EPIGENETIC and AGING

Abstract

Aging is a complex process characterized by the decline of cellular functions and the overall performance of the organism, arising from the interaction of genetic, environmental, and stochastic factors. Recent studies have demonstrated that epigenetic changes play a crucial role in the aging process. Epigenetic mechanisms, which regulate gene expression without altering the DNA sequence, shape chromatin structure and transcriptional activity, thereby playing a critical role in aging. Key epigenetic mechanisms such as DNA methylation, histone modifications, and chromatin remodeling contribute to age-associated changes in gene expression and the loss of genomic stability. Environmental stress, nutrition, caloric restriction, and lifestyle modifications can directly influence epigenetic aging. Studies conducted on model organisms have shown that caloric restriction extends lifespan by modulating epigenetic changes. Experiments in organisms such as Drosophila and C. elegans have demonstrated that genetic pathways and epigenetic modifications can extend longevity. While transposon activation leads to genomic instability in aging, certain genes have been shown to suppress this activity and provide protection against aging. Furthermore, studies on honeybee colonies and identical twins vividly illustrate the impact of epigenetic mechanisms on lifespan. In particular, the concept of the "epigenetic clock" has emerged as an important indicator in determining biological age and predicting lifespan and disease risk. The rate of epigenetic aging is associated with various diseases and phenotypes, with accelerated aging profiles observed in conditions such as smoking, obesity, HIV, and neurodegenerative disorders. Recent research has revealed that targeted interventions, including partial epigenetic reprogramming and pharmacological agents, may slow down or even reverse epigenetic aging. A better understanding of epigenetic mechanisms in aging may offer novel therapeutic strategies to promote healthy aging and extend lifespan.

Keywords

• epigenetics
• aging
• epigenetics clocks
• longevity

EPİGENETİK VE YAŞLANMA

Abstract

Yaşlanma; genetik, çevresel ve rastlantısal faktörlerin etkileşimiyle ortaya çıkan, hücresel işlevlerin bozulması ve organizmanın genel performansının azalmasıyla karakterize edilen karmaşık bir süreçtir. Son yıllarda yapılan çalışmalar, epigenetik değişimlerin yaşlanma sürecinde rol oynadığını göstermektedir. DNA dizisini değiştirmeden gen ekspresyonunu düzenleyen epigenetik mekanizmalar, kromatin yapısını ve transkripsiyonel aktiviteyi şekillendirerek yaşlanmada kritik bir rol oynamaktadır. DNA metilasyonu, histon modifikasyonları ve kromatin yeniden düzenlenmesi gibi temel epigenetik mekanizmalar, yaşa bağlı gen ekspresyon değişikliklerine ve genomik stabilite kaybına katkıda bulunmaktadır. Çevresel stres, beslenme, kalori kısıtlaması ve yaşam tarzı değişiklikleri, epigenetik yaşlanma üzerinde doğrudan etki gösterebilmektedir. Model organizmalarla yapılan çalışmalarda, kalori kısıtlamasının epigenetik değişiklikleri düzenleyerek ömrü uzattığı gösterilmiştir. Drosophila ve C. elegans gibi organizmalarda yapılan deneyler, genetik yollar ve epigenetik modifikasyonların yaşam süresini uzatabileceğini göstermektedir. Transpozonların aktivasyonu yaşlanmada genomik kararsızlığa neden olurken, bazı genlerin bu aktiviteyi baskılayarak yaşlanmaya karşı koruma sağladığı gösterilmiştir. Ayrıca, arı kolonileri ve özdeş ikiz çalışmaları epigenetik mekanizmaların uzun ömür üzerindeki etkisini canlı şekilde ortaya koymaktadır. Özellikle “epigenetik saat” kavramı, biyolojik yaşın belirlenmesinde önemli bir gösterge haline gelmiş ve yaşam süresi ile hastalık riskleri hakkında tahmin yürütmede kullanılmaktadır. Epigenetik yaşlanma hızı, çeşitli hastalıklar ve fenotiplerle bağlantılıdır ve sigara, obezite, HIV ve nörodejeneratif hastalıklar gibi durumlarda hızlanmış yaşlanma profilleri gözlenmiştir. Son çalışmalar, kısmi epigenetik yeniden programlama ve farmakolojik ajanlar gibi hedefe yönelik müdahalelerin epigenetik yaşlanmayı yavaşlatabileceğini veya tersine çevirebileceğini ortaya koymaktadır. Yaşlanmada epigenetik mekanizmaların daha iyi anlaşılması, sağlıklı yaşlanmayı teşvik etmek ve yaşam süresini uzatmak için yeni terapötik stratejiler sunabilir.

