break retention may prevent genomic instability. Mol Cancer. 2010;9:70.
40. Arand J, Chiang HR, Martin D, Snyder MP, Sage J, Reijo Pera RA, Wossidlo M. Tet enzymes are essential for early embryogenesis and completion of embryonic genome activation. EMBO Rep. 2022;23(2):e53968.
41. Guo JU, Su Y, Zhong C, Ming GL, Song H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell. 2011;145(3):423-34.
42. Schuermann D, Weber AR, Schar P. Active DNA demethylation by DNA repair: Facts and uncertainties. DNA Repair (Amst). 2016;44:92-102.
43. Grin I, Ishchenko AA. An interplay of the base excision repair and mismatch repair pathways in active DNA demethylation. Nucleic Acids Res. 2016;44(8):3713-27.
44. Gehring M, Reik W, Henikoff S. DNA demethylation by DNA repair. Trends Genet. 2009;25(2):82-90.
45. Wu X, Zhang Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat Rev Genet. 2017;18(9):517-34.
46. Melamed P, Yosefzon Y, David C, Tsukerman A, Pnueli L. Tet Enzymes, Variants, and Differential Effects on Function. Front Cell Dev Biol. 2018;6:22.
47. Kafer GR, Li X, Horii T, Suetake I, Tajima S, Hatada I, Carlton PM. 5-Hydroxymethylcytosine Marks Sites of DNA Damage and Promotes Genome Stability. Cell Rep. 2016;14(6):1283-92.
48. Mahmoud AM, Ali MM. Methyl Donor Micronutrients that Modify DNA Methylation and Cancer Outcome. Nutrients. 2019;11(3).
49. Zeisel S. Choline, Other Methyl-Donors and Epigenetics. Nutrients. 2017;9(5).
50. Miller JW, Nadeau MR, Smith J, Smith D, Selhub J. Folate-deficiency-induced homocysteinaemia in rats: disruption of S-adenosylmethionine's co-ordinate regulation of homocysteine metabolism. Biochem J. 1994;298 ( Pt 2):415-9.
51. Yang AS, Doshi KD, Choi SW, Mason JB, Mannari RK, Gharybian V, et al. DNA methylation changes after 5-aza-2'-deoxycytidine therapy in patients with leukemia. Cancer Res. 2006;66(10):5495-503.
52. Chalertpet K, Pin-On P, Aporntewan C, Patchsung M, Ingrungruanglert P, Israsena N, Mutirangura A. Argonaute 4 as an Effector Protein in RNA-Directed DNA Methylation in Human Cells. Front Genet. 2019;10:645.
53. Chen L, Dahlstrom JE, Lee SH, Rangasamy D. Naturally occurring endo-siRNA silences LINE-1 retrotransposons in human cells through DNA methylation. Epigenetics. 2012;7(7):758-71.
54. Castanotto D, Tommasi S, Li M, Li H, Yanow S, Pfeifer GP, Rossi JJ. Short hairpin RNA-directed cytosine (CpG) methylation of the RASSF1A gene promoter in HeLa cells. Mol Ther. 2005;12(1):179-83.
55. Watcharanurak P, Mutirangura A. Human RNA-directed DNA methylation methylates high-mobility group box 1 protein-produced DNA gaps. Epigenomics.0(0):null.
56. Caliri AW, Caceres A, Tommasi S, Besaratinia A. Hypomethylation of LINE-1 repeat elements and global loss of DNA hydroxymethylation in vapers and smokers. Epigenetics. 2020;15(8):816-29.
57. Fustinoni S, Rossella F, Polledri E, Bollati V, Campo L, Byun HM, et al. Global DNA methylation and low-level exposure to benzene. Med Lav. 2012;103(2):84-95.
58. Meevassana J, Serirodom S, Prabsattru P, Boonsongserm P, Kamolratanakul S, Siritientong T, et al. Alu repetitive sequence CpG methylation changes in burn scars. Burns. 2021.
59. Wongpaiboonwattana W, Tosukhowong P, Dissayabutra T, Mutirangura A, Boonla C. Oxidative stress induces hypomethylation of LINE-1 and hypermethylation of the RUNX3 promoter in a bladder cancer cell line. Asian Pac J Cancer Prev. 2013;14(6):3773-8.
