Epigenetic Clocks: Biological Aging, Disease, and Clinical Applications
References
- Yamada H. Epigenetic Clocks and EpiScore for Preventive Medicine: Risk Stratification and Intervention Models for Age-Related Diseases. J Clin Med 2025;14. https://doi.org/10.3390/jcm14103604.
- Horvath S, Raj K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet 2018;19:371–84. https://doi.org/10.1038/s41576-018-0004-3.
- Jiang S, Guo Y. Epigenetic Clock: DNA Methylation in Aging. Stem Cells Int 2020;2020. https://doi.org/10.1155/2020/1047896.
- Simpson DJ, Chandra T. Epigenetic age prediction. Aging Cell 2021;20. https://doi.org/10.1111/acel.13452.
- Tomo Y, Nakaki R. Transfer Elastic Net for Developing Epigenetic Clocks for the Japanese Population. Mathematics 2024;12. https://doi.org/10.3390/math12172716.
- Mendelson MM. Epigenetic Age Acceleration: A Biological Doomsday Clock for Cardiovascular Disease? Circ Genomic Precis Med 2018;11:e002089. https://doi.org/10.1161/CIRCGEN.118.002089.
- Dutta S, Goodrich JM, Dolinoy DC, Ruden DM. Biological Aging Acceleration Due to Environmental Exposures: An Exciting New Direction in Toxicogenomics Research. Genes (Basel) 2024;15. https://doi.org/10.3390/genes15010016.
- Johnson AA, Shokhirev MN. First-generation versus next-generation epigenetic aging clocks: Differences in performance and utility. Biogerontology 2025;26. https://doi.org/10.1007/s10522-025-10265-4.
- Horvath S. DNA methylation age of human tissues and cell types. Genome Biol 2013;14:3156-. https://doi.org/10.1186/gb-2013-14-10-r115.
- Field AE, Robertson NA, Wang T, Havas A, Ideker T, Adams PD. DNA Methylation Clocks in Aging: Categories, Causes, and Consequences. Mol Cell 2018;71:882–95. https://doi.org/10.1016/j.molcel.2018.08.008.
- Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, et al. Genome-wide Methylation Profiles Reveal Quantitative Views of Human Aging Rates. Mol Cell 2013;49:359–67. https://doi.org/10.1016/j.molcel.2012.10.016.
- Crimmins EM, Klopack ET, Kim JK. Generations of epigenetic clocks and their links to socioeconomic status in the Health and Retirement Study. Epigenomics 2024;16:1031–42. https://doi.org/10.1080/17501911.2024.2373682.
- Margiotti K, Monaco F, Fabiani M, Mesoraca A, Giorlandino C. Epigenetic Clocks: In Aging-Related and Complex Diseases. Cytogenet Genome Res 2023;163:247–56. https://doi.org/10.1159/000534561.
- Garma LD, Quintela-Fandino M. Applicability of epigenetic age models to next-generation methylation arrays. Genome Med 2024;16:116-. https://doi.org/10.1186/s13073-024-01387-4.
- Levine ME, Lu AT, Quach A, Chen BH, Assimes TL, et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY) 2018;10:573–91. https://doi.org/10.18632/aging.101414.
- Higgins-Chen AT, Thrush KL, Wang Y, Minteer CJ, Kuo PL, et al. A computational solution for bolstering reliability of epigenetic clocks: implications for clinical trials and longitudinal tracking. Nat Aging 2022;2:644–61. https://doi.org/10.1038/s43587-022-00248-2.
- Lu AT, Binder AM, Zhang J, Yan Q, Reiner AP, et al. DNA methylation GrimAge version 2. Aging (Albany NY) 2022;14:9484–549. https://doi.org/10.18632/aging.204434.
- Whitman ET, Ryan CP, Abraham WC, Addae A, Corcoran DL, et al. A blood biomarker of the pace of aging is associated with brain structure: replication across three cohorts. Neurobiol Aging 2024;136:23–33. https://doi.org/10.1016/j.neurobiolaging.2024.01.008.
- Belsky DW, Caspi A, Corcoran DL, Sugden K, Poulton R, et al. DunedinPACE, A DNA methylation biomarker of the Pace of Aging. Elife 2022;11:e73420. https://doi.org/10.7554/eLife.73420.
- Jonkman TH, van Zwet EW, Heijmans BT. Probing epi-genetic clocks as a rational markers of biological age using blood cell counts. MedRxiv Prepr Serv Heal Sci 2025. https://doi.org/10.1101/2025.05.12.25327213.
- Poulton R, Moffitt TE, Silva PA. The Dunedin Multidisciplinary Health and Development Study: overview of the first 40 years, with an eye to the future. Social Psychiatry and Psychiatric Epidemiology. 2015;50:679–693. doi: 10.1007/s00127-015-1048-8.
- Martin CL. Wave V Epigenetic Clocks User Guide 2025.
- de Lima Camillo LP, Lapierre LR, Singh R. A pan-tissue DNA-methylation epigenetic clock based on deep learning. Npj Aging 2022;8:2021.06.01.446559. https://doi.org/10.1038/s41514-022-00085-y.
