Epigenetically Mediated Health Effects of Intermittent Fasting

Abstract

Globally, the prevalence of chronic diseases such as obesity, cardiovascular disorders, diabetes, and cancer is rising. These conditions are influenced by both genetic and environmental factors, with nutrition being one of the most critical environmental determinants. Intermittent fasting (IF) is a dietary pattern that has gained attention for its potential health benefits and impact on metabolic regulation. Recent studies in the field of nutrition-epigenetics suggest that IF may exert these effects through epigenetic modifications, including DNA methylation, histone modifications, and regulation by non-coding RNAs. IF encompasses various approaches such as alternate-day fasting, time-restricted feeding, and whole-day fasting. Evidence indicates that IF can enhance lipid and glucose metabolism, support healthy aging, reduce inflammation, and improve mitochondrial and immune function by modulating gene expression epigenetically. It may also promote autophagy, stem cell renewal, and anti-cancer responses, suggesting its potential role in preventing or mitigating metabolic and neurodegenerative diseases. Despite these benefits, adverse effects of IF have also been reported. Particularly concerning are findings related to maternal IF, which may impair fetal development and metabolic health in offspring via epigenetic inheritance. Additionally, in other life stages, IF may lead to micronutrient deficiencies, hypoglycemia, hormonal imbalances, fatigue, and increased metabolic disease risk, especially in vulnerable populations or when fasting is prolonged or poorly planned. This review aims to summarize the current evidence on how IF influences health and disease through epigenetic mechanisms. Personalized recommendations considering age, health status, and nutritional needs are essential. More comprehensive human studies are needed to clarify IF’s dual role and to optimize its application for health promotion.

Keywords

• Fasting
• circadian rhythm
• diet therapy
• epigenetic processes

Aralıklı Açlık Diyetlerinin Epigenetik Aracılı Sağlık Etkileri

Abstract

Dünya genelinde obezite, kardiyovasküler hastalıklar, diyabet ve kanser gibi kronik hastalıkların görülme sıklığı artmaktadır. Bu hastalıklar hem genetik hem de çevresel faktörlerden etkilenmektedir ve beslenme, en önemli çevresel belirleyicilerden biridir. Aralıklı açlık (AA), metabolik düzenleme üzerindeki potansiyel etkileri nedeniyle sağlık yararları açısından dikkat çeken bir beslenme modelidir. Beslenme-epigenetik alanındaki güncel çalışmalar, AA’nin bu etkilerini epigenetik değişiklikler yoluyla gösterebileceğini ortaya koymaktadır. Bu değişiklikler arasında DNA metilasyonu, histon modifikasyonları ve kodlamayan RNA’ların düzenlenmesi yer almaktadır. AA; gün aşırı oruç, zaman kısıtlı beslenme ve tam gün oruç gibi farklı uygulamaları içermektedir. Kanıtlar, AA’nin lipid ve glukoz metabolizmasını iyileştirebileceğini, sağlıklı yaşlanmayı destekleyebileceğini, inflamasyonu azaltabileceğini ve mitokondriyal ile bağışıklık fonksiyonlarını iyileştirebileceğini göstermektedir. Ayrıca, ototofajiyi, kök hücre yenilenmesini ve antikanser yanıtları teşvik ederek metabolik ve nörodejeneratif hastalıkların önlenmesinde potansiyel bir rol oynayabilir. Bu yararların yanı sıra, AA’nin olumsuz etkileri de bildirilmektedir. Özellikle gebelikte uygulanan AA’nin, epigenetik kalıtım yoluyla fetüsün gelişimi ve metabolik sağlığı üzerinde olumsuz etkileri olabileceği gösterilmiştir. Ayrıca, diğer yaşam dönemlerinde de mikrobesin eksiklikleri, hipoglisemi, hormonal dengesizlikler, yorgunluk ve artmış metabolik hastalık riski gibi olumsuzluklar görülebilmektedir, özellikle kırılgan bireylerde veya yetersiz planlanmış uzun süreli AA uygulamalarında. Bu derlemede, AA’nin epigenetik mekanizmalar yoluyla sağlık ve hastalık üzerindeki etkileri güncel literatür ışığında özetlenmektedir. AA uygulamalarında yaş, sağlık durumu ve bireysel beslenme ihtiyaçları göz önünde bulundurularak kişiye özel öneriler verilmesi önemlidir. Bu alandaki insan çalışmalarının artırılması, AA’nin çift yönlü etkilerinin netleştirilmesi açısından gereklidir.