60. da Silva J. DNA damage induced by occupational and environmental exposure to miscellaneous chemicals. Mutat Res Rev Mutat Res. 2016;770(Pt A):170-82.
61. Davalos AR, Kawahara M, Malhotra GK, Schaum N, Huang J, Ved U, et al. p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes. J Cell Biol. 2013;201(4):613-29.
62. Hu H, Chen C, Shi S, Li B, Duan S. The gene mutations and subtelomeric DNA methylation in immunodeficiency, centromeric instability and facial anomalies syndrome. Autoimmunity. 2019;52(5-6):192-8.
63. Ehrlich M, Jackson K, Weemaes C. Immunodeficiency, centromeric region instability, facial anomalies syndrome (ICF). Orphanet J Rare Dis. 2006;1:2.
64. Tuck-Muller CM, Narayan A, Tsien F, Smeets DF, Sawyer J, Fiala ES, et al. DNA hypomethylation and unusual chromosome instability in cell lines from ICF syndrome patients. Cytogenet Cell Genet. 2000;89(1-2):121-8.
65. Ehrlich M. DNA methylation in cancer: too much, but also too little. Oncogene. 2002;21(35):5400-13.
66. Kim M, Trinh BN, Long TI, Oghamian S, Laird PW. Dnmt1 deficiency leads to enhanced microsatellite instability in mouse embryonic stem cells. Nucleic Acids Res. 2004;32(19):5742-9.
67. Wang KY, James Shen CK. DNA methyltransferase Dnmt1 and mismatch repair. Oncogene. 2004;23(47):7898-902.
68. Loughery JE, Dunne PD, O'Neill KM, Meehan RR, McDaid JR, Walsh CP. DNMT1 deficiency triggers mismatch repair defects in human cells through depletion of repair protein levels in a process involving the DNA damage response. Hum Mol Genet. 2011;20(16):3241-55.
69. Schermelleh L, Haemmer A, Spada F, Rosing N, Meilinger D, Rothbauer U, et al. Dynamics of Dnmt1 interaction with the replication machinery and its role in postreplicative maintenance of DNA methylation. Nucleic Acids Res. 2007;35(13): 4301-12.
70. Kunkel TA, Erie DA. Eukaryotic Mismatch Repair in Relation to DNA Replication. Annu Rev Genet. 2015;49:291-313.
71. De Cecco M, Ito T, Petrashen AP, Elias AE, Skvir NJ, Criscione SW, et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature. 2019;566 (7742):73-8.
72. Janssen A, Colmenares SU, Karpen GH. Heterochromatin: Guardian of the Genome. Annu Rev Cell Dev Biol. 2018;34:265-88.
73. Goodarzi AA, Noon AT, Deckbar D, Ziv Y, Shiloh Y, Lobrich M, Jeggo PA. ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. Mol Cell. 2008;31(2):167-77.
74. Goodarzi AA, Jeggo PA. The heterochromatic barrier to DNA double strand break repair: how to get the entry visa. Int J Mol Sci. 2012;13(9):11844-60.
75. Wang HC, Chou WC, Shieh SY, Shen CY. Ataxia telangiectasia mutated and checkpoint kinase 2 regulate BRCA1 to promote the fidelity of DNA end-joining. Cancer Res. 2006;66(3):1391-400.
76. Suyarnsestakorn C, Thanasupawat T, Leelahavanichkul K, Gutkind JS, Mutirangura A. Ataxia telangiectasia mutated nuclear localization in head and neck cancer cells is PPP2R2B-dependent. Asian Biomedicine. 2010;4(3):373-83.
77. Phokaew C, Kowudtitham S, Subbalekha K, Shuangshoti S, Mutirangura A. LINE-1 methylation patterns of different loci in normal and cancerous cells. Nucleic Acids Res. 2008;36(17):5704-12.
78. Yasom S, Khumsri W, Boonsongserm P, Kitkumthorn N, Ruangvejvorachai P, Sooksamran A, et al. B1 siRNA Increases de novo DNA Methylation of B1 Elements and Promotes Wound Healing in Diabetic Rats. Front Cell Dev Biol. 2021;9:802024.