Keywords

• Epigenetik
• Yaşlanma
• Epigenetik saat
• uzun ömür

References

1. Basu, A., & Tiwari, V. K. (2021). Epigenetic reprogramming of cell identity: lessons from development for regenerative medicine. Clinical Epigenetics 2021 13(1), 1-11. https://doi.org/10.1186/S13148-021-01131-4
2. Bocklandt, S., Lin, W., Sehl, M. E., Sánchez, F. J., Sinsheimer, J. S., Horvath, S., & Vilain, E. (2011). Epigenetic Predictor of Age. PLOS ONE, 6(6), e14821. https://doi.org/10.1371/JOURNAL.PONE.0014821
3. Booth, L. N., & Brunet, A. (2016). The Aging Epigenome. Molecular Cell, 62(5), 728-744. https://doi.org/10.1016/J.MOLCEL.2016.05.013
4. Breitling, L. P., Saum, K. U., Perna, L., Schöttker, B., Holleczek, B., & Brenner, H. (2016). Frailty is associated with the epigenetic clock but not with telomere length in a German cohort. Clinical Epigenetics, 8(1), 1-8. https://doi.org/10.1186/S13148-016-0186-5/TABLES/4
5. Cardoso-Júnior, C. A. M., Guidugli-Lazzarini, K. R., & Hartfelder, K. (2018). DNA methylation affects the lifespan of honey bee (Apis mellifera L.) workers – Evidence for a regulatory module that involves vitellogenin expression but is independent of juvenile hormone function. Insect Biochemistry and Molecular Biology, 92, 21-29. https://doi.org/10.1016/J.IBMB.2017.11.005
6. Chen, L., Dong, Y., Bhagatwala, J., Raed, A., Huang, Y., & Zhu, H. (2019). Effects of Vitamin D3 Supplementation on Epigenetic Aging in Overweight and Obese African Americans With Suboptimal Vitamin D Status: A Randomized Clinical Trial. The Journals of Gerontology: Series A, 74(1), 91-98. https://doi.org/10.1093/GERONA/GLY223
7. Cheng, Y., He, C., Wang, M., Ma, X., Mo, F., Yang, S., Han, J., & Wei, X. (2019). Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Transduction and Targeted Therapy 2019, 4(1), 1-39. https://doi.org/10.1038/s41392-019-0095-0
8. Cheung, P., Vallania, F., Warsinske, H. C., Donato, M., Schaffert, S., Chang, S. E., Dvorak, M., Dekker, C. L., Davis, M. M., Utz, P. J., Khatri, P., & Kuo, A. J. (2018). Single-Cell Chromatin Modification Profiling Reveals Increased Epigenetic Variations with Aging. Cell, 173(6), 1385-1397.e14. https://doi.org/10.1016/J.CELL.2018.03.079

9. Clement, J., Yan, Q., Agrawal, M., Coronado, R. E., Sturges, J. A., Horvath, M., Lu, A. T., Brooke, R. T., & Horvath, S. (2022). Umbilical cord plasma concentrate has beneficial effects on DNA methylation GrimAge and human clinical biomarkers. Aging Cell, 21(10), e13696. https://doi.org/10.1111/ACEL.13696
10. Delcuve, G. P., Rastegar, M., & Davie, J. R. (2009). Epigenetic control. Journal of Cellular Physiology, 219(2), 243-250. https://doi.org/10.1002/JCP.21678
11. Duan, R., Fu, Q., Sun, Y., & Li, Q. (2022). Epigenetic clock: A promising biomarker and practical tool in aging. Ageing Research Reviews, 81, 101743. https://doi.org/10.1016/J.ARR.2022.101743
12. Foret, S., Kucharski, R., Pellegrini, M., Feng, S., Jacobsen, S. E., Robinson, G. E., & Maleszka, R. (2012). DNA methylation dynamics, metabolic fluxes, gene splicing, and alternative phenotypes in honey bees. Proceedings of the National Academy of Sciences of the United States of America, 109(13), 4968-4973. https://doi.org/10.1073/PNAS.1202392109
13. Fraga, M. F., Ballestar, E., Paz, M. F., Ropero, S., Setien, F., Ballestar, M. L., Heine-Suñer, D., Cigudosa, J. C., Urioste, M., Benitez, J., Boix-Chornet, M., Sanchez-Aguilera, A., Ling, C., Carlsson, E., Poulsen, P., Vaag, A., Stephan, Z., Spector, T. D., Wu, Y. Z., … Esteller, M. (2005). Epigenetic differences arise during the lifetime of monozygotic twins. Proceedings of the National Academy of Sciences of the United States of America, 102(30), 10604-10609. https://doi.org/10.1073/PNAS.0500398102
14. Franzago, M., Pilenzi, L., Di Rado, S., Vitacolonna, E., & Stuppia, L. (2022). The epigenetic aging, obesity, and lifestyle. Frontiers in Cell and Developmental Biology, 10, 985274. https://doi.org/10.3389/FCELL.2022.985274