Keywords

• Açlık
• sirkadiyen ritm
• diyet terapi
• epigenetik süreçler

References

1. 1. Hoddy KK, Marlatt KL, Çetinkaya H, Ravussin E. Intermittent fasting and metabolic health: From religious fast to time restricted feeding. Obesity. 2020;28(S1).
2. 2. Asif S, Morrow NM, Mulvihill EE, Kim KH. Understanding dietary intervention-mediated epigenetic modifications in metabolic diseases. Front Genet. 2020;11.
3. 3. Varady KA, Cienfuegos S, Ezpeleta M, Gabel K. Clinical application of intermittent fasting for weight loss: Progress and future directions. Nat Rev Endocrinol. 2022;18(5):309–21.
4. 4. Tinsley GM, La Bounty PM. Effects of intermittent fasting on body composition and clinical health markers in humans. Nutr Rev. 2015;73(10):661–74.
5. 5. Nowosad K, Sujka M. Effect of various types of intermittent fasting (if) on weight loss and improvement of diabetic parameters in human. Curr Nutr Rep. 2021;10(2):146–54.
6. 6. Elortegui Pascual P, Rolands MR, Eldridge AL, et al. A meta-analysis comparing the effectiveness of alternate day fasting, the 5:2 diet, and time-restricted eating for weight loss [published correction appears in Obesity (Silver Spring). 2025;33(5):817-1011. doi: 10.1002/oby.24266.]. Obesity (Silver Spring). 2023;31Suppl1(Suppl1):9-21. doi: 10.1002/oby.23568.
7. 7. Moro T, Tinsley G, Bianco A, et al. Effects of eight weeks of time-restricted feeding (16/8) on basal metabolism, maximal strength, body composition, inflammation, and cardiovascular risk factors in resistance-trained males. J Transl Med. 2016;14(1):290.
8. 8. Venegas-Borsellino C, Sonikpreet, Martindale RG. From religion to secularism: The benefits of fasting. Curr Nutr Rep. 2018;7:131–138. doi: 10.1007/s13668-018-0233-2.