79. Meevassana J, Nacharoenkul P, Wititsuwannakul J, Kitkumthorn N, Hamill KJ, Angspatt A, Mutirangura A. B1 repetitive sequence methylation enhances wound healing of second-degree burns in rats. Biomed Rep. 2022;16(3):20.
80. Skoruppa E, Nomidis SK, Marko JF, Carlon E. Bend-Induced Twist Waves and the Structure of Nucleosomal DNA. Phys Rev Lett. 2018;121(8):088101.
81. Ramstein J, Lavery R. Energetic coupling between DNA bending and base pair opening. Proc Natl Acad Sci U S A. 1988;85(19):7231-5.
82. Teves SS, Henikoff S. DNA torsion as a feedback mediator of transcription and chromatin dynamics. Nucleus. 2014;5(3):211-8.
83. Roca J. Transcriptional inhibition by DNA torsional stress. Transcription. 2011;2(2):82-5.
84. Joshi RS, Pina B, Roca J. Positional dependence of transcriptional inhibition by DNA torsional stress in yeast chromosomes. EMBO J. 2010;29(4):740-8.
85. Vilenchik MM, Knudson AG. Endogenous DNA double-strand breaks: production, fidelity of repair, and induction of cancer. Proc Natl Acad Sci U S A. 2003;100(22):12871-6.
86. Pongpanich M, Patchsung M, Mutirangura A. Pathologic Replication-Independent Endogenous DNA Double-Strand Breaks Repair Defect in Chronological Aging Yeast. Front Genet. 2018;9:501.
87. Lange SS, Mitchell DL, Vasquez KM. High mobility group protein B1 enhances DNA repair and chromatin modification after DNA damage. Proc Natl Acad Sci U S A. 2008;105(30):10320-5.
88. Chen C, Zhou M, Ge Y, Wang X. SIRT1 and aging related signaling pathways. Mech Ageing Dev. 2020;187:111215.
89. Alcendor RR, Gao S, Zhai P, Zablocki D, Holle E, Yu X, et al. Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ Res. 2007;100(10):1512-21.
90. Moazed D. Small RNAs in transcriptional gene silencing and genome defence. Nature. 2009;457(7228):413-20.
91. Ei ZZ, Mutirangura A, Arunmanee W, Chanvorachote P. The Role of Box A of HMGB1 in Enhancing Stem Cell Properties of Human Mesenchymal Cells: A Novel Approach for the Pursuit of Anti-aging Therapy. In Vivo. 2023;37(5):2006-17.
92. Takahashi T, Shishido T, Kinoshita D, Watanabe K, Toshima T, Sugai T, et al. Cardiac Nuclear High-Mobility Group Box 1 Ameliorates Pathological Cardiac Hypertrophy by Inhibiting DNA Damage Response. JACC Basic Transl Sci. 2019;4(2):234-47.
93. Funayama A, Shishido T, Netsu S, Narumi T, Kadowaki S, Takahashi H, et al. Cardiac nuclear high mobility group box 1 prevents the development of cardiac hypertrophy and heart failure. Cardiovasc Res. 2013;99(4):657-64.
94. Serrano M, Barzilai N. Targeting senescence. Nat Med. 2018;24(8):1092-4.
95. Di Micco R, Krizhanovsky V, Baker D, d'Adda di Fagagna F. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat Rev Mol Cell Biol. 2021;22(2):75-95.
96. Amaya-Montoya M, Perez-Londono A, Guatibonza-Garcia V, Vargas-Villanueva A, Mendivil CO. Cellular Senescence as a Therapeutic Target for Age-Related Diseases: A Review. Adv Ther. 2020;37(4):1407-24.
97. Ying W, Alano CC, Garnier P, Swanson RA. NAD+ as a metabolic link between DNA damage and cell death. J Neurosci Res. 2005;79(1-2):216-23.
98. Shimizu I, Yoshida Y, Suda M, Minamino T. DNA damage response and metabolic disease. Cell Metab. 2014;20(6):967-77.
99. Chen RJ, Wu PH, Ho CT, Way TD, Pan MH, Chen HM, et al. P53-dependent downregulation of hTERT protein expression and telomerase activity induces senescence in lung cancer cells as a result of pterostilbene treatment. Cell Death Dis. 2017;8(8):e2985.
100. Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, Moll UM. p53 has a direct apoptogenic role at the mitochondria. Mol Cell. 2003;11(3):577-90.
101. White E. Autophagy and p53. Cold Spring Harb Perspect Med. 2016;6(4): a026120.
102. Mirzayans R, Andrais B, Hansen G, Murray D. Role of p16(INK4A) in Replicative Senescence and DNA Damage-Induced Premature Senescence in p53-Deficient Human Cells. Biochem Res Int. 2012;2012:951574.
103. Belenky P, Bogan KL, Brenner C. NAD+ metabolism in health and disease. Trends Biochem Sci. 2007;32(1):12-9.
104. Mendelsohn AR, Larrick JW. Interacting NAD(+) and Cell Senescence Pathways Complicate Antiaging Therapies. Rejuvenation Res. 2019;22(3):261-6.
105. Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000;403(6771): 795-800.
106. Canto C, Auwerx J. Targeting sirtuin 1 to improve metabolism: all you need is NAD(+)? Pharmacol Rev. 2012;64(1):166-87.
107. Rayess H, Wang MB, Srivatsan ES. Cellular senescence and tumor suppressor gene p16. Int J Cancer. 2012;130(8):1715-25.
108. Papadopoli D, Boulay K, Kazak L, Pollak M, Mallette F, Topisirovic I, Hulea L. mTOR as a central regulator of lifespan and aging. F1000Res. 2019;8.
109. Buj R, Chen CW, Dahl ES, Leon KE, Kuskovsky R, Maglakelidze N, et al. Suppression of p16 Induces mTORC1-Mediated Nucleotide Metabolic Reprogramming. Cell Rep. 2019;28(8):1971-80 e8.
110. Grosse L, Wagner N, Emelyanov A, Molina C, Lacas-Gervais S, Wagner KD, Bulavin DV. Defined p16(High) Senescent Cell Types Are Indispensable for Mouse Healthspan. Cell Metab. 2020;32(1):87-99 e6.
111. Thongsroy J, Matangkasombut O, Thongnak A, Rattanatanyong P, Jirawatnotai S, Mutirangura A. Replication-independent endogenous DNA double-strand breaks in Saccharomyces cerevisiae model. PLoS One. 2013;8(8):e72706.
112. Yu Y, Tang D, Kang R. Oxidative stress-mediated HMGB1 biology. Front Physiol. 2015;6:93.
113. Vaziri C, Saxena S, Jeon Y, Lee C, Murata K, Machida Y, et al. A p53-dependent checkpoint pathway prevents rereplication. Mol Cell. 2003;11(4):997-1008.
114. Horvath S, Raj K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet. 2018;19(6):371-84.
115. Rakyan VK, Down TA, Maslau S, Andrew T, Yang TP, Beyan H, et al. Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res. 2010;20(4):434-9.
116. Horvath S, Zhang Y, Langfelder P, Kahn RS, Boks MP, van Eijk K, et al. Aging effects on DNA methylation modules in human brain and blood tissue. Genome Biol. 2012;13 (10):R97.
117. Debes C, Papadakis A, Gronke S, Karalay O, Tain LS, Mizi A, et al. Ageing-associated changes in transcriptional elongation influence longevity. Nature. 2023;616(7958): 814-21.
118. Tang D, Kang R, Livesey KM, Cheh CW, Farkas A, Loughran P, et al. Endogenous HMGB1 regulates autophagy. J Cell Biol. 2010;190(5):881-92.
119. Lu H, Zhang Z, Barnie PA, Su Z. Dual faced HMGB1 plays multiple roles in cardiomyocyte senescence and cardiac inflammatory injury. Cytokine Growth Factor Rev. 2019;47:74-82.
120. Andersson U, Yang H, Harris H. Extracellular HMGB1 as a therapeutic target in inflammatory diseases. Expert Opin Ther Targets. 2018;22(3):263-77.
121. Paudel YN, Angelopoulou E, Piperi C, Othman I, Aamir K, Shaikh MF. Impact of HMGB1, RAGE, and TLR4 in Alzheimer's Disease (AD): From Risk Factors to Therapeutic Targeting. Cells. 2020;9(2).