15. Galkin, F., Kovalchuk, O., Koldasbayeva, D., Zhavoronkov, A., & Bischof, E. (2023). Stress, diet, exercise: Common environmental factors and their impact on epigenetic age. Ageing Research Reviews, 88, 101956. https://doi.org/10.1016/j.arr.2023.101956
16. Gao, Z., Yin, J., Zhang, J., Ward, R. E., Martin, R. J., Lefevre, M., Cefalu, W. T., & Ye, J. (2009). Butyrate Improves Insulin Sensitivity and Increases Energy Expenditure in Mice. Diabetes, 58(7), 1509-1517. https://doi.org/10.2337/DB08-1637
17. Gardner, A., Montgomery, P., Wang, M., Shen, B., Zhang, S., Pomilla, W., Gallager, I., Torres, J., Alcantara-Lee, R., Thadani, C., Britton, R., Czirr, E., Braithwaite, S. P., Kheifets, V., Seldeen, K., Thiyagarajan, R., Leiker, M., Berman, R., Redae, Y., … White, J. (2021). Chronic Exposure to Youthful Circulation Leads to Epigenetic Reprogramming and Lifespan Extension. Innovation in Aging, 5(Suppl 1), 677. https://doi.org/10.1093/GERONI/IGAB046.2551
18. Gems, D., Virk, R. S., & de Magalhães, J. P. (2024). Epigenetic clocks and programmatic aging. Ageing Research Reviews, 101, 102546. https://doi.org/10.1016/J.ARR.2024.102546
19. Gensous, N., Bacalini, M. G., Pirazzini, C., Marasco, E., Giuliani, C., Ravaioli, F., Mengozzi, G., Bertarelli, C., Palmas, M. G., Franceschi, C., & Garagnani, P. (2017). The epigenetic landscape of age-related diseases: the geroscience perspective. Biogerontology 2017 18:4, 18(4), 549-559. https://doi.org/10.1007/S10522-017-9695-7
20. Gibney, E. R., & Nolan, C. M. (2010). Epigenetics and gene expression. Heredity 2010 105:1, 105(1), 4-13. https://doi.org/10.1038/hdy.2010.54
21. Gonzalo, S. (2010). Epigenetic alterations in aging. Journal of Applied Physiology, 109(2), 586-597. https://doi.org/10.1152/JAPPLPHYSIOL.00238.2010/ASSET/IMAGES/LARGE/ZDG0081091370005.JPEG
22. Gravina, S., & Vijg, J. (2010). Epigenetic factors in aging and longevity. Pflugers Archiv European Journal of Physiology, 459(2), 247-258. https://doi.org/10.1007/S00424-009-0730-7/FIGURES/3
23. Han, S., Schroeder, E. A., Silva-García, C. G., Hebestreit, K., Mair, W. B., & Brunet, A. (2017). Mono-unsaturated fatty acids link H3K4me3 modifiers to C. elegans lifespan. Nature 2017 544:7649, 544(7649), 185-190. https://doi.org/10.1038/nature21686
24. Hannum, G., Guinney, J., Zhao, L., Zhang, L., Hughes, G., Sadda, S. V., Klotzle, B., Bibikova, M., Fan, J. B., Gao, Y., Deconde, R., Chen, M., Rajapakse, I., Friend, S., Ideker, T., & Zhang, K. (2013). Genome-wide Methylation Profiles Reveal Quantitative Views of Human Aging Rates. Molecular Cell, 49(2), 359-367. https://doi.org/10.1016/J.MOLCEL.2012.10.016/ATTACHMENT/4D7A0F39-B7D4-4C31-91AB-B3466364DCAC/MMC5.XLSX
25. Harrison, I. F., Crum, W. R., Vernon, A. C., & Dexter, D. T. (2015). Neurorestoration induced by the HDAC inhibitor sodium valproate in the lactacystin model of Parkinson’s is associated with histone acetylation and up-regulation of neurotrophic factors. British Journal of Pharmacology, 172(16), 4200-4215. https://doi.org/10.1111/BPH.13208/SUPPINFO
26. Hearn, J., Plenderleith, F., & Little, T. J. (2021). DNA methylation differs extensively between strains of the same geographical origin and changes with age in Daphnia magna. Epigenetics and Chromatin, 14(1), 1-14. https://doi.org/10.1186/S13072-020-00379-Z/FIGURES/3
27. Henagan, T. M., Stefanska, B., Fang, Z., Navard, A. M., Ye, J., Lenard, N. R., & Devarshi, P. P. (2015). Sodium butyrate epigenetically modulates high-fat diet-induced skeletal muscle mitochondrial adaptation, obesity and insulin resistance through nucleosome positioning. British Journal of Pharmacology, 172(11), 2782-2798. https://doi.org/10.1111/BPH.13058/SUPPINFO
28. Horvath, S. (2013). DNA methylation age of human tissues and cell types. Genome Biology, 14(10), 1-20. https://doi.org/10.1186/GB-2013-14-10-R115/FIGURES/8
29. Horvath, S., Erhart, W., Brosch, M., Ammerpohl, O., Von Schönfels, W., Ahrens, M., Heits, N., Bell, J. T., Tsai, P. C., Spector, T. D., Deloukas, P., Siebert, R., Sipos, B., Becker, T., Röcken, C., Schafmayer, C., & Hampe, J. (2014). Obesity accelerates epigenetic aging of human liver. Proceedings of the National Academy of Sciences of the United States of America, 111(43), 15538-15543. https://doi.org/10.1073/PNAS.1412759111/SUPPL_FILE/PNAS.1412759111.SD01.XLSX