9. 9. Trepanowski JF, Bloomer RJ. The impact of religious fasting on human health. Nutr J. 2010;9:57. doi: 10.1186/1475-2891-9-57.
10. 10. Lessan N, Ali T. Energy metabolism and ıntermittent fasting: The Ramadan perspective. Nutrients. 2019;11(5):1192. doi: 10.3390/nu11051192.
11. 11. Alghafli Z, Hatch TG, Rose AH, Abo-Zena MM, Marks LD, Dollahite DC. A qualitative study of Ramadan: A month of fasting, family, and faith. Religions. 2019;10(2):123.
12. 12. Al-Arouj M, Assaad-Khalil S, Buse J, et al. Recommendations for management of diabetes during Ramadan: Update 2010. Diabetes Care. 2010;33(8):1895-1902.
13. 13. Boccardi V, Pigliautile M, Guazzarini AG, Mecocci P. The potential of fasting-mimicking diet as a preventive and curative strategy for alzheimer's disease. Biomolecules. 2023;13(7):1133. doi: 10.3390/biom13071133.
14. 14. Roos PR, van den Burg EL, Schoonakker MP, et al. Fasting-mimicking diet in type 2 diabetes reduces myocardial triglyceride content: A 12-month randomised controlled trial. Nutr Metab Cardiovasc Dis. 2025;35(7):103860
15. 15. Van den Burg EL, Schoonakker MP, van Peet PG, et al. A fasting-mimicking diet programme reduces liver fat and liver inflammation/fibrosis measured by magnetic resonance imaging in patients with type 2 diabetes. Clin Nutr. 2025;47:136-145.
16. 16. Chaix A, Lin T, Le HD, Chang MW, Panda S. Time-restricted feeding prevents obesity and metabolic syndrome in mice lacking a circadian clock. Cell Metab. 2019;29(2):303-319.e4.
17. 17. Das M, Ellies LG, Kumar D, et al. Time-restricted feeding normalizes hyperinsulinemia to inhibit breast cancer in obese postmenopausal mouse models. Nat Commun. 2021;12(1):565. doi: 10.1038/s41467-020-20743-7.
18. 18. Guo Y, Luo S, Ye Y, Yin S, Fan J, Xia M. Intermittent fasting ımproves cardiometabolic risk factors and alters gut microbiota in metabolic syndrome patients. J Clin Endocrinol Metab. 2021;106(1):64-79. doi: 10.1210/clinem/dgaa644.
19. 19. Kord Varkaneh H, Salehi Sahlabadi A, Găman MA, et al. Effects of the 5:2 intermittent fasting diet on non-alcoholic fatty liver disease: A randomized controlled trial. Front Nutr. 2022;9:948655. doi: 10.3389/fnut.2022.948655.
20. 20. Sulaj A, Kopf S, von Rauchhaupt E, et al. Six-month periodic fasting in patients with type 2 diabetes and diabetic nephropathy: A proof-of-concept study. J Clin Endocrinol Metab. 2022;107(8):2167-2181. doi: 10.1210/clinem/dgac197.
21. 21. Mitchell SJ, Bernier M, Mattison JA, et al. Daily fasting improves health and survival in male mice independent of diet composition and calories. Cell Metab. 2019;29(1):221-228.e3. doi: 10.1016/j.cmet.2018.08.011.
22. 22. Sutton EF, Beyl R, Early KS, Cefalu WT, Ravussin E, Peterson CM. Early time-restricted feeding improves ınsulin sensitivity, blood pressure, and oxidative stress even without weight loss in men with prediabetes. Cell Metab. 2018;27(6):1212-1221.e3.
23. 23. Weng ML, Chen WK, Chen XY, et al. Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression. Nat Commun. 2020;11(1):1869. doi: 10.1038/s41467-020-15795-8.
24. 24. Longo VD, Di Tano M, Mattson MP, Guidi N. Intermittent and periodic fasting, longevity and disease. Nat Aging. 2021;1(1):47–59. doi: 10.1038/s43587-020-00013-3.
25. 25. Joseph B, Shimojo G, Li Z, et al. Glucose activates vagal control of hyperglycemia and inflammation in fasted mice. Sci Rep. 2019;9(1). doi: 10.1038/s41598-018-36298-z.
26. 26. Stekovic S, Hofer SJ, Tripolt N, et al. Alternate day fasting improves physiological and molecular markers of aging in healthy, non-obese humans. Cell Metab. 2019;30(3).