- Martínez-Enguita D, Hillerton T, Åkesson J, Kling D, Lerm M, Gustafsson M. Precise and interpretable neural networks reveal epigenetic signatures of aging across youth in health and disease. Front Aging 2024;5:1526146. https://doi.org/10.3389/fragi.2024.1526146.
- de Lima Camillo LP, Lapierre LR, Singh R. A pan-tissue DNA-methylation epigenetic clock based on deep learning. Npj Aging 2022;8:4-. https://doi.org/10.1038/s41514-022-00085-y.
- Kalyakulina A, Yusipov I, Kondakova E, Bacalini MG, Franceschi C, et al. Small immunological clocks identified by deep learning and gradient boosting. Front Immunol 2023;14:1177611. https://doi.org/10.3389/fimmu.2023.1177611.
- Trapp A, Kerepesi C, Gladyshev VN. Profiling epigenetic age in single cells. Nat Aging 2021;1:1189–201. https://doi.org/10.1038/s43587-021-00134-3.
- Guo H, Zhu P, Wu X, Li X, Wen L, Tang F. Single-Cell methylome landscapes of mouse embryonic stem cells and early embryos analyzed using reduced representation bisulfite sequencing. Genome Res 2013;23:2126–35. https://doi.org/10.1101/gr.161679.113.
- Karemaker ID, Vermeulen M. Single-Cell DNA Methylation Profiling: Technologies and Biological Applications. Trends Biotechnol 2018;36:952–65. https://doi.org/10.1016/j.tibtech.2018.04.002.
- Oursler KK, Marconi VC, Wang Z, Xu K, Montano M, et al. Epigenetic Age Acceleration Markers Are Associated With Physiologic Frailty and All-Cause Mortality in People With Human Immunodeficiency Virus. Clin Infect Dis 2023;76:E638–44. https://doi.org/10.1093/cid/ciac656.
- Tajuddin SM, Hernandez DG, Chen BH, Noren Hooten N, Mode NA, et al. Novel age-associated DNA methylation changes and epigenetic age acceleration in middle-aged African Americans and whites. Clin Epigenetics 2019;11:119-. https://doi.org/10.1186/s13148-019-0722-1.
- Smith JA, Raisky J, Ratliff SM, Liu J, Kardia SLR, et al. Intrinsic and extrinsic epigenetic age acceleration are associated with hypertensive target organ damage in older African Americans. BMC Med Genomics 2019;12:141. https://doi.org/10.1186/s12920-019-0585-5.
- Horvath S, Ritz BR. Increased epigenetic age and granulocyte counts in the blood of Parkinson’s disease patients. Aging (Albany NY) 2015;7:1130–42. https://doi.org/10.18632/aging.100859.
- Mareckova K, Mendes-Silva AP, Jáni M, Pacinkova A, Piler P, et al. Mitochondrial DNA variants and their impact on epigenetic and biological aging in young adulthood. Transl Psychiatry 2025;15. https://doi.org/10.1038/s41398-025-03235-4.
- Hong X, Cao H, Cao W, Lv J, Yu C, et al. Trends of genetic contributions on epigenetic clocks and related methylation sites with aging: A population-based adult twin study. Aging Cell 2025;24. https://doi.org/10.1111/acel.14403.
- McCartney DL, Min JL, Richmond RC, Lu AT, Sobczyk MK, et al. Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging. Genome Biol 2021;22. https://doi.org/10.1186/s13059-021-02398-9.
- Lu AT, Xue L, Salfati EL, Chen BH, Ferrucci L, et al. GWAS of epigenetic aging rates in blood reveals a critical role for TERT. Nat Commun 2018;9:387. https://doi.org/10.1038/s41467-017-02697-5.
- Koliada AK, Krasnenkov DS, Vaiserman AM. Telomeric aging: Mitotic clock or stress indicator? Front Genet 2015;5:82. https://doi.org/10.3389/fgene.2015.00082.
- Dong Q, Song N, Qin N, Chen C, Li Z, et al. Genome-wide association studies identify novel genetic loci for epigenetic age acceleration among survivors of childhood cancer. Genome Med 2022;14:32. https://doi.org/10.1186/s13073-022-01038-6.
- Mozhui K, Lu AT, Li CZ, Haghani A, Sandoval-Sierra JV, et al. Genetic loci and metabolic states associated with murine epigenetic aging. Elife 2022;11. https://doi.org/10.7554/eLife.75244.
- Yusipov I, Kalyakulina A, Trukhanov A, Franceschi C, Ivanchenko M. Map of epigenetic age acceleration: A worldwide analysis. Ageing Res Rev 2024;100:2024.03.17.585398. https://doi.org/10.1016/j.arr.2024.102418.
- Feldkamp JD, Vetter VM, Arends CM, Lang TJL, Bullinger L, et al. Clonal hematopoiesis of indeterminate potential-related epigenetic age acceleration correlates with clonal hematopoiesis of indeterminate potential clone size in patients with high morbidity. Haematologica 2022;107:1703–8. https://doi.org/10.3324/haematol.2021.280021.