30. Horvath, S., Garagnani, P., Bacalini, M. G., Pirazzini, C., Salvioli, S., Gentilini, D., Di Blasio, A. M., Giuliani, C., Tung, S., Vinters, H. V., & Franceschi, C. (2015). Accelerated epigenetic aging in Down syndrome. Aging Cell, 14(3), 491-495. https://doi.org/10.1111/ACEL.12325
31. Horvath, S., Gurven, M., Levine, M. E., Trumble, B. C., Kaplan, H., Allayee, H., Ritz, B. R., Chen, B., Lu, A. T., Rickabaugh, T. M., Jamieson, B. D., Sun, D., Li, S., Chen, W., Quintana-Murci, L., Fagny, M., Kobor, M. S., Tsao, P. S., Reiner, A. P., … Assimes, T. L. (2016). An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease. Genome Biology, 17(1), 1-23. https://doi.org/10.1186/S13059-016-1030-0/FIGURES/7
32. Horvath, S., Langfelder, P., Kwak, S., Aaronson, J., Rosinski, J., Vogt, T. F., Eszes, M., Faull, R. L. M., Curtis, M. A., Waldvogel, H. J., Choi, O. W., Tung, S., Vinters, H. V., Coppola, G., & Yang, X. W. (2016). Huntington’s disease accelerates epigenetic aging of human brain and disrupts DNA methylation levels. Aging (Albany NY), 8(7), 1485. https://doi.org/10.18632/AGING.101005
33. Horvath, S., & Levine, A. J. (2015). HIV-1 Infection Accelerates Age According to the Epigenetic Clock. The Journal of Infectious Diseases, 212(10), 1563-1573. https://doi.org/10.1093/INFDIS/JIV277
34. Huidobro, C., Fernandez, A. F., & Fraga, M. F. (2013). Aging epigenetics: Causes and consequences. Molecular Aspects of Medicine, 34(4), 765-781. https://doi.org/10.1016/J.MAM.2012.06.006
35. Inbar-Feigenberg, M., Choufani, S., Butcher, D. T., Roifman, M., & Weksberg, R. (2013). Basic concepts of epigenetics. Fertility and Sterility, 99(3), 607-615. https://doi.org/10.1016/J.FERTNSTERT.2013.01.117
36. Jiang, S., & Guo, Y. (2020). Epigenetic Clock: DNA Methylation in Aging. Stem Cells International, 2020(1), 1047896. https://doi.org/10.1155/2020/1047896
37. Jin, C., Li, J., Green, C. D., Yu, X., Tang, X., Han, D., Xian, B., Wang, D., Huang, X., Cao, X., Yan, Z., Hou, L., Liu, J., Shukeir, N., Khaitovich, P., Chen, C. D., Zhang, H., Jenuwein, T., & Han, J. D. J. (2011). Histone demethylase UTX-1 regulates C. elegans life span by targeting the insulin/IGF-1 signaling pathway. Cell Metabolism, 14(2), 161-172. https://doi.org/10.1016/J.CMET.2011.07.001/ATTACHMENT/13A2D2E4-F49A-4134-A6F3-6F28E380735E/MMC1.PDF
38. Kerepesi, C., Zhang, B., Lee, S. G., Trapp, A., & Gladyshev, V. N. (2021). Epigenetic clocks reveal a rejuvenation event during embryogenesis followed by aging. Science Advances, 7(26), 6082-6107. https://doi.org/10.1126/SCIADV.ABG6082/SUPPL_FILE/ABG6082_TABLE_S1.XLSX
39. Khan, A. H., Zou, Z., Xiang, Y., Chen, S., & Tian, X. L. (2019). Conserved signaling pathways genetically associated with longevity across the species. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1865(7), 1745-1755. https://doi.org/10.1016/J.BBADIS.2018.09.001
40. Knight, J. A. (2001). The biochemistry of aging (1-62). https://doi.org/10.1016/S0065-2423(01)35014-X
41. Kucharski, R., Maleszka, J., Foret, S., & Maleszka, R. (2008). Nutritional control of reproductive status in honeybees via DNA methylation. Science, 319(5871), 1827-1830. https://doi.org/10.1126/SCIENCE.1153069/SUPPL_FILE/KUCHARSKI.SOM.PDF
42. Kurian, L., Sancho-Martinez, I., Nivet, E., Aguirre, A., Moon, K., Pendaries, C., Volle-Challier, C., Bono, F., Herbert, J. M., Pulecio, J., Xia, Y., Li, M., Montserrat, N., Ruiz, S., Dubova, I., Rodriguez, C., Denli, A. M., Boscolo, F. S., Thiagarajan, R. D., … Izpisua Belmonte, J. C. (2013). Conversion of human fibroblasts to angioblast-like progenitor cells. Nature Methods 2012 10:1, 10(1), 77-83. https://doi.org/10.1038/nmeth.2255
43. Laplante, M., & Sabatini, D. M. (2012). MTOR signaling in growth control and disease. Cell, 149(2), 274-293. https://doi.org/10.1016/J.CELL.2012.03.017/ASSET/5F1E8878-88EC-48BB-8F0F-15E69FC66CA0/MAIN.ASSETS/GR4.JPG