27. 27. Wei M, Brandhorst S, Shelehchi M, et al. Fasting-mimicking diet and markers/ risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci Transl Med. 2017;9(377):eaai8700. doi: 10.1126/scitranslmed.aai8700.
28. 28. Schroder JD, Falqueto H, Mânica A, et al. Effects of time-restricted feeding in weight loss, metabolic syndrome and cardiovascular risk in obese women. J Transl Med. 2021;19(1).
29. 29. Wilkinson MJ, Manoogian ENC, Zadourian A, et al. Ten-hour time-restricted eating reduces weight, blood pressure, and atherogenic lipids in patients with metabolic syndrome. Cell Metab. 2020;31(1):92-104.e5. doi: 10.1016/j.cmet.2019.11.004.
30. 30. Yuan X, Wang J, Yang S, et al. Effect of intermittent fasting diet on glucose and lipid metabolism and insulin resistance in patients with impaired glucose and lipid metabolism: A systematic review and meta-analysis. Int J Endocrinol. 2022;2022:6999907.
31. 31. de Groot S, Lugtenberg RT, Cohen D, et al. Fasting mimicking diet as an adjunct to neoadjuvant chemotherapy for breast cancer in the multicentre randomized phase 2 direct trial. Nat Commun. 2020;11(1). doi: 10.1038/s41467-020-16138-3.
32. 32. Brandhorst S, Choi IY, Wei M, et al. A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and Healthspan. Cell Metab. 2015;22(1):86–99. doi: 10.1016/j.cmet.2015.05.012.
33. 33. Li G, Xie C, Lu S, et al. Intermittent fasting promotes white adipose browning and decreases obesity by shaping the gut microbiota. Cell Metab. 2017;26(5):801.
34. 34. Liu H, Javaheri A, Godar RJ, et al. Intermittent fasting preserves beta-cell mass in obesity-induced diabetes via the autophagy-lysosome pathway. Autophagy. 2017;13(11):1952–68.
35. 35. Goede P, Wüst RC, Schomakers BV, et al. Time restricted feeding during the inactive phase abolishes the daily rhythm in mitochondrial respiration in rat skeletal muscle. FASEB J. 2022;36(2). doi: 10.1096/fj.202100707r.
36. 36. Regmi P, Chaudhary R, Page AJ, et al. Early or delayed time-restricted feeding prevents metabolic impact of obesity in mice. J Endocrinol. 2021;248(1):75-86.
37. 37. Ng GYQ, Sheng DP, Bae HG, et al. Integrative epigenomic and transcriptomic analyses reveal metabolic switching by intermittent fasting in brain. GeroScience. 2022;44(4):2171–94. doi: 10.1007/s11357-022-00537-z.
38. 38. Vemuganti R, Arumugam TV. Molecular mechanisms of intermittent fasting-induced ischemic tolerance. Cond Med. 2020;3(1):9-17.
39. 39. Lorenzo PM, Izquierdo AG, Rodriguez-Carnero G, et al. Epigenetic effects of healthy foods and lifestyle habits from the Southern European Atlantic Diet Pattern: A narrative review. Adv Nutr. 2022;13(5):1725–47. doi: 10.1093/advances/nmac038.
40. 40. Farsetti A, Illi B, Gaetano C. How epigenetics impacts on human diseases. Eur J Intern Med. 2023;114:15-22. doi: 10.1016/j.ejim.2023.05.036.
41. 41. Zhang B, Jiang H, Dong Z, Sun A, Ge J. The critical roles of m6A modification in metabolic abnormality and cardiovascular diseases. Genes Dis. 2020;8(6):746-758.
42. 42. Xu Z, Qin Y, Lv B, Tian Z, Zhang B. Intermittent fasting improves high-fat diet-induced obesity cardiomyopathy via alleviating lipid deposition and apoptosis and decreasing M6A methylation in the heart. Nutrients. 2022;14(2):251. doi: 10.3390/nu14020251.
43. 43. Godar RJ, Ma X, Liu H, et al. Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury. Autophagy. 2015;11(9):1537-60. doi: 10.1080/15548627.2015.1063768.
44. 44. Ahmet I, Wan R, Mattson MP, Lakatta EG, Talan MI. Chronic alternate-day fasting results in reduced diastolic compliance and diminished systolic reserve in rats. J Card Fail. 2010;16(10):843-853. doi: 10.1016/j.cardfail.2010.05.007.