- Nachun D, Lu AT, Bick AG, Natarajan P, Weinstock J, et al. Clonal hematopoiesis associated with epigenetic aging and clinical outcomes. Aging Cell 2021;20:e13366. https://doi.org/10.1111/acel.13366.
- Ahmad H, Jahn N, Jaiswal S. Clonal Hematopoiesis and Its Impact on Human Health. Annu Rev Med 2023;74:249–60. https://doi.org/10.1146/annurev-med-042921-112347.
- Yang T, Xiao Y, Cheng Y, Huang J, Wei Q, et al. Epigenetic clocks in neurodegenerative diseases: A systematic review. J Neurol Neurosurg Psychiatry 2023;94:1064–70. https://doi.org/10.1136/jnnp-2022-330931.
- Kenanoğlu S, Yüksel EB, Dündar M. Current Advances in Breast Cancer: Implications for Developing New Treatment Strategies Through Epi-Drugs on the Road to Modifying the Epigenome. J Clin Pract Res. 2023 Jul 31;45(5):427-434. doi: 10.14744/cpr.2023.08208.
- Cerantonio A, Greco BM, Citrigno L, De Benedittis S, Qualtieri A, et al. Epigenetic Clocks and Their Prospective Application in the Complex Landscape of Aging and Alzheimer’s Disease. Genes (Basel) 2025;16. https://doi.org/10.3390/genes16060679.
- Fan J, Liu Q, Liu X, Gong M, Leong II, et al. The effect of epigenetic aging on neurodegenerative diseases: a Mendelian randomization study. Front Endocrinol (Lausanne) 2024;15:1372518. https://doi.org/10.3389/fendo.2024.1372518.
- Peng L, Nie S, Sun Y, Wang S, Wang Y, Liu Z. Unraveling the causal association of epigenetic age acceleration with common oral diseases and its underlying mechanisms: findings from Mendelian randomization and integrative genetic analysis. Clin Epigenetics 2025;17:189. https://doi.org/10.1186/s13148-025-02005-9.
- An Y, Wang Q, Gao K, Zhang C, Ouyang Y, et al. Epigenetic Regulation of Aging and its Rejuvenation. MedComm 2025;6:e70369. https://doi.org/10.1002/mco2.70369.
- Fahy GM, Brooke RT, Watson JP, Good Z, Vasanawala SS, et al. Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell 2019;18:e13028. https://doi.org/10.1111/acel.13028.
- Gensous N, Garagnani P, Santoro A, Giuliani C, Ostan R, et al. One-year Mediterranean diet promotes epigenetic rejuvenation with country- and sex-specific effects: a pilot study from the NU-AGE project. GeroScience 2020;42:687–701. https://doi.org/10.1007/s11357-019-00149-0.
- Thymus Regeneration, Immunorestoration, and Insulin Mitigation Extension Trial - Full Text View - ClinicalTrials.gov n.d. https://clinicaltrials.gov/study/NCT04375657 (accessed June 18, 2026).
- Johnson AA, English BW, Shokhirev MN, Sinclair DA, Cuellar TL. Human age reversal: Fact or fiction? Aging Cell 2022;21:e13664. https://doi.org/10.1111/acel.13664.
- Johnson AA, Sinclair DA. Turning back time: a comprehensive list of interventions that decrease next-generation epigenetic aging clocks in humans. Front Genet 2026;17:1836446. https://doi.org/10.3389/FGENE.2026.1836446.
- Kenanoglu S, Gokce N, Akalin H, Ergoren MC, Beccari T, Bertelli M, Dundar M. Implication of the Mediterranean diet on the human epigenome. J Prev Med Hyg. 2022 Oct 17;63(2 Suppl 3):E44-E55. doi: 10.15167/2421-4248/jpmh2022.63.2S3.2746.
- Borsky P, Holmannova D, Parova H, Horvath S, Sramek P, Brooke RT, Milciute M, Gordevicius J, Fiala Z, Andrys C, Kremlacek J, Rehacek V, Baranova I, Matyasovska N, Borska L. Human clinical trial of plasmapheresis effects on biomarkers of aging (efficacy and safety trial). Sci Rep. 2025 Jul 1;15(1):21059. doi: 10.1038/s41598-025-05396-0.
DOI: https://doi.org/10.2478/ebtj-2026-0014 | Journal eISSN: 2564-615X
Language: English
Page range: 183 - 192
Published on: Jul 23, 2026
Published by: European Biotechnology Thematic Network Association
In partnership with: Paradigm Publishing Services
Publication frequency: 4 issues per year
Keywords:
Related subjects:
© 2026 A. Baki Yildirim, Duygu T. Yildirim, Hilal Akalin, Satya Prakash, Ratnesh Lal, Ariola Bacu, Radke Kaneva, Lembit Nei, M. Cerkez Ergoren, Nikolai Zhelev, Martin Koller, Maria Rachele Ceccarini, Munis Dundar, published by European Biotechnology Thematic Network Association
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.