44. Levine, M. E., Lu, A. T., Bennett, D. A., & Horvath, S. (2015). Epigenetic age of the pre-frontal cortex is associated with neuritic plaques, amyloid load, and Alzheimer’s disease related cognitive functioning. Aging (Albany NY), 7(12), 1198. https://doi.org/10.18632/AGING.100864
45. Lu, A. T., Hannon, E., Levine, M. E., Crimmins, E. M., Lunnon, K., Mill, J., Geschwind, D. H., & Horvath, S. (2017). Genetic architecture of epigenetic and neuronal ageing rates in human brain regions. Nature Communications 2017 8:1, 8(1), 1-14. https://doi.org/10.1038/ncomms15353
46. Lu, Y., Brommer, B., Tian, X., Krishnan, A., Meer, M., Wang, C., Vera, D. L., Zeng, Q., Yu, D., Bonkowski, M. S., Yang, J. H., Zhou, S., Hoffmann, E. M., Karg, M. M., Schultz, M. B., Kane, A. E., Davidsohn, N., Korobkina, E., Chwalek, K., … Sinclair, D. A. (2020). Reprogramming to recover youthful epigenetic information and restore vision. Nature 2020 588:7836, 588(7836), 124-129. https://doi.org/10.1038/s41586-020-2975-4
47. Maierhofer, A., Flunkert, J., Oshima, J., Martin, G. M., Haaf, T., & Horvath, S. (2017). Accelerated epigenetic aging in Werner syndrome. Aging (Albany NY), 9(4), 1143. https://doi.org/10.18632/AGING.101217
48. Marioni, R. E., Shah, S., McRae, A. F., Ritchie, S. J., Muniz-Terrera, G., Harris, S. E., Gibson, J., Redmond, P., Cox, S. R., Pattie, A., Corley, J., Taylor, A., Murphy, L., Starr, J. M., Horvath, S., Visscher, P. M., Wray, N. R., & Deary, I. J. (2015). The epigenetic clock is correlated with physical and cognitive fitness in the Lothian Birth Cohort 1936. International Journal of Epidemiology, 44(4), 1388-1396. https://doi.org/10.1093/IJE/DYU277
49. Martin-Herranz, D. E., Aref-Eshghi, E., Bonder, M. J., Stubbs, T. M., Choufani, S., Weksberg, R., Stegle, O., Sadikovic, B., Reik, W., & Thornton, J. M. (2019). Screening for genes that accelerate the epigenetic aging clock in humans reveals a role for the H3K36 methyltransferase NSD1. Genome Biology, 20(1), 1-19. https://doi.org/10.1186/S13059-019-1753-9/TABLES/1
50. Matsuyama, M., WuWong, D. J., Horvath, S., & Matsuyama, S. (2019). Epigenetic clock analysis of human fibroblasts in vitro: effects of hypoxia, donor age, and expression of hTERT and SV40 largeT. Aging (Albany NY), 11(10), 3012. https://doi.org/10.18632/AGING.101955
51. McCartney, D. L., Zhang, F., Hillary, R. F., Zhang, Q., Stevenson, A. J., Walker, R. M., Bermingham, M. L., Boutin, T., Morris, S. W., Campbell, A., Murray, A. D., Whalley, H. C., Porteous, D. J., Hayward, C., Evans, K. L., Chandra, T., Deary, I. J., McIntosh, A. M., Yang, J., … Marioni, R. E. (2019). An epigenome-wide association study of sex-specific chronological ageing. Genome Medicine, 12(1), 1-11. https://doi.org/10.1186/S13073-019-0693-Z/FIGURES/4
52. Meiliana, A., Dewi, N. M., & Wijaya, A. (2022). The Aging Epigenome and The Rejuvenation Strategies. The Indonesian Biomedical Journal, 14(1), 11-28. https://doi.org/10.18585/INABJ.V14I1.1777
53. Montesanto, A., Dato, S., Bellizzi, D., Rose, G., & Passarino, G. (2012). Epidemiological, genetic and epigenetic aspects of the research on healthy ageing and longevity. Immunity & Ageing 2012 9:1, 9(1), 1-12. https://doi.org/10.1186/1742-4933-9-6
54. Morandin, C., Brendel, V. P., Sundström, L., Helanterä, H., & Mikheyev, A. S. (2019). Changes in gene DNA methylation and expression networks accompany caste specialization and age-related physiological changes in a social insect. Molecular Ecology, 28(8), 1975-1993. https://doi.org/10.1111/MEC.15062;REQUESTEDJOURNAL:JOURNAL:1365294X;PAGE:STRING:ARTICLE/CHAPTER
55. Muñoz-Najar, U., & Sedivy, J. M. (2011). Epigenetic control of aging. Antioxidants and Redox Signaling, 14(2), 241-259. https://doi.org/10.1089/ARS.2010.3250
56. Murach, K. A., Dimet-Wiley, A. L., Wen, Y., Brightwell, C. R., Latham, C. M., Dungan, C. M., Fry, C. S., & Watowich, S. J. (2022). Late-life exercise mitigates skeletal muscle epigenetic aging. Aging Cell, 21(1), e13527. https://doi.org/10.1111/ACEL.13527