45. 45. Maloney B, Lahiri DK. Epigenetics of dementia: Understanding the disease as a transformation rather than a state. Lancet Neurol. 2016;15(7):760-774.
46. 46. Selvaraji S, Efthymios M, Foo RS, et al. Time-restricted feeding modulates the DNA methylation landscape, attenuates Hallmark Neuropathology and cognitive impairment in a mouse model of vascular dementia. Theranostics. 2022;12(7):3007–23.
47. 47. Mattson MP, Arumugam TV. Hallmarks of brain aging: Adaptive and pathological modification by metabolic states. Cell Metab. 2018;27(6):1176-1199.
48. 48. Le Bras A. (2020). Dietary restriction exacerbates alzheimer’s features in mice. Lab Animal. 2020;49(3):76. doi: 1038/s41684-020-0493-5.
49. 49. Lazic D, Tesic V, Jovanovic M, et al. Every-other-day feeding exacerbates inflammation and neuronal deficits in 5XFAD mouse model of Alzheimer's disease. Neurobiol Dis. 2020;136:104745. doi: 10.1016/j.nbd.2020.104745.
50. 50. Byun S, Seok S, Kim YC, et al. Fasting-induced FGF21 signaling activates hepatic autophagy and lipid degradation via JMJD3 histone demethylase. Nat Commun. 2020;11(1). doi: 10.1038/s41467-020-14384-z.
51. 51. Seok S, Kim YC, Byun S, et al. Fasting-induced JMJD3 histone demethylase epigenetically activates mitochondrial fatty acid β-oxidation. J Clin Invest. 2018;128(7):3144–59.
52. 52. Purushotham A, Schug TT, Xu Q, Surapureddi S, Guo X, Li X. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab. 2009;9(4):327-38. doi: 10.1016/j.cmet.2009.02.006.
53. 53. Fazeli PK, Lun M, Kim SM, Bredella MA, Wright S, Zhang Y, et al. FGF21 and the late adaptive response to starvation in humans. J Clin Invest. 2015;125(12):4601-11.
54. 54. Boutant M, Kulkarni SS, Joffraud M, Raymond F, Métairon S, Descombes P, et al. SIRT1 gain of function does not mimic or enhance the adaptations to ıntermittent fasting. Cell Rep. 2016;14(9):2068-2075. doi: 10.1016/j.celrep.2016.02.007.
55. 55. Du W, Liu G, Shi N, et al. A microRNA checkpoint for Ca2+ signaling and overload in acute pancreatitis. Mol Ther. 2022;30(4):1754-1774. doi: 10.1016/j.ymthe.2022.01.033.
56. 56. Ali SA, Peffers MJ, Ormseth MJ, Jurisica I, Kapoor M. The non-coding RNA interactome in joint health and disease. Nat Rev Rheumatol. 2021;17(11):692-705.
57. 57. Landrier JF, Derghal A, Mounien L. MicroRNAs in obesity and related metabolic disorders. Cells. 2019;8(8):859. doi: 10.3390/cells8080859.
58. 58. Saini SK, Singh A, Saini M, Gonzalez-Freire M, Leeuwenburgh C, Anton SD. Time-restricted eating regimen differentially affects circulatory MIRNA expression in older overweight adults. Nutrients. 2022;14(9):1843. doi: 10.3390/nu14091843.
59. 59. Ruan X, Li P, Cangelosi A, Yang L, Cao H. A long non-coding RNA, lncLGR, regulates hepatic glucokinase expression and glycogen storage during fasting. Cell Rep. 2016;14(8):1867–75. doi: 10.1016/j.celrep.2016.01.062.
60. 60. Brocker CN, Kim D, Melia T, et al. Long non-coding RNA GM15441 attenuates hepatic inflammasome activation in response to PPARA agonism and fasting. Nat Commun. 2020;11(1). doi: 10.1038/s41467-020-19554-7.
61. 61. Liu B, Hutchison AT, Thompson CH, Lange K, Heilbronn LK. Markers of adipose tissue inflammation are transiently elevated during intermittent fasting in women who are overweight or obese. Obes Res Clin Pract. 2019;13(4):408-415.
62. 62. Madkour MI, Malhab LJ, Abdel-Rahman WM, Abdelrahim DN, Saber-Ayad M, Faris ME. Ramadan diurnal intermittent fasting is associated with attenuated FTO gene expression in subjects with overweight and obesity: A prospective cohort study. Front Nutr. 2022;8.