57. Murach, K. A., Mobley, C. B., Zdunek, C. J., Frick, K. K., Jones, S. R., McCarthy, J. J., Peterson, C. A., & Dungan, C. M. (2020). Muscle memory: myonuclear accretion, maintenance, morphology, and miRNA levels with training and detraining in adult mice. Journal of Cachexia, Sarcopenia and Muscle, 11(6), 1705-1722. https://doi.org/10.1002/JCSM.12617
58. Ocampo, A., Mrabti, C., Yang, N., Desdín-Micó, G., Alonso-Calleja, A., Vílchez-Acosta, A., Pico, S., Parras, A., Piao, Y., Schoenfeldt, L., Luo, S., Haghani, A., Brooke, R. T., Maza, M. del C., Branchina, C., Maroun, C. Y., von Meyenn, F., Naveiras, O., Horvath, S., … Bignon, Y. (2024). Loss of H3K9 trimethylation leads to premature aging. Research Square, rs.3.rs-4012025. https://doi.org/10.21203/RS.3.RS-4012025/V1
59. Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., Li, M., Lam, D., Kurita, M., Beyret, E., Araoka, T., Vazquez-Ferrer, E., Donoso, D., Roman, J. L., Xu, J., Rodriguez Esteban, C., Nuñez, G., Nuñez Delicado, E., Campistol, J. M., … Izpisua Belmonte, J. C. (2016). In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell, 167(7), 1719-1733.e12. https://doi.org/10.1016/J.CELL.2016.11.052/ATTACHMENT/F1E53D0C-7AAC-4A98-B8FB-88930A0705C8/MMC1.PDF
60. O’Sullivan, R. J., & Karlseder, J. (2012). The great unravelling: Chromatin as a modulator of the aging process. Trends in Biochemical Sciences, 37(11), 466-476. https://doi.org/10.1016/J.TIBS.2012.08.001/ASSET/E331D257-DA4F-48BF-8C31-11FDABFD62D7/MAIN.ASSETS/GR4.SML
61. Pagiatakis, C., Musolino, E., Gornati, R., Bernardini, G., & Papait, R. (2021). Epigenetics of aging and disease: a brief overview. Aging Clinical and Experimental Research, 33(4), 737-745. https://doi.org/10.1007/S40520-019-01430-0/FIGURES/3
62. Pal, S., & Tyler, J. K. (2016). Epigenetics and aging. Science Advances, 2(7). https://doi.org/10.1126/SCIADV.1600584/ASSET/16967970-B910-4964-A673-123454700F13/ASSETS/GRAPHIC/1600584-F4.JPEG
63. Pamplona, R., Jové, M., Gómez, J., & Barja, G. (2023). Whole organism aging: Parabiosis, inflammaging, epigenetics, and peripheral and central aging clocks. The ARS of aging. Experimental Gerontology, 174, 112137. https://doi.org/10.1016/J.EXGER.2023.112137
64. Pereira, B., Correia, F. P., Alves, I. A., Costa, M., Gameiro, M., Martins, A. P., & Saraiva, J. A. (2024). Epigenetic reprogramming as a key to reverse ageing and increase longevity. Ageing Research Reviews, 95, 102204. https://doi.org/10.1016/J.ARR.2024.102204
65. Poulsen, P., Esteller, M., Vaag, A., & Fraga, M. F. (2007). The Epigenetic Basis of Twin Discordance in Age-Related Diseases. Pediatric Research 2007 61:7, 61(7), 38-42. https://doi.org/10.1203/pdr.0b013e31803c7b98
66. Quach, A., Levine, M. E., Tanaka, T., Lu, A. T., Chen, B. H., Ferrucci, L., Ritz, B., Bandinelli, S., Neuhouser, M. L., Beasley, J. M., Snetselaar, L., Wallace, R. B., Tsao, P. S., Absher, D., Assimes, T. L., Stewart, J. D., Li, Y., Hou, L., Baccarelli, A. A., … Horvath, S. (2017). Epigenetic clock analysis of diet, exercise, education, and lifestyle factors. Aging (Albany NY), 9(2), 419. https://doi.org/10.18632/AGING.101168
67. Raj, K., & Horvath, S. (2020). Current perspectives on the cellular and molecular features of epigenetic ageing. Experimental Biology and Medicine, 245(17), 1532-1542. https://doi.org/10.1177/1535370220918329
68. Renard, T., Martinet, B., De Souza Araujo, N., & Aron, S. (2023). DNA methylation extends lifespan in the bumblebee Bombus terrestris. Proceedings of the Royal Society B, 290(2012). https://doi.org/10.1098/RSPB.2023.2093
69. Rothermund, K., Englert, C., & Gerstorf, D. (2023). Explaining Variation in Individual Aging, Its Sources, and Consequences: A Comprehensive Conceptual Model of Human Aging. Gerontology, 69(12), 1437-1447. https://doi.org/10.1159/000534324
70. Sailani, M. R., Halling, J. F., Møller, H. D., Lee, H., Plomgaard, P., Pilegaard, H., Snyder, M. P., & Regenberg, B. (2019). Lifelong physical activity is associated with promoter hypomethylation of genes involved in metabolism, myogenesis, contractile properties and oxidative stress resistance in aged human skeletal muscle. Scientific Reports 2019 9:1, 9(1), 1-11. https://doi.org/10.1038/s41598-018-37895-8
71. Sarkar, T. J., Quarta, M., Mukherjee, S., Colville, A., Paine, P., Doan, L., Tran, C. M., Chu, C. R., Horvath, S., Qi, L. S., Bhutani, N., Rando, T. A., & Sebastiano, V. (2020). Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells. Nature Communications 2020 11:1, 11(1), 1-12. https://doi.org/10.1038/s41467-020-15174-3
72. Saul, D., & Kosinsky, R. L. (2021). Epigenetics of Aging and Aging-Associated Diseases. International Journal of Molecular Sciences 2021, Vol. 22, Page 401, 22(1), 401. https://doi.org/10.3390/IJMS22010401
73. Schumacher, B., Pothof, J., Vijg, J., & Hoeijmakers, J. H. J. (2021). The central role of DNA damage in the ageing process. Nature 2021 592:7856, 592(7856), 695-703. https://doi.org/10.1038/s41586-021-03307-7
74. Shi, Y. Y., Huang, Z. Y., Zeng, Z. J., Wang, Z. L., Wu, X. B., & Yan, W. Y. (2011). Diet and Cell Size Both Affect Queen-Worker Differentiation through DNA Methylation in Honey Bees (Apis mellifera, Apidae). PLOS ONE, 6(4), e18808. https://doi.org/10.1371/JOURNAL.PONE.0018808
75. Simpkin, A. J., Hemani, G., Suderman, M., Gaunt, T. R., Lyttleton, O., Mcardle, W. L., Ring, S. M., Sharp, G. C., Tilling, K., Horvath, S., Kunze, S., Peters, A., Waldenberger, M., Ward-Caviness, C., Nohr, E. A., Sørensen, T. I. A., Relton, C. L., & Smith, G. D. (2016). Prenatal and early life influences on epigenetic age in children: a study of mother–offspring pairs from two cohort studies. Human Molecular Genetics, 25(1), 191-201. https://doi.org/10.1093/HMG/DDV456
76. Simpson, D. J., & Chandra, T. (2021). Epigenetic age prediction. Aging Cell, 20(9), e13452. https://doi.org/10.1111/ACEL.13452
77. Simpson, D. J., Olova, N. N., & Chandra, T. (2021). Cellular reprogramming and epigenetic rejuvenation. Clinical Epigenetics 2021 13:1, 13(1), 1-10. https://doi.org/10.1186/S13148-021-01158-7
78. Slagboom, P. E., Beekman, M., Passtoors, W. M., Deelen, J., Vaarhorst, A. A. M., Boer, J. M., Van Den Akker, E. B., Van Heemst, D., De Craen, A. J. M., Maier, A. B., Rozing, M., Mooijaart, S. P., Heijmans, B. T., & Westendorp, R. G. J. (2011). Genomics of human longevity. Philosophical Transactions of the Royal Society B: Biological Sciences, 366(1561), 35-42. https://doi.org/10.1098/RSTB.2010.0284
79. Sturm, Á., Saskői, É., Hotzi, B., Tarnóci, A., Barna, J., Bodnár, F., Sharma, H., Kovács, T., Ari, E., Weinhardt, N., Kerepesi, C., Perczel, A., Ivics, Z., & Vellai, T. (2023). Downregulation of transposable elements extends lifespan in Caenorhabditis elegans. Nature Communications, 14(1), 1-18. https://doi.org/10.1038/S41467-023-40957-9;
80. Taylor, J. R., Wood, J. G., Mizerak, E., Hinthorn, S., Liu, J., Finn, M., Gordon, S., Zingas, L., Chang, C., Klein, M. A., Denu, J. M., Gorbunova, V., Seluanov, A., Boeke, J. D., Sedivy, J. M., & Helfand, S. L. (2022). Sirt6 regulates lifespan in Drosophila melanogaster. Proceedings of the National Academy of Sciences of the United States of America, 119(5), e2111176119. https://doi.org/10.1073/PNAS.2111176119
81. Thier, M., Wörsdörfer, P., Lakes, Y. B., Gorris, R., Herms, S., Opitz, T., Seiferling, D., Quandel, T., Hoffmann, P., Nöthen, M. M., Brüstle, O., & Edenhofer, F. (2012). Direct conversion of fibroblasts into stably expandable neural stem cells. Cell Stem Cell, 10(4), 473-479. https://doi.org/10.1016/j.stem.2012.03.003
82. Turner, D. C., Gorski, P. P., Maasar, M. F., Seaborne, R. A., Baumert, P., Brown, A. D., Kitchen, M. O., Erskine, R. M., Dos-Remedios, I., Voisin, S., Eynon, N., Sultanov, R. I., Borisov, O. V., Larin, A. K., Semenova, E. A., Popov, D. V., Generozov, E. V., Stewart, C. E., Drust, B., … Sharples, A. P. (2020). DNA methylation across the genome in aged human skeletal muscle tissue and muscle-derived cells: the role of HOX genes and physical activity. Scientific Reports 2020 10:1, 10(1), 1-19. https://doi.org/10.1038/s41598-020-72730-z