63. 63. Madkour MI, T. El-Serafi A, Jahrami HA, et al. Ramadan diurnal intermittent fasting modulates SOD2, TFAM, NRF2, and Sirtuins (SIRT1, SIRT3) gene expressions in subjects with overweight and obesity. Diabetes Res Clin Pract. 2019;155:107801.
64. 64. Ajabnoor GM, Bahijri S, Shaik NA, et al. Ramadan fasting in Saudi Arabia is associated with altered expression of clock, DUSP and il-1alpha genes, as well as changes in cardiometabolic risk factors. PLoS One. 2017;12(4). doi: 10.1371/journal.pone.0174342.
65. 65. Zhu Y, Yan Y, Gius DR, Vassilopoulos A. Metabolic regulation of Sirtuins upon fasting and the implication for cancer. Curr Opin Oncol. 2013;25(6):630-636.
66. 66. Zullo A, Simone E, Grimaldi M, Musto V, Mancini FP. Sirtuins as mediator of the anti-ageing effects of calorie restriction in skeletal and cardiac muscle. Int J Mol Sci. 2018;19(4):928. doi: 10.3390/ijms19040928.
67. 67. Wegman MP, Guo MH, Bennion DM, et al. Practicality of intermittent fasting in humans and its effect on oxidative stress and genes related to aging and metabolism. Rejuvenation Res. 2015;18(2):162-72.
68. 68. Karbowska J, Kochan Z. Intermittent fasting up-regulates Fsp27/Cidec gene expression in white adipose tissue. Nutrition. 2012;28(3):294-9. doi: 10.1016/j.nut.2011.06.009.
69. 69. Vasim I, Majeed CN, DeBoer MD. Intermittent fasting and metabolic health. Nutrients. 2022;14(3):631. doi: 10.3390/nu14030631.
70. 70. Beshyah SA, Hassanein M, Ahmedani MY, et al. Diabetic hypoglycaemia during Ramadan fasting: A trans-national observational real-world study. Diabetes Res Clin Pract. 2019;150:315-321. doi: 10.1016/j.diabres.2019.01.039.
71. 71. Ahmet I, Wan R, Mattson MP, Lakatta EG, Talan MI. Chronic alternate-day fasting results in reduced diastolic compliance and diminished systolic reserve in rats. J Card Fail. 2010;16(10):843-853. doi: 10.1016/j.cardfail.2010.05.007.
72. 72. Munhoz AC, Vilas-Boas EA, Panveloski-Costa AC, et al. Intermittent fasting for twelve weeks leads to ıncreases in fat mass and hyperinsulinemia in young female wistar rats. Nutrients. 2020;12(4):1029. doi: 10.3390/nu12041029.
73. 73. Neves PAR, Gatica-Domínguez G, Santos IS, et al. Poor maternal nutritional status before and during pregnancy is associated with suspected child developmental delay in 2-year old Brazilian children. Sci Rep. 2020;10(1):1851. doi: 10.1038/s41598-020-59034-y.
74. 74. Masibo PK, Humwa F, Macharia TN. The double burden of overnutrition and undernutrition in mother-child dyads in Kenya: Demographic and health survey data, 2014. J Nutr Sci. 2020;9:e5. doi: 10.1017/jns.2019.39.
75. 75. Krishnaveni GV, Srinivasan K. Maternal nutrition and offspring stress response-implications for future development of non-communicable disease: A perspective from India. Front Psychiatry. 2019;10:795. doi: 10.3389/fpsyt.2019.00795.
76. 76. Yin W, Liang Y, Sun L, Yin Y, Zhang W. Maternal intermittent fasting before mating alters hepatic DNA methylation in offspring. Epigenomics. 2021;13(5):341–56.
77. 77. Alkhalefah A, Dunn WB, Allwood JW, et al. Maternal intermittent fasting during pregnancy induces fetal growth restriction and down-regulated placental system a amino acid transport in the rat. Clin Sci (Lond). 2021;135(11):1445–66. doi: 10.1042/cs20210137.
78. 78. Yin W, Sun L, Liang Y, et al. Maternal intermittent fasting deteriorates offspring metabolism via suppression of hepatic mtorc1 signaling. FASEB J. 2023;37(4).
79. 79. Hussain R, Tassabehji M, Ashton N, Glazier J. A rat model of maternal intermittent fasting during pregnancy impairs fetal growth but does not alter maternofetal folate transport. Placenta. 2017;57:286. doi: 10.1016/j.placenta.2017.07.201.