83. Van Dongen, J., Nivard, M. G., Willemsen, G., Hottenga, J. J., Helmer, Q., Dolan, C. V., Ehli, E. A., Davies, G. E., Van Iterson, M., Breeze, C. E., Beck, S., Suchiman, H. E., Jansen, R., Van Meurs, J. B., Heijmans, B. T., Slagboom, P. E., & Boomsma, D. I. (2016). Genetic and environmental influences interact with age and sex in shaping the human methylome. Nature Communications 2016 7:1, 7(1), 1-13. https://doi.org/10.1038/ncomms11115
84. Vetter, V. M., Spira, D., Banszerus, V. L., & Demuth, I. (2020). Epigenetic Clock and Leukocyte Telomere Length Are Associated with Vitamin D Status but not with Functional Assessments and Frailty in the Berlin Aging Study II. The Journals of Gerontology: Series A, 75(11), 2056-2063. https://doi.org/10.1093/GERONA/GLAA101
85. Vijg, J. (2021). From DNA damage to mutations: All roads lead to aging. Ageing Research Reviews, 68, 101316. https://doi.org/10.1016/J.ARR.2021.101316
86. Wang, K., Liu, H., Hu, Q., Wang, L., Liu, J., Zheng, Z., Zhang, W., Ren, J., Zhu, F., & Liu, G. H. (2022). Epigenetic regulation of aging: implications for interventions of aging and diseases. Signal Transduction and Targeted Therapy 2022 7:1, 7(1), 1-22. https://doi.org/10.1038/s41392-022-01211-8
87. Wang, T., Tsui, B., Kreisberg, J. F., Robertson, N. A., Gross, A. M., Yu, M. K., Carter, H., Brown-Borg, H. M., Adams, P. D., & Ideker, T. (2017). Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment. Genome Biology, 18(1), 1-11. https://doi.org/10.1186/S13059-017-1186-2/FIGURES/3
88. Wen, Y., Dungan, C. M., Mobley, C. B., Valentino, T., Von Walden, F., & Murach, K. A. (2021). Nucleus Type-Specific DNA Methylomics Reveals Epigenetic “Memory” of Prior Adaptation in Skeletal Muscle. Function, 2(5). https://doi.org/10.1093/FUNCTION/ZQAB038
89. Wiley, J. C., Pettan-Brewer, C., & Ladiges, W. C. (2011). Phenylbutyric acid reduces amyloid plaques and rescues cognitive behavior in AD transgenic mice. Aging Cell, 10(3), 418-428. https://doi.org/10.1111/J.1474-9726.2011.00680.X;WGROUP:STRING:PUBLICATION
90. Wood, J. G., Jones, B. C., Jiang, N., Chang, C., Hosier, S., Wickremesinghe, P., Garcia, M., Hartnett, D. A., Burhenn, L., Neretti, N., & Helfand, S. L. (2016). Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila. Proceedings of the National Academy of Sciences of the United States of America, 113(40), 11277-11282. https://doi.org/10.1073/PNAS.1604621113/SUPPL_FILE/PNAS.1604621113.SD01.XLS
91. Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. Clinical Epigenetics, 11(1), 1-9. https://doi.org/10.1186/S13148-019-0777-Z/FIGURES/5
92. Takahashi, K., Okita, K., & Nakagawa, M. Yamanaka, S. (2007). Induction of pluripotent stem cells from fibroblast cultures. Nature Protocols 2007 2(12), 3081-3089. https://doi.org/10.1038/nprot.2007.418
93. Yoo, Y. E., & Ko, C. P. (2011). Treatment with trichostatin A initiated after disease onset delays disease progression and increases survival in a mouse model of amyotrophic lateral sclerosis. Experimental Neurology, 231(1), 147-159. https://doi.org/10.1016/J.EXPNEUROL.2011.06.003
94. Yousefzadeh, M., Henpita, C., Vyas, R., Soto-Palma, C., Robbins, P., & Niedernhofer, L. (2021). Dna damage—how and why we age? eLife, 10, 1-17. https://doi.org/10.7554/ELIFE.62852
95. Yu, G., Wu, Q., Gao, Y., Chen, M., & Yang, M. (2019). The Epigenetics of Aging in Invertebrates. International Journal of Molecular Sciences 2019, Vol. 20, Page 4535, 20(18), 4535. https://doi.org/10.3390/IJMS20184535
96. Zhang, B., Lee, D. E., Trapp, A., Tyshkovskiy, A., Lu, A. T., Bareja, A., Kerepesi, C., McKay, L. K., Shindyapina, A. V., Dmitriev, S. E., Baht, G. S., Horvath, S., Gladyshev, V. N., & White, J. P. (2023). Multi-omic rejuvenation and life span extension on exposure to youthful circulation. Nature Aging, 3(8), 948-964. https://doi.org/10.1038/S43587-023-00451-9;TECHMETA=13,23,38,91;SUBJMETA=176,1988,208,443,631,7;KWRD=AGEING,DNA+METHYLATION
97. Zhang, W., Qu, J., Liu, G. H., & Belmonte, J. C. I. (2020). The ageing epigenome and its rejuvenation. Nature Reviews Molecular Cell Biology 2020 21(3), 137-150. https://doi.org/10.1038/s41580-019-0204-5